Molecular cloning of the chicken progesterone receptor.
To define the functional domains of the progesterone receptor required for gene regulation, complementary DNA (cDNA) clones encoding the chicken progesterone receptor have been isolated from a chicken oviduct lambda gt11 cDNA expression library. Positive clones expressed antigenic determinants that cross-reacted with six monospecific antibodies derived from two independent sources. A 36-amino acid peptide sequence obtained by microsequencing of purified progesterone receptor was encoded by nucleotide sequences in the longest cDNA clone. Analysis of the amino acid sequence of the progesterone receptor deduced from the cDNA clones revealed a cysteine-rich region that was homologous to a region found in the estrogen and glucocorticoid receptors and to the avian erythroblastosis virus gag-erb-A fusion protein. Northern blot analysis with chicken progesterone receptor cDNA's indicated the existence of at least three messenger RNA species. These messages were found only in oviduct and could be induced by estrogens.


A Dyadic Pain Management Program for Community-Dwelling Older Adults with Chronic Pain: Study Protocol for a Cluster Randomized Controlled Trial.
Community-dwelling older adults suffer from chronic pain. Pain negatively affects their physical and psychosocial wellbeing. The majority of pain management education and programs focus only on older adults. Their informal caregivers should be involved in pain management. A dyadic pain management program for reducing pain and psychological health symptoms, and improving pain self-efficacy, quality of life, and physical function in older adults is proposed for evaluation of its effectiveness. This will be a cluster randomized controlled trial. Community-dwelling older adults aged 60 or above and their informal caregivers will be recruited. The dyadic pain management program will be an eight-week group-based program. The participants in the experimental group will receive four weeks of center-based, face-to-face activities and four weeks of digital-based activities via a WhatsApp group. The control group will receive the usual care and a pain management pamphlet. Data will be collected at baseline, and at the eighth-week and sixteenth-week follow-up session. The outcome measurements will include pain intensity, pain self-efficacy, perceived quality of life, depression, anxiety, and stress levels. Data on the caregiver burden will be collected from the informal caregivers. Because of the COVID-19 pandemic, all social activities have been suspended. In the near future, as the pandemic subsides, the dyadic pain management program will be launched to benefit community-dwelling older adults and informal caregivers and to reduce their pain and the care burden, respectively.


Radiographic lung volumes predict progression to COPD in smokers with preserved spirometry in SPIROMICS.
The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post hoc analysis of 849 current and former smokers (≥20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling.Among these subjects with normal forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio, CT-measured residual volume (RVCT) to total lung capacity (TLCCT) ratio varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RVCT/TLCCT had a greater differential rate of decline in FEV1/FVC; those in the upper RVCT/TLCCT tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current) or smoking burden (pack-years). Accordingly, subjects with higher RVCT/TLCCT were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper versus lower RVCT/TLCCT tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RVCT/TLCCT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.


Seroepidemiology of dengue in travellers: a paired sera analysis.
Dengue is a frequent cause of fever in travellers. The true extent is unknown as many infections are asymptomatic or undiagnosed. We used paired sera, with pre- and post-travel specimens from Swiss travellers to tropical destinations, to evaluate the seroepidemiology of travel-related dengue. Post-travel specimens were tested for the presence of IgG and IgM antibodies to dengue antigen serotypes (1, 2, 3 and 4) using an indirect enzyme-linked immunosorbent assay (ELISA). All post-travel sera that screened as positive for dengue IgG or IgM antibodies were re-tested with the corresponding pre-travel sera as paired assays in order to detect seroconversion. There were 285 travellers with specimens available for analysis. Two hundred and fifty seven of the 285 individuals (90.2%) had negative dengue serology post-travel. Of the remaining 28 cases, 25 were dengue IgG positive and 3 had equivocal results. This corresponds to IgG seropositivity in 8.9%. Eighteen of these 25 individuals had a pre-travel specimen available for testing, of which 15 were positive for IgG consistent with possible past exposure. Three of the 18 had negative serology pre-travel, indicating possible recent infection. This corresponds to an attack rate of possible dengue of 1.1% and an incidence rate of 6.7 per 1000 person-months (95% CI 0-60.0). Two of these three individuals had received yellow fever vaccine for their trip, raising the potential of cross-reactivity. The confirmed dengue attack rate therefore was 0.23% with a corresponding incidence rate of 2.2 per 1000 person-months (95% CI-0-33.1). Seroepidemiology provides additional evidence of an appreciable risk of acute dengue infection among travellers to tropical destinations.


Direct paraventricular thalamus-basolateral amygdala circuit modulates neuropathic pain and emotional anxiety.
The comorbidity of chronic pain and mental dysfunctions such as anxiety disorders has long been recognized, but the underlying mechanisms remained poorly understood. Here, using a mouse model of neuropathic pain, we demonstrated that the thalamic paraventricular nucleus (PVT) played a critical role in chronic pain-induced anxiety-like behavioral abnormalities. Fiber photometry and electrophysiology demonstrated that chronic pain increased the activities in PVT glutamatergic neurons. Chemogenetic manipulation revealed that suppression of PVT glutamatergic neurons relieved pain-like behavior and anxiety-like behaviors. Conversely, selective activation of PVT glutamatergic neurons showed algesic and anxiogenic effects. Furthermore, the elevated excitability of PVT glutamatergic neurons resulted in increased excitatory inputs to the basolateral complex (BLA) neurons. Optogenetic manipulation of the PVT-BLA pathway bilaterally modulates both the pain-like behavior and anxiety-like phenotypes. These findings shed light on how the PVT-BLA pathway contributed to the processing of pain-like behavior and maladaptive anxiety, and targeting this pathway might be a straightforward therapeutic strategy to both alleviate nociceptive hypersensitivity and rescue anxiety behaviors in chronic pain conditions.


A common single nucleotide polymorphism A118G of the μ opioid receptor alters its N-glycosylation and protein stability.
The A118G SNP (single nucleotide polymorphism) of the hMOPR [human MOPR (μ opioid receptor)] gene OPRM1 results in an amino acid substitution (N40D). Subjects homozygous for the 118G allele have been reported to require higher morphine doses to achieve adequate analgesia, and the 118G allele is more prevalent among drug abusers. However, changes in the MOPR protein associated with this SNP are unknown. Using a knockin mouse model (G/G mice; mice homozygous for the 112G allele of MOPR) that possesses the equivalent nucleotide/amino acid substitution (A112G; N38D) of the A118G SNP in the hMOPR gene, we investigated the N-linked glycosylation status of thalamic and striatal MOPR in G/G mice compared with A/A mice (wild-type mice homozygous for the 112A allele of MOPR). The molecular mass of MOPR determined by immunoblotting was lower in G/G mice than in A/A mice. Following treatment with peptide N-glycosidase F, which removes all N-linked glycans, both MOPR variants had an identical molecular mass, indicating that this discrepancy was due to a lower level of N-glycosylation of the MOPR in G/G mice. In Chinese-hamster ovary cells stably expressing hMOPRs, 118G/Asp40-hMOPR had a lower molecular mass than 118A/Asn40-hMOPR, which was similarly due to differential N-glycosylation. Pulse-chase studies revealed that the half-life of the mature form of 118G/Asp40-hMOPR (~12 h) was shorter than that of 118A/Asn40-hMOPR (~28 h). Thus the A118G SNP reduces MOPR N-glycosylation and protein stability.


Provocation of hypotension and pain during upright tilt table testing in adults with fibromyalgia.
Fibromyalgia is a common but poorly understood problem characterized by widespread pain and chronic fatigue. Because chronic fatigue has been associated with neurally mediated hypotension, we examined the prevalence of abnormal responses to upright tilt table testing in 20 patients with fibromyalgia and 20 healthy controls. Each subject completed a symptom questionnaire and underwent a three stage upright tilt table test (stage 1:45 minutes at 70 degrees tilt; stage 2, 15 minutes at 70 degrees tilt with isoproterenol 1-2 micrograms/min; stage 3, 10 minutes at 70 degrees tilt with isoproterenol 3-4 micrograms/min). An abnormal response to upright tilt was defined by syncope or presyncope in association with a drop in systolic blood pressure of at least 25 mm Hg and no associated increase in heart rate. During stage 1 of upright tilt, 12 of 20 fibromyalgia patients (60%), but no controls had an abnormal drop in blood pressure (P < 0.001). Among those with fibromyalgia, all 18 who tolerated upright tilt for more than 10 minutes reported worsening or provocation of their typical widespread fibromyalgia pain during stage 1. In contrast, controls were asymptomatic (P < 0.001). These results identify a strong association between fibromyalgia and neurally mediated hypotension. Further studies will be needed to determine whether the autonomic response to upright stress plays a primary role in the pathophysiology of pain and other symptoms in fibromyalgia.


Temperature control in molecular dynamic simulations of non-equilibrium processes.
Thermostats are often used in various condensed matter problems, e.g. when a biological molecule undergoes a transformation in a solution, a crystal surface is irradiated with energetic particles, a crack propagates in a solid upon applied stress, two surfaces slide with respect to each other, an excited local phonon dissipates its energy into a crystal bulk, and so on. In all of these problems, as well as in many others, there is an energy transfer between different local parts of the entire system kept at a constant temperature. Very often, when modelling such processes using molecular dynamics simulations, thermostatting is done using strictly equilibrium approaches serving to describe the NVT ensemble. In this paper we critically discuss the applicability of such approaches to non-equilibrium problems, including those mentioned above, and stress that the correct temperature control can only be achieved if the method is based on the generalized Langevin equation (GLE). Specifically, we emphasize that a meaningful compromise between computational efficiency and a physically appropriate implementation of the NVT thermostat can be achieved, at least for solid state and surface problems, if the so-called stochastic boundary conditions (SBC), recently derived from the GLE (Kantorovich and Rompotis 2008 Phys. Rev. B 78 094305), are used. For SBC, the Langevin thermostat is only applied to the outer part of the simulated fragment of the entire system which borders the surrounding environment (not considered explicitly) serving as a heat bath. This point is illustrated by comparing the performance of the SBC and some of the equilibrium thermostats in two problems: (i) irradiation of the Si(001) surface with an energetic CaF(2) molecule using an ab initio density functional theory based method, and (ii) the tribology of two amorphous SiO(2) surfaces coated with self-assembled monolayers of methyl-terminated hydrocarbon alkoxylsilane molecules using a classical atomistic force field. We discuss the differences in behaviour of these systems due to applied thermostatting, and show that in some cases a qualitatively different physical behaviour of the simulated system can be obtained if an equilibrium thermostat is used.


