Effectiveness of personalised risk information and taster sessions to increase the uptake of smoking cessation services (Start2quit): a randomised controlled trial.
National Health Service Stop Smoking Services (SSSs) offer help to smokers motivated to quit; however, attendance rates are low and recent figures show a downward trend. We aimed to assess the effectiveness of a two-component personalised intervention on attendance at SSSs. We did this randomised controlled trial in 18 SSSs in England. Current smokers (aged ≥16 years) were identified from medical records in 99 general practices and invited to participate by their general practitioner. Individuals who gave consent, were motivated to quit, and had not attended the SSS within the past 12 months, were randomly assigned (3:2), via computer-generated randomisation with permuted blocks (block size of five), to receive either an individually tailored risk letter and invitation to attend a no-commitment introductory session run by the local SSS (intervention group) or a standard generic letter advertising the local SSS (control group). Randomisation was stratified by sex. Masking of participants to receipt of a personal letter and invitation to a taster session was not possible. The personal letter was generated by a research assistant, but the remainder of the research team were masked to group allocation. General practitioners, practice staff, and SSS advisers were unaware of their patients' allocation. The primary outcome was attendance at the first session of an SSS course within 6 months from randomisation. We did analysis by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN 76561916. Recruitment, collection of baseline data, delivery of the intervention, and follow up of participants took place between Jan 31, 2011, and July 12, 2014. We randomly assigned 4384 smokers to the intervention group (n=2636) or the control group (n=1748); 4383 participants comprised the intention-to-treat population. Attendance at the first session of an SSS course was significantly higher in the intervention group than in the control group (458 [17·4%] vs 158 [9·0%] participants; unadjusted odds ratio 2·12 [95% CI 1·75-2·57]; p<0·0001). Delivery of personalised risk information alongside an invitation to an introductory session more than doubled the odds of attending the SSS compared with a standard generic invitation to contact the service. This result suggests that a more proactive approach, combined with an opportunity to experience local services, can reduce patient barriers to receiving treatment and has high potential to increase uptake. National Institutes of Health Research Health Technology Assessment.


Reactions of morphine derivatives with phenyliodo(III)diacetate (PIDA): synthesis of new morphine analogues.
The reactions of morphine and its derivatives with phenyliodo(III)diacetate (PIDA) have been studied. This methodology has not been introduced to morphine alkaloids, despite the fact that such a strategy would ensure dearomatization of the electrophilic aromatic ring of morphine derivatives leading to nucleophilic ortho-quinoidal structures with potential pharmacological interest. The products, formed in regio- and diastereoselective or diastereospecific reactions, carry mixed-acetal or 1,3-dioxolane moieties. At low concentrations 6a has mu-opioid agonist character but in higher concentrations showed a non receptorial antagonist effect on isolated mouse vas deferens.


Outcomes of Patients Presenting With Clinical Indices of Spontaneous Reperfusion in ST-Elevation Acute Coronary Syndrome Undergoing Deferred Angiography.
Few data are available regarding the optimal management of ST-elevation myocardial infarction patients with clinically defined spontaneous reperfusion (SR). We report on the characteristics and outcomes of patients with SR in the primary percutaneous coronary intervention era, and assess whether immediate reperfusion can be deferred. Data were drawn from a prospective nationwide survey, ACSIS (Acute Coronary Syndrome Israeli Survey). Definition of SR was predefined as both (1) ≥70% reduction in ST-segment elevation on consecutive ECGs and (2) ≥70% resolution of pain. Of 2361 consecutive ST-elevation-acute coronary syndrome patients in Killip class 1, 405 (17%) were not treated with primary reperfusion therapy because of SR. Intervention in SR patients was performed a median of 26 hours after admission. These patients were compared with the 1956 ST-elevation myocardial infarction patients who underwent primary reperfusion with a median door-to-balloon of 66 minutes (interquartile range 38-106). Baseline characteristics were similar except for slightly higher incidence of renal dysfunction and prior angina pectoris in SR patients. Time from symptom onset to medical contact was significantly greater in SR patients. Patients with SR had significantly less in-hospital heart failure (4% versus 11%) and cardiogenic shock (0% versus 2%) (P<0.01 for all). No significant differences were found in in-hospital mortality (1% versus 2%), 30-day major cardiac events (4% versus 4%), and mortality at 30 days (1% versus 2%) and 1 year (4% versus 4%). Patients with clinically defined SR have a favorable prognosis. Deferring immediate intervention seems to be safe in patients with clinical indices of spontaneous reperfusion.


Treatment-Seeking Behavior Towards Epilepsy Among Rural Residents in Ethiopia: A Cross-Sectional Study.
Even though a large number of patients live with epilepsy, few of them receive effective treatment. Most people with epilepsy, particularly those from rural communities, do not seek medical care as they are convinced that solutions lie only with traditional healers (traditional leaders, prophets and community elders). Therefore, studying treatment-seeking behavior regarding this major neurological problem would provide additional knowledge and help to identify a gap which needs to be addressed when tackling related problems. This rural community-based cross-sectional study was conducted in Gedeo zone, Ethiopia, among 755 participants. Data were collected using face-to-face interview-based questionnaires. Collected data were entered into EpiData version 3.01 and analyzed using SPSS version 20. Bivariate and multivariate logistic regression analysis was conducted to identify associated factors. The strengths of associations were presented as adjusted odds ratios with 95% confidence intervals. The prevalence of poor treatment-seeking behavior was 54.6% (95% CI 51.4, 58.2). Poor knowledge (adjusted odds ratio [AOR]=3.21, 95% CI 2.14, 4.81), poor social support (AOR=2.48, 95% CI 1.12, 5.53), unfavorable attitude (AOR=1.84, 95% CI 1.34, 2.54) and having no history of experiencing others' seizures (AOR=2.17, 95% CI 1.47, 3.2) were variables strongly associated with poor help-seeking behavior towards epilepsy. The study showed that more than half of the participants had poor treatment-seeking behavior towards epilepsy. This indicates the need to implement measures to raise community awareness regarding treatment options for epilepsy.


Revisiting Transfer Learning Method for Tuberculosis Diagnosis.
Transfer learning (TL) has been proven to be a good strategy for solving domain-specific problems in many deep learning (DL) applications. Typically, in TL, a pre-trained DL model is used as a feature extractor and the extracted features are then fed to a newly trained classifier as the model head. In this study, we propose a new ensemble approach of transfer learning that uses multiple neural network classifiers at once in the model head. We compared the classification results of the proposed ensemble approach with the direct approach of several popular models, namely VGG-16, ResNet-50, and MobileNet, on two publicly available tuberculosis datasets, i.e., Montgomery County (MC) and Shenzhen (SZ) datasets. Moreover, we also compared the results when a fully pre-trained DL model was used for feature extraction versus the cases in which the features were obtained from a middle layer of the pre-trained DL model. Several metrics derived from confusion matrix results were used, namely the accuracy (ACC), sensitivity (SNS), specificity (SPC), precision (PRC), and F1-score. We concluded that the proposed ensemble approach outperformed the direct approach. Best result was achieved by ResNet-50 when the features were extracted from a middle layer with an accuracy of 91.2698% on MC dataset.Clinical Relevance- The proposed ensemble approach could increase the detection accuracy of 7-8% for Montgomery County dataset and 4-5% for Shenzhen dataset.


Atrioventricular nodal ablation in atrial fibrillation: a meta-analysis and systematic review.
In the treatment of patients with refractory atrial fibrillation (AF), the safety and efficacy of atrioventricular nodal ablation (AVNA) versus pharmacotherapy alone remains unclear. Additionally, the impact of AVNA in patients with reduced systolic function is of growing interest. A total of 5 randomized or prospective trials were included for efficacy review (314 patients), 11 studies for effectiveness review (810 patients), and 47 studies for safety review (5632 patients). All-cause mortality was similar between AVNA and medical therapy (3.1% versus 3.3%; relative risk ratio, 1.05; 95% confidence interval [CI], 0.29-3.85). There was no significant difference in exercise duration or ejection fraction (EF) with AVNA relative to pharmacotherapy. In subgroup analysis, patients with baseline systolic dysfunction (116 patients; mean EF, 44%) showed significant relative improvement in EF after AVNA (+4% greater; 95% CI, 3.11-4.89). In pooled observational analysis, AVNA was also associated with significant improvement in EF only in patients with systolic dysfunction (+7.44%; 95% CI, 5.4-9.5). The incidence of procedure-related mortality (0.27%) and malignant arrhythmia (0.57%) was low. At mean follow-up of 26.5 months, the incidence of sudden cardiac death after AVNA was 2.1%. There was significant heterogeneity in quality-of-life scales used; compared with pharmacotherapy, AVNA was associated with significant improvement in several symptoms (palpitations, dyspnea). In the management of refractory AF, AVNA is associated with improvement in symptoms and quality of life, with a low incidence of procedure morbidity. In patients with reduced systolic function, AVNA demonstrates small but significantly improved echocardiographic outcomes relative to medical therapy alone.


Acupuncture for treatment of insomnia in patients with traumatic brain injury: a pilot intervention study.
: To assess the efficacy of acupuncture in treating insomnia in traumatic brain injury (TBI) survivors as compared to medication, to determine whether acupuncture has fewer cognitive and affective adverse effects than does medication. : Twenty-four adult TBI survivors, randomized to acupuncture or control arms. : Outpatient rehabilitation clinic. : Insomnia Severity Index (degree of insomnia); actigraphy (sleep time); Hamilton Depression Rating Scale (depression); Repeatable Battery for the Assessment of Neuropsychological Status and Paced Auditory Serial Addition Test (cognitive function) administered at baseline and postintervention. : Sleep time did not differ between the treatment and control groups after intervention, whereas cognition improved in the former but not the latter. : Acupuncture has a beneficial effect on perception of sleep or sleep quality and on cognition in our small sample of patients with TBI. Further studies of this treatment modality are warranted to validate these findings and to explore factors that contribute to treatment efficacy.


