Ovarian function and childbearing issues in breast cancer survivors.
The increasing number of breast cancer survivors makes the issues of ovarian dysfunction and childbearing ability more and more relevant for the quality of life of these patients. The incidence of ovarian dysfunction is related to patient age, the specific agents used and the total dose administered, especially the dose of alkylating agents such as cyclophosphamide. Amenorrhea rates following combination chemotherapy consisting of cyclophosphamide + methotrexate + 5-flurouracil (CMF regimen) range from 21 to 71% in women aged 40 years and younger, and from 40 to 100% in older ones. In most series anthracycline-based adjuvant chemotherapy regimens appear to have a lower incidence of amenorrhea, which is probably due to the lower cumulative cyclophosphamide dose administered compared with that given in the CMF regimen. Few data are currently available regarding ovarian function in women treated with taxane-based chemotherapy. In a recent retrospective study on 191 patients, the amenorrhea rate was 64% for women who received doxorubicin + cyclophosphamide (AC regimen) followed by a taxane, compared with 55% (p = 0.05) for those treated with AC alone. Forty percent of women aged 40 years or younger resumed menstruation, whereas the amenorrhea was more likely to be irreversible in older women; however, the addition of a taxane did not change the reversibility rate. Ovarian reserve can be tested with serum assays of follicle-stimulating hormone, inhibin B, estradiol and anti-Müllerian hormone, as well as by ultrasound assessment of antral follicle count. A review of literature data failed to show that a subsequent pregnancy increases the risk of recurrence and death in breast cancer survivors, and some series have even detected longer survival for patients who get pregnant after breast cancer treatment. This apparent survival benefit, probably due to a selection bias called the 'healthy mother effect', suggests that breast cancer survivors who subsequently conceive are a self-selecting group of women with better prognosis. The little available information appears to show no increase in the incidence of prematurity, stillbirth or congenital malformations in their babies. In conclusion, future pregnancy is a viable option for a woman treated for early-stage breast cancer and does not appear to be detrimental to either the mother or her offspring.


Hip fracture outcome: is there a "July effect"?
We assessed the differential complications and mortality rates of teaching versus nonteaching hospitals in July against other month-to-month differences in a cohort of 324,988 elderly patients hospitalized for a femoral neck or intertrochanteric fracture (data taken from the 1998-2003 National Inpatient Sample). Demographics were similar between teaching and nonteaching hospitals and across admission months. The overall mortality rate was 3.64% and was slightly higher in teaching hospitals compared with nonteaching hospitals (3.69% vs. 3.61%, relative risk [RR] = 1.0062, 95% CI 0.99-1.02). The adjusted relative risk (RR) for mortality in July/August was significantly higher than the overall adjusted RR and compared with all other month pairs, indicating higher in-hospital mortality rates in teaching hospitals compared with nonteaching hospitals. Intraoperative complications and length of stay were statistically significantly greater in teaching hospitals but did not demonstrate a "July effect." Teaching hospitals had lower perioperative complication rates. Elderly hip fracture patients treated at teaching hospitals had 12% greater relative risk of mortality in July/August (ie, experience a "July effect") compared with nonteaching hospitals during that time period (1998-2003). Although various methods exist for exploring the "July effect," it is critical to take into account inherent month-to-month variation in outcomes and to use nonteaching hospitals as a control group.


Diluted sodium hypochlorite (bleach) in dogs: antiseptic efficacy, local tolerability and in vitro effect on skin barrier function and inflammation.
Diluted sodium hypochlorite represents an inexpensive and widely available topical antiseptic, but there are no tolerability and efficacy data in veterinary dermatology. To determine the in vivo antibacterial effect and tolerability of topical diluted bleach application and to assess its in vitro effect on skin barrier lipids and anti-inflammatory properties on keratinocytes. Topical hypochlorite at 0.05% and tap water were applied to both sides of the thorax of four healthy dogs. The anti-inflammatory effect on canine keratinocytes was determined by real-time polymerase chain reaction; skin barrier integrity was assessed by evaluating stratum corneum lipid changes in canine stratified epidermal constructs. The cell viability of primary keratinocytes treated with water and diluted hypochlorite at 0.005 and 0.01%, reduced the percentage of viable cells by 10%. The exposure of primary keratinocytes to 0.005% diluted hypochlorite significantly reduced the induction of inflammatory genes chemokine ligand-2 (CCL2; P = 0.015) and thymus and activation-regulated chemokine (TARC/CCL17, P = 0.032). There were no changes in skin lipid ceramide and nonceramide fractions in stratified epidermal constructs cultured for 17 days with 0.05% hypochlorite. Topical hypochlorite at 0.05% and tap water were well-tolerated without signs of skin irritation. Although a marked reduction in bacterial counts was seen within 20 min of diluted bleach application compared to the tap water control, this was only marginally significant (P = 0.06). The results indicate that a topical diluted bleach solution, at either 0.05 or 0.005% hypochlorite concentrations, is a well-tolerated antiseptic that also exhibits anti-inflammatory properties.


Resolutions of the Coulomb operator. Part III. Reduced-rank Schrödinger equations.
We consider a modified Schrödinger equation wherein the electron-electron repulsion terms r(ij)(-1) are approximated by truncated one-particle resolutions. Numerical results for the He atom and H2 molecule at the Hartree-Fock, second-order Møller-Plesset, and configuration interaction levels show that the solutions of the resulting reduced-rank Schrödinger equations converge rapidly, and that even low-rank approximations can yield energies with chemical accuracy.


The costs and benefits of temporal predictability: impaired inhibition of prepotent responses accompanies increased activation of task-relevant responses.
While the benefit of temporal predictability on sensorimotor processing is well established, it is still unknown whether this is due to efficient execution of an appropriate response and/or inhibition of an inappropriate one. To answer this question, we examined the effects of temporal predictability in tasks that required selective (Simon task) or global (Stop-signal task) inhibitory control of prepotent responses. We manipulated temporal expectation by presenting cues that either predicted (temporal cues) or not (neutral cues) when the target would appear. In the Simon task, performance was better when target location (left/right) was compatible with the hand of response and performance was improved further still if targets were temporally cued. However, Conditional Accuracy Functions revealed that temporal predictability selectively increased the number of fast, impulsive errors. Temporal cueing had no effect on selective response inhibition, as measured by the dynamics of the interference effect (delta plots) in the Simon task. By contrast, in the Stop-signal task, Stop-signal reaction time, a covert measure of a more global form of response inhibition, was significantly longer in temporally predictive trials. Therefore, when the time of target onset could be predicted in advance, it was harder to stop the impulse to respond to the target. Collectively, our results indicate that temporal cueing compounded the interfering effects of a prepotent response on task performance. We suggest that although temporal predictability enhances activation of task-relevant responses, it impairs inhibition of prepotent responses.


Total Synthesis and Structural Revision of Monocillin VII.
The first asymmetric total synthesis of macrolactone monocillin VII and its C-10' epimer was achieved starting from a known chiral pure epoxide in 16 longest linear sequences. The present synthesis highlights the macrolactone formation involving an alkyne-dicobalt carbonyl complex under De Brabander's conditions followed by an unexpected regioselective hydration. The asymmetric total synthesis resulted in the revision of the configuration at C10' and reassignment of the absolute configuration of the natural product.


Issues in Developing a Surveillance Case Definition for Nonfatal Suicide Attempt and Intentional Self-harm Using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) Coded Data.
Suicide and intentional self-harm are among the leading causes of death in the United States. To study this public health issue, epidemiologists and researchers often analyze data coded using the International Classification of Diseases (ICD). Prior to October 1, 2015, health care organizations and providers used the clinical modification of the Ninth Revision of ICD (ICD-9-CM) to report medical information in electronic claims data. The transition in October 2015 to use of the clinical modification of the Tenth Revision of ICD (ICD-10-CM) resulted in the need to update methods and selection criteria previously developed for ICD-9-CM coded data. This report provides guidance on the use of ICD-10-CM codes to identify cases of nonfatal suicide attempts and intentional self-harm in ICD-10-CM coded data sets. ICD-10-CM codes for nonfatal suicide attempts and intentional self-harm include: X71-X83, intentional self-harm due to drowning and submersion, firearms, explosive or thermal material, sharp or blunt objects, jumping from a high place, jumping or lying in front of a moving object, crashing of motor vehicle, and other specified means; T36-T50 with a 6th character of 2 (except for T36.9, T37.9, T39.9, T41.4, T42.7, T43.9, T45.9, T47.9, and T49.9, which are included if the 5th character is 2), intentional self-harm due to drug poisoning (overdose); T51-T65 with a 6th character of 2 (except for T51.9, T52.9, T53.9, T54.9, T56.9, T57.9, T58.0, T58.1, T58.9, T59.9, T60.9, T61.0, T61.1, T61.9, T62.9, T63.9, T64.0, T64.8, and T65.9, which are included if the 5th character is 2), intentional self-harm due to toxic effects of nonmedicinal substances; T71 with a 6th character of 2, intentional self-harm due to asphyxiation, suffocation, strangulation; and T14.91, Suicide attempt. Issues to consider when selecting records for nonfatal suicide attempts and intentional self-harm from ICD-10-CM coded administrative data sets are also discussed.


