Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice.
Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n=105), was administered systemic bromodeoxyuridine (BrdU, 50mg/kg) (n=52) or intracerebral retroviral injection into the DG (n=53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation.


Insulin-like growth factor 1 signaling in tenocytes is required for adult tendon growth.
Tenocytes serve to synthesize and maintain collagen fibrils and other extracellular matrix proteins in tendon. Despite the high prevalence of tendon injury, the underlying biologic mechanisms of postnatal tendon growth and repair are not well understood. IGF1 plays an important role in the growth and remodeling of numerous tissues but less is known about IGF1 in tendon. We hypothesized that IGF1 signaling is required for proper tendon growth in response to mechanical loading through regulation of collagen synthesis and cell proliferation. To test this hypothesis, we conditionally deleted the IGF1 receptor (IGF1R) in scleraxis (Scx)-expressing tenocytes using a tamoxifen-inducible Cre-recombinase system and caused tendon growth in adult mice via mechanical overload of the plantaris tendon. Compared with control Scx-expressing IGF1R-positive (Scx:IGF1R+) mice, in which IGF1R is present in tenocytes, mice that lacked IGF1R in their tenocytes [Scx-expressing IGF1R-negative (Scx:IGF1RΔ) mice] demonstrated reduced cell proliferation and smaller tendons in response to mechanical loading. Additionally, we identified that both the PI3K/protein kinase B and ERK pathways are activated downstream of IGF1 and interact in a coordinated manner to regulate cell proliferation and protein synthesis. These studies indicate that IGF1 signaling is required for proper postnatal tendon growth and support the potential use of IGF1 in the treatment of tendon disorders.-Disser, N. P., Sugg, K. B., Talarek, J. R., Sarver, D. C., Rourke, B. J., Mendias, C. L. Insulin-like growth factor 1 signaling in tenocytes is required for adult tendon growth.


Sexual minority youth, social change, and health: A developmental collision.
Few societal attitudes and opinions have changed as quickly as those regarding sexual minority people and rights. In the context of dramatic social change in the space of a single generation, there have been multiple policy changes toward social inclusion and rights for lesbian, gay, and bisexual (LGB) people, and perceptions that the sociocultural context for LGB people - perhaps particularly for youth - has improved. Yet recent evidence from the developmental sciences points to paradoxical findings: in many cases there have been growing rather than shrinking health disparities. In light of swift sociocultural changes, combined with emergent findings regarding the health and wellbeing of sexual minority youth, we suggest that there is a developmental collision between normative adolescent developmental processes and sexual minority youth identities and visibility. The result is a new reality for sexual minority youth health and disparities.


Bilateral spontaneous pneumothorax with pulmonary metastases from synovial cell sarcoma.
The association of bilateral spontaneous pneumothroax with pulmonary metastases is rare. The clinical and radiological features of bilateral spontaneous pneumothorax with pulmonary metastases from a synovial cell sarcoma are described in a 16-year-old Punjabi student.


Imprinting. An electron microscopic study of chick hyperstriatum ventrale.
Fourteen chicks were hatched and reared in darkness to approximately equal to 21 h when they were exposed to overhead illumination for 0.5 h and then to an imprinting stimulus (a pulsing red light) for 20 min. The chicks were then matched in pairs on the basis of their activity. One member of each pair was returned to the dark and the other was trained for a further 120 min. All chicks were killed approximately equal to 6.5 h after the onset of training and perfused with fixative. Blocks were removed bilaterally from a restricted part of the hyperstriatum ventrale and prepared for electron-microscopy. Various synaptic features were measured, all counts being performed 'blind'. In undertrained chicks the length of the synaptic apposition zone in this part of the left hemisphere was shorter than that in the right by a mean value of 35 +/- 11.4 (SEM) nm. Further training eliminated this difference. No other synaptic measurements were affected by prolonging the period of training.


Aromatase in the human choriocarcinoma JEG-3: inhibition by R 76 713 in cultured cells and in tumors grown in nude mice.
The aromatase enzyme and its inhibition by R 76 713 were characterized in the JEG-3 choriocarcinoma cell line in culture and in JEG-3 tumors grown in nude mice. Optimal cell culture parameters and enzyme reaction conditions for the determination of aromatase activity were established. Under these conditions, in vitro JEG-3 aromatase was inhibited by R 76 713 with IC50-values of 7.6 +/- 0.5 nM and 2.7 +/- 1.1 nM using 500 nM of androstenedione and testosterone as substrate respectively. The Km-value of the aromatase enzyme with androstenedione as substrate was 62 +/- 19 nM; with testosterone as substrate, a value of 166 +/- 27 nM was found. In the presence of increasing concentrations of R 76 713, the Km-values increased while the Vmax remained unchanged. Using androstenedione and testosterone as substrate Lineweaver-Burk analysis of the data showed Ki-values for R 76 713 of 0.43 +/- 0.06 nM and 0.47 +/- 0.39 nM respectively. R 76 713 appeared to competitively inhibit the JEG-3 aromatase. Aromatase could easily be measured in homogenates of JEG-3 tumors grown in nude mice and showed Km-values similar to those found for JEG-3 cells in vitro. IC50-values for inhibition of tumor aromatase by R 76 713 were also similar to those found in cultured cells. Tumor aromatase measured ex vivo, 2 h after a single oral administration of R 76 713 was dose-dependently inhibited. An ED50-value of 0.05 mg/kg was calculated. The JEG-3 choriocarcinoma proved to be a useful aromatase model enabling the comparative study of aromatase inhibition in vitro and in vivo.


Transient terminal U wave inversion as a more specific marker for myocardial ischemia.
Transient U wave inversion can be caused either by regional myocardial ischemia or by an elevation of systemic blood pressure. The characteristics of U wave inversion during chest pain attacks in 21 patients with variant angina were compared with those observed in 38 patients with hypertension without apparent ischemic heart disease. Differentiation was possible according to the ECG phase in which U wave inversion appeared. U wave inversion was considered to be significant if there was a discrete negative deflection of more than 0.05 mV within the TP segment. U wave inversion proceeded to positive deflection of U wave in patients with hypertension without ischemic heart disease (initial U wave inversion). In contrast, inverted U wave occurred after positive U wave deflection during attacks in patients with variant angina (terminal U wave inversion). When cold pressor test was performed in patients with variant angina during treatment with calcium entry blockers, no patient had either anginal attacks or ischemic ST-segment deviation, but 9 of 21 patients (43%) had transient initial U wave inversion, which was followed by positive U wave deflection. U wave inversion can be classified as initial U wave inversion and terminal U wave inversion according to the phasic relationship to positive U wave deflection; the latter is observed in association with regional myocardial ischemia. The former seems to be related to elevated blood pressure rather than to myocardial ischemia.


Perspectives of Caregivers Experiencing Persistent Food Insecurity at an Academic Primary Care Clinic.
Food insecurity (FI) is often transitory and instigated by changes in family circumstances or environmental events. Clinics have developed interventions to address FI, yet families may face persistent FI. Little is known about persistently food insecure families' experiences with clinic-based interventions. The objective of this study was to evaluate the perspectives of caregivers experiencing persistent FI in a clinical setting. We conducted 40 semistructured interviews at one academic primary care clinic between July 2019 and December 2019. The clinic routinely screened families for FI at every visit; families screening positive could meet with a care navigator and receive bags of nonperishable foods. Caregivers who received food bags at ≥3 visits, spoke English or Spanish, and were ≥18 years old were eligible to participate. Interviews were recorded, de-identified, transcribed, and systematically coded using inductive content analysis. A modified constant comparative method was used to iteratively review codes, identify emerging themes, and resolve differences through consensus. Forty caregivers were interviewed; all were women; 45% were Hispanic/Latinx and 37.5% African American/Black. Three major themes emerged: 1) unmet social and medical needs and the challenges of caregiving complicate FI; 2) social supports help address FI and other social challenges that present barriers to accessing resources; and 3) caregivers provide practical recommendations for addressing persistent FI. Families experiencing persistent FI described important social supports that help address FI and other social challenges that present barriers to accessing resources. Clinic-based resources were welcomed interventions, but their impact may be limited; practical recommendations were made.


Neurotoxic effects of two different pyrethroids, bioallethrin and deltamethrin, on immature and adult mice: changes in behavioral and muscarinic receptor variables.
We have recently shown that two pyrethroids, bioallethrin and deltamethrin, affect muscarinic cholinergic receptors (MAChR) in the neonatal mouse brain when given to suckling mice during the period of rapid brain growth. Such early exposure to these pyrethroids can also lead to permanent changes in the MAChR and behavior in the mice as adults. In the present study, male NMRI mice were given bioallethrin (0.7 mg), deltamethrin (0.7 mg), or a 20% fat emulsion vehicle (10 ml) per kilogram of body weight per os once daily between the 10th and 16th postnatal day. The mice were subjected to behavioral tests upon reaching the age of 17 days and at 4 months. Within 1-2 weeks after the behavioral tests the mice were killed by decapitation and crude synaptosomal fractions (P2) were prepared from the cerebral cortex, hippocampus, and striatum. The densities of MAChR were assayed by measuring the amounts of quinuclidinyl benzilate ([3H]QNB) specifically bound in the P2 fraction. The proportions of high-affinity (HA) and low-affinity (LA) binding sites of MAChR were assayed in a displacement study using [3H]QNB/carbachol. The behavioral tests at an adult age of 4 months indicated a significant increase in spontaneous motor behavior in both bioallethrin- and deltamethrin-treated mice. There was also a significant decrease and a tendency toward a decrease in the density of MAChR in the cerebral cortex in mice receiving bioallethrin and deltamethrin, respectively. The proportions of HA- and LA-binding sites of MAChR were not changed. This study further supports that disturbances of the cholinergic system during rapid development in the neonatal mouse can lead to permanent changes in cholinergic and behavioral variables in the animals as adults.