Inhibition of bone marrow colony formation by human natural killer cells and by natural killer cell-derived colony-inhibiting activity.
Incubation of human peripheral blood lymphocytes with bone marrow cells resulted in significant inhibition of colony formation by committed myeloid and erythroid cells. Using positively selected homogeneous natural killer (NK) cell preparations and lymphocyte subpopulations depleted of or enriched for NK cells, we definitively characterize as NK cells the cells in normal peripheral blood that are responsible for inhibition of bone marrow colony growth. The inhibitory effect of NK cells on hematopoiesis can be mediated by a soluble factor that is produced only by NK cells upon culture with HLA-DR+ hematopoietic cells and with NK-sensitive cell lines. Both NK cells and the NK-produced, colony-inhibiting activity (NK-CIA) are suppressive for allogeneic and autologous bone marrow CFU-GEMM (colony-forming units, granulocyte, erythroid, monocyte, megakaryocyte), CFU-E (CFU, erythroid), and early CFU-GM (CFU, granulocyte, monocyte), but not for either BFU-E (burst-forming units, erythroid) or late CFU-GM. [3H]Thymidine incorporation was inhibited by NK-CIA-containing supernatants in HLA-DR+ but not HLA-DR- bone marrow cell populations stimulated to proliferative by colony-stimulating factor (CSF). These data suggest that the NK cell-mediated inhibitory effect on proliferation and differentiation of hematopoietic precursor cells is mediated in part or completely by the secreted NK-CIA. The concentration of NK-CIA reached in the supernatant of the mixture of NK cell-containing lymphocyte populations with bone marrow cells is sufficient to account for the inhibitory effect mediated by NK cells. Our data support the hypothesis that human NK cells play a major role in the control of hematopoiesis, down-regulating it under conditions in which the NK cells are functionally activated.


Endobronchial Inflammatory Myofibroblastic Tumour-A Case Report.
Lung malignancies are on the rise and sadly present at an advanced stage. Fiberoptic bronchoscopy is used for staging as well as in diagnosis of lung malignancies. However, not all endobronchial growth are malignant. Inflammatory Myofibroblastic Tumour (IMT) is one of the rare tumours of the lung. A controversy regarding the benign versus malignant nature of the tumour is still ongoing. The management of these tumours can be challenging because there are no established treatment protocols. Although IMT most commonly arises from lung, endobronchial presentation is very rare. We report a case of endobronchial presentation of IMT and discuss about its aetiology and treatment options.


Myelogenous production and maturation of B lymphocytes in the mouse.
Cells of the B lymphocyte lineage in young adult murine bone marrow were identified and resolved into compartments based on cell size and the expression of the mu heavy chain of IgM in the cytoplasm (cmu) or on the cell surface (smu). The proliferative status, renewal rate, and intercompartmental transit of cells through the defined compartments were determined using established protocols of in vivo tritiated thymidine (3H-TdR) administration, followed by radioautography of bone marrow smears. In addition, we specifically tested whether any of the defined cell compartments were derived from long-lived lymphocytes that are known to enter the marrow. Only large cells immediately incorporated the DNA precursor and both small cmu+ smu- and cmu+ smu+ cells were postmitotic lymphocytes. Large cmu+ smu- cells were found to be a rapid transit compartment in which the last mitosis of B lymphocyte differentiation takes place. All large cmu+ smu- cells divided only once, and both daughter cells entered the postmitotic small cmu+ smu- population. Large cmu+ smu- cells relied for their maintenance entirely on cell input from an Ig- progenitor compartment. Progenitors of cmu+ smu- large cells were not small lymphocytes, proliferated less rapidly than their descendants, and maintained the input of large cmu+ smu- cells for up to 40 hr. Approximately 70% of small cmu+ smu- cells were the immediate division products of large cmu+ smu- cells, whereas the remainder were derived from a precursor with no detectable mu synthesis. Small cmu+ smu+ cells were the maturation products of small cmu+ smu- cells. This conversion appeared to take place at random rather than as a function of postmitotic age. Renewal times for small cmu+ cells without or with detectable smu were calculated to be 48 and 96 hr, respectively. Only the cmu- smu+ compartment included long-lived cells. All other mu+ populations either proliferated or were replaced by newly produced cells. A conspicuous minor population of large smu+ B cells were detected, and the data relating to these were subjected to several interpretations. These observations provide insight into the origin and fate of B lineage precursors in the marrow and suggest a scheme for the terminal stages of B lymphocytes formation that is similar to the myelogenous production of other hemopoietic cells.


Association between male pattern baldness and testicular germ cell tumor: a meta-analysis.
The relationship between male pattern baldness and incidence of testicular cancer remains inconclusive. Hence, we performed the present meta-analysis based on all eligible case-control studies. A comprehensive literature search was performed in July 30th 2018 based on PUBMED, EMBASE and Web of science database. Pooled odds ratio(OR) and its 95% confidence intervals (95% CIs) was calculated with a DerSimonian and Laird random-effects. The pooled results were included in this meta-analysis. Overall, We have demonstrated statistically signification between baldness(any pattern) and testicular cancer was identified (OR: 0.61, 95% CI:0.50-0.74). There was no obvious heterogeneity across included studies (P = 0.22 for heterogeneity, I2 = 30%). When subgroup analysis by types of baldness, We found a statistically significant association was observed that baldness(I-VII) might become a protective factor for the risk of testicular germ cell tumor(TGCT). There was no definite connection between alopecia and the different types of TGCT. Individuals with any pattern baldness may have a decreased risk of testicular cancer, all of analyses studies are warranted to confirm our preliminary findings. According to subgroup analysis of different hair loss grades, we found that 2 stage(II) hair loss can decrease more strongly testicular cancer risk than any other grades. Despite of our findings, We still need further researches to advance knowledge in this field.


[Effectiveness of the combined use of an inactivated vaccine and a proteolysis inhibitor in the prevention of experimental influenza].
The prophylactic effects produced by different types of antiviral preparations, used separately or in combination, in experimental lethal infection induced by influenza virus AO/32 (H0N1) in mice are compared. The use of inactivated vaccine and E-aminocaproic acid (E-ACA), a proteolysis-inhibiting agent, was studied. The qualitative characterization and quantitative evaluation of the anti-influenza effect were carried out by the method of multifactor analysis with the use of a computer after the optimum second-order plan based on the mathematical theory of experiment. This made it possible to determine the best combination of the preparations and their doses, to establish the time of the formation of reliable protection from influenza in mice. The prophylactic effect produced by the use of E-ACA alone and the capacity of this preparation for enhancing the protective action of inactivated influenza vaccine were established. Mathematical analysis revealed the optimum value of the four factors under study: the dose of the vaccine, the dose of E-ACA, the lapse of time between the injection of the preparations and the challenge of the animals, as well as the infective dose of the pathogenic virus. A special experiment made in the study of these data confirmed that the specific formation of a high level of anti-influenza protection in mice can be achieved by the combined use of the vaccine and the inhibitor of proteolysis.


Adding value to security services.
The need of the security manager to market himself or herself and the value of the services he or she performs has become a critical element of security operations today in all industries, including health care. In this article, the author reviews the wide range of options to be considered in offering security services both inside and outside your facility.


Edaravone protects the retina against ischemia/reperfusion‑induced oxidative injury through the PI3K/Akt/Nrf2 pathway.
Retinal ischemia/reperfusion (I/R) injury can occur as a result of a number of ocular diseases or ischemic events in the brain, leading to possible vision loss if not treated properly. The overproduction of reactive oxygen species is important in the process of I/R injury. Edaravone, a free radical scavenger, has been demonstrated to have a neuroprotective effect in cerebral ischemia; however, its effect against retinal I/R injury remains to be fully elucidated. Therefore, the present study investigated the effects of edaravone on the oxidative parameters, retinal inflammation and apoptosis induced by I/R injury, and treated photoreceptor‑derived 661W cells with hydrogen peroxide (H2O2) and edaravone to examine the underlying mechanism. For the in vivo study, oxidative parameters (malondialdehyde, DNA fragmentation, total antioxidant status, superoxide dismutase and glutathione) in the retina, retinal thickness, and apoptotic index in the ganglionic cell layer and inner nuclear layer were measured. For the in vitro study, the effects of edaravone or nuclear factor erythroid‑2‑related factor 2 (Nrf2) small interfering RNA or phosphatidylinositol 3‑kinase (PI3K)/Akt inhibitors on cell viability, membrane integrity, levels of phosphorylated‑Akt, Akt and nuclear Nrf2 of H2O2‑treated 661W cells were examined. The results demonstrated that edaravone inhibited the oxidative injury in the retina induced by the retinal I/R procedure and increased retinal inflammation, and apoptosis. The results of the in vitro experiments demonstrated that edaravone effectively protected the viability and the membrane integrity of the H2O2‑treated 661W cells via the phosphatidylinositol 3‑kinase (PI3K)/Akt/Nrf2pathway. These results indicated the potential protective effect of edaravone against retinal I/R injury and provided a novel explanation for the protective effects of edaravone.


Pallidal neuronal activity: implications for models of dystonia.
Dystonia is a neurological syndrome involving sustained contractions of opposing muscles leading to abnormal movements and postures. Recent studies report abnormally low pallidal neuronal activity in patients with generalized dystonia, suggesting hyperkinetic disorders result from underactive basal ganglia output. We examined this hypothesis in 11 patients with segmental and generalized dystonia undergoing microelectrode exploration of the internal globus pallidus (GPi) before pallidotomy or deep brain stimulation (DBS) implantation. The mean firing rates and firing patterns were compared with those in six patients with Parkinson's disease (PD). In seven patients who underwent surgery under local anesthesia, the mean GPi firing rate was 77 Hz, similar to the 74 Hz observed in the PD patients. However, in three dystonic patients under propofol anesthesia, GPi mean firing rate was much reduced (31 Hz), and the firing pattern was distinguished by long pauses in activity, as reported by others. Low-dose propofol in one other dystonia patient also seemed to suppress GPi firing. These results indicate that an abnormally low basal ganglia output is not the sine qua non of dystonia. The widely accepted pathophysiological models of dystonia that propose global decreases in basal ganglia output need to be viewed with caution in light of these findings.