[Incidence of side effects of a 3-stage preparation administered to 10,034 women].
In an open multicentre study, 10,034 women received a low-dose three-phase combination of levonorgestrel and ethinylestradiol for oral hormonal contraception. Duration of this treatment was three months. During this time, incidence of side effects were documented by reports of the patients or in reply to questions of the treating gynaecologists. Data has been analysed with special regard to smoking, obesity and increase of blood pressure. Upon inquiry, 38.1% of women had complaints before and 28.5% after treatment with this oral contraceptive, whereby in 16.9% of patients, complaints were noted for the first time. The observed side effects were more pronounced in smokers than in non-smokers, in obese women more than in those with normal weight, and more pronounced in patients with increased blood pressure compared to normal controls. Cycles became regular, whereas the number of spottings increased. Dysmenorrhoea disappeared almost completely. In the same time interval, genital infections were less prominent. During treatment, 26 patients (0.26%) became pregnant. It is concluded, that this triphasic combination with its varying ratios of ethinylestradiol and levonorgestrel is an effective and well tolerated oral contraceptive. It is shown, that the incidence of side effects is affected by additional risk factors.


Connections of midbrain periaqueductal gray in the monkey. I. Ascending efferent projections.
1. To obtain a comprehensive map of the ascending projection of the midbrain periaqueductal gray, small amounts of [3H]leucine were injected into discrete regions of the periaqueductal gray (PAG) of the monkey. 2. Despite the fact that different regions of the PAG were injected in separate animals, the majority of the PAG's efferent projections to the forebrain remained constant. 3. The diencephalic projection areas include the nucleus reticularis thalami, the nucleus medialis dorsalis, the midline thalamic nuclei, the intralaminar thalamic nuclei, the preoptic area, and the anterior, dorsal, periventricular, ventromedial, periarcurate, lateral, and posterior hypothalamic nuclei. 4. More caudal areas receiving a projection from the PAG include the zona incerta and the mesencephalic reticular formation. 5. The main route for PAG-diencephalic projections is through the periventricular bundle. This implies that if a stimulating electrode was placed in this region, both the diencephalic leads to PAG and PAG leads to diencephalic pathways would be stimulated. This observation may explain the wide variety of side effects often encountered in stimulation-produced analgesia in humans. 6. These results support our hypothesis that the PAG functions as a visceral, nociceptive, and cognitive integrator.


Identification of novel endogenous cytochrome p450 arachidonate metabolites with high affinity for cannabinoid receptors.
Arachidonic acid is an essential constituent of cell membranes that is esterified to the sn-2-position of glycerophospholipids and is released from selected lipid pools by phospholipase cleavage. The released arachidonic acid can be metabolized by three enzymatic pathways: the cyclooxygenase pathway forming prostaglandins and thromboxanes, the lipoxygenase pathway generating leukotrienes and lipoxins, and the cytochrome P450 (cP450) pathway producing epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids. The present study describes a novel group of cP450 epoxygenase-dependent metabolites of arachidonic acid, termed 2-epoxyeicosatrienoylglycerols (2-EG), including two regioisomers, 2-(11,12-epoxyeicosatrienoyl)glycerol (2-11,12-EG) and 2-(14,15-epoxyeicosatrienoyl)glycerol (2-14,15-EG), which are both produced in the kidney and spleen, whereas 2-11,12-EG is also detected in the brain. Both 2-11,12-EG and 2-14,15-EG activated the two cannabinoid (CB) receptor subtypes, CB1 and CB2, with high affinity and elicited biological responses in cultured cells expressing CB receptors and in intact animals. In contrast, the parental arachidonic acid and epoxyeicosatrienoic acids failed to activate CB1 or CB2 receptors. Thus, these cP450 epoxygenase-dependent metabolites are a novel class of endogenously produced, biologically active lipid mediators with the characteristics of endocannabinoids. This is the first evidence of a cytochrome P450-dependent arachidonate metabolite that can activate G-protein-coupled cell membrane receptors and suggests a functional link between the cytochrome P450 enzyme system and the endocannabinoid system.


Investigation of Genetic Causes in a Developmental Disorder: Oculoauriculovertebral Spectrum.
Oculoauriculovertebral spectrum (OAVS) is a genetically and clinically heterogeneous disorder that occurs due to a developmental field defect of the first and second pharyngeal arches. Even though recent whole exome sequencing studies (WES) have led to identification of several genes associated with this spectrum in a subset of individuals, complete pathogenesis of OAVS remains unsolved. In this study, molecular genetic etiology of OAVS was systematically investigated. A cohort of 23 Turkish patients with OAVS, referred to Hacettepe University Hospital, Department of Pediatric Genetics from 2008 to 2018, was included in this study. Minimal diagnostic criteria for OAVS were considered as unilateral microtia or hemifacial microsomia with preauricular skin tag. The cohort was clinically reevaluated for craniofacial and extracranial findings. Molecular etiology was investigated using candidate gene sequencing following copy number variant (CNV) analysis. WES was also performed for 2 of the selected patients. Patients in the study cohort presented similar demographic and phenotypic characteristics to previously described patients in the literature except for a higher frequency of bilaterality, cardiac findings, and intellectual disability/developmental delay. CNV analysis revealed a possible genetic etiology for 3 patients (13%). Additional WES in 1 of the 2 patients uncovered a novel heterozygous nonsense variant in Elongation factor Tu GTP-binding domain-containing 2 (EFTUD2) causing mandibulofacial dysostosis with microcephaly (MFDM), which clinically overlaps with OAVS. Detailed clinical evaluation for any patient with OAVS is recommended due to a high rate of accompanying systemic findings. We further expand the existing genetic heterogeneity of OAVS by identifying several CNVs and a phenotypically overlapping disorder, MFDM.


Paediatric supratentorial tumours do not cause microstructural alterations in contralateral white matter: a preliminary study.
Intracranial tumours in children can exhibit different characteristics compared to those in adults. Understanding the microstructural changes in the contralateral normal-appearing white matter (NAWM) in children with primary intracranial masses is essential for optimizing treatment strategies. This study aimed to investigate the apparent diffusion coefficient (ADC) changes in contralateral NAWM using fully automated methods and deep learning algorithms. We included 22 paediatric patients with primary supratentorial intracranial masses (23% high-grade) in the study. ADC values of the contralateral NAWM in the patient group were compared to those of a control group. Deep learning algorithms were utilized to analyse diffusion changes in NAWM. The mean ADC values of contralateral NAWM in the patient group were 0.80 ± 0.03 × 10-3 mm2/s, while the control group had a mean ADC value of 0.81 ± 0.03 × 10-3 mm2/s. There was no statistically significant difference between the groups (p = 0.39). Our findings indicate that there are no significant diffusion changes in the contralateral white matter of children with supratentorial intracranial masses. Primary supratentorial intracranial masses in children do not cause microstructural changes in contralateral normal-appearing white matter. This could be attributed to the less infiltrative nature and different biochemical profile of these tumour groups in the paediatric population. Further studies using advanced imaging techniques could provide additional insights into the distinct characteristics of paediatric intracranial tumours and improve patient management.


Comparison of high-frequency and ultrahigh-frequency probes in chronic inflammatory demyelinating polyneuropathy.
High-frequency ultrasound (HFUS 18-20 MHz) performed on patients with chronic inflammatory demyelinating polyneuropathy (CIDP) shows a focal enlargement, particularly in the proximal segments of upper-arm motor nerves. Ultrahigh frequency ultrasound (UHFUS 30-70 MHz), having a higher spatial resolution, enables a better characterization of nerve structures. The aim of this study was to compare the two ultrasound probes in the evaluation of motor nerve characteristics in CIDP patients. Eleven patients with definite or probable CIDP underwent an ultrasound evaluation of median and ulnar nerves, bilaterally. Nerve and fascicle cross-sectional area (CSA), vascularization, and echogenicity were assessed. Nerve and fascicle CSA were increased in the proximal segments, especially in the median nerve, in 9/11 patients and in 10/11 patients at the HFUS and UHFUS evaluations, respectively. A statistically significant difference between CSA values obtained with the two probes was found only for fascicle values. UHFUS allowed for a more precise estimation of fascicle size and number than the HFUS. We were able to identify nerve vascularization in 4/11 patients at UHFUS only. UHFUS gives more detailed information on the changes in the internal nerve structure in CIDP patients. In particular, it permits to better characterize fascicle size and morphology, and to have a precise estimation of their number. Its frequency range also allows to evaluate nerve vascularization. Ultrasound evaluation could become an adjunctive diagnostic tool for CIDP. Further studies are needed to validate the examined parameters as biomarkers for the evaluation and follow-up of CIDP patients.


Developments and Challenges Involving Triplet Transfer across Organic/Inorganic Heterojunctions for Singlet Fission and Photon Upconversion.
In this Perspective, we provide an overview of recent advances in harvesting triplets for photovoltaic and photon upconversion applications from two angles. In singlet fission-sensitized solar cells, the triplets are harvested through a low band gap semiconductor such as Si. Recent literature has shown how a thin interlayer or orientation of the singlet fission molecule can successfully lead to triplet transfer. On the other hand, the integration of transition metal dichalcogenides (TMDCs) with suitable organic molecules has shown triplet-triplet annihilation upconversion (TTA-UC) of near-infrared photons. We consider the theoretical aspect of the triplet transfer process between a TMDC and organic semiconductors. We discuss possible bottlenecks that can limit the harvesting of energy from triplets and perspectives to overcome these.


Do exploratory arm movements contribute to maximum reach distance judgements?
Exploratory movements provide information about agents' action capabilities in a given environment. However, little is known about the specifics of these exploratory movements, such as which movements are necessary to perceive a given action capability. This experiment tested whether arm movements contributed to judgements of maximum reach distance. Participants made judgements about their maximum reach distance by walking to the point farthest from an object from which they still perceived the object to be reachable. Over the course of two sets of nine judgements, participants' arms either swung naturally by their sides (Unrestricted Condition) or were held together behind their backs (Restricted Condition). Arm movement restriction increased maximum reach distance judgement error when compared with unrestricted judgements. In addition, judgement error improved over trials only when exploratory arm movements were unrestricted, and the improvements did not carry over to subsequent judgements made when exploratory arm movements were restricted. Arm movement restriction did not increase the variability of judgement error when compared with unrestricted judgements. The results indicate that exploration is necessary to generate affordance information, show that restricted exploration degrades affordance perception, and suggest that maximum reach distance exists at the global array level. In addition, they have practical implications for operational situations in which actors' arm movements are restricted, such as when military personnel wear body armour.