The use of an implantable left ventricular assist device following irreversible ventricular fibrillation secondary to massive myocardial infarction.
A TCI1 rough surface left ventricular assist device (LVAD) was implanted in a 47-year-old man who had sustained a recent massive myocardial infarction complicated by ventricular failure which remained unresponsive to intra-aortic balloon pump therapy and which was further complicated by irreversible ventricular fibrillation. Following implantation of the device and while awaiting a suitable donor organ for transplantation, further extension of the previous infarct resulted in left ventricular rupture and massive haemorrhage which led to his death. We report the successful use of the device in providing haemodynamic support, but caution against inordinate delay in bridging to transplantation patients who are at risk of extension of infarction.


Hydroxyindole-O-methyltransferase in the chicken retina: immunocytochemical localization and daily rhythm of mRNA.
In the vertebrate retina and pineal gland, melatonin production displays diurnal variations with high levels at night. Hydroxyindole-O-methyltransferase (HIOMT, EC 184.108.40.206) catalyses the last step of melatonin biosynthesis. In the present study, a cDNA encoding chicken HIOMT was used to examine the effects of environmental lighting on HIOMT mRNA expression in the chicken retina. A day/night rhythm of HIOMT mRNA level was observed, with an average 5-fold increase during the night. Light strongly suppressed the night-time rise in HIOMT mRNA concentration while darkness prevented its daytime fall. An antibody directed against chicken HIOMT was used for immunocytochemical identification of retinal melatoninergic cells. HIOMT immunoreactivity could be observed in rods as well as in cones. However, the lowest levels of HIOMT immunoreactivity were always observed in the accessory cones of double cones. A few HIOMT-positive cell bodies could also be observed in the inner nuclear layer. Altogether, these data indicate that HIOMT gene expression in the retina is organized on a daily basis as a direct response to light, and that the different types of photoreceptors may not be equally involved in melatonin production.


Correlating ROS1 Protein Expression With ROS1 Fusions, Amplifications, and Mutations.
In this study, we sought to further characterize ROS1 protein expression in solid tumors with the complete spectrum of ROS1 genomic alterations. ROS1 immunohistochemistry (IHC) was performed using the ROS1 (SP384) class I assay per manufacturer's instructions on a variety of solid tumors (n = 32) with known ROS1 genomic alterations. Genomic alterations included fusions (n = 17), gene amplifications (n = 10), and short-variant mutations (n = 11). Of the 32 cases with ROS1 IHC results, 100% (11 of 11) with canonical ROS1 fusions were positive for ROS1 IHC. Among noncanonical ROS1 fusions, only two (of five) cases with SQSTM1-ROS1 and RDX-ROS1 fusions were positive for ROS1 IHC whereas PTPRK-ROS1 (two) and TTC28-ROS1 fusions were negative for ROS1 IHC. One sample with a canonical ROS1 fusion and co-occurring ROS1 resistance mutation (6094G>A, p.G2032R) was positive for ROS1 IHC. A total of 10% (one of 10) of ROS1 amplified tumors were positive for ROS1 IHC. None of the cases (zero of five) with ROS1 short-variant mutations were positive for ROS1 protein expression. These findings suggest that if ROS1 IHC was used as a screening tool for ROS1 fusion, a subset of fusion-negative tumors will reveal positive IHC staining highlighting the value of reflexing to genomic profiling to confirm the presence of a targetable fusion-driver before the initiation of therapy. In addition, the ability of comprehensive genomic profiling to detect ROS1 resistance mutations will be important for clinical decision making.


Comparison of intraosseous versus intravenous loading of phenytoin in pigs and effect on bone marrow.
Much recent literature supports the resurgence of the intraosseous route of access in pediatrics. Intraosseous lines provide a timely noncollapsable route to the circulation in medical or traumatic emergencies when intravenous access is not possible. There has been no controlled study comparing intravenous and intraosseous loading of phenytoin. A 15 mg/kg dose of phenytoin was administered over 15 minutes to pigs by either the intravenous (n = 6) or tibial intraosseous route (n = 6). Femoral artery blood samples were drawn every 5 minutes for 35 minutes after initiation of infusion to determine phenytoin levels. There was no statistical difference between the two groups using analysis of variance repeated measures (P = .160). Microscopic examination of the cortex and marrow at the intraosseous site in these pigs was normal 5 weeks postinfusion. The authors conclude that the intraosseous route is an effective alternative to intravenous loading of phenytoin without permanent damage to the marrow.


The differential expression of peroxisome proliferators-activated receptors in various duck tissues.
Peroxisome proliferators-activated receptors (PPARs) plays important role in regulate a variety of target genes which involves in lipid metabolism. In the present study, 1,430 bp of PPARalpha and 1,650 bp of PPARgamma in Peking duck (Anas platyrhynchos) were cloned by reverse transcription (RT)-PCR. The cloned sequences of PPARalpha and PPARgamma were highly conserved, although relevant changes with respect to human, mouse, chicken, and goose were identified. Real-time quantitative RT-PCR was used to determine if the PPARalpha and PPARgamma were expressed in different tissues of male and female Peking ducks. The expression of PPARalpha and PPARgamma were widely distributed in all examined tissues. The expression level of PPARalpha was highest in liver and lowest in kidney in male and female ducks. And it was highest in abdominal fat and lowest in small intestine of PPARgamma in male and female ducks.


Morphometric study of the ciliary ganglion and its pertinent intraorbital procedure.
Ciliary ganglion (CG) can be easily injured without notice in many intraorbital procedures. Surgical procedures approaching the lateral side of the orbit are at risk of CG injury which results in transient mydriasis and tonic pupil. This study aims to focus on the morphometric study of the CG which is pertinent to intraoperative procedure. Forty embalmed cadaveric globes were dissected to observe the location, shape and size of CG, characteristics and number of roots reaching CG, number of short ciliary nerve in the orbit. Distances from CG to posterior end of globe, optic nerve, lateral rectus muscle and its scleral insertion were measured. Ciliary ganglion was located between optic nerve and lateral rectus in every case. Its shape could be oval, round and irregular. Mean width of CG was 2.24 mm and mean length was 3.50 mm. Concerning the roots, all 3 roots were present in 29 (72.5%) cases. Absence of motor root was found in 7 (17.5%) cases. Absence of sympathetic root was found in 4 (5%) cases. The number of motor root could be 1, 2 and also 3 roots. Three motor roots were found in 1 case which originated from nerve to inferior oblique muscle. Only one sensory root was found in every specimen. One sympathetic root could be observed in most of the specimens and 6-14 short ciliary nerves were found. Mean distances from CG to posterior end of globe, optic nerve, lateral rectus muscle and its scleral insertion were 16.04 mm, 1.47 mm, 2.88 mm, and 31.53 mm, respectively. This study described the characteristic of CG, number of its nerve root and some measurements relevant to intraorbital procedures in Asian population. Moreover, a new parameter was the distance between CG and scleral insertion of the lateral rectus muscle. This parameter should be considered when performing operation involved the lateral rectus muscle and BTX-A injection to lateral rectus muscle to reduce CG injury.


Diabetic retinopathy--biomolecules and multiple pathophysiology.
One of the major complications in patients with diabetes is diabetic retinopathy (DR), a leading cause of blindness worldwide. It causes visual impairment and finally blindness, a result of long-term accumulated damage to the small blood vessels in the retina. It takes several years before any clinical symptoms of retinopathy appear in diabetic patients. Consequently, glycemic control, blood pressure and lipid-lowering therapy have all shown benefits in reducing the incidence and progression of DR. A number of hyperglycemia-induced metabolic stresses have been implicated in the pathophysiology of DR. The microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, including the activation of protein kinase C (PKC), increased advanced glycation end-products (AGEs) formation, polyol pathway and oxidative stress. There is an accumulating body of evidence indicating that inflammation and neurodegeneration play an important role in the pathogenesis of DR.


New medicines for malaria.
Development of new medicines for malaria is a challenging and important topic of applied research because malarial parasites rapidly adapt to man-made interventions. Best studied examples are widely used drugs such as chloroquine, sulfadoxin-pyrimethamine (SP), and, recently, artemisinins; all of them can lose efficacy after large-scale introduction. In addition to drugs, malaria vaccines re-emerged on the agenda of funding bodies and research institutions after a period of quietness and desperation. This time the communities' aims are high: a registered and effective malaria-vaccine. So far, only one candidate shows modest efficacy, a quantum leap in malaria vaccine research, whereas others have not met the high expectations. In this overview, I will summarize basic thoughts and principles behind our work and illustrate them with examples of current projects of my group.


Genital organ-associated lymphoid tissues arranged in a ring in the mucosa of cow vaginal vestibules.
Female reproductive tracts are equipped with local and mucosal immune systems; however, structural information remains unclear for farm animals. In this study, the mucosa-associated lymphoid tissue-like structures in cow reproductive tracts were described. Vaginal vestibule (VV) and external parts of the genital organ, including the clitoris and vulva, were morphologically analyzed. Whole-mount specimens revealed several hematoxylin-positive spots arranged in a ring in the mucosa. Histologically, these spots were aggregated immune cells and defined as genital organ-associated lymphoid tissues (GOALTs). GOALTs were composed of lymphatic follicles (LFs) or diffuse lymphoid tissues (DLTs) at different depths of lamina propria. LFs frequently contained germinal centers. Scattered lymphocytes occupied the border area between follicles and epithelium, whereas DLTs had indefinite shapes. GOALTs contained immune cells and high endothelial venules. B cells were dominant both in LFs and DLTs. Abundant collagenous fibers were stretched across VV lamina propria, whereas reticular fibers were primarily observed in the DLT rather than LF. The epithelium covering of GOALTs was partially or fully disrupted by the invasion of immune cells toward the VV lumen. These findings suggest GOALTs function as a "genital lymphoid ring" as in Waldeyer's pharyngeal ring and act as immunological gate systems in cow reproductive tracts.