Predictors of accurate maternal perception of their preschool child's weight status among Hispanic WIC participants.
Childhood obesity is a growing problem in the United States. Parental perception of their children's weight status is a key factor that needs to be considered when developing prevention programs for preschool children. Using a randomly selected sample of participants of Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in Los Angeles County, we assessed accuracy of maternal perceptions of their children's weight status by comparing children's weight classification to the mothers' response to the question "Do you consider your child to be overweight, underweight or about right weight for (his) (her) height?" Additionally, we identified possible predictors of accurate maternal perception of their children's weight status by conducting a logistic regression model with child's gender, child's birth weight, maternal age, maternal BMI, maternal education, maternal acculturation level, and maternal language preference as potential predictors. Almost all mothers in the study classified their overweight or obese child as being about the right weight (93.6% and 77.5% of mothers, respectively). Maternal BMI and child's birth weight were the only predictors of maternal perception of their child's weight. Both were negatively associated with accuracy, with higher maternal BMI and higher infant birthweight associated with less accurate maternal perception of child weight. Parents need to be educated on the importance of childhood obesity and how to identify if their children are overweight or obese. If parents fail to recognize that their overweight child is overweight, then it is unlikely that they will recognize that interventions targeting obesity are relevant to their families.


Unravelling cancer subtype-specific driver genes in single-cell transcriptomics data with CSDGI.
Cancer is known as a heterogeneous disease. Cancer driver genes (CDGs) need to be inferred for understanding tumor heterogeneity in cancer. However, the existing computational methods have identified many common CDGs. A key challenge exploring cancer progression is to infer cancer subtype-specific driver genes (CSDGs), which provides guidane for the diagnosis, treatment and prognosis of cancer. The significant advancements in single-cell RNA-sequencing (scRNA-seq) technologies have opened up new possibilities for studying human cancers at the individual cell level. In this study, we develop a novel unsupervised method, CSDGI (Cancer Subtype-specific Driver Gene Inference), which applies Encoder-Decoder-Framework consisting of low-rank residual neural networks to inferring driver genes corresponding to potential cancer subtypes at the single-cell level. To infer CSDGs, we apply CSDGI to the tumor single-cell transcriptomics data. To filter the redundant genes before driver gene inference, we perform the differential expression genes (DEGs). The experimental results demonstrate CSDGI is effective to infer driver genes that are cancer subtype-specific. Functional and disease enrichment analysis shows these inferred CSDGs indicate the key biological processes and disease pathways. CSDGI is the first method to explore cancer driver genes at the cancer subtype level. We believe that it can be a useful method to understand the mechanisms of cell transformation driving tumours.


Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms.
Although limited understanding exists for the presence of specific genetic mutations and aberrantly methylated genes in pancreatobiliary intraductal papillary mucinous neoplasms (IPMNs), the fundamental understanding of the dynamics of methylation expansion across CpG dinucleotides in specific gene promoters during carcinogenesis remains unexplored. Expansion of DNA methylation in some gene promoter regions, such as EFEMP1, one of the fibulin family, with tumor progression has been reported in several malignancies. We hypothesized that DNA hypermethylation in EFEMP1 promoter would expand with the tumor grade of IPMN. A sample of 65 IPMNs and 30 normal pancreatic tissues was analyzed. IPMNs were divided into the following three subsets according to pathological findings: 31 with low-grade dysplasia (low grade), 11 with high-grade dysplasia (high grade), and 23 with associated invasive carcinoma (invasive Ca). Mutations in the KRAS or GNAS genes were analyzed by Sanger sequencing, and methylation status of two discrete regions within the EFEMP1 promoter, namely region 1 and region 2, was analyzed by bisulfite sequencing and fluorescent high-sensitive assay for bisulfite DNA (Hi-SA). Expression status of EFEMP1 was investigated by immunohistochemistry (IHC). KRAS mutations were detected in 39, 55, and 70 % of low-grade, high-grade, and invasive Ca, respectively. GNAS mutations were observed in 32, 55, and 22 % of low-grade, high-grade, and invasive Ca, respectively. The methylation of individual regions (region 1 or 2) in the EFEMP1 promoter was observed in 84, 91, and 87 % of low-grade, high-grade, and invasive Ca, respectively. However, simultaneous methylation of both regions (extensive methylation) was exclusively detected in 35 % of invasive Ca (p = 0.001) and five of eight IPMNs (63 %) with extensive methylation, whereas 20 of 57 (35.1 %) tumors of unmethylation or partial methylation of the EFEMP1 promoter region showed weak staining EFEMP1 in extracellular matrix (p = 0.422). In addition, extensive EFEMP1 methylation was particularly present in malignant tumors without GNAS mutations and associated with disease-free survival of patients with IPMNs (p < 0.0001). Extensive methylation of the EFEMP1 gene promoter can discriminate invasive from benign IPMNs with superior accuracy owing to their stepwise accumulation of tumor progression.


The effect of lipid emulsion infusion on postmortem ropivacaine concentrations in swine: endeavoring to comprehend a soldier's death.
Lipid emulsion (20%) is advocated as a rescue drug for local anesthetic toxicity. No study has measured the impact of lipid emulsion therapy on postmortem local anesthetic serum levels. We anesthetized Yorkshire swine (n = 11) and standard monitors were placed. The swine received 1.5 mg/kg/min IV ropivacaine until death (asystole). Blood samples were drawn before infusion (baseline) and at 5-minute intervals during the infusion for measurement of blood gases and free, bound, and total serum ropivacaine concentrations via high-performance liquid chromatography. Five swine received ropivacaine only, and 6 swine received ropivacaine plus a single bolus dose of 20% lipid emulsion (1 mg/kg) when the mean arterial blood pressure reached 50 mm Hg. Ropivacaine infusions were terminated at asystole and no resuscitation was initiated. Total ropivacaine dose and time to death were recorded. The swine were cooled (mean temperature, 25.5°C ± 0.8°C at 6 hours postmortem) to reflect morgue conditions. Serum samples were drawn at asystole, 1, 3, and 6 hours postmortem for analysis. Additionally, a craniotomy and laparotomy were performed at those times to remove 1.5 to 3 g each of brain, lung, liver, kidney, and muscle for analysis. Analysis of the postmortem serum ropivacaine concentrations in the control and the lipid-treated animals indicated that both the total (bound and not bound to proteins) and free (not bound to proteins) ropivacaine concentrations were significantly higher in the lipid-treated animals (P = 0.0094 and P = 0.0063, respectively). Furthermore, time had a significant effect on increasing the postmortem free ropivacaine concentrations (P = 0.0095). The lipid group had a statistically significant earlier onset of death (asystole) compared with the control group (P = 0.0274). Tissue analysis indicated that the ropivacaine concentration significantly decreased postmortem in the lung, kidney, and brain tissues of the lipid-treated animals (P = 0.0168, P = 0.0073, and P = 0.0018, respectively). Tissue drug concentrations in the control animals remained unchanged after death. Our data show that postmortem blood samples in swine that experience local anesthetic cardiovascular collapse and are treated with lipid emulsions will result in measurements that cannot be directly extrapolated to premortem drug concentrations.


Functional validation of the oncogenic cooperativity and targeting potential of tuberous sclerosis mutation in medulloblastoma using a MYC-amplified model cell line.
Medulloblastoma is the most common malignant brain tumor of childhood. To identify targetable vulnerabilities, we employed inhibitor screening that revealed mTOR inhibitor hypersensitivity in the MYC-overexpressing medulloblastoma cell line, D341. Concomitant exome sequencing unveiled an uncharacterized missense mutation, TSC2A415V , in these cells. We biochemically demonstrate that the TSC2A415V mutation is functionally deleterious, leading to shortened half-life and proteasome-mediated protein degradation. These data suggest that MYC cooperates with activated kinase pathways, enabling pharmacologic intervention in these treatment refractory tumors. We propose that identification of activated kinase pathways may allow for tailoring targeted therapy to improve survival and treatment-related morbidity in medulloblastoma.


A survey on brain tumor image analysis.
Medical imaging, also known as radiology, is the field of medicine in which medical professionals recreate various images of parts of the body for diagnostic or treatment purposes. Medical imaging procedures include non-invasive tests that allow doctors to diagnose injuries and diseases without being intrusive TechTarget (n.d.). A number of tools and techniques are used to automate the analysis of medical images acquired with various image processing methods. The brain is one of the largest and most complex organs of the human body and anomaly detection from brain images (i.e., MRI, CT, PET, etc.) is one of the major research areas of medical image analysis. Image processing methods such as filtering and thresholding models, geometry models, graph models, region-based analysis, connected component analysis, machine learning (ML) models, the recent deep learning (DL) models, and various hybrid models are used in brain image analysis. Brain tumors are one of the most common brain diseases with a high mortality rate, and it is difficult to analyze from brain images for the versatility of the shape, location, size, texture, and other characteristics. In this paper, a comprehensive review on brain tumor image analysis is presented with basic ideas of brain tumor, brain imaging, brain image analysis tasks, brain image analysis models, brain tumor image features, performance metrics used for evaluating the models, and some available datasets on brain tumor/medical images. Some challenges of brain tumor analysis are also discussed including suggestions for future research directions. The graphical abstract summarizes the contributions of this paper.


Assessing the impact of a doctor in remote areas of Brazil.
The More Doctors Program (MDP) is an ongoing Brazilian policy that aims to improve healthcare by providing physicians to the most vulnerable municipalities. We aimed to measure the impact of MDP in mortality and infant mortality rate, the proportion of live births with low weight, prenatal appointments, childbirths at first and fifth min Apgar, public health investment and immunization in Brazil. Municipal health indicators were collected before and after the intervention (2012 and 2015). Effects were measured by applying propensity score matching with difference-in-differences. Our findings show that infant mortality presented the highest improvement during the period (a decrease in 11 infant deaths per 1000 live births, p < 0.01). A significant effect, albeit smaller, was also found for the age-standardized total mortality (a decrease in five deaths per 10,000 residents), proportion of children with Apgar score lower than 8 in the fifth min and children with low birth weight. MDP contributed to improve important health indicators, highlighting the importance of a doctor in remote areas of Brazil.