Asymptomatic carotid stenosis: Medicine alone or combined with carotid revascularization.
Two positive randomized trials established carotid endarterectomy (CEA) as a superior treatment to medical management alone for the treatment of asymptomatic carotid artery stenosis. However, advances in medical therapy have led to an active and spirited debate about the best treatment for asymptomatic carotid stenosis. The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST 2) trial aims to better define the best treatment for the average patient with severe asymptomatic carotid stenosis. Enrollment in the trial may be hampered by strong opinions on either side of the debate. It is important to realize that equipoise exists and that neither the old data on CEA nor the new data on optimal medical therapy provide a rigorous answer. The assumption that medical therapy has already been proven superior to revascularization procedures may hinder both enrollment in the trial and technical advancements in revascularization procedures.


Analgesic efficacy of local infiltration analgesia in hip and knee arthroplasty: a systematic review.
In recent years, there has been an increasing interest in local infiltration analgesia (LIA) as a technique to control postoperative pain. We conducted a systematic review of randomized clinical trials investigating LIA for total knee arthroplasty (TKA) and total hip arthroplasty (THA) to evaluate the analgesic efficacy of LIA for early postoperative pain treatment. In addition, the analgesic efficacy of wound catheters and implications for length of hospital stay (LOS) were evaluated. Twenty-seven randomized controlled trials in 756 patients operated on with THA and 888 patients operated on with TKA were selected for inclusion in the review. In THA, no additional analgesic effect of LIA compared with placebo was reported in trials with low risk of bias when a multimodal analgesic regimen was administered perioperatively. Compared with intrathecal morphine and epidural analgesia, LIA was reported to have similar or improved analgesic efficacy. In TKA, most trials reported reduced pain and reduced opioid requirements with LIA compared with a control group treated with placebo/no injection. Compared with femoral nerve block, epidural or intrathecal morphine LIA provided similar or improved analgesia in the early postoperative period but most trials had a high risk of bias due to different systemic analgesia between groups. Overall, the use of wound catheters for postoperative administration of local anaesthetic was not supported in the included trials, and LOS was not related to analgesic efficacy. Despite the many studies of LIA, final interpretation is hindered by methodological insufficiencies in most studies, especially because of differences in use of systemic analgesia between groups. However, LIA provides effective analgesia in the initial postoperative period after TKA in most randomized clinical trials even when combined with multimodal systemic analgesia. In contrast, LIA may have limited additional analgesic efficacy in THA when combined with a multimodal analgesic regimen. Postoperative administration of local anaesthetic in wound catheters did not provide additional analgesia when systemic analgesia was similar and LOS was not related to use of LIA with a fast-track set-up.


Interobserver variability of clinical scores in hidradenitis suppurativa is low.
Hidradenitis suppurativa (HS) is a chronic recurrent disease with scars and sinus tract formation that causes substantial impact on quality of life. For evaluation of HS and treatment results, a scoring system for disease severity (Hidradenitis Suppurativa Score, HSS) has been proposed. To describe the interobserver reliability of the HSS and further to document its correlation with risk factors and other measures of disease severity. Sixty-one consecutive patients with HS, referred to a clinical centre with special interest in the disease, were scored according to the HSS protocol: eight patients by four dermatologists together, 23 patients by all four observers independently and 30 patients by a single observer. Interobserver variability in HSS between the four observers was investigated in the group of 23 patients. Patients' reports of weight and height, smoking habits etc., were collected, as well as Dermatology Life Quality Index (DLQI) questionnaires. The interobserver concordance of HSS was 0·95. Median (interquartile range, IQR) HSS for all patients was 40 (18-73); women 39 (16-68); men 60·5 (30-95). Median (IQR) HSS for nonsmokers was 26 (12-65); former smokers 30 (10-56); smokers 44 (26-108). Median (IQR) HSS for normal weight patients was 12 (10-30); overweight 43 (25-58); obese 51 (24-95). Mean ± SD DLQI for all patients was 11·3 ± 8·6. HSS is simple to use and shows low interobserver variability. The score correlates with suggested risk factors, indicating that it reflects a valid estimation of disease severity.


[Effect of bilateral destruction of the structures of the medial hypothalamus on the course of anaphylactic shock].
Anaphylactic shock induced in rabbits by the preliminary injury of various areas of the medial hypothalamus coursed more severly than in control. Irrespective of the localization of the foci of injury a more pronounced hypotensive reaction and a slower compensatory elevation of the blood pressure occurred in response to the administration of the reactive dose of the antigen. The severity of anaphylactic shock depended on the time lapse from the moment of hypothalamic injury to the moment of administration of the reactive dose of the antigen.


Molecular chaperone gp96 is a novel therapeutic target of multiple myeloma.
gp96 (grp94) is a key downstream chaperone in the endoplasmic reticulum (ER) to mediate unfolded protein response (UPR) and the pathogenesis of multiple myeloma is closely linked to dysregulated UPR. In this study, we aimed to determine the roles of gp96 in the initiation and progression of multiple myeloma in vivo and in vitro. We generated a mouse model with overexpression of XBP1s and conditional deletion of gp96 in B-cell compartment simultaneously to identify the roles of gp96 in the development of multiple myeloma in vivo. Using a short hairpin RNA (shRNA) system, we silenced gp96 in multiple human multiple myeloma cells and examined the effect of gp96 knockdown on multiple myeloma cells by cell proliferation, cell-cycle analysis, apoptosis assay, immunohistochemistry, and human myeloma xenograft model. The anticancer activity of gp96 selective inhibitor, WS13, was evaluated by apoptosis assay and MTT assay. Genetic deletion of gp96 in XBP1s-Tg mice attenuates multiple myeloma. Silencing of gp96 causes severe compromise in human multiple myeloma cell growth through inhibiting Wnt-LRP-survivin pathway. We also confirmed that knockdown of gp96 decreased human multiple myeloma growth in a murine xenograft model. The targeted gp96 inhibitor induced apoptosis and blocked multiple myeloma cell growth, but did not induce apoptosis in pre-B leukemic cells. We have demonstrated that myeloma growth is dependent on gp96 both genetically and pharmacologically. gp96 is essential for multiple myeloma cell proliferation and survival, suggesting that gp96 is a novel therapeutic target for multiple myeloma. Clin Cancer Res; 19(22); 6242-51. ©2013 AACR.


The Signaling Network Controlling C. elegans Vulval Cell Fate Patterning.
EGF, emitted by the Anchor Cell, patterns six equipotent C. elegans vulval precursor cells to assume a precise array of three cell fates with high fidelity. A group of core and modulatory signaling cascades forms a signaling network that demonstrates plasticity during the transition from naïve to terminally differentiated cells. In this review, we summarize the history of classical developmental manipulations and molecular genetics experiments that led to our understanding of the signals governing this process, and discuss principles of signal transduction and developmental biology that have emerged from these studies.


Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study.
Treatment for negative symptoms and cognitive deficits, core elements of schizophrenia, remains inadequate. Stimulation of the prefrontal cortex via transcranial magnetic stimulation (TMS) yields only moderate results, possibly due to limited stimulation depth. Deep-TMS enables deeper and wider stimulation than before. This preliminary study is the first to examine deep-TMS as a possible add-on treatment for negative symptoms and cognitive deficits of schizophrenia. The effect of 20 daily deep-TMS sessions (20 Hz, 120% motor threshold) over the prefrontal cortex of 15 patients indicated improvement in cognition and negative symptoms that was maintained at 2-wk post-treatment follow-up.


Argatroban therapy in heparin-induced thrombocytopenia.
Argatroban is a direct thrombin inhibitor approved for anticoagulation in heparin-induced thrombocytopenia (HIT; in several countries) and in patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI; in the USA). HIT is a relatively common extreme prothrombotic condition. When HIT is reasonably suspected, an alternative anticoagulant should be promptly initiated. In historical controlled studies, argatroban reduced new thrombosis, mortality from thrombosis and the composite of death, amputation or thrombosis, without increasing bleeding. With intravenous infusion, advantages include short half-life, easy monitoring and elimination primarily by hepatobiliary (rather than renal) means. In patients undergoing PCI, argatroban with or without glycoprotein IIb/IIIa inhibition leads to high rates of procedural success with low bleeding risk. Herein we review argatroban therapy for HIT and for PCI.


Increased insulin sensitivity and responsiveness during lactation in rats.
In 12-day lactating rats blood glucose and plasma insulin were decreased by, respectively, 20 and 35% when compared with nonlactating rats, despite a 25% increase of their glucose turnover rate. Then, by using the euglycemic hyperinsulinemic clamp technique, dose-response curves for the effects of insulin on glucose production and utilization in lactating and nonlactating rats were performed. Glucose production rate was totally suppressed at 250 microU/ml of insulin in lactating rats and for plasma insulin concentrations higher than 500 microU/ml in nonlactating rats. Plasma insulin level inducing half-maximal inhibition of glucose production was decreased by 60% during lactation. The maximal effect of insulin on glucose utilization rate and glucose metabolic clearance rate was, respectively, increased 1.5- and 2.4-fold during lactation and was obtained for plasma insulin concentrations lower in lactating than in nonlactating rats (250 vs. 500 microU/ml). Insulin concentrations inducing half-maximal stimulation of glucose utilization and glucose metabolic clearance were decreased by 50% during lactation. In conclusion, this study has shown that insulin sensitivity and responsiveness of liver and peripheral tissues are improved at peak lactation in the rat.