[Antiphospholipid antibodies in children with idiopathic thrombocytopenic purpura].
Three antiphospholipid antibodies (aPLs), namely, antiphosphatidylinositol antibody (antiinositol antibody), antiphosphatidylserine antibody (antiserine antibody), and anticardiolipin. beta 2-glycoprotein I complex antibody (antiCL. beta 2-GPI antibody), were determined in 49 children with idiopathic thrombocytopenic purpura (ITP) consisting of 14 newly-diagnosed cases and 35 chronic cases. Determination of aPL was performed twice in the newly-diagnosed patients, once each during the acute and convalescent phases, and once in the chronic patients. The positive rates in the acute and convalescent phases of the newly-diagnosed group and in the chronic group were, respectively, 14.3%, 28.6%, and 18.8% for the antiinositol antibody, 14.3%, 14.3%, and 15.6% for the antiserine antibody, and 21.4%, 28.6%, and 25.0% for either of these 2 antibodies. Thus, antiinositol and antiserine aPLs were present at high incidences; however, all patients were negative for the antiCL. beta 2-GPI antibody. No correlation was noted between either the antiinositol or the antiserine antibody and peripheral platelet count, anti-GP IIb/IIIa antibody or PAIgG. Thus, although some aPLs are present in both acute and chronic pediatric ITP, the aPLs seems to be of an infectious disease type. No results that suggest possible involvement of aPLs in ITP pathology were obtained.


Large magnetodielectric response of PST/LSMO/LCMO film over a wide temperature range.
Pb0.6Sr0.4TiO3/La0.7Sr0.3MnO3/La0.7Ca0.3MnO3 (PST/LSMO/LCMO) film is grown on Si substrate by chemical solution deposition method. The film crystallizes perfectly into perovskite phases with a random crystalline orientation. The La0.7Sr0.3MnO3/La0.7Ca0.3MnO3/Si layer exhibits low resistivity and obvious negative magnetoresistivity (MR); the PST/LSMO/LCMO film shows notable magnetocapacitance (MC) above 350 K, from 102.9% to 29.5%. Near room temperature, there is no distinguished magnetoelectric coupling; the MC is 34.3% @ 250 K, 29.5% @ 300 K and 32.8% @ 350 K respectively. The mechanism can be explained in light of the Maxwell-Wagner (MW) model and the enhanced MR origin from the successive mixed manganite phases and spin dependent tunneling across the junctions of PST/LSMO/LCMO. This work provides a new approach for designing and developing novel composites with promising MC.


Additional Progress in the Development and Application of a Direct, Rapid Immunohistochemical Test for Rabies Diagnosis.
Laboratory-based surveillance is fundamental to effective rabies prevention and control. The direct fluorescent antibody (AB) test (FAT) is the gold standard for rabies diagnosis. Recently, additional tests besides the FAT have been developed, such as the direct rapid immunohistochemical test (DRIT). In this study, our objective was to further refine technical aspects of the DRIT using a combination of two monoclonal ABs (MABs), 502 and 802, conduct additional testing among rabies reference laboratories using a diversity of animal species and rabies virus (RV) variants and compare the potential utility of the DRIT for end users via proficiency testing (PT) against the FAT. Considering the ideal molar ratios of biotin to AB in formulation of the DRIT conjugate, 3.9 was found to be superior to 7.4, for detection of RV antigens in the brain of a naturally infected raccoon. Optimization of the DRIT conjugate may also be dependent upon the apparent choice of specific viral antigens for testing, as a gray fox RV variant reacted less strongly than a raccoon RV variant in determining the working dilution of the MAB cocktail. Using the same MABs and protocol, the DRIT was compared to the FAT using more than 800 samples of mammalian brains, representative of more than 25 taxa, including in excess of 250 animal rabies cases from Europe and North America. Sensitivity was determined at 98% (96⁻100%, 95% CI) and specificity was calculated at 95% (92⁻96%, 95% CI). In a comparison among end users, PT of laboratory personnel resulted in values of 77⁻100% sensitivity and 86-100% specificity. Based upon these and previously reported results, the DRIT appears to be a suitable alternative to the FAT for use in lyssavirus diagnosis.


Sociodemographic and etiological differences of head and neck squamous cell carcinoma in young and old patients in southern Iran.
Head and neck squamous cell carcinoma (HNSCC) is typically seen in middle-aged to elderly men but, recently, is increasing in young adults. The aim of this study was to compare the demographic and etiological data of young and old patients with HNSCC in southern Iran. Patients with HNSCC were divided into 2 groups: the young (<or=40 y old) and the old (>or=50 y old). Both groups showed male predilection. The nasopharynx was the most common site in the young group (68.5%), whereas the oral cavity (40%) was the most common site in the old group. In the young group, 68.4% showed none of the usual risk factors. The results suggest that factors other than tobacco and alcohol may be implicated in the development of HNSCC in young patients in southern Iran.


[Monocrotaline-induced pulmonary hypertension in animals].
Monocrotaline (MCT) is a pyrrolizidine alkaloid extracted from seeds of Crotalaria spectabilis that has been used to induce structural changes in the pulmonary arteries associated with progressive pulmonary hypertension in rodents. Recent studies have demonstrated that several mediators such as elastase, vasoconstrictors (Endotheline-1), vasodilators (Nitric oxide, PGI2) and cytokines (IL-1, MCP-1) play important roles in MCT-induced pulmonary hypertension, and that the changes in pulmonary hemodynamics are required for neointimal formation in pulmonary arteries. We have recently provided the evidence that macrophage migration inhibitory factor (MIF) is also involved in this model. The MCT-induced pulmonary hypertension in animals is useful as an experimental model for understanding the pathophysiology of primary pulmonary hypertension.


[Place and role of laparoscopy in the obstetric-gynecologic division of a municipal hospital].
An analysis was done of 125 diagnostic laparoscopies performed in the Obstetric-Gynaecological Division, Municipal Hospital in Pruszków in the years 1988-1992. Indications to operations were in the first place adnexal pathological processes (including diagnosis of extrauterine pregnancy), infertility diagnosis, lower abdominal pain of unclear origin, primary and secondary amenorrhoea, postmenopausal bleeding. In 92% of cases pathological processes were found in the small pelvis, and in almost 34% this method made the initial diagnosis more precise, and in 38% pathological changes were detected owing to laparoscopy. On the basis of the above material the significant role of laparoscopy was demonstrated in the diagnosis of pathological processes in the small pelvis, especially in adnexa, in the work of municipal hospital division.


Comprehensive Analysis of CRIP1 Expression in Acute Myeloid Leukemia.
Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy that imposes great challenges in terms of drug resistance and relapse. Previous studies revealed heterogeneous leukemia cells and their relevant gene markers, such as CRIP1 as clinically prognostic in t (8;21) AML patients. However, the expression and role of CRIP1 in AML are poorly understood. We used the single-cell RNA sequencing and gene expression data from t (8;21) AML patients to analyze the immune and regulation networks of CRIP1. Two independent cohorts from GSE37642 and The Cancer Genome Atlas (TCGA) datasets were employed as validation cohorts. In addition, the methylation data from TCGA were used to analyze the methylation effect of the CRIP1 expression. Gene expression profile from t (8;21) AML patients showed that the CRIP1-high group exhibited an enrichment of immune-related pathways, including tumor necrosis factor (TNF)α signaling via nuclear factor kappa B (NFκB) pathways. Further studies using CIBERSORT showed that the CRIP1-high group had a significantly higher infiltration of exhausted CD8 T cells and activated mast cells. The CRIP1 expression was validated in the GSE37642-GPL96, GSE37642-GPL570, and TCGA datasets. In addition, with the methylation data, four CpG probes of CRIP1 (cg07065217, cg04411625, cg25682097, and 11763800) were identified as negatively associated with the CRIP1 gene expression in AML patients. Our data provide a comprehensive overview of the regulation of CRIP1 expression in AML patients. The evaluation of the TNFα-NFκB signaling pathway as well as the immune heterogeneity might provide new insights for exploring improvements in AML treatment.