TopoSZ: Preserving Topology in Error-Bounded Lossy Compression.
Existing error-bounded lossy compression techniques control the pointwise error during compression to guarantee the integrity of the decompressed data. However, they typically do not explicitly preserve the topological features in data. When performing post hoc analysis with decompressed data using topological methods, preserving topology in the compression process to obtain topologically consistent and correct scientific insights is desirable. In this paper, we introduce TopoSZ, an error-bounded lossy compression method that preserves the topological features in 2D and 3D scalar fields. Specifically, we aim to preserve the types and locations of local extrema as well as the level set relations among critical points captured by contour trees in the decompressed data. The main idea is to derive topological constraints from contour-tree-induced segmentation from the data domain, and incorporate such constraints with a customized error-controlled quantization strategy from the SZ compressor (version 1.4). Our method allows users to control the pointwise error and the loss of topological features during the compression process with a global error bound and a persistence threshold.


A molecular and morphological study of Ascaris suum in a human-pig contact scenario in northeastern Brazil.
The aim of the present study was to assess morphologic and genetic data on ascariasis in swine (Sus scrofa domesticus) and humans in low-resource rural and periurban communities in the state of Piauí, Brazil. Our cross-sectional survey included 100 fecal samples obtained from swine and 682 samples from humans. Fifteen pigs were necropsied. Human and porcine fecal samples were examined to identify Ascaris eggs. Parasites obtained in the swine necropsies were studied using scanning electron microscopy (SEM), and the mitochondrial gene encoding the cytochrome oxidase 1 (cox1) enzyme was partially amplified and sequenced for molecular taxonomy and phylogenetic analyses. The overall prevalence of Ascaris eggs in the swine fecal samples was 16/100 (16%). No Ascaris eggs were identified in the human fecal samples. SEM of six worms recovered from pigs demonstrated morphological characteristics of A. suum. Cox1 sequences were compatible with A. suum reference sequences. Original and reference (GenBank) nucleotide sequences were organized into clusters that did not segregate the parasites by host species or and region. The largest haplogroups were dominated by haplotypes H01, H02 and H31. In the communities studied, there was no epidemiological evidence of the zoonotic transmission of ascariasis at the human-swine interface.


Heterology of mitochondrial DNA from mammals detected by electron microscopic heteroduplex analyses.
Heteroduplex analysis of mitochondrial DNA (mtDNA) from evolutionary closely related mammals (rat vs. mouse, man vs. monkey) are analyzed and compared to heteroduplex analysis of mt-DNA from more distantly related mammals (rat vs. man, rat vs. monkey, mouse vs. man, mouse vs. monkey and man vs. cow). Each analysis is transformed into a heteroduplex map and all maps are aligned to restriction enzyme maps and to genetic maps and where possible compared with the known sequence. We show that early evolutionary changes are seen mainly in URF2, URFA6L, URF6 and the D-loop region. The regions of rRNA, URF1, COI and COIII are generally very conserved regions but areas with some evolutionary activity can be localized. Heteroduplex analysis between distantly related species show much more heterology than do closely related species and the heteroduplex maps between all the distantly related species show a common pattern of heterology. Comparisons between the DNA sequence of mtDNA from man, cow and mouse and the equivalent heteroduplex maps show that base pair homologies higher than 73% are displayed as homologous regions. In the heteroduplex analysis of mtDNA's from more closely related species very few heterologies are displayed at 50% formamide but an increase in formamide concentration to 65-70% demonstrate also in these instances general heterologous regions.


Liver transplantation from controlled non-heart-beating donors.
The use of organs from non-heart-beating donors (NHBDs) has been proposed as one way to increase the donor pool. However, few centers have transplanted livers from NHBDs. We report here the results of 19 liver transplants from controlled NHBDs. From January 1993 through August 1999, 364 liver transplantations were performed from heart-beating donors (HBDs) and 19 liver transplantations were performed from NHBDs. Donor and recipient characteristics, posttransplant complications, and patient and allograft survival were compared. No differences in hepatic artery, portal vein, or biliary complications were noted between the groups. However, the rate of primary nonfunction was higher in recipients of livers from NHBDs (10.5% vs. 1.3%; P = .04). No difference in patient survival was seen between recipients of NHBDs or HBDs (72.6% vs. 84.8%; P =.36); however, allograft survival was lower in recipients who received livers from NHBDs (53.8% vs. 80.9%; P =.007). Liver transplantation from controlled NHBDs results in similar patient survival and post-transplant complications. However, primary nonfunction was higher and allograft survival was less in recipients of livers from NHBDs. The results of liver transplantation from controlled NHBDs are encouraging and should continue to be cautiously pursued as one way to help alleviate the current shortage of donor livers.


[Effect of prenatal alcohol exposure on rhythmic respiratory discharge activity in medullary slices of neonatal rats].
To investigate the effects of prenatal alcohol exposure on rhythmic respiratory discharge activity (RRDA) in the medullary slices of neonatal rats. Ten pregnant female SD rats were exposed to 0, 4%, 6%, 8%, and 10% alcohol in drinking water from 1 week before till 3 days after delivery. The medullary slices of the neonatal rats containing the medial region of the nucleus retrofacialis (mNRF) with the hypoglossal nerve rootlets were prepared and perfused with modified Kreb's solution to record RRDA from the hypoglossal nerve rootlets using suction electrodes. No significant difference was found in RRDA in 50 min among the neonatal rats with prenatal exposure to 0, 4%, 6%, and 8% alcohol, but the RRDA in 10% alcohol exposure group became irregular. Prenatal exposure to increased alcohol concentrations caused attenuated RRDA attenuated in the neonatal rats, shown by shortened inspiratory time (TI), decreased respiratory frequency (RF), and reduced integral amplitude (IA) as compared with those in the control group. Prenatal alcohol exposure inhibits RRDA in medullary slices of neonatal rats, which might be a mechanism by which maternal alcohol exposure causes suppressed offspring respiratory functions.


Comorbid depression and risk of cardiac events and cardiac mortality in people with diabetes: A systematic review and meta-analysis.
To examine the association of comorbid occurrence of diabetes and depression with risk of cardiovascular endpoints including cardiovascular mortality, coronary heart disease and stroke. A systematic review and metaanalysis. We searched PUBMED/MEDLINE, Medscape, Cochrane Library, CINAHL, EMBASE and Scopus databases assessing cardiac events and mortality associated with depression in diabetes up until 1 December 2018. Pooled hazard ratios were calculated using random- effects models. Nine studies met the inclusion criteria. The combined pooled hazard ratios showed a significant association of cardiac events in people with depression and type 2 diabetes, compared to those with type 2 diabetes alone. For cardiovascular mortality the pooled hazard ratio was 1.48 (95% CI: 1.185, 1.845), p = 0.001, for coronary heart disease 1.37 (1.165, 1.605), p < 0.001 and for stroke 1.33 (1.291, 1.369), p < 0.001. Heterogeneity was high in the meta-analysis for stroke events (I-squared = 84.7%) but was lower for coronary heart disease and cardiovascular mortality (15% and 43.4% respectively). Meta-regression analyses showed that depression was not significantly associated with the study level covariates mean age, duration of diabetes, length of follow-up, BMI, sex and ethnicity (p < 0.05 for all models). Only three studies were found that examined the association of depression in type 1 diabetes, there was a high degree of heterogeneity and data synthesis was not conducted for these studies. We have demonstrated a 47.9% increase in cardiovascular mortality, 36.8% increase in coronary heart disease and 32.9% increase in stroke in people with diabetes and comorbid depression. The presence of depression in a person with diabetes should trigger the consideration of evidence-based therapies for cardiovascular disease prevention irrespective of the baseline risk of cardiovascular disease or duration of diabetes.


[Hypomethylation and multiple sclerosis, the susceptibility factor?].
Azathioprine, off-label used long time ago to treat multiple sclerosis (MS) patients, has recently received approval from the Spanish Medicine Agency (Agencia Española del Medicamento) in relapsing-remitting (RR) forms of this condition. Clinical efficacy of azathioprine is due to the enzymatic conversion to 6-thioguanine (the active metabolite). The key enzyme in this process is thio purine methyl transferase (TPMT), converting 6-MP to 6-methylMP. A specific genetic polymorphism has been described affecting this enzyme. With the aim of optimizing purine therapy in a variety of autoimmune diseases, monitoring of TPMT phenotype has been performed in a vast number of patients. The TPMT activity frequency distribution histogram from a Spanish population sample has been compared with the corresponding ones to Crohn's disease, ulcerative colitis and MS patients. TPMT activity has been studied in red blood cells obtained from 3,640 clinical laboratory samples in Spain of which 1,249 corresponded to patients affected by Crohn's disease, 589 to ulcerative colitis, 348 to MS, 487 to several autoimmune diseases apart from the previously mentioned and 967 to a group of blood donors. The mean TPMT activity in the MS group (17.1 6.1 U/ml) was significantly lower (p < 0.001) than in Crohn's disease (20.0 5.8 U/ml), ulcerative colitis (19.7 6.1 U/ml) and donors group (19.9 6.3 U/ml). Defective methylation profile and subsequent hyperhomocysteinemia leading to a widespread impairment of the methyl-transferase activity (in this case affecting MBP methylation) is a vicious circle we propose as a MS susceptibility factor.


[The sterilization effect of formaldehyde fumigating on the catheter place vertically].
The aim of this paper is to investigate the effect of formaldehyde fumigating on the sterilization of catheters with different diameters and placed in different positions. The lumen of cleaned catheters with different diameters was filled with a solution of live bacilli coil. The catheters were then dried by a drier and divided into 3 groups for formaldehyde fumigating sterilization. A segment of 5 cm of the middle section of the sterilized catheters was cut and incubated at 36 degrees C for 48 h with bouillon medium. For those segments with positive culture, bacteriologic identification was done. Group A, U = 6.85 and P < 0.01; Group B, chi 2 = 8 and P < 0.01; Group C, chi 2 = 13, P < 0.01. in the same conditions, fumigating in vertical direction is better than fumigation in horizontal direction and save time; in the same conditions, the positive culture rate is inversely related to the diameter of the catheters; for catheter with a diameter greater than 0.75 cm, fumigating vertically for 2 h is enough to obtain satisfactory sterilization effects.