Additive intraocular pressure lowering effect of various medications with latanoprost.
To determine the additive intraocular pressure reduction of various topical glaucoma agents used adjunctively with latanoprost. Retrospective interventional case series. Retrospective evaluation of 73 eyes of 73 patients with glaucoma and inadequate intraocular pressure control on latanoprost alone. Each patient received adjunctive treatment with an additional glaucoma agent (dorzolamide, brimonidine, timolol, or other beta-blockers) for 1 year. When added to latanoprost, dorzolamide lowered intraocular pressure an additional 3.9 mm Hg (19.7%, P <.001); beta-blockers further reduced intraocular pressure by 2.0 mm Hg (12.3%, P <.001), and brimonidine further reduced intraocular pressure by 2.0 mm Hg (9.3%, P =.0011). Dorzolamide dosed twice or three times daily was as effective as adjunctive therapy with latanoprost (P =.92). Adjunctive therapy with dorzolamide provided a statistically significant intraocular pressure reduction at 1 year in eyes that were inadequately controlled with latanoprost alone.


Helix-turn-helix, zinc-finger, and leucine-zipper motifs for eukaryotic transcriptional regulatory proteins.
Four distinct structural motifs have been proposed for the DNA-binding domains of eukaryotic transcriptional regulatory proteins; the helix-turn-helix, two kinds of zinc finger, and the leucine zipper. Within each structural motif, there are often families of related proteins that recognize similar DNA sequences and are conserved throughout the eukaryotic kingdom. However, the processes of transcriptional activation and repression appear to be independent of the specific type of protein-DNA interaction.


Population median imputation was noninferior to complex approaches for imputing missing values in cardiovascular prediction models in clinical practice.
To compare the validity and robustness of five methods for handling missing characteristics when using cardiovascular disease risk prediction models for individual patients in a real-world clinical setting. The performance of the missing data methods was assessed using data from the Swedish National Diabetes Registry (n = 419,533) with external validation using the Scottish Care Information - diabetes database (n = 226,953). Five methods for handling missing data were compared. Two methods using submodels for each combination of available data, two imputation methods: conditional imputation and median imputation, and one alternative modeling method, called the naïve approach, based on hazard ratios and populations statistics of known risk factors only. The validity was compared using calibration plots and c-statistics. C-statistics were similar across methods in both development and validation data sets, that is, 0.82 (95% CI 0.82-0.83) in the Swedish National Diabetes Registry and 0.74 (95% CI 0.74-0.75) in Scottish Care Information-diabetes database. Differences were only observed after random introduction of missing data in the most important predictor variable (i.e., age). Validity and robustness of median imputation was not dissimilar to more complex methods for handling missing values, provided that the most important predictor variables, such as age, are not missing.


Magnetic resonance imaging findings associated with posterior ankle impingement syndrome are prevalent in elite ballet dancers and athletes.
To report the prevalence of MRI features commonly associated with posterior ankle impingement syndrome in elite ballet dancers and athletes and to compare findings between groups. Thirty-eight professional ballet dancers (47.4% women) were age- and sex-matched to 38 elite soccer or cricket fast bowler athletes. All participants were training, playing, and performing at full workload and underwent 3.0-T standardised magnetic resonance imaging of one ankle. De-identified images were assessed by one senior musculoskeletal radiologist for findings associated with posterior ankle impingement syndrome (os trigonum, Stieda process, posterior talocrural and subtalar joint effusion-synovitis, flexor hallucis longus tendon pathology and tenosynovitis, and posterior ankle bone marrow oedema). Imaging scoring reliability testing was performed. Posterior talocrural effusion-synovitis (90.8%) and subtalar joint effusion-synovitis (93.4%) were common in both groups, as well as the presence of either an os trigonum or Stieda process (61.8%). Athletes had a higher prevalence of either os trigonum or Stieda process than dancers (74%, 50% respectively, P = 0.03). Male athletes had a higher prevalence of either os trigonum or Stieda process than male dancers (90%, 50% respectively, P = 0.01), or female athletes (56%, P = 0.02). Posterior subtalar joint effusion-synovitis size was larger in dancers than athletes (P = 0.02). Male and female dancers had similar imaging findings. There was at least moderate interobserver and intraobserver agreement for most MRI findings. Imaging features associated with posterior impingement were prevalent in all groups. The high prevalence of os trigonum or Stieda process in male athletes suggests that this is a typical finding in this population.


Pseudomyxoma originating from the interatrial septum in a heart transplant patient.
This report describes the echocardiographic diagnosis of an intracardiac mass in a heart transplant patient. The typical morphology of the lesions, its attachment to the interatrial septum, and the absence of a nidus focus for thrombus formation led to the preoperative assumption that it was a myxoma. The mass was successfully excised at the time of operation and the patient had an uneventful recovery. Pathology findings revealed a thrombus. Thus, echocardiography may have limited specificity for the differentiation of intracardiac tumors and thrombus.


Production of the radioactive antitumoral cisplatin.
This work presents the preparation of radiolabelled cis-dichlorodiammineplatinum (II), CDDP*, sealed in a cadmium capsule. The irradiation of CDDP covered by cadmium, employing exposure times longer than 2 h, demonstrated good chemical purity and high specific activity. This finding allowed a better detection of in vivo CDDP* and suggests that it may be a good tool for studies of long-term biodistribution of pharmaceutical formulations containing this drug.


Efficacy and safety of sorafenib plus hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma.
Sorafenib is the standard treatment for patients with advanced HCC with improvement in survival and radiologic progression of the disease. Recently, few studies have advocated the Sorafenib + HAIC combination therapy results in better overall survival and progression-free survival than Sorafenib monotherapy in patients with advanced HCC. Herein, we aim to identify the best possible treatment option among the above two lines of therapy for patients with advanced HCC. The fixed effects and a random-effects model were used to perform a meta-analysis for overall response rate overall survival, and adverse events. Subgroup analysis of the data of univariate analysis in each included trial was performed to identify the specific patient population who could be benefitted from the combination therapy. Four RCTs containing 609 patients were included in the final analysis. The overall response rate (OR: 3.81; 95% CI 1.01 to 14.42; P = 0.05) and overall survival (HR: 0.70; 95% CI 0.40 to 1.24; P > 0.05) were comparable. Subgroup analysis of OS showed that patients with Child-Pugh score B (HR: 0.30; 95% CI 0.13 to 0.72; P < 0.05) and AFP <400 ng/ml (HR: 0.72; 95% CI 0.52 to 0.99; P < 0.05) were associated with significantly improved survival in the Sorafenib + HAIC group. Bone marrow suppression (OR: 3.76; 95% CI 2.58 to 5.48; P < 0.001) was significantly higher in the Sorafenib + HAIC group, but hepatic function impairment, constitutional symptoms, gastrointestinal events, and dermatological events were comparable (p > 0.05). Patients with Child-Pugh score B and AFP <400 ng/ml may be benefited most from Sorafenib + HAIC combination therapy.


Simultaneous enantioselective quantification of methadone and of 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine in oral fluid using capillary electrophoresis.
A capillary electrophoresis method was developed for the enantioselective quantification of methadone (MTD) and its main metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine (EDDP). The enantiomers of MTD and EDDP were resolved by CE in 5min using 0.2% highly sulphated gamma-cyclodextrins as chiral selectors and a 50mM phosphate solution at pH 4.5 as background electrolyte. The optimized method was applied and validated for oral fluid testing. Linear relationships were obtained for MTD enantiomers in the range of 8.1-625ng/mL and in the range of 7.6-500ng/mL for EDDP enantiomers. The detection limits ranged from 2.3 to 2.4ng/mL, whereas the limits of quantification ranged from 7.6 to 8.1ng/mL. Intra- and inter-assay precision and accuracy were acceptable, respectively. The method was applied to the analyses of 60 oral fluid specimens obtained from patients enrolled in a MTD maintenance programme. Our data pointed out that higher concentrations of (R)-MTD and the enantioselective excess of (S)-EDDP in OF may reflect the free fraction of MTD and EDDP enantiomers in plasma.


Sex differences in efficacy and safety of PCSK9 monoclonal antibodies: A real-world registry.
Proprotein convertase subtilisin/kexin 9 monoclonal antibodies (PCSK9 mAbs) reduce low-density lipoprotein (LDL-c) with a favourable safety profile. Available data from PCSK9 antibody trials suggest LDL-c reduction is lower in women compared to men. Data in real-world setting is scarce. The aim of this study was to assess sex differences in efficacy and safety of PCSK9 antibodies in clinical care. All patients starting with evolocumab or alirocumab in our lipid clinic were included in a prospective registry. We collected clinical information, including baseline and follow-up mean LDL-C levels after initiation of PCSK9 mAbs treatment. In addition, side effects and PCSK9 mAbs discontinuation were recorded. We analysed 436 patients (209 women), mean age 58 ± 11 years. Women had higher baseline LDL-c levels compared to men (4.7 ± 1.6 mmol/L vs 4.1 ± 1.4 mmol/L, p < 0.01). PCSK9 mAbs resulted in less relative LDL-c reduction in women compared to men (50% vs 61% p<0.01), but equal absolute LDL-c reduction (respectively 2.3 ± 1.3 mmol/L vs 2.5 ± 1.1 mmol/L, p = 0.087). Women less often reached LDL-c target levels than men (50% vs 72%). No sex differences were observed in reporting of side effects (women 32% vs men 27% p = 0.26) or PCSK9 mAbs discontinuation (women 13% vs men 10%, p = 0.46). In clinical practice, PCSK9 mAbs are less effective in reducing LDL-c levels in women compared to men and equally safe, implying the importance of sex differences in PCSK9 metabolism.


Ecological responses to contamination: a meta-analysis of experimental marine studies.
Identifying general response patterns to contamination in the environment is critical for reliable assessments of ecosystem health. However, it is not often clear if there are biases in the information used to understand general effects of contamination. To investigate this we conducted a review of 314 studies that experimentally manipulated contaminants and measured the effects on marine invertebrate taxa. The majority of studies investigated the effects of metals (54%) on individual taxa (mainly bivalves, amphipods, copepods). Ecologically relevant responses to contamination were measured in only 22% of the studies. A meta-analysis using studies that measured ecological responses to copper illustrated a general negative effect of copper and highlighted the bias towards field or laboratory experiments that measure community or individual-level responses. There is a need for diversification of studies that investigate the ecological effects of contamination as an important advancement in ecotoxicology and ecological research and environmentally relevant risk assessments.