Analysis of Temperature-Programmed Desorption via Equilibrium Thermodynamics.
Temperature-programmed desorption (TPD) experiments in surface science are usually analyzed using the Polanyi-Wigner equation and/or transition-state theory. These methods are far from straightforward, and the determination of the pre-exponential factor is often problematic. We present a different method based on equilibrium thermodynamics, which builds on an approach previously used for TPD by Kreuzer et al. (Surf. Sci. 1988). Equations for the desorption rate are presented for three different types of surface-adsorbate interactions: (i) a 2D ideal hard-sphere gas with a negligible diffusion barrier, (ii) an ideal lattice gas, that is, fixed adsorption sites without interaction between the adsorbates, and (iii) a lattice gas with a distribution of (site-dependent) adsorption energies. We show that the coverage dependence of the sticking coefficient for adsorption at the desorption temperature determines whether the desorption process can be described by first- or second-order kinetics. The sticking coefficient at the desorption temperature must also be known for a quantitative determination of the adsorption energy, but it has a rather weak influence (like the pre-exponential factor in a traditional TPD analysis). Quantitative analysis is also influenced by the vibrational contributions to the energy and entropy. For the case of a single adsorption energy, we provide equations to directly convert peak temperatures into adsorption energies. These equations also provide an approximation of the desorption energy in cases that cannot be described by a fixed pre-exponential factor. For the case of a distribution of adsorption energies, the desorption spectra cannot be considered a superposition of desorption spectra corresponding to the different energies. Nevertheless, we present a method to extract the distribution of adsorption energies from TPD spectra, and we rationalize the energy resolution of TPD experiments. The analytical results are complemented by a program for simulation and analysis of TPD data.


Endothelial cell-specific roles for tetrahydrobiopterin in myocardial function, cardiac hypertrophy, and response to myocardial ischemia-reperfusion injury.
The cofactor tetrahydrobiopterin (BH4) is a critical regulator of nitric oxide synthase (NOS) function and redox signaling, with reduced BH4 implicated in multiple cardiovascular disease states. In the myocardium, augmentation of BH4 levels can impact on cardiomyocyte function, preventing hypertrophy and heart failure. However, the specific role of endothelial cell BH4 biosynthesis in the coronary circulation and its role in cardiac function and the response to ischemia has yet to be elucidated. Endothelial cell-specific Gch1 knockout mice were generated by crossing Gch1fl/fl with Tie2cre mice, generating Gch1fl/flTie2cre mice and littermate controls. GTP cyclohydrolase protein and BH4 levels were reduced in heart tissues from Gch1fl/flTie2cre mice, localized to endothelial cells, with normal cardiomyocyte BH4. Deficiency in coronary endothelial cell BH4 led to NOS uncoupling, decreased NO bioactivity, and increased superoxide and hydrogen peroxide productions in the hearts of Gch1fl/flTie2cre mice. Under physiological conditions, loss of endothelial cell-specific BH4 led to mild cardiac hypertrophy in Gch1fl/flTie2cre hearts. Endothelial cell BH4 loss was also associated with increased neuronal NOS protein, loss of endothelial NOS protein, and increased phospholamban phosphorylation at serine-17 in cardiomyocytes. Loss of cardiac endothelial cell BH4 led to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia-reperfusion injury. Taken together, these studies reveal a specific role for endothelial cell Gch1/BH4 biosynthesis in cardiac function and the response to cardiac ischemia-reperfusion injury. Targeting endothelial cell Gch1 and BH4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction and ischemia-reperfusion injury.NEW & NOTEWORTHY We demonstrate a critical role for endothelial cell Gch1/BH4 biosynthesis in coronary vascular function and cardiac function. Loss of cardiac endothelial cell BH4 leads to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia/reperfusion injury. Targeting endothelial cell Gch1 and BH4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction, ischemia injury, and heart failure.


Vascular and Neural Complications in Type 2 Diabetic Rats: Improvement by Sacubitril/Valsartan Greater Than Valsartan Alone.
Previously, we had shown that a vasopeptidase inhibitor drug containing ACE and neprilysin inhibitors was an effective treatment for diabetic vascular and neural complications. However, side effects prevented further development. This led to the development of sacubitril/valsartan, a drug containing angiotensin II receptor blocker and neprilysin inhibitor that we hypothesized would be an effective treatment for diabetic peripheral neuropathy. Using early and late intervention protocols (4 and 12 weeks posthyperglycemia, respectively), type 2 diabetic rats were treated with valsartan or sacubitril/valsartan for 12 weeks followed by an extensive evaluation of vascular and neural end points. The results demonstrated efficacy of sacubitril/valsartan in improving vascular and neural function was superior to valsartan alone. In the early intervention protocol, sacubitril/valsartan treatment was found to slow progression of these deficits and, with late intervention treatment, was found to stimulate restoration of vascular reactivity, motor and sensory nerve conduction velocities, and sensitivity/regeneration of sensory nerves of the skin and cornea in a rat model of type 2 diabetes. These preclinical studies suggest that sacubitril/valsartan may be an effective treatment for diabetic peripheral neuropathy, but additional studies will be needed to investigate these effects further.


Clinical factors and high-resolution manometry predicting response to surgery for achalasia in children.
Esophageal achalasia is an uncommon condition in children. Although many interventions exist for the management of this disorder, esophageal (Heller) myotomy offers one of the most durable treatments. Our institution sought to review patients undergoing Heller myotomy concentrating on preoperative clinical factors that might predict postoperative outcomes. All patients from January 1, 2007, to December 31, 2016, who underwent surgical treatment for achalasia at our tertiary pediatric hospital were identified and included in the study cohort. Electronic medical records for these patients were reviewed for clinical presentation variables, nonsurgical preoperative treatment, surgical approach, clinical response to surgery, need for postoperative treatment for ongoing symptoms, and high-resolution manometry (HRM) data. Twenty-six patients were included in the study, and all underwent myotomy with partial fundoplication (median age: 14.4 y [interquartile range 11.6-15.5]). At a median follow-up of 9.75 mo (interquartile range 3.5-21 mo), 16 (61.5%) patients reported good resolution of their dysphagia symptoms with surgery alone. Two patients (7.7%) had perforation of the gastrointestinal tract requiring surgical intervention. Eight patients (30.8%) required additional treatment for achalasia, with 5 (19.2%) of these undergoing additional surgery or endoscopic treatment. Patients who had preoperative dilation did not have good resolution of their dysphagia (n = 2; P = 0.037). Two of four patients undergoing postoperative dilation had preoperative dilation. None of these patients underwent preoperative manometry. There was a statistically significant difference in the ages of patients who required postoperative intervention and those who did not (14.1 versus 15.2 y old, respectively; P = 0.043). In patients who reported improvement of gastroesophageal reflux disease/reflux type symptoms after Heller myotomy, lower esophageal residual pressure (29.1 versus 18.7 mmHg; P = 0.018) on preoperative HRM was significantly higher than in those who did not report improvement after surgery. Higher upper esophageal mean pressure (66.6 versus 47.8 mmHg; P = 0.05) also predicted good gastroesophageal reflux disease/reflux symptom response in a similar manner. Current analysis suggests that preoperative dilation should be used cautiously and older patients may have a better response to surgery without need for postoperative treatment. In addition, preoperative HRM can aid in counseling patients in the risk of ongoing symptoms after surgery and may aid in determining if a fundoplication should be completed at the index procedure. Further research is needed to delineate these factors. Level III.


Drug use, crime and the attitudes of magistrates.
In a study concerned with the views of magistrates' on crime related to drug use, a 27-item attitudinal questionnaire was sent to a random sample of 154 subjects drawn from all magistrates in the London area. The response rate was 72%. There was broad agreement on the seriousness of crime related to drug use but there were also interesting differences of opinion. A principal components analysis revealed three factors which accounted for 67% of the variance. Factor 1, labelled 'seriousness' relates to the attitude that the extent of drug use and drug-related crimes such as possession, are serious offences. Factor 2, labelled 'intervention', reflects the view that sentencing and treatment are valuable in dealing with drug-related crime. Factor 3, labelled 'responsibility' describes the attitude that drug users are responsible for their offences and for the contents of statements made when withdrawing from drugs. There were differences between the magistrates on items concerning cannabis, personal responsibility for drug-related crime and the value of sentencing options. Magistrates tended to value psychiatric court-reports but some found them unclearly worded and partial to the defendant. Implications for the legal and medical response to drug use and crime are discussed.