Fecal microbiota transplantation from mice exposed to chronic intermittent hypoxia elicits sleep disturbances in naïve mice.
Obstructive sleep apnea (OSA) is a chronic prevalent condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). Evidence suggests that OSA can alter the gut microbiome (GM) diversity and composition that may then promote the occurrence of some of the OSA-associated morbidities. However, it is unclear whether perturbations in the GM caused by IH can elicit sleep disturbances that underlie the increased sleep propensity that occurs in IH-exposed mice. To evaluate this issue, we exposed C57Bl/6 J mice to IH or room air (RA) for 6 weeks, and fecal matter was collected and frozen. C57Bl/6 J naïve mice were then randomly assigned to a fecal microbiota transfer (FMT) protocol for 3 weeks with either IH or RA fecal slur, and their GM was then analyzed using 16 s rRNA sequencing. In addition, FMT recipients underwent sleep recordings using piezoelectric approaches for 3 consecutive days. As anticipated, FMT-IH and FMT-RA mice showed different taxonomic profiles that corresponded to previous effects of IH on GM. Furthermore, FMT-IH mice exhibited increased sleep duration and the frequency of longer sleep bouts during the dark cycle, suggesting increased sleepiness (p < 0.0001 vs. FMT-RA mice). Thus, alterations of GM diversity induced by IH exposures can elicit sleep disturbances in the absence of concurrent IH, suggesting that sleep disturbances can be mediated, at least in part, by IH-induced alterations in GM.


Ultra stable all-fiber telecom-band entangled photon-pair source for turnkey quantum communication applications.
We demonstrate a novel alignment-free all-fiber source for generating telecom-band polarization-entangled photon pairs. Polarization entanglement is created by injecting two relatively delayed, orthogonally polarized pump pulses into a piece of dispersion-shifted fiber, where each one independently engages in four-photon scattering, and then removing any distinguishability between the correlated photon-pairs produced by each pulse at the fiber output. Our scheme uses a Michelson-interferometer configuration with Faraday mirrors to achieve practically desirable features such as ultra-stable performance and turnkey operation. Up to 91.7% two-photon-interference visibility is observed without subtracting the accidental coincidences that arise from background photons while operating the source at room temperature.


Right lower lobe oedema as a rare sign of left heart failure.
Two cases of right lower lobe oedema are presented as a supposedly very rare sign of left heart failure after myocardial infarction in the presence of acute mitral regurgitation. Causes of unilateral oedema and its clinical relevance in the diagnostic and therapeutic perspectives are discussed, and a review of the literature on this topic is presented.


DNA barcode analysis of butterfly species from Pakistan points towards regional endemism.
DNA barcodes were obtained for 81 butterfly species belonging to 52 genera from sites in north-central Pakistan to test the utility of barcoding for their identification and to gain a better understanding of regional barcode variation. These species represent 25% of the butterfly fauna of Pakistan and belong to five families, although the Nymphalidae were dominant, comprising 38% of the total specimens. Barcode analysis showed that maximum conspecific divergence was 1.6%, while there was 1.7-14.3% divergence from the nearest neighbour species. Barcode records for 55 species showed <2% sequence divergence to records in the Barcode of Life Data Systems (BOLD), but only 26 of these cases involved specimens from neighbouring India and Central Asia. Analysis revealed that most species showed little incremental sequence variation when specimens from other regions were considered, but a threefold increase was noted in a few cases. There was a clear gap between maximum intraspecific and minimum nearest neighbour distance for all 81 species. Neighbour-joining cluster analysis showed that members of each species formed a monophyletic cluster with strong bootstrap support. The barcode results revealed two provisional species that could not be clearly linked to known taxa, while 24 other species gained their first coverage. Future work should extend the barcode reference library to include all butterfly species from Pakistan as well as neighbouring countries to gain a better understanding of regional variation in barcode sequences in this topographically and climatically complex region.


Loss and dysfunction of Vδ2⁺ γδ T cells are associated with clinical tolerance to malaria.
Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vδ2(+) subset of γδ T cells have intrinsic reactivity to malaria antigens, can mediate killing of Plasmodium falciparum merozoites, and expand markedly in vivo after malaria infection in previously naïve hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated γδ T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of Vδ2(+) γδ T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of proinflammatory Vδ2(+) γδ T cells were associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of Vδ2(+) γδ T cells that may facilitate immunological tolerance of the parasite.


Multidetector CT findings of bowel transection in blunt abdominal trauma.
Though a number of CT findings of bowel and mesenteric injuries in blunt abdominal trauma are described in literature, no studies on the specific CT signs of a transected bowel have been published. In the present study we describe the incidence and new CT signs of bowel transection in blunt abdominal trauma. We investigated the incidence of bowel transection in 513 patients admitted for blunt abdominal trauma who underwent multidetector CT (MDCT). The MDCT findings of 8 patients with a surgically proven complete bowel transection were assessed retrospectively. We report novel CT signs that are unique for transection, such as complete cutoff sign (transection of bowel loop), Janus sign (abnormal dual bowel wall enhancement, both increased and decreased), and fecal spillage. The incidence of bowel transection in blunt abdominal trauma was 1.56%. In eight cases of bowel transection, percentage of CT signs unique for bowel transection were as follows: complete cutoff in 8 (100%), Janus sign in 6 (100%, excluding duodenal injury), and fecal spillage in 2 (25%). The combination of complete cutoff and Janus sign were highly specific findings in patients with bowel transection. Complete cut off and Janus sign are the unique CT findings to help detect bowel transection in blunt abdominal trauma and recognition of these findings enables an accurate and prompt diagnosis for emergency laparotomy leading to reduced mortality and morbidity.


[Post-caesarian precocious eating-ingested matter tolerance].
This is a report on a modification of a protocol at the Catalonian General Hospital which received a prize in the Annual Scientific Prize Contest in the nursing category. The objective of this study consisted in determining whether or not precocious eating/digestion is well-tolerated without significantly increasing gastrointestinal morbidity by patients who have undergone a caesarian. The authors carried out a prospective study to evaluate precocious eating-digestion tolerance in women who had a caesarian under local anesthesia, spinal or peridural. This study concluded that there is no significant increase in noxious effects on normal intestinal functioning, the initial time for peristalsis diminished and the wellbeing of patients who start precocious post-caesarian oral feeding increased in a subjective form.


Comparative analysis of Klebsiella pneumoniae genomes identifies a phospholipase D family protein as a novel virulence factor.
Klebsiella pneumoniae strains are pathogenic to animals and humans, in which they are both a frequent cause of nosocomial infections and a re-emerging cause of severe community-acquired infections. K. pneumoniae isolates of the capsular serotype K2 are among the most virulent. In order to identify novel putative virulence factors that may account for the severity of K2 infections, the genome sequence of the K2 reference strain Kp52.145 was determined and compared to two K1 and K2 strains of low virulence and to the reference strains MGH 78578 and NTUH-K2044. In addition to diverse functions related to host colonization and virulence encoded in genomic regions common to the four strains, four genomic islands specific for Kp52.145 were identified. These regions encoded genes for the synthesis of colibactin toxin, a putative cytotoxin outer membrane protein, secretion systems, nucleases and eukaryotic-like proteins. In addition, an insertion within a type VI secretion system locus included sel1 domain containing proteins and a phospholipase D family protein (PLD1). The pld1 mutant was avirulent in a pneumonia model in mouse. The pld1 mRNA was expressed in vivo and the pld1 gene was associated with K. pneumoniae isolates from severe infections. Analysis of lipid composition of a defective E. coli strain complemented with pld1 suggests an involvement of PLD1 in cardiolipin metabolism. Determination of the complete genome of the K2 reference strain identified several genomic islands comprising putative elements of pathogenicity. The role of PLD1 in pathogenesis was demonstrated for the first time and suggests that lipid metabolism is a novel virulence mechanism of K. pneumoniae.


Blind prediction of homo- and hetero-protein complexes: The CASP13-CAPRI experiment.
We present the results for CAPRI Round 46, the third joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo-oligomers and 6 heterocomplexes. Eight of the homo-oligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homodimers, 3 heterodimers, and two higher-order assemblies. These were more difficult to model, as their prediction mainly involved "ab-initio" docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups, was very good to excellent for the nine easy targets. Poorer performance was achieved by predictors for the 11 difficult targets, with medium and high quality models submitted for only 3 of these targets. A similar performance "gap" was displayed by scorer groups, highlighting yet again the unmet challenge of modeling the conformational changes of the protein components that occur upon binding or that must be accounted for in template-based modeling. Our analysis also indicates that residues in binding interfaces were less well predicted in this set of targets than in previous Rounds, providing useful insights for directions of future improvements.


The occurrence of helminth parasites in the gastrointestinal of catfish (Silurus glanis Linnaeus 1758) from the Zarrine-roud river, Iran.
This investigation was undertaken to verify the prevalence of helminths parasites in the gastrointestinal tract of catfish. A total number of 116 catfish (Silurus glanis) were collected from Zarrine-roud river and examined for helminths. Fish were examined after washing contents of gastrointestinal tract and observed for the presence of helminths using a stereo microscope and a light microscope. Results indicated that 18.96% of the examined catfish were infected with digenean trematodes including Orientocreadium siluri (27%), Crowcrocoecum skrjabini (39%), and cestode Bothriocephalus gowkongensis (34%). All the parasites were found in the intestine. Mid-gut followed by foregut appeared to be the most commonly infected parts of the alimentary tract of hosts. The results showed that there was a significant correlation between infection rate, catfish body size, and weight (P < 0.05).


Prevention of experimental Haemophilus ducreyi infection: a randomized, controlled clinical trial.
Human subjects were infected with Haemophilus ducreyi. All subjects developed papules and were randomized to treatment with a single dose of azithromycin (1 g) or ciprofloxacin (500 mg). At weekly intervals, volunteers were reinoculated with H. ducreyi, and drug concentrations were measured in peripheral blood mononuclear cells (PBMC). When papules developed, the subjects were treated with antibiotics and dismissed from the study. Eight of the ciprofloxacin-treated subjects developed papules 1 week after the initial treatment, and the ninth subject developed disease 2 weeks after treatment. The 9 azithromycin-treated subjects developed papules 4-10 weeks (mean, 6.8) after the initial treatment (P < .001). Azithromycin was detected in PBMC for 3-6 weeks (mean, 4). Pre- and posttreatment lesions had histology typical of experimental chancroid or were culture positive. Azithromycin prevents experimental chancroid for nearly 2 months. These findings have implications for strategies to prevent chancroid.