Time-domain Brillouin scattering theory for probe light and acoustic beams propagating at an angle and acousto-optic interaction at material interfaces.
A theory has been developed to interpret time-domain Brillouin scattering (TDBS) experiments involving coherent acoustic pulse (CAP) and light pulse beams propagating at an angle to each other. It predicts the influence of the directivity pattern of their acousto-optic interaction on TDBS signals when heterodyne detection of acoustically scattered light is in backward direction to incident light. The theory reveals relationships between the carrier frequency, amplitude and duration of acoustically induced "wave packets" in light transient reflectivity signals, and factors such as CAP duration, widths of light and sound beams, and their interaction angle. It describes the transient dynamics of these wave packets when the light and CAP encounter material interfaces, and how the light scattering by the incident CAP transforms into scattering by the reflected and transmitted CAPs. The theory suggests that single-point TDBS experiments can determine not only depth positions of buried interfaces but also their local inclinations/orientations.


A novel packing arrangement of AcrB in the lipid bilayer membrane.
The central component AcrB of the Escherichia coli drug efflux complex AcrA-AcrB-TolC has been extensively investigated by X-ray crystallography of detergent-protein 3-D crystals. In these crystals, AcrB packs as trimers - the functional unit. We visualized the AcrB-AcrB interaction in its native environment by examining E. coli lipid reconstituted 2-D crystals, which were overwhelmingly formed by asymmetric trimers stabilized by strongly-interacting monomers from adjacent trimers. Most interestingly, we observed lattices formed by an arrangement of AcrB monomers distinct from that in traditional trimers. This hitherto unobserved packing, might play a role in the biogenesis of trimeric AcrB.


Identification properties of a recombinant class I hydrophobin rHGFI.
Hydrophobins fulfill various functions in fungal growth and morphology. These proteins can self-assemble at hydrophilic/hydrophobic interfaces and form amphipathic membranes. Based on their physical properties and hydropathy patterns, hydrophobins are divided into two classes (I and II). In order to identify the recombinant class I hydrophobin rHGFI, the different properties between rHGFI and the typical class II hydrophobin rHFBI were investigated. In contrast to rHGFI, no rodlet structure was observed on rHFBI coated mica surface, and the membranes formed on siliconized glass surfaces by rHFBI were not robust enough to resist treatment with 60% ethanol and 2% hot SDS. In contrast, the membranes formed by rHGFI on siliconized glass surfaces were so strong that could resist hot detergent and alcohol solution washing. Moreover, self-assembly of rHFBI at the water-air interface was not accompanied by a change in secondary structure. Meanwhile, β-sheet structures dramatically increased after rHGFI self-assembled at water-air interface, which could cause the fluorescence intensity of Thioflavin T increased and Congo Red and CD absorption spectra shift. Water-insoluble erythrosin B dispersion prepared with rHGFI and rHFBI were both stable for more than one month, which indicated that the interaction between erythrosin B and rHGFI/rHFBI was strong. This might promote rHGFI and rHFBI to be considered as potential dispersing agents to stabilize water-insoluble erythrosin B.


Effect of histocompatibility factors on pulmonary retention of indium-111-labeled granulocytes.
Granulocyte transfusions are associated with a number of side effects including febrile transfusion reactions and occasionally pulmonary infiltrates. There is evidence that the presence of preformed antibodies may be a cause of these complications. In this study, allogeneic 111Indium-labeled granulocytes were used to evaluate the pulmonary retention of radioactivity in alloimmunized and non-alloimmunized patients in an attempt to assess antibody effect on granulocyte migration. After injection of labeled allogeneic granulocytes into neutropenic patients, the ratios of lung to heart activity were calculated for the first 30 min of scanning. There was significantly greater retention of radioactivity from cells in the lungs of patients who were alloimmunized, having both lymphocytotoxic (anti-HLA) and leuko-agglutinating antibodies, compared to the activity in the lungs of non-alloimmunized patients (P less than .001) or of patients receiving autologous granulocytes (P less than .001). This study demonstrates that labeled, mismatched granulocytes may be retained in the lungs for a significantly longer time in patients with preformed antibodies. This implies that transfusion of large numbers of such mismatched granulocytes, i.e., granulocyte transfusions, may also be retained in the lungs of alloimmunized patients, which could lead to pulmonary compromise. Therefore, granulocyte transfusions from random donors should not be given to alloimmunized patients.


Effects of temperature and dose level on in vivo dynamics of unlabelled bovine insulin in eels (Anguilla anguilla L.).
The in vivo dynamics of bolus-injected, unlabelled bovine insulin in eels (Anguilla anguilla L.), analysed by compartmental and noncompartmental methods, were found to be significantly influenced by acclimation temperature and insulin dose level. At 12 degrees, plasma clearance of insulin was essentially monoexponential, whereas at 22 degrees, the disappearance curves could be resolved into two exponential components. Metabolic clearance rate (MCR) and apparent distribution volume (Vdist) of insulin were significantly higher at 22 degrees than 12 degrees, and irrespective of temperature, MCR was more rapid at a lower (130 mU/kg) than a higher (260 mU/kg) dose, while Vdist was more variable in this respect. These results indicate that the dynamics of insulin in eels are temperature-sensitive, and that over the dose range employed, routes of insulin elimination are saturable. Of particular significance were the inordinately high values for derived Vdist indicating that following bolus injection, substantial loss of the hormone occurred.


Whole-Genome Sequence of the Mycoplasma mucosicanis Type Strain.
Whole-genome sequencing of Mycoplasma mucosicanis type strain 1642 was performed to support efforts to better understand the clinical significance of Mycoplasma infection in canine health. The availability of this sequence will also further the development of highly specific diagnostic tests.


Age-related associations between work over-commitment and zest for work among Swedish employees from a cross-sectional and longitudinal perspective.
In aging societies, zest for work may be pivotal when deciding to stay occupationally active longer. Psychosocial work stress is a prevalent public health problem and may have an impact on zest for work. Work over-commitment (WOC) is a personal coping strategy for work stress with excessive striving and a health risk. However, the long-term effect of WOC on zest for work is poorly understood. To investigate the age-related associations of work over-commitment with zest for work. During 1996-1998 and 2000-2003, predominantly industrial workers (n = 2940) participated in the WOLF-Norrland study and responded to a questionnaire referring to socio-demographics, WOC, zest for work, effort-reward imbalance proxies, and mental health. Age-adjusted multiple logistic regressions were performed with original and imputed datasets. Cross-sectionally, work overcommitted middle-aged employees had an increased prevalence of poor zest for work compared to their contemporaries without WOC (OR: 3.74 [95%-CI 2.19; 6.40]). However, in a longitudinal analysis associations between onset of 'poor zest for work' and the WOC subscales 'need for approval' (OR: 3.29 [95%-CI 1.04; 10.37]) and 'inability to withdraw from work' (OR: 5.14 [95%-CI 1.32; 20.03]) were observed. The longitudinal findings among older employees could be relevant regarding the expected need to remain occupationally active longer.


Successful laparoscopic repair for reduction en masse of infantile inguinal hernia: a case report of this rare condition.
Reduction en masse (REM) is a rare condition following manual inguinal hernia (IH) reduction in which a hernia sac is reduced back into the preperitoneal space with a loop of the bowel incarcerated at the neck of the sac. It resembles successful manual reduction and may thus be overlooked easily. We herein report an infantile case of REM of an IH that was successfully treated laparoscopically. A 10-month-old boy with a surgical history of bilateral open IH repair at 4 months old presented with a bulge in his left groin and vomiting. A left incarcerated recurrent IH was suspected, and manual reduction was performed. The hernia was apparently reduced successfully, but abdominal distention and vomiting persisted. He was admitted for further observation due to the symptoms. On day 2 after admission, abdominal X-ray showed extensive small bowel obstruction (SBO). Enhanced computed tomography (CT) revealed protrusion of the small bowel with a closed-loop in the left groin. A closed-loop SBO due to postoperative adhesion or an internal hernia was suspected. To assess the etiology of SBO, emergent laparoscopic exploration with hernia repair was planned. Laparoscopy revealed REM of the left incarcerated IH with a thickened peritoneum at the neck of the sac. Laparoscopic reduction was performed, and the incarcerated small bowel showed no signs of ischemia. The hernia sac was not associated with the previously ligated processes vaginalis, which had been closed by a previous Potts' procedure. It was located at the inside of the processes vaginalis. The sac was successfully closed by laparoscopic percutaneous extraperitoneal closure procedures, and iliopubic tract repair was also performed via the previous inguinal incision. The postoperative course was uneventful. Pediatric IH is due to the patent processes vaginalis, and REM is extremely rare. Laparoscopic surgery for REM is a relatively common and useful approach for the diagnosis and treatment of adults. In our infantile case, the laparoscopic approach was similarly effective for both investigating the cause of SBO and performing high ligation of the sac for this rare condition with IH.


CEFTO-CURE study: CEFTObiprole Clinical Use in Real-lifE - a multi-centre experience in Italy.
Ceftobiprole is approved in Europe for treatment of community-acquired pneumonia and non-ventilator-associated hospital-acquired pneumonia (HAP) in adults. Real-world data are limited. This multi-centre, observational, ambispective investigator-initiated study was undertaken in Italy from January 2018 to December 2019 in order to evaluate the use of ceftobiprole in a real-world setting. Overall, 195 patients from 10 centres were evaluated (68% retrospectively). Male sex was prevalent (n=121, 62%). Median age was 67 [interquartile range (IQR) 53-75] years. Median Charlson Comorbidity Index score was 5 (IQR 3-7). The most common indication was pneumonia (151/195, 77%), especially HAP. Other uses were skin and soft tissue infections (5%), endocarditis (4%) and bone infections (4%). Ceftobiprole was usually an empiric choice (65%), in combination with other drugs (66%) and as second-line therapy (58%). A causative agent was found in 39% of cases. A diagnosis of sepsis was made in 59 cases (30%). Success in the clinically evaluable population (excluding 12 cases due to isolation of pathogens outside ceftobiprole's spectrum of activity) was obtained in 79% of cases, with all-cause mortality of 20%. On multi-level analysis, three predictors were positively associated with clinical success: male gender, pneumonia and detection of causal agent. Sepsis was a negative predictor. Nine factors were independently associated, favourably or unfavourably, with fatal outcome. Ceftobiprole is a safe and effective therapeutic choice, even in a real-world setting. More data are needed to establish its efficacy in patients with sepsis.