Transcytosis of albumin in astrocytes activates the sterol regulatory element-binding protein-1, which promotes the synthesis of the neurotrophic factor oleic acid.
We have recently reported that albumin, a serum protein present in the developing brain, stimulates the synthesis of oleic acid by astrocytes, which promotes neuronal differentiation. In this work, we gain insight into the mechanism by which albumin induces the synthesis of this neurotrophic factor. Our results show that astrocytes internalize albumin in vesicle-like structures by receptor-mediated endocytosis. Albumin uptake was followed by transcytosis, including passage through the endoplasmic reticulum, which was required to induce the synthesis of oleic acid. Oleic acid synthesis is feedback-regulated by the sterol regulatory element-binding protein-1, which induces the transcription of stearoyl-CoA 9-desaturase, the key rate-limiting enzyme for oleic acid synthesis. In our research, the presence of albumin activated the sterol regulatory element-binding protein-1 and increased stearoyl-CoA 9-desaturase mRNA. Moreover, when the activity of sterol regulatory element-binding protein-1 was inhibited by overexpression of a truncated form of this protein, albumin did not affect stearoyl-CoA 9-desaturase mRNA, indicating that the effect of albumin is mediated by this transcription factor. The effect of albumin was abolished when traffic to the endoplasmic reticulum was prevented or when albumin was accompanied with oleic acid. In conclusion, our results suggest that the transcytosis of albumin includes passage through the endoplasmic reticulum, where oleic acid is sequestrated, initiating the signal cascade leading to an increase in its own synthesis.


Weighted Kernel Fuzzy C-Means-Based Broad Learning Model for Time-Series Prediction of Carbon Efficiency in Iron Ore Sintering Process.
A key energy consumption in steel metallurgy comes from an iron ore sintering process. Enhancing carbon utilization in this process is important for green manufacturing and energy saving and its prerequisite is a time-series prediction of carbon efficiency. The existing carbon efficiency models usually have a complex structure, leading to a time-consuming training process. In addition, a complete retraining process will be encountered if the models are inaccurate or data change. Analyzing the complex characteristics of the sintering process, we develop an original prediction framework, that is, a weighted kernel-based fuzzy C-means (WKFCM)-based broad learning model (BLM), to achieve fast and effective carbon efficiency modeling. First, sintering parameters affecting carbon efficiency are determined, following the sintering process mechanism. Next, WKFCM clustering is first presented for the identification of multiple operating conditions to better reflect the system dynamics of this process. Then, the BLM is built under each operating condition. Finally, a nearest neighbor criterion is used to determine which BLM is invoked for the time-series prediction of carbon efficiency. Experimental results using actual run data exhibit that, compared with other prediction models, the developed model can more accurately and efficiently achieve the time-series prediction of carbon efficiency. Furthermore, the developed model can also be used for the efficient and effective modeling of other industrial processes due to its flexible structure.


Dentatorubral-pallidoluysian atrophy (DRPLA) with a small ganglioglioma component containing neurofibrillary tangles and polyglutamine aggregation.
Dentatorubral-pallidoluysian atrophy (DRPLA), one of the polyglutamine diseases, has not been reported in combination with ganglioglioma (GG). Herein, we report an autopsy case of a 72-year-old man with DRPLA with a small GG component harboring neurofibrillary tangles (NFTs) and polyglutamine aggregates. NFTs, cytoplasmic accumulations of hyper-phosphorylated tau, are mainly observed in Alzheimer's disease (AD) and other tau-associated neurodegenerative disorders. NFTs can also be present in normal aging, and are occasionally observed in low-grade central nervous system (CNS) neoplasms such as GG. In the present case, whole brain examination demonstrated widespread deposition of polyglutamine aggregates, including GG, whereas NFTs were restricted to the GG component. In addition, no other AD or aging-related neuropathological structures were detected throughout the CNS. These findings may provide us with clues to elucidate the pathogenetic mechanisms that neuronal neoplasms may have to develop NFTs regardless of aging, and that polyglutamine may accumulate in neoplastic neurons in polyglutamine disease.


[Clinical study of guchong zhixue decoction in treating dysfunctional uterine bleeding of anovulatory type].
To observe the efficacy of Guchong Zhixue Decoction (GCZXD) in treating dysfunctional uterine bleeding of anovulatory type with Qi-deficiency and blood stasis syndrome, and to systematically explore its hemostasis mechanism. Sixty patients were randomly divided into the treated group (n = 30, treated by GCZXD taken orally) and the control group (n=30, treated by Yigong Zhixue Oral Liquid, taken orally). Hemostatic effect of treatment, improvements of clinical symptoms, thickness of endometrium, prothrombin time (PT) and activated partial prothrombin time (APTT), serum level of Ca2+, endocrine hormone, levels of PGE2 and PGF2alpha in menstrual blood serum, and contents of endometrial estrogen receptor (ER) and progestin receptor (PR) before and after treatment were observed. Results The total effective rate of GCZXD in hemostasis was 93.3% in the treated group, which was significantly better than that in the control group (70.0%, P < 0.05). Significant difference was shown in improving clinical symptoms, thickness of endometrium, PT and APTT, serum level of Ca2+, endocrine hormone, levels of PGE2 and PGF2alpha in menstrual blood serum, and contents of endometrial ER and PR in the treated group when compared with before treatment (P < 0.05, P < 0.01) also when compared with the control group after treatment (P < 0.05). GCZXD has favorable hemostatic effect in treating dysfunctional uterine bleeding of Qi deficiency and blood stasis syndrome, and it also con improve the accompanied symptoms significantly.


U2AF participates in the binding of TAP (NXF1) to mRNA.
TAP/NXF1 is a conserved mRNA export receptor serving as a link between messenger ribonucleoproteins (mRNPs) and the nuclear pore complex. The mechanism by which TAP recognizes its export substrate is unclear. We show here that TAP is added to spliced mRNP in human cells. We identified a distinct region of TAP that targets it to mRNP. Using yeast two-hybrid screens and in vitro binding studies, we found that this region coincides with a direct binding site for U2AF35, the small subunit of the splicing factor U2AF. This interaction is evolutionarily conserved across metazoa, indicating its significance. We further found in human cells that the exogenously expressed large U2AF subunit, U2AF65, accumulates in spliced mRNP, leading to the recruitment of U2AF35 and TAP. Similarly to TAP, U2AF65 stimulated directly the nuclear export and expression of an mRNA that is otherwise retained in the nucleus. Together with our finding that U2AF is continuously exported from the nucleus, these data suggest that U2AF participates in nuclear export, by facilitating TAP's addition to its mRNA substrates.


Alternaria fungal dermatitis in a free-ranging javelina (Pecari tajacu).
We report a javelina from Pinal County, Arizona, USA, with severe fungal dermatitis and cellulitis. Extreme emaciation and rostral disfiguration, including left-lateral displacement of the nasal planum, justified euthanasia. A pus-filled tract within the rostrum was observed. Histopathology revealed granulomatous inflammation with hyphae morphologically consistent with Alternaria sp. isolated by culture.


Can varicella be eliminated by vaccination? Potential clinical and economic effects of universal childhood varicella immunisation in Germany.
Varicella is a potentially serious infection not only in immunocompromised individuals but also in otherwise healthy adults and children. Vaccination plays an important role in preventing the disease and its sequelae. A universal vaccination in childhood is expected to reduce substantially the number of uncomplicated cases of varicella and decrease the number of complicated cases requiring hospitalisation. To generate data as basis for decisions of the health authorities concerning prevention of varicella, epidemiological and health-economic data were collected in two studies. Using an age-structured decision analytic model the benefits, costs and cost effectiveness of a varicella immunisation program for a period of 30 years were assessed. It was shown that after the first year of life seroprevalence rates increased steadily and reached 62% among the 4- to 5-year olds and 94% among the 10- to 11-year olds, respectively; 90% of varicella patients were younger than 12 years. A severe course was assessed for 16.3% of the cases. Overall incidence of complications was estimated to be 5.7%. A routine varicella vaccination program targeting healthy children could prevent 82.7% of varicella cases and over 4,700 major complications per year provided the coverage level was 85%. Under these conditions the elimination of varicella is predicted to be achievable within 18 years. It is expected that a combined measles, mumps, rubella and varicella vaccine could provide the required coverage. Average yearly discounted net cost savings of universal childhood vaccination are 51 million Euro with a benefit-cost ratio of 4.12. Childhood vaccination with catch-up of adolescents provides additional clinical benefits. The break-even point indicating first net savings could be achieved already 3 years after the implementation of the vaccination program. In summary, routine childhood varicella vaccination appears to be a highly efficient strategy to significantly reduce the sizeable burden of varicella and would lead to net savings from both the societal but also the payer perspective.