Predictive Factors of Resistance to High-Dose Steroids Therapy in Acute Attacks of Neuromyelitis Optica Spectrum Disorder.
High-dose steroids, the first-line therapy for acute attacks in neuromyelitis optica spectrum disorder (NMOSD), were ineffective in a proportion of NMOSD attacks. This study aimed to explore possible predictors of high-dose steroid resistance. Demographics and disease characteristics of acute attacks were compared between those who responded to high-dose intravenous methylprednisolone (IVMP) and those resistant to IVMP. In total, 197 attacks in 160 patients were identified in our NMOSD registry. Compared with responders, attacks resistant to high-dose steroids tended to have a higher proportion of previous history of immunosuppressive use (25.5 vs. 15.5%, p = 0.080). Significantly higher levels of proteins in the cerebrospinal fluid (CSF) were found in non-responders than in responders [485.5 (388-656) vs. 387 (291.5-532) mg/L, p = 0.006]. More active lesions were found in the brain stem of non-responders (8 attacks in 55, 14.5%), especially in the pons (7.3%) and medulla (14.5%), as opposed to responders (7 patients in 142, 4.9%). Multivariable logistic regression showed that resistance to high-dose steroid treatment was associated with previous immunosuppressant use [odds ratio (OR), 2.31; 95% confidence interval (CI) 1.002-5.34, p = 0.049], CSF protein level above 450 mg/L (OR 3.42, 95% CI 1.72-6.82, p < 0.001), and active lesions in the brainstem (OR 3.80, 95% CI 1.17-12.32, p = 0.026). In conclusion, NMOSD patients with previous use of immunosuppressants, higher levels of CSF protein, and active lesions in the brainstem are more likely to respond poorly to high-dose IVMP alone during an acute attack.


Substrate polypeptide presents a load on the apical domains of the chaperonin GroEL.
A conundrum has arisen in the study of the structural states of the GroEL-GroES chaperonin machine: When either ATP or ADP is added along with GroES to GroEL, the same asymmetric complex, with one ring in a GroES-domed state, is observed by either x-ray crystallographic study or cryoelectron microscopy. Yet only ATP/GroES can trigger productive folding inside the GroES-encapsulated cis cavity by ejecting bound polypeptide from hydrophobic apical binding sites during attendant rigid body elevation and twisting of these domains. Here, we show that this difference occurs because polypeptide substrate in fact presents a load on the apical domains, and, although ATP can counter this load effectively, ADP cannot. We monitored apical domain movement in real time by fluorescence resonance energy transfer (FRET) between a fixed equatorial fluorophore and one attached to the mobile apical domain. In the absence of bound polypeptide, addition of either ATP/GroES or ADP/GroES to GroEL produced the same rapid rate and extent of decrease of FRET (t(1/2) < 1 sec), reflecting similarly rapid apical movement to the same end-state and explaining the results of the structural studies, which were all carried out in the absence of substrate polypeptide. But in the presence of bound malate dehydrogenase or rhodanese, whereas similar rapid and extensive FRET changes were observed with ATP/GroES, the rate of FRET change with ADP/GroES was slowed by >100-fold and the extent of change was reduced, indicating that the apical domains opened in a slow and partial fashion. These results indicate that the free energy of gamma-phosphate binding, measured earlier as 43 kcal per mol (1 cal = 4.184 J) of rings, is required for driving the forceful excursion or "power stroke" of the apical domains needed to trigger release of the polypeptide load into the central cavity.


Differential distribution and defence involvement of antimicrobial peptides in mussel.
In previous papers, we characterised 3 types of 4-kDa, cysteine-rich, cationic antimicrobial peptides: MGDs (for Mytilus galloprovincialis defensins), mytilins and myticins, which are abundant in the mussel hemocytes. In the present work, we revealed a differential distribution of the cells expressing the different genes. In addition, using confocal and electron microscopy, we confirmed that defensins and mytilins were partially located in different sub-types of circulating hemocytes although the peptides can be located in the same cell, and even in the same granule. We also demonstrated that mytilins exert their microbicidal effect within the cells through the process of phagosome-mytilin granule fusion leading to the co-location of ingested bacteria and mytilins.


Phytotherapy in endometriosis: an up-to-date review.
Endometriosis is a benign gynecological disease which symptoms can provide a severe impact on patient's quality of life with subsequent impact on psychological well-being. Different therapeutic strategies are available to treat this disease, such as surgery, hormonal therapies, and nonsteroidal anti-inflammatory drugs. Nevertheless, the efficacy of conventional medical treatments is limited or intermittent in most of the patients due to the associated side effects. Therefore, a woman with endometriosis often search for additional and alternative options, and phytotherapy might be a promising alternative and complementary strategy. Different medicinal plants, multicomponent herbal preparations, and phytochemicals were investigated for pharmacological proprieties in endometriosis therapy. In most of the cases, the effect on endometriosis was related to phenolic compounds, such as flavonoids and phenolic acids reporting anti-inflammatory, proapoptotic, antioxidant, and immunomodulatory functions. Moreover, some phytochemicals have been related to a strong phytoestrogenic effect modulating the estrogen activity. Although promising, available evidence is based on in vitro and animal models of endometriosis with a limited number of well-performed clinical studies. There are almost none randomized control trials in this area. Therefore, properly constructed clinical trials are mandatory to achieve more conclusive results about the promising role of phytotherapy in the management of endometriosis.


[From legitimation to (re-)signification: the therapeutic itinerary of workers with RSIs/WMSDs].
Repetitive Strain Injuries (RSIs)/Work-Related Musculoskeletal Disorders (WMSDs) are a major issue in Brazilian public health. The way such sickness is produced, its multidetermined origin and the troubled care provided to sufferers point to the very contradictions of the capitalist production system. This work aims at understanding the macrosocial processes surfaced in the workers' search for cure of RSIs/WMSDs, paying close attention to the negotiation and (re-)signification processes present in those trajectories. By drawing on 'explanatory models' and the concept of 'therapeutic itinerary', 'thematic analysis' of in-depth interviews with Brazilian workers receiving Social Security compensation was used to approach the socioeconomic and political realms. Culpability and excess were reported in connection with etiology whereas pain, tiredness and stress were shown to be related to symptom initiation. Legal medical assessment, rehabilitation programs and prognosis were all along (re-) signified by the interviewees in an attempt to create an 'ideal type' of productive worker despite the injury. It is then urged that public health policies responsive to the wider organization and processes of power and class related to the care of RSIs/WMSDs are devised.


Reliability and validity of inexpensive and easily administered anthropometric clinical evaluation methods of postural asymmetry measurement in adolescent idiopathic scoliosis: a systematic review.
As accurate and reproducible measurements of spinal curvature are crucial in the examination of patients with adolescent idiopathic scoliosis (AIS), this systematic review aims to report on the reliability and validity of a range of inexpensive and easily administered anthropometric methods of postural asymmetry measurement in an AIS population, to inform practice in a clinical setting. A systematic search of health research databases located studies assessing reliability and validity of inexpensive and easily administered anthropometric measures. Fourteen studies satisfied eligibility criteria. The methodological quality of included studies ranged from low to high. Validity studies were of moderate to high quality. In total, nine clinically applicable, inexpensive and easily administered anthropometric methods were identified, for assessing AIS curvature. All methods demonstrated high to very high inter-observer and intra-observer reliability. Reported criterion validity of the scoliometer and 2D photographs, when compared to Cobb angle assessed from radiographs, ranged from low to very high. iPhone measurements correlated well with scoliometer measurements. 2D photography results had a moderate to high correlation with 3D topography results. Overall, strong levels of evidence exist for iPhone and scoliometer measurements, with a high to very high reliability and moderate to very high validity. Moderate levels of evidence exist for scoliometer with mathematical formula and clinical examination with moderate and low validity, respectively. Limited evidence exists for aesthetic tools TRACE and AI and 2D photography. These results indicate there are accurate and reproducible anthropometric measures that are inexpensive and applicable in therapy settings to assess postural asymmetry; however, these only exist for measurement in the transverse plane, despite 3D characteristics of AIS. Further research is required into an inexpensive and easily administered method that can assess postural asymmetry in all anatomical planes.


Willingness to Travel for Cellular Therapy: The Influence of Follow-Up Care Location, Oncologist Continuity, and Race.
Patients weigh competing priorities when deciding whether to travel to a cellular therapy center for treatment. We conducted a choice-based conjoint analysis to determine the relative value they place on clinical factors, oncologist continuity, and travel time under different post-treatment follow-up arrangements. We also evaluated for differences in preferences by sociodemographic factors. We administered a survey in which patients with diffuse large B-cell lymphoma selected treatment plans between pairs of hypothetical options that varied in travel time, follow-up arrangement, oncologist continuity, 2-year overall survival, and intensive care unit admission rate. We determined importance weights (which represent attributes' value to participants) using generalized estimating equations. Three hundred and two patients (62%) responded. When all follow-up care was at the center providing treatment, plans requiring longer travel times were less attractive (v 30 minutes, importance weights [95% CI] of -0.54 [-0.80 to -0.27], -0.57 [-0.84 to -0.29], and -0.17 [-0.49 to 0.14] for 60, 90, and 120 minutes). However, the negative impact of travel on treatment plan choice was mitigated by offering shared follow-up (importance weights [95% CI] of 0.63 [0.33 to 0.93], 0.32 [0.08 to 0.57], and 0.26 [0.04 to 0.47] at 60, 90, and 120 minutes). Black participants were less likely to choose plans requiring longer travel, regardless of follow-up arrangement, as indicated by lower value importance weights for longer travel times. Reducing travel burden through shared follow-up may increase patients' willingness to travel to receive cellular therapies, but additional measures are required to facilitate equitable access.