Triton, a new species-level database of Cenozoic planktonic foraminiferal occurrences.
Planktonic foraminifera are a major constituent of ocean floor sediments, and thus have one of the most complete fossil records of any organism. Expeditions to sample these sediments have produced large amounts of spatiotemporal occurrence records throughout the Cenozoic, but no single source exists to house these data. We have therefore created a comprehensive dataset that integrates numerous sources for spatiotemporal records of planktonic foraminifera. This new dataset, Triton, contains >500,000 records and is four times larger than the previous largest database, Neptune. To ensure comparability among data sources, we have cleaned all records using a unified set of taxonomic concepts and have converted age data to the GTS 2020 timescale. Where ages were not absolute (e.g. based on biostratigraphic or magnetostratigraphic zones), we have used generalised additive models to produce continuous estimates. This dataset is an excellent resource for macroecological and macroevolutionary studies, particularly for investigating how species responded to past climatic changes.


How to support the application of multiple criteria decision analysis? Let us start with a comprehensive taxonomy.
Decision making is a complex task that involves a multitude of perspectives, constraints, and variables. Multiple Criteria Decision Analysis (MCDA) is a process that has been used for several decades to support decision making. It includes a series of steps that systematically help Decision Maker(s) (DM(s)) and stakeholders in structuring a decision making problem, identifying their preferences, and building a decision recommendation consistent with those preferences. Over the last decades, many studies have demonstrated the conduct of the MCDA process and how to select an MCDA method. Until now, there has not been a review of these studies, nor a proposal of a unified and comprehensive high-level representation of the MCDA process characteristics (i.e., features), which is the goal of this paper. We introduce a review of the research that defines how to conduct the MCDA process, compares MCDA methods, and presents Decision Support Systems (DSSs) to recommend a relevant MCDA method or a subset of methods. We then synthesize this research into a taxonomy of characteristics of the MCDA process, grouped into three main phases, (i) problem formulation, (ii) construction of the decision recommendation, and (iii) qualitative features and technical support. Each of these phases includes a subset of the 10 characteristics that helps the analyst implementing the MCDA process, while also being aware of the implication of these choices at each step. By showing how decision making can be split into manageable and justifiable steps, we reduce the risk of overwhelming the analyst, as well as the DMs/stakeholders during the MCDA process. A questioning strategy is also proposed to demonstrate how to apply the taxonomy to map MCDA methods and select the most relevant one(s) using real case studies. Additionally, we show how the DSSs for MCDA method recommendation can be grouped into three main clusters. This proposal can enhance a traceable and categorizable development of such systems.


Novel biomarkers of intervertebral disc cells and evidence of stem cells in the intervertebral disc.
Rat intervertebral disc (IVD) is one of the most commonly used and cost-effective alternative models for human IVD. Many IVD related clinical studies need to be pre-tested on rat IVDs. However, studies on the heterogeneous cell clusters of the rat IVD are inadequate, and a further understanding of the marker genes and cell phenotypes of healthy mature IVD cells is essential. In this study, we used the 10X Genomics technology to analyze the single-cell transcriptome of purified wild-type rat IVDs. We identified potentially new gene markers of IVDs via single-cell sequencing. Based on the unsupervised cluster analysis of 13,578 single-cell transcripts, 3 known IVD cell types were identified. We provided a complete single-cell gene expression map of the IVD. Immunohistochemical and immunofluorescence images of rat disc sections confirmed the new marker genes of all cell types. One group of heterologous cell groups expressed multi-functional stem cell (MSC)-specific genes, indicating the stem cell potential of IVD cells. We provided the phenotype and marker genes of IVD cells at the single-cell level, reconfirmed existing data, and proposed new marker genes, including MSC marker genes. By identifying more accurate target cells and genes, our results pave the way for further study of the response of individual disc cells to disease states and provide the basis for future disc regeneration therapies.


Global dynamics of an age-dependent multiscale hepatitis C virus model.
In this paper, we focus on the global dynamics of a multiscale hepatitis C virus model. The model takes into account the evolution of the virus in cells and RNA. For the model, we establish the globally asymptotical stability of both infection-free and infected equilibria. We first give the basic reproduction number [Formula: see text] of the model, and then find that the system holds infected equilibrium when [Formula: see text]. Using eigenvalue analysis, Lyapunov functional, persistence theory and so on, it is proved that infection-free and infected equilibria are globally asymptotically stable when [Formula: see text] and [Formula: see text], respectively. Thus, extinction and persistence of viruses in cells are theoretically judged. Finally, we show our theoretical results by means of numerical simulation.


[Pyoderma gangrenosum associated with anti-proteinase 3 antineutrophil cytoplasmic antibodies (PR3-ANCA) induced by propylthiouracil].
Synthetic antithyroid drugs are often used in the treatment of hyperthyroidism, regardless of aetiology. They may cause various side effects, including the development of anti-neutrophil cytoplasmic antibodies (ANCA), ANCA-associated vasculitis, and neutrophilic dermatoses. Propylthiouracil (PTU) is the antithyroid drug most frequently implicated in ANCA-associated diseases specifically involving anti-myeloperoxidase ANCA (MPO-ANCA). To our knowledge, there are no clinical reports describing the association of pyoderma gangrenosum (PG) and anti-proteinase3-ANCA (PR3-ANCA) induced by PTU, with ANCA levels decreasing after antithyroid drug withdrawal. A 68-year-old woman was treated with propylthiouracil (PTU) for toxic multinodular goitre. She presented necrotic ulceration of the lower abdomen. The patient's history, physical examination, and bacteriological and histological samples led to a diagnosis of pyoderma gangrenosum. This pyoderma involved ANCA with antigenic specificity for proteinase 3. Withdrawal of PTU and a short course of corticosteroids and cyclosporine resulted in rapid and complete resolution of the pyoderma gangrenosum as well as a decrease in ANCA. No relapse was observed one year after cessation of treatment. We report a case of PG associated with PR3-ANCA induced by PTU, without any demonstrable vasculitis.


Membrane fluidity and bile salt damage.
The lysis, by bile salts, of membranes of different fluidities was studied; it was shown that membranes of low fluidity were less readily lysed than membranes of higher fluidity. Membrane fluidity levels were controlled (i) by the use of erythrocytes, from different species, systematically differing in their lipid composition; (ii) by using each membrane at a range of temperatures; and (iii) by incorporating into the membranes the fluidizing agent, benzyl alcohol, at a range of concentrations. Membrane fluidity (and order) in each case was monitored by measuring the degree of polarization of fluorescence from the hydrophobic probe molecule, 1,6-diphenyl-1,3,5-hexatriene. The response of lytic behaviour to modulations of membrane fluidity also indicated a difference between the bile salts, glycodeoxycholate and glycocholate; the former initiates lysis close to (at or below) its critical micellar concentrations whereas the latter only causes lysis above, and often substantially above, its critical micellar concentration. In their respective ranges of lytic concentrations, both bile salts are far less effective with membranes of low fluidity. The results are discussed with regard to the features of a membrane which would be expected to be resistant to high concentrations of bile salts in vivo, i.e., the plasma membranes of the bile canaliculus and lumenal surface of biliary tract cells.


[Incorporation of radioactive leucine into lizard epididymis proteins. Study during the sexual cycle and after injection of testosterone to untreated or castrated animals].
Lizard epididymis activity during the reproductive cycle and after testosterone administration results in a marked increase of radioactive leucine incorporation in vivo and in vitro. The electrophoretic distribution of soluble proteins shows different peaks of radioactivity. Comparison between histological response and pattern of electrophoresis suggests that one of these peaks may correspond to an activity of secretion.


Microscale synthesis of phosphatidyl-[3H]choline from 1,2-diacylglycerol. Assessment of isomerization by reversed-phase high-performance liquid chromatography.
The synthesis of rac-1-palmitoyl-2-oleoylglycero-3-phospho-[3H]choline of high specific activity was carried out on a microscale by making 7 mumol of rac-1-palmitoyl-2-oleoylglycerol react first with an equimolar amount of POCl3 and then of [3H]choline. After purification by thin-layer chromatography and normal-phase high-performance liquid chromatography and normal-phase high-performance liquid chromatography (HPLC), the yield of the synthesis of [3H]phosphatidylcholine (120 microCi/mumol) was 22%. rac-1-Palmitoyl-2-oleoylglycerol was purified before use by reversed-phase HPLC under conditions which were nonisomerizing and allowed the separation of 1,2- and 1,3-isomers of diacylglycerol. Ethanol, but not benzene, was shown to cause isomerization of long-chain diacylglycerol and, therefore, was not used for drying the substrate before reaction. A rapid and complete separation of 1,2- and 1,3-isomers of long-chain phosphatidylcholine was obtained by reversed-phase HPLC using 20 mM choline chloride in methanol/acetonitrile/water (50:50:1, by vol) isocratically as the mobile phase. Under these conditions, analysis of the synthesized rac-1-palmitoyl-2-oleoylglycero-3-phospho-[3H]choline showed a total absence of 1,3-isomer.


An examination of parkinsonian versus anhedonia contributions to self-stimulation impairments induced by dopamine dysfunction.
Interference with brain dopamine neurotransmission can severely impair brain stimulation reward behavior. The significance of this impairment in reward behavior, however, has been a problematic issue. That is, it has been difficult to determine whether the dopamine dysfunction has attenuated the reward effect of the stimulation or has merely rendered the animal less able to generate the behavior required to obtain reinforcement. To experimentally re-assess this issue, the present studies examine the effect of unilateral 6-hydroxydopamine lesions of forebrain dopamine neurons on brain stimulation reward in animals. In general, these studies highlight the substantial motoric deficits produced by the lesion treatments. By combining lesion and neuroleptic drug treatments, however, it appeared that effects on reward could be detected.