MRI T2 and T2* relaxometry to visualize neuromelanin in the dorsal substantia nigra pars compacta.
Visualizing gradual changes in neuromelanin distribution within the substantia nigra is an important metric used to monitor the progression of Parkinsonism. This study aimed to identify the origin of the mismatch region between magnetic resonance transverse relaxation times (T2 and T2*) in the substantia nigra and investigate its feasibility and implications for in vivo detection of neuromelanin as a clinical biomarker. The relationships between neuromelanin distribution assessed by histological staining and the area of T2 and T2* mismatch determined by high- and low-resolution magnetic resonance relaxometry at 7T were directly compared in two normal and one depigmented substantia nigra collected at postmortem. In vivo feasibility of assessing T2 and T2* mismatch, clinically, was investigated using 3T magnetic resonance imaging. In the normal postmortem substantia nigra tissue, the T2 and T2* mismatch region exhibiting a linear pattern was strongly colocalized with neuromelanin distribution along the dorsal substantia nigra pars compacta, but a negligible amount of dorsal mismatch was observed in the depigmented brain. The regions of T2 and T2* mismatch from MRI, neuromelanin pigments from histology, and elevated iron signals from mass spectrometry were spatially overlapped for a normal postmortem brain. In preliminary in vivo studies, a similar, linear T2 and T2* mismatch region was observed in the dorsal area of the substantia nigra in eight normal subjects; this mismatch was significantly obscured in eight Parkinson's disease patients. The length of the dorsal linear mismatch line based on the T2*-T2 mask was significantly shorter in the Parkinson's disease patients compared to normal controls; this result was corroborated by reduced striatal uptake of [18F] FP-CIT dopamine transporters assessed by positron emission tomography scans. In conclusion, the measurement of T2 and T2* mismatch could serve as a complementary imaging biomarker to visualize the dorsal region of the substantia nigra pars compacta, which contains large amounts of neuromelanin.


A prospective study of social difficulties, acculturation and persistent depression in Pakistani women living in the UK.
The reasons for the high prevalence of depressive disorders in women of Pakistani origin living in the UK are not clear. The aim of this study was to determine the relative importance of life events, chronic social difficulties and acculturation in a population-based sample of British Pakistani women. A cross-sectional and prospective cohort study of 18- to 65-year-old Pakistani women in UK was carried out. The Schedule for Clinical Assessment in Neuropsychiatry for diagnosis, the Life Events and Difficulties Schedule for social stress and an acculturation questionnaire were used. Depressive disorder at baseline was associated with older age, social isolation and marked difficulties involving health and close relationships. Depressive disorder at follow-up was associated with severity of depression at baseline, difficulties in close relationships and two aspects of acculturation, especially less acculturation in relation to use of the English language. Lack of acculturation, especially less familiarity with the English language, is an independent predictor of persistence of depression in Pakistani women in UK. This needs to be taken into consideration when planning treatment, which also needs to address the personal difficulties associated with persistent depression. The implication of this work is that women of Pakistani origin with depression should be encouraged to receive help in the use of English as one part of treatment that may prevent relapse.


Adverse Childhood Experiences and COVID-19 Stress on Changes in Mental Health among Young Adults.
The COVID-19 pandemic has been linked to poor mental health outcomes and may be particularly damaging for young adults who may be more affected by governmental pandemic responses such as mandatory school and work closures, online schooling, and social isolation. Exposure to Adverse Childhood Experiences (ACEs) has also been shown to have a significant impact on mental health among young adults. This prospective study examined whether young adults with higher ACE profiles were more vulnerable to COVID-19 stressors. Using pre-COVID-19 data from the Niagara Longitudinal Heart Study and a follow-up online survey during COVID-19, we examined 171 young adults and found that high COVID-19-related stress, especially emotional and relationship stress, led to a greater reduction in mental health among young adults with higher levels of ACEs. Findings indicate that young adults with high ACE profiles may benefit from resources and intervention programs directed at mental health in times of crisis, such as the COVID-19 pandemic.


Effects of Litter Size and Parity Number on Mammary Secretions Including, Insulin-Like Growth Factor-1, Immunoglobulin G and Vitamin A of Black Bengal, Saanen and Their Crossbred Goats in Thailand.
The present study aims to investigate the composition including concentrations of IGF-1, IgG and Vit A in colostrum and their effects by litter size and goat parity in 3 groups of goats; Black Bengal (BB), Saanen (SA) and their crossbred (BBSA). Thirty-eight goats were used (23 BB, 7 BBSA and 8 SA). The composition (fat, protein, lactose and total solid; TS) in colostrum (Day 0; D0) and milk (Day 4; D4 and Day 7; D7) were measured. The IGF-1, IgG concentrations were analysed in some samples collected at D0, D4 and D7 while Vit A was analysed only in colostrum. The results showed that colostrum components were similar among experimental groups. However, the colostral IGF-1 concentration of BBSA (983.0 ± 163.6 ng/mL) was higher than that of BB (340.7 ± 85.5 ng/mL, p < 0.01) and SA (417.1 ± 93.9 ng/mL, p < 0.01). The colostral IgG concentration of BB (8.2 ± 0.9 mg/mL) was lower than that of BBSA (12.9 ± 1.7 mg/mL, p < 0.05) and SA (12.9 ± 1.0 mg/mL, p < 0.01). Colostral Vit A concentration in BBSA (787.2 ± 152.6 µg/100 gm) was higher than that in BB (388.9 ± 84.3 µg/100 gm, p < 0.05) but was not different from SA (522.8 ± 96.9 µg/100 gm). Colostrum from all groups contained higher protein and TS but was lower in lactose concentration than milk. The IGF-1 and IgG concentrations in colostrum were much higher than in milk both D4 and D7 (p < 0.001). Additionally, litter size had no effects on colostrum contents but colostrum from goats with a higher parity number had higher IgG concentration. It is concluded that colostrum from BBSA may be superior when fed to BB newborn goats in terms of higher IGF-1, IgG and Vit A contents. Moreover, colostrum from goats with a high parity number contained more IgG content.


Design and optimization of complex mechanism flip shaping subsystem based on genetic algorithm and rigid-flexible coupled dynamic model.
In this paper, the cam connecting rod system of the high-speed group vertical machine flipping shaping mechanism is the research object. In order to solve the key problem that the flipping shaping mechanism cannot accurately complete the action when the vibration of the mechanism is large. In this paper, the finite element method is used to construct the dynamic model of the connecting rod subsystem of the flipped shaping mechanism. And The dynamic model of cam roller subsystem is established by centralized parameter method. Based on the MATLAB Genetic Algorithm toolbox and using Newmark's method, the dynamic equations of the flipped plastic mechanism system are solved. The optimal parameters of the connecting rod of the mechanism, the cam profile curve and the swing power and swing torque of the mechanism at different speeds are analyzed. The results show that the speed and convex contour line are important factors affecting the performance of the mechanism. And the pendulum force (swing torque) is the main cause of the vibration of the mechanism on the frame. Therefore, the mechanism pendulum dynamic and the swing moment are selected as the objective functions of the optimization model. By selecting the node parameters of the sixth order spline motion law and the cross-section parameters of the connecting rod as the design variables. The cam linkage system is optimally designed to obtain the optimal value. Finally, the optimal design of the flipped shaping mechanism was analyzed and compared with the original mechanism.


Supplementation with red palm oil increases β-carotene and vitamin A blood levels in patients with cystic fibrosis.
Patients with cystic fibrosis (CF) show decreased plasma concentrations of antioxidants due to malabsorption of lipid soluble vitamins and consumption by chronic pulmonary inflammation. β-Carotene is a major source of retinol and therefore is of particular significance in CF. The aim of this study was to investigate the effect of daily intake of red palm oil (RPO) containing high amounts of β-carotene on the antioxidant levels in CF patients. Sixteen subjects were recruited and instructed to enrich their food with 2 to 3 tablespoons of RPO (~1.5 mg of β-carotene) daily over 8 weeks. Carotenoids, retinol, and α-tocopherol were measured in plasma at baseline and after intervention. In addition β-carotene, lycopene, α-tocopherol, and vitamin C were measured in buccal mucosa cells (BMC) to determine the influence of RPO on antioxidant tissue levels. Eleven subjects completed the study properly. Plasma β-carotene, retinol, and α-carotene of these patients increased, but plasma concentrations of other carotenoids and α-tocopherol as well as concentrations of β-carotene, lycopene, α-tocopherol, and vitamin C in BMC remained unchanged. Since RPO on a daily basis did not show negative side effects the data suggest that RPO may be used to elevate plasma β-carotene in CF.