Epicardial fat tissue may predict new-onset atrial fibrillation in patients with non-ST-segment elevation myocardial infarction.
In recent years, epicardial fat tissue (EFT) has been found to be strongly associated with the development of atrial fibrillation (AF). It was also reported to be a predictor of cardiac arrhythmias in different clinical situations. However, in the current literature, the role of EFT thickness in the development of AF in patients with non-ST-segment elevation myocardial infarction (NSTEMI) has not been studied. In this study, we aimed to investigate the relationship between EFT thickness and the development of new-onset AF in patients with NSTEMI during in-hospital follow-up. We enrolled 493 consecutive patients who were diagnosed NSTEMI in this study. During in-hospital follow-up, 68 patients developed AF, and the remaining 425 patients were determined as the control group. The thrombolysis in myocardial infarction (TIMI) risk score for NSTEMI was calculated. All clinical, echocardiographic, and laboratory parameters were compared between the 2 groups. EFT thickness was higher in the AF group than in the controls (p<0.001). The TIMI risk scores were higher in the AF group (p<0.001). Logistic regression analysis demonstrated that EFT was an independent determinant for the development of AF (odds ratio 3.521, 95% confidence interval 1.616-6.314, p<0.001). Incident AF was observed more frequently in patients with NSTEMI and higher EFT thickness. EFT was an important determinant of AF in patients with NSTEMI.


Reconstruction of extensive maxillary defects using zygomaticus implants.
Maxillary reconstruction after maxillectomy remains a great challenge for the reconstructive oral and maxillofacial surgeon. This article is a clinical retrospective analysis of patients reconstructed with zygomaticus implants after maxillary ablation. The design of the study was a retrospective review of 9 patients requiring near-total or total maxillectomy for pathologic reasons. Clinical records, photographs, and radiographs were studied. Financial billing statements were reviewed to determine charges for implant reconstruction and method of payment. Maxillary reconstruction using zygomaticus and standard endosseous implants was performed in 9 patients. Maxillary resection was performed for the following reasons: salivary gland malignancy (n = 2), squamous cell carcinoma (n = 5), maxillary mucormycosis (n = 1), and extensive maxillary atrophy and infection secondary to subperiosteal maxillary implant placement (n = 1). A total of 28 zygomaticus implants and 10 standard endosseous implants were used to reconstruct the 9 patients. Six zygomaticus implants and 3 standard endosseous implants failed. The time of zygomaticus implant placement ranged from placement at the time of resection to 3.2 years after the resection. Five patients received radiation therapy. Five patients have been reconstructed with a maxillary obturator and have been functioning with the prosthesis for a minimum of 2 years. The combination of zygomaticus and standard endosseous implants can be used to reliably reconstruct patients after extensive resection of the maxilla.


RNA activation-independent DNA targeting of the Type III CRISPR-Cas system by a Csm complex.
The CRISPR-Cas system is an adaptive and heritable immune response that destroys invading foreign nucleic acids. The effector complex of the Type III CRISPR-Cas system targets RNA and DNA in a transcription-coupled manner, but the exact mechanism of DNA targeting by this complex remains elusive. In this study, an effector Csm holocomplex derived from Thermococcus onnurineus is reconstituted with a minimalistic combination of Csm1121334151, and shows RNA targeting and RNA-activated single-stranded DNA (ssDNA) targeting activities. Unexpectedly, in the absence of an RNA transcript, it cleaves ssDNA containing a sequence complementary to the bound crRNA guide region in a manner dependent on the HD domain of the Csm1 subunit. This nuclease activity is blocked by a repeat tag found in the host CRISPR loci. The specific cleavage of ssDNA without a target RNA suggests a novel ssDNA targeting mechanism of the Type III system, which could facilitate the efficient and complete degradation of foreign nucleic acids.


Educational patterning in biological health seven years apart: Findings from the Tromsø Study.
Social-to-biological processes is one set of mechanisms underlying the relationship between social position and health. However, very few studies have focused on the relationship between social factors and biology at multiple time points. This work investigates the relationship between education and the dynamic changes in a composite Biological Health Score (BHS) using two time points seven years apart in a Norwegian adult population. We used data from individuals aged 30 years and above who participated in Tromsø6 (2007-2008) and Tromsø7 (2015-2016) (n = 8117). BHS was defined using ten biomarkers measured from blood samples and representing three physiological systems (cardiovascular, metabolic, inflammatory). The higher the BHS, the poorer the health status. Linear regression models carried out on BHS revealed a strong educational gradient at two distinct time points but also over time. People with lower educational attainment were at higher risk of poor biological health at a given time point (βlow education Tromsø6=0.30 [95 %-CI=0.18-0.43] and βlow education Tromsø7=0.30 [95 %-CI=0.17-0.42]). They also presented higher longitudinal BHS compared to people with higher education (βlow education = 0.89 [95 %-CI=0.56-1.23]). Certain biomarkers related to the cardiovascular system and the metabolic system were strongly socially distributed, even after adjustment for sex, age, health behaviours and body mass index. This longitudinal analysis highlights that participants with lower education had their biological health deteriorated to a greater extent over time compared to people with higher education. Our findings provide added evidence of the biological embodiment of social position, particularly with respect to dynamic aspects for which little evidence exists.


Inhibition of subunit dissociation and release of the stimulatory G-protein, Gs, by beta gamma-subunits and somatostatin in S49 lymphoma cell membranes.
We examined the interaction between the stimulatory guanine-nucleotide-binding protein, Gs, and the inhibitory guanine-nucleotide-binding protein, Gi, in cell membranes of S49 lymphoma cells. In these cells, beta-adrenergic receptors stimulate the activity of adenylate cyclase via Gs, whereas inhibition via somatostatin receptors is transduced by an inhibitory G-protein, Gi. Using an antibody that selectively recognizes alpha s, the monomeric, but not the heterotrimeric, alpha-subunit of Gs, we quantified the extent of dissociation of Gs in a competitive e.l.i.s.a. Incubation of S49-cell plasma membranes with 0.1 microM-isoprenaline, 100 microM free Mg2+ and 100 microM-GTP produced substantial subunit dissociation of Gs, which was reversible by addition of purified beta gamma-subunit dimer or somatostatin. Somatostatin produced an immediate (without a lag) time- and concentration-dependent decrease in the concentration of dissociated Gs (kinhib. for somatostatin = 51 +/- 12 nM) and in the activity of adenylate cyclase (kinhib. = 121 +/- 20 nM). By contrast, after addition of a 10-fold molar excess of beta gamma-dimer relative to alpha s, there was a 2-3 min lag, after which the beta gamma-dimer re-associated Gs. Isoprenaline-induced dissociation of Gs was accompanied by a release of alpha s from the incubated membranes to a post-100,000 g supernatant, and somatostatin could reverse this release. Immunoblot analysis with both a C-terminal anti-peptide antibody and an antibody directed against a sequence near the N-terminal also showed release of alpha s by the beta-agonist and reversal by somatostatin. Membrane release of Gs by isoprenaline that could be blocked by somatostatin was also confirmed in reconstitution studies of supernatant fraction into cyc- S49-cell membranes. We conclude that in native cell membranes somatostatin-induced activation of Gi dissociates Gi and interferes with the Gs activation cycle by providing beta gamma-dimer, which acts to prevent or reverse formation of monomeric alpha s. Because alpha s can be released from the cell membrane, regulation of the local concentration of GTP-liganded dissociated alpha s is likely to be an important factor in modulating the activity of adenylate cyclase.


PEDF Prevents Mitochondrial Function Decay and ER Stress Induced by Rotenone in Aging RPE Cells.
Neurodegenerative diseases, including age-related macular degeneration (AMD), may be linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress. We examined whether Pigment epithelium-derived factor (PEDF) could prevent changes in the structure and function of these organelles by accelerating by rotenone (ROT), a mitochondrial inhibitor, in human retinal pigment epithelium (RPE) cells of chronological age. RPE cells from 9-20, 50-55, 60-70, and >70-year-old donors were isolated, grown as primary cultures, harvested, and treated with ROT and PEDF for electron microscope (EM), western blot analysis, and polymerase chain reaction (PCR). Reactive oxygen species (ROS) and cytoplasmic calcium [Ca2+]c and mitochondrial calcium [Ca2+]m levels were measured by flow cytometry using 2',7'-dichlorodihydrofluorescin diacetate (H2-DCF-DA), fluo-3/AM, and Rhod-2/AM, and ATP levels were measured using a luciferin/luciferase-based assay. Mitochondrial membrane potential (ΔΨm) was detected using 5,5',6,6'-tetrachloro1,1',3,3'-tetraethylbenzimid azolocarbocyanine iodide (JC-1), and susceptibility of the cells to ROT toxicity and PEDF-protective effect was determined by propidium iodide (PI) staining and lactate dehydrogenase (LDH) assay. The expression of ER stress-related genes was detected using real-time (RT)-PCR. We observed decay in the mitochondria of aged RPE cells, including matrix abnormalities, elongation, loss of cristae, and disruption of membrane integrity after ROT treatment. We also observed lower [Ca2+]c, higher ROS and [Ca2+]m levels, decreased ΔΨm after ROT treatment, and greater susceptibility to ROT toxicity in aged RPE cells. PEDF can protect the cristae and integrity of the mitochondrial membrane, increase ATP levels and ΔΨm, and lower ROS, [Ca2+]c, and [Ca2+]m in aged RPE cells induced by ROT. In addition, there was an increase in RDH expression in RPE cells with increasing age after PEDF treatment. Similarly, PEDF decreased the expression of ROT-induced ER stress-related genes. Our study provides evidence that PEDF can reduce bioenergetic deficiencies, mitochondrial decay, and ER stress in aging RPE, a condition that may trigger the onset of retinal diseases such as AMD.


The ototoxic effects of ethacrynic acid in man and animals.
A review of the literature was carried out to summarize the ototoxic effects of ethacrynic acid on man and animal. The effects of this drug on the electrolytes of the endolymphatic and perilymphatic systems, on the cochlear potentials and the auditory cortical-evoked responses, were reviewed. Histological animal studies determined by light and electron microscopy were described. Potentiation of this drug with previous aminoglycoside therapy was discussed. In this paper, a human case report with temporal bone findings was present in addition to the histopathological effects of this drug which were shown in a series of animals receiving this drug over a period of time. Edematous and cellular changes in the stria vascularis, especially with animals receiving large doses of the drug, were described. No permanent alterations in the cochlear potentials resulted from the long-term therapy with ethacrynic acid.