[Epidemiology, diagnosis, complications and surgery in inflammatory bowel disease].
In Digestive Disease Week 2012, held in San Diego, numerous studies were presented on the epidemiology of inflammatory bowel disease. Some of these studies were population-based, providing greater information on known risk factors and helping to eliminate proposed risk factors for which there is no known evidence. In this meeting, special attention was paid to the natural history of the disease as well as surgery in patients aged more than 65 years old who should clearly be treated as a separate subgroup from the standard population in clinical trials from which older individuals are excluded. Another especially important topic were extraintestinal complications and manifestations, with Clostridium difficile and primary sclerosing cholangitis as the main culprits. Finally, with reference to diagnosis, calprotectin was confirmed as an essential marker in distinct scenarios and new imaging techniques such as virtual chromoendoscopy (i-scan) will be important in the management of these patients, although their precise role remains to be defined.


Detection of ESR1 Mutations in Primary Tumors and Plasma Cell-Free DNA in High-Grade Serous Ovarian Carcinoma Patients.
ESR1 mutations have been recently associated with resistance to endocrine therapy in metastatic breast cancer and their detection has led to the development and current evaluation of novel, highly promising therapeutic strategies. In ovarian cancer there have been just a few reports on the presence of ESR1 mutations. The aim of our study was to evaluate the frequency and the clinical relevance of ESR1 mutations in high-grade serous ovarian cancer (HGSOC). Drop-off droplet digital PCR (ddPCR) was first used to screen for ESR1 mutations in 60 primary tumors (FFPEs) from HGSOC patients and in 80 plasma cell-free DNA (cfDNA) samples from advanced and metastatic ovarian cancer patients. We further used our recently developed ESR1-NAPA assay to identify individual ESR1 mutations in drop-off ddPCR-positive samples. We report for the first time the presence of ESR1 mutations in 15% of FFPEs and in 13.8% of plasma cfDNA samples from advanced and metastatic ovarian cancer patients. To define the clinical significance of this finding, our results should be further validated in a large and well-defined cohort of ovarian cancer patients.


Effects of pyruvate on pyruvate dehydrogenase kinase of rat heart.
Sensitivity of rat heart pyruvate dehydrogenase kinase (PDHK) to pyruvate inhibition was tested under various conditions using pyruvate dehydrogenase complex (PDC) in mitochondria (mPDC) and in a high speed precipitate of whole tissue homogenates (hPDC). In the latter preparation pyruvate in the range of concentration 1-10 mM caused increasing inhibition of PDHK when the enzyme was prepared from animals fed ad libitum but had no effect when the enzyme was prepared from 48 h starved animals. Similar behaviour was observed in mPDC from fed and starved animals when rotenone was present, pyruvate at 1 mM concentration stimulated PDHK from hearts of fed animals but was without effect at 10 mM. When mPDC or hPDC from hearts of starved animals was incubated at 30 degrees C for 30 min, inhibition of PDHK by pyruvate was restored.


Prognostic Factors of Liver Transplantation for Hepatocellular Carcinoma: A Surveillance, Epidemiology, and End Results (SEER) Database Analysis.
We aimed to identify new, more accurate risk factors of liver transplantation for liver cancer through using the Surveillance, Epidemiology, and End Results (SEER) database. Using the SEER database, we identified patients that had undergone surgical resection for non-metastatic hepatocellular carcinoma (HCC) and subsequent liver transplantation between 2010 and 2017. Overall survival (OS) was estimated using Kaplan-Meier plotter. Cox proportional hazards regression modelling was used to identify factors independently associated with recurrent disease [presented as adjusted hazard ratios (HR) with 95% CIs]. Totally, 1530 eligible patients were included in the analysis. There were significant differences in ethnicity (P=0.04), cancer stage (P<0.001), vascular invasion (P<0.001) and gall bladder involvement (P<0.001) between the groups that survived, died due to cancer, or died due to other causes. In the Cox regression model, there were no significant differences in OS at 5 years with different operative strategies (autotransplantation versus allotransplantation), nor at survival at 1 year with neoadjuvant radiotherapy. However, neoadjuvant radiotherapy did appear to improve survival at both 3 years (HR: 0.540, 95% CI: 0.326-0.896, P=0.017) and 5 years (HR: 0.338, 95% CI: 0.153-0.747, P=0.007) from diagnosis. This study demonstrated differences in patient characteristics between prognostic groups after liver resection and transplantation for HCC. These criteria can be used to inform patient selection and consent in this setting. Preoperative radiotherapy may improve long-term survival post-transplantation.


Cholesterol sulphate levels in the hair and nails of patients with recessive X-linked ichthyosis.
Cholesterol sulphate (CS) has been suggested as an intercellular glue for corneocyte-corneocyte cohesion from studies on patients with recessive X-linked ichthyosis (RXLI). Pathological stratum corneum of RXLI patients was found to show a significant elevation of CS. In the present study hair and nails, unaffected keratinized tissues in RXLI patients, were examined for CS levels. The results demonstrated significantly elevated CS levels in both tissues in RXLI patients (P less than 0.001). In particular the mean CS level in the hair of RXLI patients was five times greater than normal. The present study suggests that hair is a useful material for the diagnosis of RXLI.


Density-controlled quantum Hall ferromagnetic transition in a two-dimensional hole system.
Quantum Hall ferromagnetic transitions are typically achieved by increasing the Zeeman energy through in-situ sample rotation, while transitions in systems with pseudo-spin indices can be induced by gate control. We report here a gate-controlled quantum Hall ferromagnetic transition between two real spin states in a conventional two-dimensional system without any in-plane magnetic field. We show that the ratio of the Zeeman splitting to the cyclotron gap in a Ge two-dimensional hole system increases with decreasing density owing to inter-carrier interactions. Below a critical density of ~2.4 × 1010 cm-2, this ratio grows greater than 1, resulting in a ferromagnetic ground state at filling factor ν = 2. At the critical density, a resistance peak due to the formation of microscopic domains of opposite spin orientations is observed. Such gate-controlled spin-polarizations in the quantum Hall regime opens the door to realizing Majorana modes using two-dimensional systems in conventional, low-spin-orbit-coupling semiconductors.


Potassium transporter KUP9 regulates plant response to K+ deficiency and affects carbohydrate allocation in A.thaliana.
Due to the essential roles of K+ in plants, its up to 10% share in plant dry matter, and its mostly low availability in soil, effective potassium management poses a significant challenge for the plant. To enable efficient uptake and allocation of K+, numerous transporters and channels have evolved. During the last two decades, efforts have been made to characterise these transport proteins in Arabidopsis thaliana using knock-out mutants. Several KT/HAK/KUP transporters have been assigned specific functions. In this work, we contribute to an understanding of the role of AtKUP9 in plant adaptation to low K+ availability. We found that in vitro, atkup9 has reduced lateral root growth under low-K conditions, and root apical meristem proliferation is reduced in lateral roots compared with the primary root. We also documented AtKUP9 expression in both roots and shoots and showed that AtKUP9 expression is modulated during plant ontogeny and as a result of K+ deprivation. Altered carbohydrate allocation was also documented in atkup9. Mutants exported more soluble saccharides from leaves under K+ rich conditions and, under K+ deficiency, atkup9 accumulated more soluble saccharides in the shoots. A possible role of AtKUP9 in these processes is discussed.


Inflammatory markers as predictors of postoperative adverse outcome in octogenarian surgical patients: an observational prospective study.
The value of inflammatory proteins, interleukin-6 and alpha-1-acid glycoprotein as prognostic factors in elderly people undergoing surgery has not been determined yet. To know whether preoperatively determined inflammatory markers may predict the postoperative outcome of elderly patients undergoing surgery. A scoring system for predicting postoperative morbidity was assessed. Hospital-based observational prospective study, with geriatric surgical patients. Preoperative determination of following data: age, gender, scheduled or urgent operation, comorbid diseases, malignancy, physical, mental and nutritional profile. Biochemical markers of inflammation, C Reactive Protein, interleukin-6, and alpha-1-acid glycoprotein were also studied. Preoperative data and postoperative complications were recorded. Binary logistic regression analysis was used to obtain a morbidity risk prediction model. A total of 225 patients were included. Fifty-five patients (24.4%) had postoperative complications, with a mortality rate of 5.3%. Binary logistic regression analysis showed an independent relation between morbidity and the variables malignancy, alpha-1-acid glycoprotein and interleukin-6. The risk (R) of postoperative morbidity adjusted by age was calculated. The model showed a 22.2% sensitivity, 94.8% specificity, and a percentage of correct classification of 78.3%. The area under the ROC curve was 0.781 (95% CI: 0.703-0.858). An age-adjusted equation for predicting 30-day morbidity that included malignancy, serum IL-6 and alpha 1-acid glycoprotein levels may be useful for risk assessment in octogenarian surgical patients.


Serine phosphorylation differentially affects RhoA binding to effectors: implications to NGF-induced neurite outgrowth.
Activation of RhoA prevents NGF-induced outgrowth and causes retraction of neurites in neuronal cells, including PC12 cells. Despite its inhibitory effect on neurite outgrowth, NGF activates GTP loading of and effector binding to RhoA, setting up an apparent contradiction. According to the molecular switch hypothesis of GTPase function GTP-loading of RhoA should be sufficient to activate its effectors uniformly. However, when monitoring NGF-induced binding of GTP-RhoA to multiple targets, we noted differential interactions with its effectors. We found that NGF elicits a protein kinase A-mediated phosphorylation of RhoA on serine(188), which renders it unable to bind to Rho-associated kinase (ROK), whereas it retains the ability to interact with other RhoA targets including rhotekin, mDia-1 and PKN. We show in vitro and in vivo that phosphorylation of serine(188) represents an additional switch, capable of directing signals among effector pathways. In the context of PC12 cell differentiation, NGF-induced phosphorylation of RhoA on serine(188) prevents it from interacting with ROK, which would otherwise block neurite outgrowth. Transfection of RhoA(S188A) mutant into PC12 cells prevents NGF-induced neurite outgrowth, just like constitutively activated RhoA(14V) does, indicating the requirement of this phosphorylation site. Replacement of serine(188) with the phosphomimetic glutamate residue in RhoA(V14/S188E) selectively impairs interaction with ROK and when transfected into PC12 cells restores NGF-induced neurite outgrowth. Therefore, phosphorylation of serine(188) may serve as a novel secondary switch of RhoA capable of overriding GTP-binding-elicited effector activation to a subset of targets such as ROK, which interact with the C-terminus of RhoA.