Comprehensive metabolomics of Philippine Stichopus cf. horrens reveals diverse classes of valuable small molecules for biomedical applications.
Stichopus cf. horrens is an economically important sea cucumber species in Southeast Asia due to their presumed nutritional and medicinal benefits. However, compared to other sea cucumbers such as Apostichopus japonicus, there are no biochemical studies on which compounds contribute to the purported bioactivities of S. cf. horrens. To address this, a high-throughput characterization of the global metabolite profile of the species was performed through LC-MS/MS experiments and utilizing open-access platforms such as GNPS, XCMS, and metaboAnalyst. Bioinformatics-based molecular networking and chemometrics revealed the abundance of phospholipids such as phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidylinositols (PIs), and phosphatidylserines (PSs) in the crude samples. Body wall extracts were observed to have higher levels of structural, diacylated PCs, while the viscera have higher relative abundance of single-tail PCs and PEs that could be involved in digestion via nutrient absorption and transport for sea cucumbers. PEs and sphingolipids could also be implicated in the ecological response and morphological transformations of S. cf. horrens in the presence of predatory and other environmental stress. Interestingly, terpenoid glycosides and saponins with reported anti-cancer benefits were significantly localized in the body wall. The sulfated alkanes and sterols present in S. cf. horrens bear similarity to known kairomones and other signaling molecules. All in all, the results provide a baseline metabolomic profile of S. cf. horrens that may further be used for comparative and exploratory studies and suggest the untapped potential of S. cf. horrens as a source of bioactive molecules.


A comparative study of laparoscopic and open Nissen fundoplication for GERD in Georgia.
The study compares and analyzes the effectiveness and outcomes of open A. Chernousov modified Nissen fundoplication (CMNF) and laparoscopic total fundoplication in Georgia for gastroesophageal reflux disease (GERD) concerning perioperative course, postoperative complications, symptomatic relief, recurrent disease and the need for reinterventional surgery. A prospective randomized trial was performed. Twohundred fortythree patients with GERD were randomized, 123 patients underwent open CMNF procedure and 120 patients of laparoscopic total fundoplication. Pre- and postoperative tests included endoscopy, X-Ray, patient questionnaire (GERD - HQRL scale) and clinical assessment. Patients were followed for 10 years. This prospective randomized trial showed good and excellent long-term results after open and laparoscopic total fundoplication for GERD (92,7% vs 88,5% respectively) (p=0,03). After open CMNF procedure there were 3 cases of postoperative ventral hernia, 9 cases of mild dysphagia. There was no recurrence. After laparoscopic approach there were 7 cases of solid and transient dysphagia, 3 cases of hard stenosis of cardiacs caused by wrap. There were 2 cases of recurrence, 3 cases of reflux and 1 case of epigastral trocar hernia. In Georgia as well as throughout the world laparoscopic total fundoplication at the present time is the preferred method of choice for the treatment of GERD. It has best cosmetic effect, less pain and wound problems, shorter hospital stay, early return to work. Open CMNF is safe and effective procedure too. It prevents slippage syndrome and is characterized by better control of reflux and less frequency of recurrence and guarantees slightly better long-term functional results. Antireflux surgery, GERD, Modified Nissen fundoplication, Prospective randomized trial.


Postoperative quadriceps weakness and male sex are risk factors for patellofemoral articular cartilage lesions after anatomical anterior cruciate ligament reconstruction.
Patellofemoral (PF) compartment cartilage lesions are a frequent problem after anterior cruciate ligament (ACL) reconstruction. This study aimed to determine the factors that influence PF cartilage lesions after anatomical ACL reconstruction. This study enrolled a total of 114 patients who did not manifest PF compartment cartilage lesions during anatomical ACL reconstruction and underwent second-look arthroscopy 18 months postoperatively. Arthroscopy using the International Cartilage Repair Society (ICRS) classification was used to assess cartilage lesions. The correlation between surgical findings, radiographic factors, and clinical factors and change of ICRS grade was analysed. Multivariate regression analysis was conducted to reveal the independent risk factors for PF cartilage lesions among patients' demographic data and parameters that correlated with the change of ICRS grade in the correlation analyses. ICRS grade changes in PF cartilage were significantly correlated with age, sex, quadriceps strength at 1 year postoperatively, hamstrings strength at pre- and 1 year postoperatively, and single leg hop test at 1 year postoperatively. However, no significant correlation was found between the time between injury and surgery, posterior tibial slope angle, pre- and postoperative Tegner activity scale, graft type, initial graft tension, meniscus injury, meniscus injury treatment, pre- and postoperative range of motion, anteroposterior laxity and preoperative quadriceps strength, and the change in ICRS grade. Multivariate regression analysis revealed male (P = 0.019) and quadriceps strength weakness at 1 year postoperatively (P = 0.009) as independent risk factors for PF cartilage lesions. Quadriceps strength weakness 1 year after ACL reconstruction and males were correlated with a new PF cartilage lesion after anatomical ACL reconstruction, with no significant correlation between bone-patellar tendon-bone autograft, initial graft tension, or extension deficit and new PF cartilage lesion. Rehabilitation that focuses on quadriceps strength after ACL reconstruction is recommended to prevent new PF cartilage lesions. Level IV.


Free DNA in cystic fibrosis airway fluids correlates with airflow obstruction.
Chronic obstructive lung disease determines morbidity and mortality of patients with cystic fibrosis (CF). CF airways are characterized by a nonresolving neutrophilic inflammation. After pathogen contact or prolonged activation, neutrophils release DNA fibres decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs). NETs have been described to act in a beneficial way for innate host defense by bactericidal, fungicidal, and virucidal actions. On the other hand, excessive NET formation has been linked to the pathogenesis of autoinflammatory and autoimmune disease conditions. We quantified free DNA structures characteristic of NETs in airway fluids of CF patients and a mouse model with CF-like lung disease. Free DNA levels correlated with airflow obstruction, fungal colonization, and CXC chemokine levels in CF patients and CF-like mice. When viewed in combination, our results demonstrate that neutrophilic inflammation in CF airways is associated with abundant free DNA characteristic for NETosis, and suggest that free DNA may be implicated in lung function decline in patients with CF.


Numerical modelling of non-ionic microgels: an overview.
Microgels are complex macromolecules. These colloid-sized polymer networks possess internal degrees of freedom and, depending on the polymer(s) they are made of, can acquire a responsiveness to variations of the environment (temperature, pH, salt concentration, etc.). Besides being valuable for many practical applications, microgels are also extremely important to tackle fundamental physics problems. As a result, these last years have seen a rapid development of protocols for the synthesis of microgels, and more and more research has been devoted to the investigation of their bulk properties. However, from a numerical standpoint the picture is more fragmented, as the inherently multi-scale nature of microgels, whose bulk behaviour crucially depends on the microscopic details, cannot be handled at a single level of coarse-graining. Here we present an overview of the methods and models that have been proposed to describe non-ionic microgels at different length-scales, from the atomistic to the single-particle level. We especially focus on monomer-resolved models, as these have the right level of details to capture the most important properties of microgels, responsiveness and softness. We suggest that these microscopic descriptions, if realistic enough, can be employed as starting points to develop the more coarse-grained representations required to investigate the behaviour of bulk suspensions.


Pedicled free-style perforator flaps for trunk reconstruction: a reliable method.
By exploring the perforating vessels that supply the soft tissues adjacent to a given defect, a perforator flap can be designed in free-style fashion. From 2009 to 2013, 14 defects of the trunk (excluding the abdomen) were reconstructed using pedicle free-style perforator flaps at the Department of Plastic Surgery, E-Da Hospital, Taiwan. Several perforators at the periphery of the defect were detected and marked preoperatively using a handheld Doppler probe. Then, they were explored intraoperatively through the existing wound edge after wide excision of lesions. The most suitable perforator was selected by means of direct vision and chosen as the pivot point, and then the flap was designed around it, taking into consideration the axiality of the vessel and the ability to achieve direct donor-site closure. All of the flaps survived completely, except for one flap that partially failed because of congestion, and for which the salvage procedure was a skin graft. Full coverage of the defect with excellent contour and color matching and primary closure of the donor sites was achieved in all of the patients. The free-style approach to trunk reconstruction allows the surgeon to complete a robust like-for-like reconstruction while confining the scar burden to a single site. Using the handheld Doppler device and visualizing the perforators directly through the wound edge eliminates the need for preoperative imaging, and allows for the optimal flap to be designed based on vessel size and quality and minimizes donor-site morbidity. Therapeutic, IV.


Ulipristal Acetate Before Hysteroscopic Myomectomy: A Systematic Review.
Uterine leiomyomas, also referred to as myomas or fibroids, are the most common benign tumors of the reproductive tract. Ulipristal acetate (UPA) is an active selective progesterone receptor modulator used as preoperative treatment for uterine myomas. The aim of this review is to provide an overview of the literature about the effects of UPA administration before hysteroscopic myomectomy. The clinical question in "PICO" format was in patients affected by uterine myomas undergoing operative hysteroscopic management, "Does UPA impact the surgical outcomes?" We performed a systematic literature search in PubMed/MEDLINE and Embase for original studies written in English (registered in PROSPERO CRD42018092201), using the terms "hysteroscopy" AND "ulipristal acetate" published up to March 2019. Original articles about UPA treatment before hysteroscopic myomectomy (randomized, observational, retrospective studies) were considered eligible. Our literature search produced 32 records. After exclusions, 4 studies were considered eligible for analysis. Results show that UPA does not worsen the overall technical difficulty of hysteroscopic myomectomy. Moreover, it may increase the chance of complete primary myomectomy in complex hysteroscopic procedures. Despite the positive results presented in this systematic review, low-quality evidence exists yet on the impact of UPA treatment before hysteroscopic myomectomy. High-quality prospective randomized controlled trials are required to establish the impact of UPA on surgical outcomes of patients treated for uterine myomas by hysteroscopy. Moreover, long-term outcomes of myomectomies after UPA treatment (such as frequency of myoma recurrence, recovery time, and quality of life) should be determined.