The Southeastern Minnesota Beacon Project for Community-driven Health Information Technology: Origins, Achievements, and Legacy.
The Southeastern (SE) Minnesota Beacon organized all the health care providers, county public health organizations, and school districts in the deployment and integration of health information exchange (HIE) and targeted health communication around childhood asthma and diabetes. The community cooperated to establish a clinical data repository for all residents in the 11-county region. Through this community of practice approach that involved traditional and nontraditional providers, the SE Minnesota Beacon was able to realize unique applications of this technology. This manuscript overviews the associated organization and infrastructure of this community collaboration. The Office of the National Coordinator for Health Information Technology (ONC), as part of the American Recovery and Reinvestment Act of 2009 (ARRA) stimulus, established 17 projects throughout the United States targeting the introduction and meaningful use of health information technology (HIT). These 17 communities were intended to serve as an example of what could be accomplished. The SE Minnesota Beacon is one of these communities. The community ultimately opted for peer-to-peer HIE, using Nationwide Health Information Network (NwHIN) Connect software. The clinical data repository was established using the infrastructure developed by the Regenstrief Institute, which operated as a trusted third party. As an extension to HIE, the consortium of county public health departments created a patient data portal for use by school nurses and parents. Childhood asthma was addressed by creating, exchanging, and maintaining an "asthma action plan" for each affected child, shared throughout the community, including through the patient portal. Diabetes management introduced patient treatment decision tools and patient quality of life measures, facilitating care. Influenza vaccination was enhanced by large-scale community reporting in partnership with the state vaccination registry. The methodology and principles for arriving at these solutions included community engagement, sustainability, scalability, standards, and best practices that fit a variety of organizations-from large, robust providers to small organizations. The SE Minnesota Beacon demonstrated that all providers for a geographically defined population can cooperate in the development and shared governance of a low-cost, sustainable HIE, and the operation of a community-managed clinical data repository. Furthermore, these infrastructures can be leveraged to collaboratively improve the care of patients, as demonstrated for childhood asthma and adult diabetes mellitus. The shared governance of HIT by a community can palpably change the scope and success of collaborations targeted to improve patient and community health care.


Geometric properties of graph layouts optimized for greedy navigation.
The graph layouts used for complex network studies have been mainly developed to improve visualization. If we interpret the layouts in metric spaces such as Euclidean ones, however, the embedded spatial information can be a valuable cue for various purposes. In this work, we focus on encoding useful navigational information to geometric coordinates of vertices of spatial graphs, which is a reverse problem of harnessing geometric information for better navigation. In other words, the coordinates of the vertices are a map of the topology, not the other way around. We use a recently developed user-centric navigation protocol to explore spatial layouts of complex networks that are optimal for navigation. These layouts are generated with a simple simulated annealing optimization technique. We compare these layouts to others targeted at better visualization and discuss the spatial statistical properties of the optimized layouts for better navigability and its implication.


Influence of environmental stress on enumeration of indicator bacteria from natural waters.
The problems associated with recovery of pure cultures of Escherichia coli and Streptococcus faecalis from stream environments were examined utilizing membrane filter chambers. It was observed that upon exposure to the aquatic environment a significant proportion of cells lost their ability to produce colonies on a selective medium, yet retained this capability on a nutritionally rich, nonselective medium. Discrepancies in colony-forming units between nonselective and selective media indicated that a substantial portion of bacterial cells may become physiologically injured due to the environmental stress imposed by the aquatic environment. The extent of injury was observed to vary considerably among the eight different stream environments, since the amount of injury was not uniform for all types of water environments examined. It was observed that the injury acquired by a population of E. coli, during exposure to the aquatic environment, could be rapidly repaired in a nutritionally rich, nonselective medium. As the injured population of cells was exposed to the rich, nonselective broth, increasing proportions of cells were able to repair themselves such that they became insensitive to inhibitory agents in selective media.


[Paralayrinthine cholesteatoma and tympanoplasty (author's transl)].
Closed tympanoplasty techniques greatly increase the risk of recurrent cholesteatoma. This is obvious as many surgeons using these methods insist on a necessary obligatory control operation as a "second look". In this paper cholesteatomata are classified according to their tendency to extend within the petrous pyramid and the subsequent danger of invading semicircular canals, cochlea or cranial fossae. The predisposition to this type of growth is present in the well defined "medial" type of epitympanic cholesteatoma, and more in the anteriorly than the posteriorly placed ones. As infection becomes less prominent in countries with advanced medical services, especially otology, the cholesteatoma hidden behind a small dry epitympanic perforation and those even with no perforation termed "hidden primary cholesteatoma" become more frequent. They cause their own special symptomatology, not infrequently a slowly progressive facial palsy. Every cholesteatoma requires mandatory prophylactic surgery. This means the complete exposure of the danger area, the epitympanum, and nowadays the possibility of the syncronous complete reconstruction of a normal middle ear and external canal, i.e. osteoplastic epitympanotomy.


Aggregating and Predicting Sequence Labels from Crowd Annotations.
Despite sequences being core to NLP, scant work has considered how to handle noisy sequence labels from multiple annotators for the same text. Given such annotations, we consider two complementary tasks: (1) aggregating sequential crowd labels to infer a best single set of consensus annotations; and (2) using crowd annotations as training data for a model that can predict sequences in unannotated text. For aggregation, we propose a novel Hidden Markov Model variant. To predict sequences in unannotated text, we propose a neural approach using Long Short Term Memory. We evaluate a suite of methods across two different applications and text genres: Named-Entity Recognition in news articles and Information Extraction from biomedical abstracts. Results show improvement over strong baselines. Our source code and data are available online.


A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome.
Reduced levels of brain-derived neurotrophic factor (BDNF) are thought to contribute to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 mutant mice, BDNF deficits have been associated with breathing abnormalities, a core feature of RTT, as well as with synaptic hyperexcitability within the brainstem respiratory network. Application of BDNF can reverse hyperexcitability in acute brainstem slices from Mecp2-null mice, suggesting that therapies targeting BDNF or its receptor, TrkB, could be effective at acute reversal of respiratory abnormalities in RTT. Therefore, we examined the ability of LM22A-4, a small-molecule BDNF loop-domain mimetic and TrkB partial agonist, to modulate synaptic excitability within respiratory cell groups in the brainstem nucleus tractus solitarius (nTS) and to acutely reverse abnormalities in breathing at rest and during behavioral arousal in Mecp2 mutants. Patch-clamp recordings in Mecp2-null brainstem slices demonstrated that LM22A-4 decreases excitability at primary afferent synapses in the nTS by reducing the amplitude of evoked excitatory postsynaptic currents and the frequency of spontaneous and miniature excitatory postsynaptic currents. In vivo, acute treatment of Mecp2-null and -heterozygous mutants with LM22A-4 completely eliminated spontaneous apneas in resting animals, without sedation. Moreover, we demonstrate that respiratory dysregulation during behavioral arousal, a feature of human RTT, is also reversed in Mecp2 mutants by acute treatment with LM22A-4. Together, these data support the hypothesis that reduced BDNF signaling and respiratory dysfunction in RTT are linked, and establish the proof-of-concept that treatment with a small-molecule structural mimetic of a BDNF loop domain and a TrkB partial agonist can acutely reverse abnormal breathing at rest and in response to behavioral arousal in symptomatic RTT mice.


Two proteins with reverse transcriptase activities associated with hepatitis B virus-like particles.
Recent studies suggest that hepatitis B virus (HBV), despite being a DNA virus, replicates via an RNA intermediate (R. H. Miller, P. L. Marion, and S. W. Robinson, Virology 139:64-72, 1984; J. Summers and W. S. Mason, Cell 29:403-415, 1982). The HBV life cycle is therefore a permuted version of the RNA retroviral life cycle. Sequence homology between retroviral reverse transcriptase and the putative HBV polymerase gene product suggests the presence of an HBV reverse transcriptase (H. Toh, H. Hajashida, and T. Miyata, Nature (London) 305:827-829, 1983). As yet, there has been no direct evidence that reverse transcriptase activity is present in the viral particle. We used activity gel analysis to detect the in situ catalytic activities of DNA polymerases after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Our studies demonstrated that HBV-like particles secreted by a differentiated human hepatoma cell line transfected with genomic HBV DNA contain two major polymerase activities which migrate as approximately 90- and approximately 70-kilodalton (kDa) proteins. This demonstrated, for the first time, that HBV-like particles contain a novel DNA polymerase-reverse transcriptase activity. Furthermore, we propose that the 70-kDa reverse transcriptase may be produced by proteolytic self-cleavage of the 90-kDa precursor protein.


[Five-year results of IMRT for prostate cancer - toxicity].
Intensity modulated radiotherapy (IMRT) plays a crucial role in the treatment of prostate cancer thanks to its capacity for healthy tissue sparing. This work reports on the acute and late toxicity rates among 233 patients treated with high-dose IMRT. From June 2003 to December 2007, 233 men with clinically localized prostate cancer underwent radical radiotherapy. One hundred sixty patients were treated with IMRT to the prostate and the base of seminal vesicles to 78 Gy in 39 fractions, 73 patients underwent simultaneous integrated boost. Prescribed doses were 82 Gy and 73,8 Gy in 41 fractions to the prostate and seminal vesicles, respectively. Late toxicity was evaluated prospectively using a RTOG/FC-LENT score. Thirty patients (12.8%) experienced acute Grade 2 gastrointestinal (GI) toxicity. No acute Grade 3 or 4 GI toxicity developed. Forty two patients (18.1%) experienced acute Grade 2 genitourinary toxicity and 23 patients (9.9%) had Grade 3 GU toxicity. Grade 4 Genitourinary toxicity was observed in nine (3.8%) patients, due to a need of short-term urinary catheterization. With a median follow-up of 49.2 months, the estimated 5-year cumulative incidence of Grade 2 gastrointestinal toxicity was 22.4%. The estimated 5-year cumulative incidence of Grade 2 genitourinary toxicity was 17.7%. Intensity modulated radiotherapy enables dose escalation to 78-82 Gy with an acceptable toxicity.