T-even type phages can change their host range by recombination with gene 34 (tail fibre) or gene 23 (head).
T-even type phages recognize their cellular receptors with the tip of their long tail fibres. The gene products involved in receptor recognition are proteins 37 and 38. While screening libraries of phage K3 with a probe of gene 38 from phage T2, a class of weakly hybridizing clones was found in addition to the expected clones of gene 38 of K3. One of these clones was identified as being from gene 23 of the phage which codes for the major head subunit; another clone originated from gene 34, which codes for the proximal half of the long tail fibres. Neither gene product 23 nor 34 is involved in receptor recognition. Phages can recombine with the DNA of the gene 23 and gene 34 clones and change the host range.


Short-term transcriptomic response to plasma membrane injury.
Plasma membrane repair mechanisms are activated within seconds post-injury to promote rapid membrane resealing in eukaryotic cells and prevent cell death. However, less is known about the regeneration phase that follows and how cells respond to injury in the short-term. Here, we provide a genome-wide study into the mRNA expression profile of MCF-7 breast cancer cells exposed to injury by digitonin, a mild non-ionic detergent that permeabilizes the plasma membrane. We focused on the early transcriptional signature and found a time-dependent increase in the number of differentially expressed (> twofold, P < 0.05) genes (34, 114 and 236 genes at 20-, 40- and 60-min post-injury, respectively). Pathway analysis highlighted a robust and gradual three-part transcriptional response: (1) prompt activation of immediate-early response genes, (2) activation of specific MAPK cascades and (3) induction of inflammatory and immune pathways. Therefore, plasma membrane injury triggers a rapid and strong stress and immunogenic response. Our meta-analysis suggests that this is a conserved transcriptome response to plasma membrane injury across different cell and injury types. Taken together, our study shows that injury has profound effects on the transcriptome of wounded cells in the regeneration phase (subsequent to membrane resealing), which is likely to influence cellular status and has been previously overlooked.


Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications.
Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.


The effects of different velogenic NDV infections on the chicken bursa of Fabricius.
Virulent Newcastle disease virus (NDV) was reported to cause rapid depletion of chicken bursa of Fabricius. Severe pathological condition of the organ is commonly associated with high levels of virus replication, intense inflammatory response and also the degree of apoptosis. In this study, the responses of chicken bursa of Fabricius infected with two different strains of velogenic NDV, namely AF2240 and IBS002, were investigated by observing cell population changes, oxidative stress, viral replication and cytokine expression in the organ. Subsequently, apoptosis of enriched bursal IgM+ cells was determined to help us elucidate possible host pathogen relationships between the chicken bursa of Fabricius and NDV infection. The depletion of IgM+ cells and infiltration of macrophages were observed to be higher in bursa infected with AF2240 as compared to IBS002. In line with the increment of the macrophage population, higher nitric oxide (NO) and malondialdehyde (MDA) contents which indicated higher oxidative stress were also detected in bursa infected with NDV AF2240. In addition, higher pro-inflammatory cytokines and chemokine gene expression such as chicken CXCLi2, IL-18 and IFN-γ were observed in AF2240 infected bursa. Depletion of IgM+ cells was further confirmed with increased cell death and apoptosis of the cells in AF2240 infected bursa as compared to IBS002. However, it was found that the viral load for NDV strain IBS002 was comparatively higher than AF2240 although the magnitude of the pro- inflammatory cytokines expression and cell apoptosis was lower than AF2240. The results of our study demonstrated that infection of NDV strains AF2240 and IBS002 caused apoptosis in bursa IgM+ cells and its severity was associated with increased expression of pro-inflammatory cytokines/chemokine, macrophage infiltration and oxidative stress as the infection duration was prolonged. However, of the two viruses, we observed that NDV AF2240 induced a greater magnitude of apoptosis in chicken bursa IgM+ cells in comparison to IBS002. This might be due to the high level of oxidative stress and inflammatory cytokines/chemokine as well as lower IL10 expression which subsequently led to a high rate of apoptosis in the chicken bursa of Fabricius although the detected viral load of AF2240 was lower than IBS002.


Hemifacial spasm associated with benign parotid tumor.
A case of hemifacial spasm associated with a benign parotid tumor is reported. Excision of the tumor relieved the symptoms.


Formaldehyde: Another hormesis-inducing chemical.
Formaldehyde (FA) is a naturally-occurring compound, produced endogenously in diverse living organisms. It also occurs widely in the environment due to anthropogenic (e.g. used as a chemical intermediate) and natural sources (e.g. a component of the volatile organic compounds blends emitted by plants). While FA is considered a potential carcinogen, living organisms have the ability to cope with FA, and some minimum endogenous levels of FA may be required for health. Recently, genetic engineering approaches transferring biological information from one organism to another led to increased assimilation of and conferred genetic-based tolerance to FA in plants-microorganisms systems. Here, we propose that FA commonly induces hormesis, a hypothesis that we confirm by collating evidence from various published studies with animals, plants, and microorganisms. The stimulation by low doses below the no-observed-adverse-effect-level (NOAEL) was modest in magnitude, in agreement with the general hormesis literature. In plants, among the endpoints showing hormesis were growth, lipid peroxidation, and photosynthetic pigments. In various animal cells, hormesis was observed in cell proliferation and viability, responses that were related to mechanisms, such as activation of phosphorylated ERK (extra-cellular signaling-regulated kinase) expression, acceleration of the process of cell division, and enhancement of the Warburg effect (i.e. use of glycolysis by tumor cells to produce energy for rapid growth). Hormetic in vitro responses were reported in several cancerous/tumorous cell lines, suggesting that FA has the potential to influence tumor promotion within a specific concentration range and biological context. These observations suggest that FA commonly acts in an hormetic manner with implications for study designs across a broad range of biological models and in the assessment of environmental and human risks associated with FA exposures.


Speech aid prosthesis for a patient with Wegener's granulomatosis: a clinical report.
A speech aid prosthesis was fabricated to correct the hypernasality of the speech of a patient. The hypernasality was caused by velopharyngeal insufficiency related to Wegener's granulomatosis. Speech aids have been used for cleft palate patients for whom surgical treatment was not indicated, surgical treatment was declined, or before surgical treatment as an evaluation for possible speech improvement. A speech aid prosthesis can be an important treatment modality when surgical correction of a velopharyngeal defect is not indicated.


Physiological and behavioral factors related to physical activity in black women with type 2 diabetes mellitus.
To describe relationships among physical activity (PA), physiological factors, and psychological factors in Black women with type 2 diabetes mellitus (T2DM). A cross-sectional design was used (N = 109). Data were collected on PA(activity/inactivity, TV hours, bed confinement), physiology (blood pressure, lipids, hemoglobin A1c), psychology (anxiety,emotional distress, physical functioning, bodily pain, vitality), and health care provider (HCP) support. Walking was the preferred PA; TV viewing averaged 3.7 hours/day, and 24% reported confinement to bed >1 week in the last year. Inactive women had greater physiological and psychological problems than active women. Women watching TV >2 hours/day had more physiological problems than women watching TV <2 hours/day. Women reporting >1 week of confinement to bed in the last year had more physiological and psychological problems than those confined to bed <1 week. PA interventions in Black women with T2DM should promote walking, address TV viewing time, incorporate HCP's role of PA counseling/support,and address several psychological factors.


1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes.
To investigate the differentiation and activation of monocytes, the combined effects of 1,25-dihydroxyvitamin D3 (D3) and IL-4 on human blood monocytes were examined with respect to expression of MHC class-II antigens, accessory activity, and phagocytic capacity. IL-4 was reported to upregulate the expression of MHC class-II antigens and accessory activity of monocytes. The experiments described here demonstrate that D3 inhibits the expression of all three subtypes of MHC class-II antigens (HLA-DR, -DP and -DQ) as well as the accessory activity of monocytes, both in a dose- and time-dependent manner. However, D3 enhances the immunoglobulin- and complement-dependent phagocytosis by monocytes in a dose- and time-dependent manner. When monocytes are treated with both IL-4 and D3, the effects of D3 are reverted by IL-4, suggesting that IL-4 induces the development of monocytes into accessory cells, whereas D3 stimulates differentiation of monocytes into classical macrophages. These findings provide further evidence for the contention that, depending on defined stimuli, monocytes may develop either into accessory cells or into classical macrophages.


Efficacy and safety of direct aspiration versus stent-retriever for recanalization in acute cerebral infarction: A PRISMA-compliant systematic review and meta-analysis.
Whether the direct aspiration approach of thrombectomy for recanalization in patients with acute ischemic stroke has a similar efficacy and safety compared to the stent-retriever remains uncertain. We conducted a meta-analysis of 9 studies obtained through PubMed and Embase database searches to determine whether successful recanalization rate, good functional outcome at 3 months (modified Rankin score, mRS≤2), procedure time from groin puncture to maximal revascularization and procedure-related adverse events differed between patients who underwent the direct aspiration and those receiving stent-retriever for recanalization in acute cerebral infarction. There was no significant difference between the direct aspiration group and the stent-retriever group in rate of successful recanalization (summary odds ratio [OR], 0.86 [95% confidence interval (CI), 0.45-1.52]; P = .60), but a better functional outcomes in the direct aspiration group at 3 months defined as a mRS score of 0 to 2 (OR, 0.77; 95% CI, 0.66-0.97; P = .03). Furthermore, the direct aspiration patients compared with the stent-retriever patients had a tendency of shorter procedural time (Mean difference [MD], -8.77 [95% CI, from-18.90 to 1.37]; P = .09). Finally, there were less adverse events especially in symptomatic intracerebral hemorrhage (sICH) (OR, 0.56; 95% CI, 0.33-0.98; P = .04) and embolization to a new territory (ENT) (OR, 0.49; 95% CI, 0.28-0.84; P = .01) in the direct aspiration group when compared with the stent-retriever group, although no difference between them in the rate of any ICH (OR, 0.81; 95% CI, 0.41-1.60; P = .54). The results support that the direct aspiration technique for those acute ischemic stroke patients may have better functional outcomes, less procedure related-adverse events and a tendency of faster revascularization time as compared to the stent-retriever thrombectomy, with a similar successful recanalization rate. However, major limitations of current evidence (mainly from retrospective and observational studies and a small number of patients population) indicate a need for adequately powered, multicenter randomized controlled trials (RCT) to answer this question.