Sleep regularity is a stronger predictor of mortality risk than sleep duration: A prospective cohort study.
Abnormally short and long sleep are associated with premature mortality, and achieving optimal sleep duration has been the focus for sleep health guidelines. Emerging research demonstrates that sleep regularity, the day-to-day consistency of sleep-wake timing, can be a stronger predictor for some health outcomes than sleep duration. The role of sleep regularity in mortality, however, has not been investigated in a large cohort with objective data. We therefore aimed to compare how sleep regularity and duration predicted risk for all-cause and cause-specific mortality. We calculated Sleep Regularity Index (SRI) scores from >10 million hours of accelerometer data in 60,977 UK Biobank participants (62.8±7.8 years, 55.0% female, median[IQR] SRI: 81.0[73.8-86.3]). Mortality was reported up to 7.8 years after accelerometer recording in 1,859 participants (4.84 deaths per 1000 person-years, mean (±SD) follow up of 6.30±0.83 years). Higher sleep regularity was associated with a 20-48% lower risk of all-cause mortality (p<.001 to p=0.004), a 16-39% lower risk of cancer mortality (p<0.001 to p=0.017), and a 22-57% lower risk of cardiometabolic mortality (p<0.001 to p=0.048), across the top four SRI quintiles compared to the least regular quintile. Results were adjusted for age, sex, ethnicity, and sociodemographic, lifestyle, and health factors. Sleep regularity was a stronger predictor of all-cause mortality than sleep duration, by comparing equivalent mortality models, and by comparing nested SRI-mortality models with and without sleep duration (p=0.14-0.20). These findings indicate that sleep regularity is an important predictor for mortality risk and is a stronger predictor than sleep duration. Sleep regularity may be a simple, effective target for improving general health and survival.


[Aging, a frightening image of dental health?].
The combination of decreasing oral self-care and increasing risks of oral health make elderly people an oral health risk-group. In many elderly people above the age of approximately 75 the decline in functions culminates in infirmity. Frail and infirm elderly people require geriatric care, but often oral health care is not an integral part of geriatric care. Geriatric oral health care could be promoted and encouraged by dental hygienists. Unless geriatric oral health care will be promoted, ageing and especially dependent ageing seems a spectre of oral health.


Chemotherapy for malignant pleural mesothelioma.
All MPM patients with a good performance status should be considered for enrollment on clinical trials. With that said, the standard frontline therapy for fit MPM patients remains an antifolate/platinum doublet, based on large, well powered randomized clinical trials that showed not only a survival benefit for antifolate/platinum regimens but also improvements in quality of life and/or symptoms. For less fit patients, single agents can be used as frontline therapy. In the second line setting, there is benefit from retreatment with single agent pemetrexed after prior exposure to that agent, as well as after exposure to other chemotherapeutic agents. Other single chemotherapy agents and combinations are viable options for fit patients who have had relatively long time to progression after their frontline therapy. Additionally, several prognostic scales designed for MPM (CALGB and EORTC) provide additional means to better select patients for frontline and second line chemotherapy.


Problems with a diagnostic depression interview in a postpartum depression trial.
Diagnostic and Statistical Manual (DSM) IV-based depression interviews, valued for their diagnostic accuracy, are often considered to be essential for depression treatment trials. However, this requirement can be problematic because of participant burden. The purpose of this article is to describe our experience with the depression component of the Structured Clinical Interview for DSM Disorders (SCID) in a postpartum depression treatment trial. In this prospective cohort study of 506 mothers of infants from 7 primary care clinics, participants were asked to complete the depression module of the SCID interview soon after enrollment. They were asked to complete the 9-item Patient Health Questionnaire (PHQ-9) depression survey at 0 to 1, 2, 4, 6, and 9 months postpartum. Forty-five women (8.9%) had a positive SCID interview and 112 (22.1%) had a positive PHQ-9 during 0 to 9 months postpartum. Problems encountered when using the SCID depression interview included (1) lower than expected SCID-based rates of depression diagnosis (8.9%); (2) SCID noncompletion by 75 women (14.8%); SCID noncompleters (vs completers) were younger, poorer, less educated, and more likely to be single and black (vs white); and (3) inconsistent SCID/PHQ-9 results. Nineteen women with moderately severe to severe PHQ-9 score elevations (≥15) had negative SCID scores; all of these women were functionally impaired. More than 90% of women with positive PHQ-9 scores reported some degree of impairment because of their depressive symptoms. The requirement of a diagnostic depression interview resulted in selection bias and missed opportunities for depression diagnosis; these are problems that detract from the interview's key strength-its diagnostic accuracy. These problems should be considered when electing to use a DSM-IV-based depression interview in research.


Peace of mind for patients with differentiated thyroid cancer?
Differentiated thyroid carcinomas (DTC) have an excellent prognosis, with 10-year overall survival rates over 90%. In addition, DTC patients benefit from their lifelong medical surveillance. The AIM of the study was to compare the patients' overall survival with that of a matched general population. We have analyzed 1497 consecutive patients with DTC, who underwent radioiodine therapy in Münster, Germany, according to international standards. We classified our patients according to the current 7th edition of the UICC (Union Internationale Contre le Cancer) classification and we compared the overall survival of the patients with the expected survival based on age and sex of the general population as provided by the Federal Statistical Office, Germany. There were no significant differences in overall survival rates between DTC patients of the cohort in stages I to IVa compared to the expected survival based on age and sex of the general population. However, patients in stage IVc showed a significantly worse overall survival rate using the log-rank test (p < 0.0001). Patients with DTC showed excellent overall survival rates in stages I, II, III and IVa. All patients, except for those in stage IVc (M1 ≥ 45 years), had overall survival rates similar to the general population.


Surgical treatment of intraforaminal/extraforaminal lumbar disc herniations: Many approaches for few surgical routes.
Several disc disease nomenclatures and approaches for LDH exist. The traditional midline bone-destructive procedures together with approaches requiring extreme muscular retraction are being replaced by muscle sparing, targeted, stability-preserving surgical routes. The increasing speculation on LDHs and the innovative corridors described to treat them have lead to an extensive production of papers frequently treating the same topic but adopting different terminologies and reporting contradictory results. The review of such literature somehow confounding gave us the chance to regroup by surgical corridors the vast amount of approaches for LDH differently renamed over time. Likewise, LDHs were simplified in intra-foraminal (ILDH), extra-foraminal (ELDH), and intra-/extra-foraminal (IELDH) in relation to precise anatomical boundaries and extent of bulging disc. Through the analysis of the papers, it was possible to identify ideal surgical corridors for ILDHs, ELDHs, and IELDHs, distinguishing for each approach the exposure provided and the technical advantages/disadvantages in terms of muscle trauma, biomechanical stability, and nerve root preservation. A significant disproportion was noted between studies discussing traditional midline approaches or variants of the posterolateral route and those investigating pros and cons of simple or combined alternative corridors. Although rarely discussed, these latter represent valuable strategies particularly for the challenging IELDHs, thanks to the optimal compromise between herniation exposure and bone-muscle preservation. The integration of adequate mastery of traditional approaches together with a greater confidence through unfamiliar surgical corridors can improve the development of combined mini-invasive procedures, which seem promising for future targeted LDH excisions.


DDQ as a versatile and easily recyclable oxidant: a systematic review.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is the most widely used quinone with a high reduction potential, and it commonly mediates hydride transfer reactions and shows three accessible oxidation states: quinone (oxidized), semiquinone (one-electron-reduced), and hydroquinone (two-electron-reduced). DDQ has found broad utility as a stoichiometric oxidant in the functionalization of activated C-H bonds and the dehydrogenation of saturated C-C, C-O, and C-N bonds. The cost and toxicity of DDQ triggered recent efforts to develop methods that employ catalytic quantities of DDQ in combination with alternative stoichiometric oxidants. The aerobic catalytic approach was established for the selective oxidation of non-sterically hindered electron-rich benzyl methyl ethers and benzylic alcohols, and effectively extended to the oxidative deprotection of p-methoxybenzyl ethers to generate the alcohols in high selectivity. A combination of DDQ and protic acid is known to oxidize several aromatic donors to the corresponding cation radicals. The excited-state DDQ converts benzyls, heteroarenes, fluoroarenes, benzene, and olefins into their radical cation forms as well as chloride and other anions into their respective radicals. These reactive intermediates have been employed for the generation of C-C and C-X (N, O, or Cl) bonds in the synthesis of valuable natural products and organic compounds. To the best of our knowledge, however, there is still no review article exclusively describing the applications of DDQ in organic synthesis. Therefore, in the present review, we provide an overview of DDQ-induced organic transformations with their scope, limitations and the proposed reaction mechanisms.


How Internet Contracts Impact Research: Content Analysis of Terms of Service on Consumer Product Websites.
Companies use brand websites as a promotional tool to engage consumers on the web, which can increase product use. Given that some products are harmful to the health of consumers, it is important for marketing associated with these products to be subject to public health surveillance. However, terms of service (TOS) governing the use of brand website content may impede such important research. The aim of this study is to explore the TOS for brand websites with public health significance to assess possible legal and ethical challenges for conducting research on consumer product websites. Using Statista, we purposefully constructed a sample of 15 leading American tobacco, alcohol, psychiatric pharmaceutical, fast-food, and gun brands that have associated websites. We developed and implemented a structured coding system for the TOS on these websites and coded for the presence versus absence of different types of restriction that might impact the ability to conduct research. All TOS stated that by accessing the website, users agreed to abide by the TOS (15/15, 100%). A total of 11 out of 15 (73%) websites had age restrictions in their TOS. All alcohol brand websites (5/15, 33%) required users to enter their age or date of birth before viewing website content. Both websites for tobacco brands (2/15, 13%) further required that users register and verify their age and identity to access any website content and agree that they use tobacco products. Only one website (1/15, 7%) allowed users to display, download, copy, distribute, and translate the website content as long as it was for personal and not commercial use. A total of 33% (5/15) of TOS unconditionally prohibited or put substantial restrictions on all of these activities and/or failed to specify if they were allowed or prohibited. Moreover, 87% (13/15) of TOS indicated that website access could be restricted at any time. A total of 73% (11/15) of websites specified that violating TOS could result in deleting user content from the website, revoking access by having the user's Internet Protocol address blocked, terminating log-in credentials, or enforcing legal action resulting in civil or criminal penalties. TOS create complications for public health surveillance related to e-marketing on brand websites. Recent court opinions have reduced the risk of federal criminal charges for violating TOS on public websites, but this risk remains unclear for private websites. The public health community needs to establish standards to guide and protect researchers from the possibility of legal repercussions related to such efforts.