Differential expression of Wnts after spinal cord contusion injury in adult rats.
Spinal cord injury is a major cause of disability that has no clinically accepted treatment. Functional decline following spinal cord injury is caused by mechanical damage, secondary cell death, reactive gliosis and a poor regenerative capacity of damaged axons. Wnt proteins are a family of secreted glycoproteins that play key roles in different developmental processes although little is known of the expression patterns and functions of Wnts in the adult central nervous system in normal or diseased states. Using qRT-PCR analysis, we demonstrate that mRNA encoding most Wnt ligands and soluble inhibitors are constitutively expressed in the healthy adult spinal cord. Strikingly, contusion spinal cord injury induced a time-dependent increase in Wnt mRNA expression from 6 hours until 28 days post-injury, and a narrow peak in the expression of soluble Wnt inhibitors between 1 and 3 days post-injury. These results are consistent with the increase in the migration shift, from day 1 to 7, of the intracellular Wnt signalling component, Dishevelled-3. Moreover, after an initial decrease by 1 day, we also found an increase in phosphorylation of the Wnt co-receptor, low-density lipoprotein receptor-related protein 6, and an increase in active β-catenin protein, both of which suffer a dramatic change, from a homogeneous expression pattern in the grey matter to a disorganized injury-induced pattern. Our results suggest a role for Wnts in spinal cord homeostasis and injury. We demonstrate that after injury Wnt signalling is activated via the Wnt/β-catenin and possibly other pathways. These findings provide an important foundation to further address the function of individual Wnt proteins in vivo and the pathophysiology of spinal cord injury.


Modelling spatiotemporal trends in the frequency of genetic mutations conferring insecticide target-site resistance in African mosquito malaria vector species.
Resistance in malaria vectors to pyrethroids, the most widely used class of insecticides for malaria vector control, threatens the continued efficacy of vector control tools. Target-site resistance is an important genetic resistance mechanism caused by mutations in the voltage-gated sodium channel (Vgsc) gene that encodes the pyrethroid target-site. Understanding the geographic distribution of target-site resistance, and temporal trends across different vector species, can inform strategic deployment of vector control tools. We develop a Bayesian statistical spatiotemporal model to interpret species-specific trends in the frequency of the most common resistance mutations, Vgsc-995S and Vgsc-995F, in three major malaria vector species Anopheles gambiae, An. coluzzii, and An. arabiensis over the period 2005-2017. The models are informed by 2418 observations of the frequency of each mutation in field sampled mosquitoes collected from 27 countries spanning western and eastern regions of Africa. For nine selected countries, we develop annual predictive maps which reveal geographically structured patterns of spread of each mutation at regional and continental scales. The results show associations, as well as stark differences, in spread dynamics of the two mutations across the three vector species. The coverage of ITNs was an influential predictor of Vgsc allele frequencies, with modelled relationships between ITN coverage and allele frequencies varying across species and geographic regions. We found that our mapped Vgsc allele frequencies are a significant partial predictor of phenotypic resistance to the pyrethroid deltamethrin in An. gambiae complex populations. Our predictive maps show how spatiotemporal trends in insecticide target-site resistance mechanisms in African An. gambiae vary across individual vector species and geographic regions. Molecular surveillance of resistance mechanisms will help to predict resistance phenotypes and track their spread.


[The technical prevention of chronic acoustic trauma].
The present legislation establishes that workers' exposure to noise, which is the cause of chronic acoustic trauma, should be limited through the adoption of measures of technical and organizational nature. Organizational actions involve a plurality of aspects, not only technical in character, which are usually more difficult to apply and less rewarding in terms of acoustic benefits as compared to the technical ones; the latter should be primarily applied to the source, but are often adopted also at the noise propagation or reception level. Following a short summary of the normative framework, the article describes the approach that may be adopted in order to establish, in a given industrial setting, the priorities of intervention aimed at minimizing the noise exposure risk for the highest number of exposed workers.


Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the Fragile X brain.
Principal neurons encode information by varying their firing rate and patterns precisely fine-tuned through GABAergic interneurons. Dysregulation of inhibition can lead to neuropsychiatric disorders, yet little is known about the molecular basis underlying inhibitory control. Here, we find that excessive GABA release from basket cells (BCs) attenuates the firing frequency of Purkinje neurons (PNs) in the cerebellum of Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mice, a model of Fragile X Syndrome (FXS) with abrogated expression of the Fragile X Mental Retardation Protein (FMRP). This over-inhibition originates from increased excitability and Ca2+ transients in the presynaptic terminals, where Kv1.2 potassium channels are downregulated. By paired patch-clamp recordings, we further demonstrate that acutely introducing an N-terminal fragment of FMRP into BCs normalizes GABA release in the Fmr1-KO synapses. Conversely, direct injection of an inhibitory FMRP antibody into BCs, or membrane depolarization of BCs, enhances GABA release in the wild type synapses, leading to abnormal inhibitory transmission comparable to the Fmr1-KO neurons. We discover that the N-terminus of FMRP directly binds to a phosphorylated serine motif on the C-terminus of Kv1.2; and that loss of this interaction in BCs exaggerates GABA release, compromising the firing activity of PNs and thus the output from the cerebellar circuitry. An allosteric Kv1.2 agonist, docosahexaenoic acid, rectifies the dysregulated inhibition in vitro as well as acoustic startle reflex and social interaction in vivo of the Fmr1-KO mice. Our results unravel a novel molecular locus for targeted intervention of FXS and perhaps autism.


Motion and deformation of a droplet in a microfluidic cross-junction.
In this paper we investigate computationally the transient deformation of a droplet flowing along the centerline of a microfluidic cross-junction device. We consider naturally buoyant droplets with size smaller than the cross-section of the square channels comprising the cross-junction, and investigate low-to-strong flow rates and a wide range of fluids viscosity ratio. Our investigation shows that the intersecting flows at the cross-junction act like a constriction, and thus the droplet shows a rich deformation behavior as it passes through the micro-junction. Our work highlights the three-dimensional effects of the asymmetric microfluidic geometry on the droplet deformation, and the different effects of the viscosity ratio on the droplet's overall length scales and the local length scales at the droplet edges. The large edge curvatures and thus the small local length scales developed transiently, especially at the tail of low-viscosity droplets, reveal that the current investigation is a multi-length interfacial dynamics problem.


Brain uptake, pharmacokinetics, and tissue distribution in the rat of neurotoxic N-butylbenzenesulfonamide.
The pharmacokinetics, cerebrovascular permeability, and tissue distribution of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS) were determined in rats. A stable isotope-labeled form ([(13)C(6)]NBBS) was used to circumvent ubiquitous contamination that was evident whenever the native form was measured. Plasticizer decline in plasma, following an iv dose of 1 mg/kg, was described by a triexponential decay function. NBBS was cleared from plasma at a rate of 25 ml/min/kg, and 24 h after administration, plasma concentrations represented 0.04% of the administered dose. These data suggest rapid elimination and uptake into tissue; however, NBBS was not accumulated by any of the tissues studied (i.e., liver, kidney, muscle, adipose tissue, and brain). Given the critical interest in NBBS neurotoxicity, the brain uptake of [(13)C(6)]NBBS was further explored in experiments using the in situ brain perfusion technique. During perfusion with protein-free saline for 15-30 s, the single-pass brain extraction for free [(13)C(6)]NBBS was very high (73-100%) with a unidirectional blood-brain barrier transfer constant (K(in)) of > 0.08 ml/s/g. No significant differences were found in [(13)C(6)]NBBS content among the measured brain regions. Plasma protein binding (70%) only slightly lowered the single-pass brain extraction to 48%. In summary, the results demonstrate that NBBS distributes rapidly to tissues, including brain. Though highly lipophilic with a Log octanol/water partition coefficient of 2.17 +/- 0.09, brain:blood ratios (2:1) for NBBS were consistent throughout the experimental duration, with little indication of accumulation.


[Sodium and calcium channels of the somatic membrane of neuroblastoma cells during artificially induced differentiation].
Sodium and calcium channels passing inward currents were studied by intracellular dialysis technique and voltage clamp in the somatic membrane of neuroblastoma cells during their morphological differentiation induced by increasing pH of the culture medium up to 8.0-8.2. Kinetic and voltage-dependent properties of sodium and calcium channels of differentiated cells and cells grown in the suspension culture were identical. Densities of sodium currents in the somatic membrane of neuroblastoma cells grown in suspension culture were about 7.3 +/- 0.8 microA/microF and from 37 +/- 5.2 microA/microF to 54.7 +/- 3.6 microA/microF of differentiated cells at different terms of cultivation. Densities of calcium currents in the membrane of cells grown in suspension were about 1.4 +/- 0.2 microA/microF, while in differentiated cells they ranged from 1.1 +/- 0.2 to 2.8 +/- 0.4 microA/microF at different terms of cultivation. Induction or reduction of differentiation by varying pH of the culture medium produced reciprocal changes in densities of sodium and calcium channels.