Endothelial cell pyroptosis plays an important role in Kawasaki disease via HMGB1/RAGE/cathespin B signaling pathway and NLRP3 inflammasome activation.
Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1β, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1β was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1β and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology.


Facing the noncommunicable disease (NCD) global epidemic--the battle of prevention starts in utero--the FIGO challenge.
Noncommunicable diseases (NCDs) are responsible for 36 million deaths every year. Of this death toll, nearly 80% (29 million) occur in low- and median-income countries. More than 9 million deaths attributed to NCDs occur in people under 60 years of age. National economies are suffering considerable losses due to premature death or disability to work resulting from heart disease, stroke, and diabetes. The knowledge that in utero and in early childhood certain processes can affect the risk of developing NCDs provides an opportunity to enforce interventions during this critical time, when they may have the greatest effect. Using appropriate protocols, the health-care provider can educate mothers about the risks of certain nutritional and environmental exposures and integrate health promotion on the agenda, as part of the social and economic development. All this could motivate a substantial reduction in the risk of NCDs. Current and future health challenges demand new and changing competencies that should form the basis for education, training, and workforce planning. The International Federation of Gynaecology and Obstetrics (FIGO) is aware of that responsibility and has joined hands with other agencies and organizations that make a considerable effort in providing appropriate prenatal care programs to prevent and treat most of the common preconditioning factors, especially in low-income countries.


Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity.
Approximately 15-30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.


Bactericidal and bacteriolytic action of peptide antibiotic AS-48 against gram-positive and gram-negative bacteria and other organisms.
A purified peptide antibiotic AS-48 from Streptococcus faecalis spp liquiefaciens S-48 exerted a bactericidal mode of action against most Gram-positive and many Gram-negative bacteria tested. In many Gram-positive bacteria and the two Myxococcus species assayed, a bacteriolytic effect, as a consequence of primary lesions, was also observed. In general, the Gram-negative bacteria were more resistant to AS-48. Escherichia coli protoplasts showed increased sensitivity and those of a resistant yeast. Saccharomyces cerevisiae 3.2, became sensitive. These data suggest that resistance is related to the cell wall structure. AS-48 adsorbed rapidly to cell walls and cytoplasmic membranes of sensitive and resistant cells. Adsorption to cytoplasmic membranes involved complete neutralization of AS-48.


Dosimetric comparison study between intensity modulated radiation therapy and three-dimensional conformal proton therapy for pelvic bone marrow sparing in the treatment of cervical cancer.
The objective was to compare intensity-modulated radiation therapy (IMRT) with 3D conformal proton therapy (3DCPT) in the treatment of cervical cancer. In particular, each technique's ability to spare pelvic bone marrow (PBM) was of primary interest in this study. A total of six cervical cancer patients (3 postoperative and 3 intact) were planned and analyzed. All plans had uniform 1.0 cm CTV-PTV margin and satisfied the 95% PTV with 100% isodose (prescription dose = 45 Gy) coverage. Dose-volume histograms (DVH) were analyzed for comparison. The overall PTV and PBM volumes were 1035.9 ± 192.2 cc and 1151.4 ± 198.3 cc, respectively. In terms of PTV dose conformity index (DCI) and dose homogeneity index (DHI), 3DCPT was slightly superior to IMRT with 1.00 ± 0.001, 1.01 ± 0.02, and 1.10 ± 0.02, 1.13 ± 0.01, respectively. In addition, 3DCPT demonstrated superiority in reducing lower doses (i.e., V30 or less) to PBM, small bowel and bladder. Particularly in PBM, average V10 and V20 reductions of 10.8% and 7.4% (p = 0.001 and 0.04), respectively, were observed. However, in the higher dose range, IMRT provided better sparing (> V30). For example, in small bowel and PBM, average reductions in V45 of 4.9% and 10.0% (p = 0.048 and 0.008), respectively, were observed. Due to its physical characteristics such as low entrance dose, spread-out Bragg peak and finite particle range of protons, 3DCPT illustrated superior target coverage uniformity and sparing of the lower doses in PBM and other organs. Further studies are, however, needed to fully exploit the benefits of protons for general use in cervical cancer.


Long-term results of the uncemented resurfacing shoulder hemiarthroplasty (Global Conservative Anatomic Prosthesis).
Treatment with uncemented resurfacing shoulder hemiarthroplasty has proved to be viable for patients with end-stage osteoarthritis at short- and mid-term follow-up. This study was essential to determine whether those outcomes will endure. This study presents the long-term results of the Global Conservative Anatomic Prosthesis (CAP) uncemented resurfacing shoulder hemiarthroplasty (DePuy Synthes, Warsaw, IN, USA). All patients with a diagnosis of glenohumeral osteoarthritis and an intact and clinically sufficient rotator cuff who underwent uncemented resurfacing shoulder hemiarthroplasty between 2007 and 2009 were included. The data of all patients who completed the 10-year follow-up assessments were used for analysis. The visual analog scale pain score, Dutch version of the Simple Shoulder Test score, Constant score, Short Form 12 scores, and physical examination findings were evaluated preoperatively and postoperatively on an annual basis. All complications and revisions were documented. Radiographs were evaluated for loosening, luxation or subluxation, migration, and glenoid erosion. Of 48 shoulders, 23 (48%, 18 women and 5 men) were available for the 10-year follow-up assessments and their data were used for analysis. The main reasons for dropout were revision (27%) and death (10%). The mean follow-up period of the remaining patients was 10.9 years (range, 9-13 years). The visual analog scale pain score (from 6.5 ± 2.1 to 0.7 ± 1.6, P < .001), Simple Shoulder Test (Dutch version) score (from 22% ± 22% to 79% ± 22%, P < .001), Constant score (from 40 ± 29 to 70 ± 8, P < .001), and Short Form 12 physical score (from 36 ± 7 to 41 ± 12, P = .001) improved significantly compared with preoperative scores. Revision surgery was performed in 13 of the initial 48 shoulders (27%). Most revisions were seen within 7 years postoperatively. Two revisions have been performed in the mid-term to long term because of increased functional outcome scores and the absence of signs of loosening. Nevertheless, the high overall revision rate of 27% between short- and long-term follow-up reflects the need to limit the use of uncemented resurfacing shoulder hemiarthroplasty for the treatment of glenohumeral osteoarthritis.


Angiography of the iliofemoral arteriovenous system supplying free groin flaps and free hypogastric flaps.
The circulatory anatomy of the iliofemoral region was elucidated by doing detailed angiography in 50 cases, and we classified the vessels into 4 types. In most cases, the s.c.i.a. predominated over the s.i.e.a. Therefore, it is probably better to plan free flaps supplied by this artery. This vessel usually arises approximately two or three fingerbreadths inferior to the intersection of the femoral artery and the inguinal ligament, and the skin flap should be designed in the area inferior and parallel to the inguinal ligament.


Treatment by low-dose brain radiation therapy improves memory performances without changes of the amyloid load in the TgF344-AD rat model.
Alzheimer's disease (AD) is a neurodegenerative condition affecting memory performance. This pathology is characterized by intracerebral amyloid plaques and tau tangles coupled with neuroinflammation. During the last century, numerous therapeutic trials unfortunately failed highlighting the need to find new therapeutic approaches. Low-dose brain radiotherapy (LD-RT) showed efficacy to reduce amyloid load and inflammation in patients with peripheral diseases. In this study, the therapeutic potential of 2 LD-RT schedules was tested on the TgF344-AD rat model of AD. Fifteen-month-old rats were irradiated with 5 fractions of 2 Gy delivered either daily or weekly. The daily treatment induced an improvement of memory performance in the Y-maze. In contrast, the weekly treatment increased the microglial reactivity in the hippocampus. A lack of effect of both regimens on amyloid pathology was unexpectedly observed. The positive effect on cognition encourages to further evaluate the LD-RT therapeutic potential and highlights the impact of the design choice of the LD-RT regimen.


Is self-compassion negatively associated with alcohol and marijuana-related problems via coping motives?
Alcohol and marijuana misuse is prevalent on many university campuses, with high rates of undergraduate students reporting experiencing alcohol and/or marijuana-related problems, which have been consistently associated with coping-motivated use. While previous studies have found dispositional mindfulness to be negatively associated with coping motives and alcohol-related problems, the present two-part study examines self-compassion, a complementary construct to mindfulness. Study One examines whether dispositional self-compassion is negatively associated with alcohol-related problems via drinking to cope with anxiety and depression, whereas Study Two extends this model by examining whether dispositional self-compassion is negatively associated with marijuana-related problems via coping-motivated marijuana use. Undergraduate students (N = 174 in Study One; N = 165 in Study Two) completed self-report measures assessing their levels of dispositional self-compassion, drinking or marijuana motives, and alcohol or marijuana-related problems. In Study One, mediation analyses showed dispositional self-compassion was negatively associated with alcohol-related problems via drinking to cope with anxiety, but not depression. In Study Two, mediation analyses showed dispositional self-compassion was negatively associated with marijuana-related problems via coping-motivated marijuana use. Future research should investigate whether self-compassion training helps reduce drinking to cope with anxiety, drinking to cope with depression, and/or coping-motivated marijuana use and the associated problems, and how this relationship differs for students who drink to cope with anxiety versus depression.