ERβ alters the chemosensitivity of luminal breast cancer cells by regulating p53 function.
Estrogen receptor α (ERα)-positive breast cancers tend to develop resistance to both endocrine therapy and chemotherapy. Despite recent progress in defining molecular pathways that confer endocrine resistance, the mechanisms that regulate chemotherapy response in luminal tumors remain largely elusive. Luminal tumors often express wild-type p53 that is a major determinant of the cellular DNA damage response. Similar to p53, the second ER subtype, ERβ, has been reported to inhibit breast tumorigenesis by acting alone or in collaboration with p53. However, a synergistic mechanism of action has not been described. Here, we suggest that ERβ relies on p53 to elicit its tumor repressive actions in ERα-positive breast cancer cells. Upregulation of ERβ and treatment with ERβ agonists potentiates the tumor suppressor function of p53 resulting in decreased survival. This effect requires molecular interaction between the two proteins that disrupts the inhibitory action of ERα on p53 leading to increased transcriptional activity of p53. In addition, we show that the same interaction alters the chemosensitivity of endocrine-resistant cells including their response to tamoxifen therapy. Our results suggest a collaboration of ERβ and p53 tumor suppressor activity in breast cancer cells that indicates the importance of ligand-regulated ERβ as a tool to target p53 activity and improve the clinical management of resistant disease.


Focus: global currents in national histories of science: the "global turn" and the history of science in Latin America.
The "global turn" in the history of science offers new ways to think about how to do national and regional histories of science, in this case the history of science in Latin America. For example, it questions structuralist and diffusionist models of the spread of science and shows the often active role that people in Latin America (and the rest of the Global South) played in the construction of "universal" scientific knowledge. It suggests that even national or regional histories of science must be situated in a global context; all too often, such histories have treated global processes as a distant backdrop. At the same time, historians need to pay constant attention to the role of power in the construction of scientific knowledge. Finally, this essay highlights a methodological tool for writing globally inflected histories of science: the method of "following".


Do Parental Education-Related Inequality Matter in Child and Adolescent Utilization of Mental Health Services: Results From a Norwegian Register Linkage Study.
Equitable access to health care point to equal access to care for those with equal needs, but pro-rich and pro-educated inequities have been documented in specialized mental health care utilization. This study aimed to investigate equity in Norwegian adolescents' use of child and adolescent mental health services (CAMHS) with regards to parental education levels, using a survey of 10 257 Norwegian 16- to 19-year-olds subsequently linked to CAMHS data from the Norwegian Patient Registry (n = 970 had been in contact with CAMHS). Analyses using concentration indices (C) suggested adolescents with parents with lower education levels had more mental health problems (ie, larger need; C = -0.032, P < .001) and were more in contact with CAMHS (C = -0.025, P < .001). Regression analysis suggested that CAMHS contact, and number of unique admissions was largely distributed according to need, but participants whose parents had basic education levels were in contact with CAMHS for slightly longer than predicted from their self-reported mental health problems, age, and sex. Results from this study suggested that contact with CAMHS was largely equitable and mostly influenced by need. There was little evidence of parental education-related inequity in access to, and use of, specialized mental health services.


Structural control energy of resting-state functional brain states reveals less cost-effective brain dynamics in psychosis vulnerability.
How the brain's white-matter anatomy constrains brain activity is an open question that might give insights into the mechanisms that underlie mental disorders such as schizophrenia. Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder with an extremely high risk for psychosis providing a test case to study developmental aspects of schizophrenia. In this study, we used principles from network control theory to probe the implications of aberrant structural connectivity for the brain's functional dynamics in 22q11DS. We retrieved brain states from resting-state functional magnetic resonance images of 78 patients with 22q11DS and 85 healthy controls. Then, we compared them in terms of persistence control energy; that is, the control energy that would be required to persist in each of these states based on individual structural connectivity and a dynamic model. Persistence control energy was altered in a broad pattern of brain states including both energetically more demanding and less demanding brain states in 22q11DS. Further, we found a negative relationship between persistence control energy and resting-state activation time, which suggests that the brain reduces energy by spending less time in energetically demanding brain states. In patients with 22q11DS, this behavior was less pronounced, suggesting a deficiency in the ability to reduce energy through brain activation. In summary, our results provide initial insights into the functional implications of altered structural connectivity in 22q11DS, which might improve our understanding of the mechanisms underlying the disease.


The Bela Schick lecture for 1985. The atopic diseases.
Review of the atopic diseases suggests a redefinition of the term "atopy" is indicated to reflect new information that has become available during the 60 years since the term was introduced. Atopy may be viewed as a manifestation of a still undefined defect. It is characterized by certain clinical findings and frequently by derangement of the immune and autonomic nervous systems. The atopic diseases are a group of seemingly unrelated conditions--eczema, asthma, rhinitis, hypertrophic sinusitis, and perhaps vernal conjunctivitis and migraine--which cluster in individuals and families. In the respiratory tract and eye, eosinophils in the tissues and secretions are characteristic and are not dependent on the presence of immediate hypersensitivity. Symptoms suggestive of basophil and mast cell mediator release are common to all the atopic diseases, and there is some evidence that nonimmunologic mediator release is enhanced in atopic patients. In the most clearly defined atopic diseases, eczema and asthma, approximately 80% of patients have an increased IgE response to normal environmental allergens. Accompanying and perhaps underlying these enhanced IgE responses are deficiencies of T cell numbers and function particularly in the suppressor T lymphocytes. Evidence exists that decreased beta-2-adrenergic and increased cholinergic and alpha-adrenergic responsiveness accompany and perhaps underlies the atopic diseases irrespective of the presence or absence of allergy.


Impact of an instructional program on nurses' accuracy in capillary blood glucose monitoring.
This experiment examined the accuracy of capillary blood glucose monitoring using the visual glucose oxidase strip (Chemstrip) procedure. Also, the effects of a certification program for nurses on the accuracy of glucose oxidase strip monitoring by registered nurses were analyzed. Seventy nurses and 123 patients participated. Data were collected from nurses' recordings of visual Chemstrip procedure results and from the concurrent laboratory blood glucose determinations for 3 months. The data included 70 Chemstrip recordings and 70 concurrent laboratory blood glucose recordings in the experimental group and 68 Chemstrip and 68 concurrent laboratory glucose recordings in the control group. Data analysis revealed that the accuracy of the nurses' performance of the glucose oxidase strip procedure was inadequate. A certification program did, however, dramatically improve the accuracy of the procedure. Proximity of time between the certification program and the performance of the glucose oxidase strip procedure did not affect accuracy.


Astrocytes - friends or foes in neurodegenerative disorders.
Astrocytes (AS) are the most abundant glial cells in the central nervous system (CNS). They have various morphologies and numerous (50-60) branching prolongations, with roles in the maintenance of the CNS function and homeostasis. AS in the optic nerve head (ONH) have specific distribution and function and are involved in the pathogenesis of glaucoma and other neural diseases, modify their morphologies, location, immune phenotype, and ultrastructure, thus being the key players in the active remodeling processes of the ONH.


Plasmid replication functions: two distinct segments of plasmid R1, RepA and RepD, express incompatibility and are capable of autonomous replication.
The genetic determinants for replication and incompatibility of plasmid R1 were investigated by gene cloning methods, and three types of R1 miniplasmid derivatives were generated. The first, exemplified by plasmid pKT300, consisted of a single BglII endonuclease-generated deoxyribonucleic acid fragment derived from the R1 region that is located between the determinants for conjugal transfer and antibiotic resistance. Two types of miniplasmids could be formed from PstI endonuclease-generated fragments of pKT300. One of these, which is equivalent to miniplasmids previously generated from plasmids R1-19 and R1-19B2, consisted of two adjacent PstI fragments that encode the RepA replication system of plasmid R1. The other type contained a segment of R1, designated the RepD replication region, that is adjacent to the RepA region and that has not been identified previously as having the capacity for autonomous replication. Plasmid R1, therefore, contained two distinct deoxyribonucleic acid segments capable of autonomous replication. The RepA-RepD miniplasmid pKT300 had a copy number about eightfold higher than that of R1 and hence lacked a determinant for the regulation of plasmid copy number. Like R1, it was maintained stably in dividing bacteria. RepA miniplasmids had copy numbers which were two- to fourfold higher than that of R1 (i.e., which were lower than that of pKT300) and were maintained slightly less stably than those of pKT300 and R1. The RepD miniplasmid was not maintained stably in dividing bacteria. Previous experiments have shown that incompatibility of IncFII group plasmids is specified by a plasmid copy control gene. Despite the fact that RepA miniplasmids of R1 were defective in copy control, they nevertheless expressed incompatibility. This suggests that two genes are responsible for plasmid copy control, one that specifies incompatibility and is located on RepA miniplasmids and another that is located outside of, but adjacent to, the RepA replication region. Hybrid plasmids composed of pBR322 and one PstI fragment from the RepA region, P-8, exhibited incompatibility towards R2 and RepA miniplasmids but not the RepD miniplasmid, whereas hybrids composed of pBR322 and the PstI fragment of the RepD region, P-3, exhibited incompatibility towards R1 and the RepD miniplasmid but not RepA miniplasmids. These results indicate that the two replication systems are functionally distinct and that, although the RepA system is the principal replication system of R1, the RepD system also plays a role in the maintenance of this plasmid.