[Epidemiological profile of cocaine users on treatment in psychiatrics hospitals, Brazil].
To describe the epidemiological profile and patterns of cocaine use among hospitalized drug users. A cross-sectional study was carried out among drug users, aged 18 years or more, hospitalized in one out six selected psychiatric hospitals in the metropolitan area of Greater S o Paulo, whose clinical conditions allowed them to reliably answer to a standardized questionnaire and who agreed to participate. Six psychiatric hospitals who attended spontaneously referred public and private patients from all Greater S o Paulo were selected. Data collection was conducted using structured interviews, individually applied by a trained psychologist. Statistical analysis was performed using Student t-test and Chi-square test at p<0.05. There was a predominance of crack use (38.4%) over intravenous drug use (1.6%). Addicts who smoked cocaine had lower education, most were unemployed and had previously lived on the streets, and used higher amounts of drugs. These addicts also had been previously incarcerated more often than addicts who used other routes for drug administration. Drug use is a serious public health problem in Greater S o Paulo, and this is shown by the great amount of hospital admissions due to drug addiction. Crack users have lower socioeconomic status and more often engage in violence and crimes.


Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells.
For epithelia to function as barriers, the intercellular space must be sealed. Sealing two adjacent cells at bicellular tight junctions (bTJs) is well described with the discovery of the claudins. Yet, there are still barrier weak points at tricellular contacts, where three cells join together. In this study, we identify tricellulin, the first integral membrane protein that is concentrated at the vertically oriented TJ strands of tricellular contacts. When tricellulin expression was suppressed with RNA interference, the epithelial barrier was compromised, and tricellular contacts and bTJs were disorganized. These findings indicate the critical function of tricellulin for formation of the epithelial barrier.


Forskolin stimulates bovine epididymal sperm motility and cyclic AMP levels.
Forskolin, a diterpene, has been reported to reversibly stimulate adenylate cyclase from a number of mammalian tissues. Adenylate cyclase preparations derived from sperm are reported to be both deficient in the guanine nucleotide subunit and insensitive to forskolin. Despite the latter observation, we report here that forskolin elevates cAMP levels in immature caput sperm, and initiates motility in the presence of "permissive" agents such as bicarbonate, procaine and dibucaine. In mature caudal sperm forskolin stimulates motility in a concentration dependent manner in the presence of the phosphodiesterase inhibitor IBMX but elevates cAMP levels only briefly before nucleotide levels return to control values. In addition, forskolin stimulates adenylate cyclase activity associated with plasma membrane preparations of caput sperm but not caudal sperm. This differential action of forskolin on these cell types could provide a basis for understanding the regulation of adenylate cyclase in both immature and mature bovine sperm.


Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes.
Mice with a cardiomyocyte (CM)-restricted knockout of signal transducer and activator of transcription 3 (STAT3-KO) develop spontaneous heart failure. We investigated the impact of STAT3-mediated regulation of microRNAs for pathophysiological alterations in the heart. MicroRNAchip and qRT-PCR analysis revealed elevated cardiac expression of miR-199a in STAT3-KO mice. Lentiviral shRNA-mediated STAT3-knock-down in neonatal rat CMs markedly increased miR-199a promoter activity and miR-199a levels indicative of a suppressive effect of STAT3 on miR-199a transcription. Up-regulated miR-199a in CM by pre-miR-199a transfection (pre-miR-199a-CM) reduced expression of components of the ubiquitin-proteasome system (UPS), i.e. the ubiquitin-conjugating enzymes Ube2g1 (mRNA and protein) and Ube2i (protein). Pre-miR-199a-CM or CM with siRNA-mediated down-regulation of Ube2i and Ube2g1 (siRNA-Ube2i/2g1-CM) displayed massive down-regulation of α- and β-myosin heavy chain expression associated with disrupted sarcomere structures. In addition, protein arginine methyltransferase I (PRMT-I) expression and asymmetric dimethylarginine (ADMA) synthesis were increased in pre-miR-199a-CM or in siRNA-Ube2i/2g1-CM. Increased ADMA in cell culture supernatant (SN) from pre-miR-199a-CM or siRNA-Ube2i/2g1-CM lowered nitric oxide (NO) bioavailability of rat cardiac endothelial cells while lowering ADMA concentration in CM SNs by the PRMT inhibitor arginine methyltransferase inhibitor 1 (AMI-1) (100 µM) improved NO bioavailability. In STAT3-KO hearts Ube2i and Ube2g1 expression were markedly reduced. Human terminal failing hearts harbouring low STAT3 protein levels displayed increased miR-199a levels and decreased Ube2g1 expression. This study identifies a novel pathophysiological circuit in the heart between reduced STAT3 protein levels, increased miR-199a expression, and subsequent impairment of the UPS that disrupts CM sarcomere structure and impairs via the release of ADMA endothelial cell function.


Natural killer cells and their therapeutic role in pancreatic cancer: A systematic review.
Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies. In this systematic review we summarise the pathophysiological adaptions of NK cells in pancreatic cancer and highlight possible (future) therapeutic NK cell-related targets. Furthermore, an extensive overview of recent therapeutic approaches with an effect on NK cells is given, including cytokine-based, viro- and bacteriotherapy and cell therapy. We also discuss ongoing clinical trials that might influence NK cells. In conclusion, although several issues regarding NK cells in pancreatic cancer remain unsolved and need further investigation, extensive evidence is already provided that support NK cell oriented approaches in pancreatic cancer.


Promoting physical activity participation and nutrition education through a telehealth intervention for children on the autism spectrum and their caregivers.
There is growing empirical support which suggests children on the autism spectrum, as well as their caregivers experience significant health disparities. The global COVID-19 pandemic has only magnified the need to address health among vulnerable populations. While there has been a growing trend in the delivery of telehealth interventions, the delivery of such methods for children on the autism spectrum, and their caregivers remains relatively under examined. The primary goal of PLANE (Physical Literacy And Nutrition Education) is to promote positive trajectories of health for children on the autism spectrum and their primary caregivers through the delivery of a telehealth physical activity and nutrition education program. The study is a pre-experimental analysis of PLANE across 12 months. All activities will be delivered virtually through weekly synchronous and asynchronous programming. A total of 180 participants will be enrolled in this intervention, including children on the autism spectrum and caregivers. Each week a new physical activity skill along with opportunities for recipe assembly will be delivered remotely. Supplemental material will be disseminated online including; step by step directions outlining behavioral skill methodology, opportunities for additional skill practice, and reading material that support weekly topics. Study outcomes will be examined in the parent-child dyad and include rates of overweight/obesity, physical activity, nutrition and quality of life. Finally, feasibility of the telehealth intervention will also be measured. Justification for the conceptualization and delivery of PLANE is well warranted, and PLANE represents a promising intervention which is scalable, sustainable, and replicable.


Ring statistics of silica bilayers.
The recent synthesis and characterisation of bilayers of vitreous silica has produced valuable new information on ring sizes and distributions. In this paper, we compare the ring statistics of experimental samples with computer generated samples. The average ring size is fixed at six by topology, but the width, skewness and other moments of the distribution of ring edges are characteristics of particular samples. We examine the Aboav-Weaire law that quantifies the propensity of smaller rings to be adjacent to larger rings, and find similar results for available experimental samples which however differ somewhat from computer-generated bilayers. We introduce a new law for the areas of rings of various sizes.


A computer designed graph for administration of atracurium by i.v. infusion.
A bi-exponential mathematical computer model was used to develop a guidance graph for atracurium infusions. The model permitted variation in infusion rates, in pharmacokinetic parameters and in "effect" thresholds. Systematic experiments revealed a relationship between the rate of recovery from a fixed bolus loading dose and the most appropriate initial infusion rate. This relationship was expressed as a guidance graph or "ready reckoner". The quality of guidance was assessed in 50 anaesthetics, given consecutively. In 39 patients optimal myoneural block for surgery was maintained for the duration of the infusion without adjustments or supplementary bolus doses. The mean operating time was 92 min and the mean duration of infusion was 59 min.


Subjective perception of load heaviness.
This study examined human subjective perception of load heaviness. Forty-two (3 boxes × 14 weights) and 27 (3 boxes × 9 weights) experimental conditions were randomly presented to male and female participants, respectively. The results showed that the participants were not able to discriminate the effect of the box on perceived weight. The participants underestimated the weight for low weights and overestimated it for high weights. The females perceived a greater increase in weight than the males for the same increase in weight. The participants' linguistic term for perceived weight was positively correlated to the magnitude of weight. Approximately 50% of the males perceived a weight of 20 kg or over as risky, while ~60% of the females perceived a weight of 14 kg or over as risky. This study supposes that the gender difference in muscular capability is responsible for the effect of gender on the risk perception of weight.