Quadriceps strength in women with radiographically progressive osteoarthritis of the knee and those with stable radiographic changes.
To explore the relationship between lower extremity weakness and the progression of established radiographic changes of knee osteoarthritis (OA). The study cohort of 342 elderly subjects was recruited from central Indiana by random digit dialing. We analyzed 79 subjects who had definite radiographic changes of unilateral or bilateral knee OA at baseline and for whom baseline data for lower extremity muscle strength and lean tissue mass and baseline and followup assessments of knee pain were available. Radiographs were graded for severity of OA at baseline and again about 2.5 years later (mean 31.5 months). Knee pain was evaluated at the same examination. Strength of the knee flexors and extensors was assessed bilaterally at baseline by isokinetic dynamometry and lower extremity muscle mass by dual energy x-ray absorptiometry. Mean peak knee extensor strength of women with progressive OA, before and after adjustment for lower extremity muscle mass, was about 9% lower than that in those with stable radiographic changes, but this difference was not statistically significant. No difference was apparent between the 2 groups with respect to knee flexor (hamstring) strength. The decrease in quadriceps strength among women with progressive OA, relative to those with stable OA, did not appear to be attributable to knee pain, and knee extensor strength at baseline bore no apparent relationship to the development or progression of knee pain among those with OA. We have shown previously that quadriceps weakness may be of etiologic importance in development of knee OA. The absence of a significant difference in quadriceps strength between subjects with radiographically stable OA and those whose joint damage progressed suggests that factors other than quadriceps weakness are more important determinants of OA progression.


Modified and complete neck dissection in the treatment of squamous cell carcinoma of the head and neck.
The relative merits and indications for complete or modified dissection of the neck are straightforward. Which operation is selected centers on the perception of the value of the preservation or the risk with the loss of one or more of three structures: the spinal accessory nerve, the internal jugular vein and the sternocleidomastoid muscle. If these were the only issues, the choice of operation would be easy. Unfortunately, some of the most contentious issues in treatment of metastasis to the neck have been linked with the concept of the modified neck dissection. Such issues as combined multimodality therapy, preoperative and postoperative radiation therapy or surgical treatment alone, prophylactic dissection and bilateral simultaneous dissection of the neck are rightly or wrongly tied in with the type of dissection of the neck. More information, such as the certainty of the real risk factors in the neck with metastatic disease, the real value, if any, of adjunctive combined therapy and basic information about the role of the nodes in the neck, is necessary before the debate on the modified versus the radical dissection of the neck will end.


Omeprazole and visual disorders: seeing alternatives.
In the WHO data base, visual disorders reported spontaneously with omeprazole, ranitidine and cimetidine, are very rare in the context of the widespread use of these drugs. There is a maximum reporting rate of severe visual impairment possibly ascribed to i.v. omeprazole of 0.94 reports per million treatment days in one year and in one country, Germany. This gives the worst quantitative case scenario for omeprazole by a single route of administration, to be compared with the worldwide reporting rate of all severe visual disorders by all routes of administration--0.008 reports per million treatment days. Moreover, the reported visual abnormalities have a varied pathophysiological aetiology and their number increased in Germany after the first signal was raised in that country. Thus, apart from a direct causal relationship, solicited reporting artifact is one alternate plausible explanation for the apparent excess of cases of visual disturbance to omeprazole compared with cimetidine and ranitidine. That reporting rates of clinical events on newly marketed drugs are generally higher than with older drugs is a second factor for higher reporting rates with omeprazole. Vasculitis has been suggested as an aetiological factor, but the even lower reporting rate of this reaction makes this an unlikely hypothesis without any other supporting evidence. The authors are unaware of any drug that has caused a vasculities solely affecting the eye. Information on the prevalence of relevant visual disorders in the community would have been of considerable help in interpreting this signal, and a case control study of visual events in relationship to severe illness would be of public health interest, since no data seems to exist concerning this.


Acetabular Labral Base Repair Versus Circumferential Suture Repair: A Matched-Paired Comparison of Clinical Outcomes.
To determine whether an acetabular labral repair technique would be superior to another repair technique based on clinical outcomes measured by patient-reported outcome (PRO) scores. We identified 465 patients who underwent labral base repair or circumferential suture repair from February 2008 to February 2012. The type of repair performed was based on labral size and tear type. The 2 groups were pair matched for age within 5 years, sex, crossover sign within 15%, coxa profunda, Workers' Compensation status, and microfracture (femur, acetabulum, or none). Data were prospectively collected and retrospectively reviewed. PROs included a visual analog scale score and the modified Harris Hip Score, Non-Arthritic Hip Score, Hip Outcome Score-Activities of Daily Living, and Hip Outcome Score-Sports-Specific Subscale. One hundred ten patients met the inclusion criteria for labral base repair and were pair matched on a 1:1 basis with 110 patients who underwent circumferential suture repair. The mean follow-up period was 30 months for both groups, with a range of 19.2 to 60 months for the labral base repair group and 19.2 to 67 months for the circumferential suture repair group. Radiographic data were similar between groups with respect to the lateral center-edge angle (P = .906), acetabular inclination (P = .329), anterior center-edge angle (P = .208), alpha angle (P = .387), and joint space width (P = .388). All preoperative PRO scores were statistically similar. Both groups showed significant improvements in all PROs. There were no statistical differences in postoperative PRO scores at latest follow-up (modified Harris Hip Score, P = .215; Hip Outcome Score-Activities of Daily Living, P = .839; Hip Outcome Score-Sports-Specific Subscale, P = .561; Non-Arthritic Hip Score, P = .333; visual analog scale score, P = .373; and satisfaction, P = .483). There were similar rates of revision (n = 10 for both groups) and conversion to arthroplasty (n = 2 for both groups). On the basis of PRO scores at 2 years' follow-up, there is no difference in outcomes based on the type of labral repair performed. Level III, retrospective comparative study.


The influence of psychological flexibility on work redesign: mediated moderation of a work reorganization intervention.
This quasi-experiment tested the extent to which an individual characteristic, psychological flexibility, moderated the effects of a control-enhancing work reorganization intervention in a call center. Results indicated that, compared with a control group, this intervention produced improvements in mental health and absence rates, particularly for individuals with higher levels of psychological flexibility. Findings also showed that these moderated intervention effects were mediated by job control. Specifically, the intervention enhanced perceptions of job control, and hence its outcomes, for the people who received it, especially for those who had greater psychological flexibility. Discussion highlights the benefits of understanding the processes (e.g., mediators, moderators, and mediated moderators) involved in work reorganization interventions.


[Sleep and wakefulness regulation: molecular players].
By combining brain section/lesion studies and sleep analysis, neurophysiologists have identified the brain areas responsible for regulating sleep and wakefulness during the first half of the 20th century. Identification of the phenotypic nature of the neurons underlying the regulation of vigilance, as well as their anatomical and functional connections led to a theoretical model based on mutual inhibitory interactions between sleep-on neurons (namely GABAergic neurons of the hypothalamic preoptic region) and wake-on neurons (mainly monoaminergic and cholinergic neurons). In addition to the corresponding neurotransmitters (serotonin, acetylcholine and GABA), other neuroactive molecules that play key roles in sleep and wakefulness regulation have recently been discovered, leading to an updated model. Hypocretin, also known as orexin, is a key neuropeptide involved in the sleep disorder narcolepsy. Extensive characterization of the respective roles of these neurotransmitters has led to the identification of novel therapeutic targets for the treatment of sleep disorders. For example, blockade of hypocretin receptors has hypnotic effects.


Human pluripotent stem-cell-derived alveolar organoids for modeling pulmonary fibrosis and drug testing.
Detailed understanding of the pathogenesis and development of effective therapies for pulmonary fibrosis (PF) have been hampered by lack of in vitro human models that recapitulate disease pathophysiology. In this study, we generated alveolar organoids (AOs) derived from human pluripotent stem cells (hPSCs) for use as an PF model and for drug efficacy evaluation. Stepwise direct differentiation of hPSCs into alveolar epithelial cells by mimicking developmental cues in a temporally controlled manner was used to generate multicellular AOs. Derived AOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells and mesenchymal cells. Treatment with transforming growth factor (TGF-β1) induced fibrotic changes in AOs, offering a PF model for therapeutic evaluation of a structurally truncated form (NP-011) of milk fat globule-EGF factor 8 (MFG-E8) protein. The significant fibrogenic responses and collagen accumulation that were induced by treatment with TGF-β1 in these AOs were effectively ameliorated by treatment with NP-011 via suppression of extracellular signal-regulated kinase (ERK) signaling. Furthermore, administration of NP-011 reversed bleomycin-induced lung fibrosis in mice also via ERK signaling suppression and collagen reduction. This anti-fibrotic effect mirrored that following Pirfenidone and Nintedanib administration. Furthermore, NP-011 interacted with macrophages, which accelerated the collagen uptake for eliminating accumulated collagen in fibrotic lung tissues. This study provides a robust in vitro human organoid system for modeling PF and assessing anti-fibrotic mechanisms of potential drugs and suggests that modified MGF-E8 protein has therapeutic potential for treating PF.


[Gastrointestinal parasitism in the common partridge (Nothoprocta perdicaria) in the Nuble Zone, Chile].
A study on gastrointestinal parasitism in wild chilean partridges (Nothoprocta perdicaria) in the Nuble province (Chile) determined that 75% of birds were infected. The species Capillaria caudinflata, Subulura suctoria, Aploparaksis tinamoui and oocysts of Eimeria sp. were observed.


The changing cultures of health and education.
Many public sector managers are facing fundamental organizational changes, as government macro reforms in health and education reach down to the managers' agenda. Cultural changes and a new set of values are demanding new management approaches and skills as managers seek to embrace an alternative organizational environment. Seeks to draw out some practical lessons and examples where successful managers in hospitals and colleges have embraced the positive aspects of change, while still preserving those aspects and values of the public sector which have provided for stability and integrity in organizations. Sets out a balance sheet for change, considering the detailed operational issues likely to arise in implementing such changes and suggests that a sensitive and pragmatic view, focusing on process and people, as well as outcome, is likely to remain a crucial skill for effective management.