Pulmonary rehabilitation--physical modalities.
This review assesses the role of controlled breathing techniques (breathing training) and chest physical therapy (PT) in the management and rehabilitation of patients with chronic obstructive pulmonary disease (COPD). The review focuses on pursed lip breathing, the head-down and bending forward postures, slow deep breathing, and diaphragmatic breathing exercises as methods of breathing training, and on postural drainage, chest percussion and vibration, and controlled cough as techniques of chest PT. These modalities may be beneficial in selected patients with COPD.


A common structural scaffold in CTD phosphatases that supports distinct catalytic mechanisms.
The phosphorylation and dephosphorylation of the carboxyl-terminal domain (CTD) of the largest RNA polymerase II (RNAPII) subunit is a critical regulatory checkpoint for transcription and mRNA processing. This CTD is unique to eukaryotic organisms and it contains multiple tandem-repeats with the consensus sequence Tyr(1) -Ser(2) -Pro(3) -Thr(4) -Ser(5) -Pro(6) -Ser(7) . Traditionally, CTD phosphatases that use metal-ion-independent (cysteine-based) and metal-ion-assisted (aspartate-based) catalytic mechanisms have been considered to belong to two independent groups. However, using structural comparisons we have identified a common structural scaffold in these two groups of CTD phosphatases. This common scaffold accommodates different catalytic processes with the same substrate specificity, in this case phospho-serine/threonine residues flanked by prolines. Furthermore, this scaffold provides a structural connection between two groups of protein tyrosine phosphatases (PTPs): Cys-based (classes I, II, and III) and Asp-based (class IV) PTPs. Redundancy in catalytic mechanisms is not infrequent and may arise in specific biological settings. To better understand the activity of the CTD phosphatases, we combined our structural analyses with data on CTD phosphatase expression in different human and mouse tissues. The results suggest that aspartate- and cysteine-based CTD-dephosphorylation acts in concert during cellular stress, when high levels of reactive oxygen species can inhibit the nucleophilic function of the catalytic cysteine, as occurs in mental and neurodegenerative disorders like schizophrenia, Alzheimer's and Parkinson's diseases. Moreover, these findings have significant implications for the study of the RNAPII-CTD dephosphorylation in eukaryotes.


The impact of climate change on mosquito-borne diseases in Africa.
Despite being one of the continents with the least greenhouse gas emissions, no continent is being struck as severely by climate change (CC) as Africa. Mosquito-borne diseases (MBD) cause major human diseases in this continent. Current knowledge suggests that MBD range could expand dramatically in response to CC. This study aimed at assessing the relationship between CC and MBD in Africa. Methods For this purpose, a systematic peer review was carried out, considering all articles indexed in PubMed, Scopus, Embase and CENTRAL. Search terms referring to MBD, CC and environmental factors were screened in title, abstract and keywords.Results A total of twenty-nine studies were included, most of them on malaria (61%), being Anopheles spp. (61%) the most commonly analyzed vector, mainly in Eastern Africa (48%). Seventy-nine percent of these studies were based on predictive models. Seventy-two percent of the reviewed studies considered that CC impacts on MBD epidemiology. MBD prevalence will increase according to 69% of the studies while 17% predicted a decrease. MBD expansion throughout the continent was also predicted. Most studies showed a positive relationship between observed or predicted results and CC. However, there was a great heterogeneity in methodologies and a tendency to reductionism, not integrating other variables that interact with both the environment and MBD. In addition, most results have not yet been tested. A global health approach is desirable in this kind of research. Nevertheless, we cannot wait for science to approve something that needs to be addressed now to avoid greater effects in the future.


To Process or to Decay: A Mechanistic View of the Nuclear RNA Exosome.
The RNA exosome was originally discovered in yeast as an RNA-processing complex required for the maturation of 5.8S ribosomal RNA (rRNA), one of the constituents of the large ribosomal subunit. The exosome is now known in eukaryotes as the major 3'-5' RNA degradation machine involved in numerous processing, turnover, and surveillance pathways, both in the nucleus and the cytoplasm. Yet its role in maturing the 5.8S rRNA in the pre-60S ribosomal particle remains probably the most intricate and emblematic among its functions, as it involves all the RNA unwinding, degradation, and trimming activities embedded in this macromolecular complex. Here, we propose a comprehensive mechanistic model, based on current biochemical and structural data, explaining the dual functions of the nuclear exosome-the constructive versus the destructive mode.


Pierre-Auguste Renoir (1841-1919) and rheumatoid arthritis.
Pierre-Auguste Renoir (1841-1919), one of the world's most celebrated impressionist painters, suffered from rheumatoid arthritis for most of his life. His symptoms developed when he was in his 50s and they became aggressive at about the age of 60 years that led to almost complete disability when he was 70 years old. Although the deformities he suffered because of the rheumatoid arthritis were disabling, Renoir never stopped painting nor decreased the quality of his work. The transition between styles adopted by the painter (Impressionist, Dry and Pearly periods) bear no relationship to the stages of flare-ups or the establishment of joint deformities due to rheumatoid arthritis. His work shows aspects of the body's ability to overcome pain and physical limitation.


A single episode of neonatal seizures permanently alters glutamatergic synapses.
The contribution of seizures to cognitive changes remains controversial. We tested the hypothesis that a single episode of neonatal seizures (sNS) on rat postnatal day (P) 7 permanently impairs hippocampal-dependent function in mature (P60) rats because of long-lasting changes at the synaptic level. sNS was induced with subcutaneously injected kainate on P7. Learning, memory, mossy fiber sprouting, spine density, hippocampal synaptic plasticity, and glutamate receptor expression and subcellular distribution were measured at P60. sNS selectively impaired working memory in a hippocampal-dependent radial arm water-maze task without inducing mossy fiber sprouting or altering spine density. sNS impaired CA1 hippocampal long-term potentiation and enhanced long-term depression. Subcellular fractionation and cross-linking, used to determine whether glutamate receptor trafficking underlies the alterations of memory and synaptic plasticity, demonstrated that sNS induced a selective reduction in the membrane pool of glutamate receptor 1 subunits. sNS induced a decrease in the total amount of N-methyl-D-aspartate receptor 2A and an increase in the primary subsynaptic scaffold, PSD-95. These molecular consequences are consistent with the alterations in plasticity and memory caused by sNS at the synaptic level. Our data demonstrate the cognitive impact of sNS and associate memory deficits with specific alterations in glutamatergic synaptic function.


[Association of sardine fishery, Sardinella aurita (Teleostei: Clupeidae) and environmental variability of the coastal upwelling ecosystem of Nueva Esparta, Venezuela].
The present research is an analysis of Spanish sardine fishing (Sardinella aurita) associated with some climatic and meteorologic parameters of the ecosystem from El Morro Nueva Esparta, Venezuela. The catch and environmental data from the area were taken in the period 1996-2000. Catch data as a function of wind speed, sea surface temperature, air temperature and rain were analyzed by means of simple lineal regression and multiple models. We found a positive correlation of catch with wind speed, and a negative correlation with sea surface temperature, air temperature, and rain. The multiple regression model with intercept had a poor fit, therefore, we made a model without intercept, which improve greatly the fit. A selection of the variables using the forward procedure verified that the independent variables "wind speed" and "air temperature" have a significant relation with catch (p < 0.001) at real time. This method suggests that sea surface temperature and rain have little influence on the catch, and suggests a major availability of resources in the months with low air temperature and the highest wind speed (January-June). Rev.


Genetic analysis of adult-specific surface antigenic differences between varieties of the nematode Caenorhabditis elegans.
We have studied developmental stage-specificity and genetic specification of surface antigens in the nematode Caenorhabditis elegans. Rabbit antisera directed against the adult C. elegans cuticle were used in conjunction with antiserum adsorption experiments to obtain antibody reagents with specificity for the adult surface. Adult-specific antibodies were used to identify several varietal strains of C. elegans that display antigen-negative phenotypes as adults. Genetic mapping results using the surface antigen phenotype as a marker indicated that a single gene (designated srf-1) or cluster of genes on linkage group II determines the adult surface antigen phenotype.


Single x-ray absorptiometry method for the quantitative mammographic measure of fibroglandular tissue volume.
This study describes the design and characteristics of a highly accurate, precise, and automated single-energy method to quantify percent fibroglandular tissue volume (%FGV) and fibroglandular tissue volume (FGV) using digital screening mammography. The method uses a breast tissue-equivalent phantom in the unused portion of the mammogram as a reference to estimate breast composition. The phantom is used to calculate breast thickness and composition for each image regardless of x-ray technique or the presence of paddle tilt. The phantom adheres to the top of the mammographic compression paddle and stays in place for both craniocaudal and mediolateral oblique screening views. We describe the automated method to identify the phantom and paddle orientation with a three-dimensional reconstruction least-squares technique. A series of test phantoms, with a breast thickness range of 0.5-8 cm and a %FGV of 0%-100%, were made to test the accuracy and precision of the technique. Using test phantoms, the estimated repeatability standard deviation equaled 2%, with a +/-2% accuracy for the entire thickness and density ranges. Without correction, paddle tilt was found to create large errors in the measured density values of up to 7%/mm difference from actual breast thickness. This new density measurement is stable over time, with no significant drifts in calibration noted during a four-month period. Comparisons of %FGV to mammographic percent density and left to right breast %FGV were highly correlated (r=0.83 and 0.94, respectively). An automated method for quantifying fibroglandular tissue volume has been developed. It exhibited good accuracy and precision for a broad range of breast thicknesses, paddle tilt angles, and %FGV values. Clinical testing showed high correlation to mammographic density and between left and right breasts.


Children's temperament and behavior problems predict their employed mothers' work functioning.
Numerous studies have been conducted on the impact of dual-earner parents' employment on their children, yet the reverse process-the impact of children and their behavior on the work functioning of their parents-has been ignored. This study investigated spillover from the mother role to the work role in a sample of more than 300 families. At 4 months, 12 months, 3.5 years, and 4.5 years of age, child's difficult temperament was significantly associated with mother's work outcomes, including work role quality and rewards from combining work and family. The evidence was consistent with a structural model in which maternal sense of parenting competence and maternal depressed affect mediated these effects.