AG490 improves the survival of human myoblasts in vitro and in vivo.
Cell therapies consist in transplanting healthy cells into a disabled tissue with the goal to repopulate it and restore its function at least partially. In muscular diseases, most of the time, myoblasts are chosen for their expansion capacity in culture. Nevertheless, cell transplantation has limitations, among them, death of the transplanted cells, during the days following the graft. One possibility to counteract this problem is to enhance the proliferation of the transplanted myoblasts before their fusion with the existing muscle fibers. AG490 is a specific inhibitor of janus tyrosine kinase 2 (JAK2). The hypothesis is to block myoblast differentiation with AG490, thus permitting their proliferation. The inhibition of myoblast fusion by AG490 was confirmed in this study by gene expression and with a myosin heavy chain staining (MyHC). Moreover, cell survival was estimated by flow cytometry. AG490 was found to protect myoblasts in vitro from apoptosis induced by H(2)O(2) or by preventing attachment of cells to their substrate. Finally, in an in vivo model of muscle regeneration, when AG490 was coinjected with the myoblasts their survival was increased by 45% at 5 days after their transplantation.


[Clinical evaluation of changes in serum zinc and copper concentrations around pulmonary operation].
Serum zinc and copper were measured in 47 patients undergoing pulmonary operation. They were divided into two groups according to the extent of the operation. Group A consisted of 32 patients with lung cancer, in whom lobectomy with lymphadenectomy was performed through the postero-lateral thoracotomy. Group B consisted of 15 patients with benign pulmonary lesion or metastatic pulmonary tumor, in whom wedge resection was performed through the axillary thoracotomy. In Group A, the serum zinc concentration most decreased 6 hours after surgery. It returned to normal level in 5-7 days and to the preoperative level within 14 days. In Group B, the maximal fall in serum zinc was at 3 hours after operation. Restoration to normal level was at 2nd postoperative day and to the preoperative level was at 5th postoperative day. The differences in serum zinc between two groups were significant (p < 0.05) from just after operation to 4th postoperative day. The degree of maximal decrease in serum zinc in Group A was more than that in Group B. Blood loss, operation time and pulmonary function did not influenced the change of serum zinc concentration in our series. These results show that degree and duration of reduction in serum zinc depends on the surgical trauma. On the other hand, no significant difference in serum copper levels was observed between two groups. The influence of pre- and post-operative pneumonia on serum zinc concentrations were followed in 3 patients. Fall and rise in serum zinc levels coincided with manifestation of and recovery from pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)


Gene-wide identification of episodic selection.
We present BUSTED, a new approach to identifying gene-wide evidence of episodic positive selection, where the non-synonymous substitution rate is transiently greater than the synonymous rate. BUSTED can be used either on an entire phylogeny (without requiring an a priori hypothesis regarding which branches are under positive selection) or on a pre-specified subset of foreground lineages (if a suitable a priori hypothesis is available). Selection is modeled as varying stochastically over branches and sites, and we propose a computationally inexpensive evidence metric for identifying sites subject to episodic positive selection on any foreground branches. We compare BUSTED with existing models on simulated and empirical data. An implementation is available on www.datamonkey.org/busted, with a widget allowing the interactive specification of foreground branches.


Intra- and Extracellular Localization of Lignin Peroxidase during the Degradation of Solid Wood and Wood Fragments by Phanerochaete chrysosporium by Using Transmission Electron Microscopy and Immuno-Gold Labeling.
The distribution of lignin peroxidase during degradation of both wood and woody fragments by the white rot fungus Phanerochaete chrysosporium was investigated by using anti-lignin peroxidase in conjunction with postembedding transmission electron microscopy and immuno-gold labeling techniques. The enzyme was localized in the peripheral regions of the fungal cell cytoplasm in association with the cell membrane, fungal cell wall, and extracellular slime materials. In solid wood, lignin peroxidase was detected in low concentrations associated with both superficial and degradation zones within secondary cell walls undergoing fungal attack. A similar but much greater level of extracellular peroxidase activity was associated with wood fragments degraded by the fungus grown under liquid culture conditions optimal for production of the enzyme. Efforts to infiltrate degraded wood pieces with high levels of lignin peroxidase showed the enzyme to be restricted to superficial regions of wood decay and to penetrate wood cell walls only where the wall structure had been modified. In this respect the enzyme was able to penetrate characteristic zones of degradation within the secondary walls of fibers to sites of lignin attack. This suggests a possibility for a close substrate-enzyme association during wood cell wall degradation.


Supportive leadership in Swedish community night nursing.
The aim of the present study was to examine the support night nurses' give to staff in community night nursing. Studies have shown that support given to staff is one of night registered nurses' (RNs') experiences of the meaning of caring. This support, that community RNs display for staff in night-time care, is sparsely described. All community night-duty nurses in a medium-sized municipal in Sweden participated in the present study. Thematic content analysis was used to analyse data from observations. The support given by RNs to staff is described using three themes: (1) a conditional supporting stance, (2) preparing propitious conditions for caring and (3) confidence in the abilities of individual staff members and adaptation to their individual needs. The results reveal that RNs consider support to staff in terms of nursing leadership. Out of 'concern for the staff' the RNs try to be there for them, which corresponds to nursing leadership. Such concern also arises from the RNs' awareness that by giving support to staff this affects the staffs' caring for older people. The current municipal social care organization of community nursing of older people in which RNs have extensive responsibilities with insufficient control, is a working condition with a risk for decreased quality of care and a high risk for work-related stress syndrome.


p-values should not be used for evaluating the strength of DNA evidence.
Recently, p-values have been suggested to explain the strength of a likelihood ratio that evaluates DNA evidence. It has been argued that likelihood ratios would be difficult to explain in court and that p-values would offer an alternative that is easily explained. In this article, we argue that p-values should not be used in this context. p-Values do not directly relate to the strength of the evidence. The likelihood ratio measures the strength of the evidence, while the p-value measures how rare it is to find evidence that is equally strong or stronger, which is something fundamentally different. In addition, a p-value is not always unambiguous. To illustrate our arguments, we present several examples from forensic genetics.


Role of citrus juices and distinctive components in the modulation of degenerative processes: genotoxicity, antigenotoxicity, cytotoxicity, and longevity in Drosophila.
It is well established that breakfast beverages contain high quantities of Citrus juices. The purpose of the present study was to assess the nutraceutical value of orange and lemon juices as well as two of their active compounds: hesperidin and limonene. Indicator assays were performed at three levels to evaluate different biological health promoter activities: (i) determination of the safety and DNA-damage protecting ability against free radicals by using the somatic mutation and recombination test (SMART) in Drosophila melanogaster, (ii) study of the modulating role for life span in Drosophila melanogaster, and (iii) measurement of the cytotoxic activity against the human tumor cell line HL60. The highest concentrations assayed for lemon juice and limonene (50% v/v and 0.73 mM, respectively) showed genotoxic activity as evidenced from SMART. Orange and lemon juices as well as hesperidin and limonene exhibit antigenotoxic activity against hydrogen peroxide used as an oxidative genotoxin. Life-span experiments revealed that the lower concentrations of orange juice, hesperidin, and limonene exerted a positive influence on the life span of Drosophila. Finally all substances showed cytotoxic activity, with hesperidin being least active. Taking into account the safety, antigenotoxicity, longevity, and cytotoxicity data obtained in the different assays, orange juice may be a candidate as a nutraceutical food as it (1) is not genotoxic, (2) is able to protect DNA against free radicals, and (3) inhibits growth of tumor cells.


The influence of aging on outgroup stereotypes: the mediating role of cognitive and motivational facets of deficient flexibility.
BACKGROUND/STUDY CONTEXT: The current study was designed to examine previously reported findings about age-related changes in drawing stereotypic inferences; specifically, that older adults are more likely than younger adults to stereotype outgroup members. The study replicates previous research and extends it by exploring the cognitive and motivational facets of deficient flexibility underlying this effect and comparing stereotypes towards ingroup and outgroup members. In the experiment, younger and older adults read stories that allowed for stereotypic inferences. They also completed the Trail Making Test (TMT) and Need for Closure Scale (NFC) as cognitive and motivational measures of deficient flexibility. The results of the experiment revealed that, compared to younger participants, older adults were more likely to rely upon stereotypic inferences when they read a story about outgroup members; however, there were no age-group differences in using stereotypes when they read a story about ingroup members. In addition, the findings showed that making more stereotypical inferences by older versus younger adults in relation to outgroup members was mediated by cognitive (TMT) and motivational (NFC) facets of deficient flexibility. A major implication of these findings is that both cognitive and motivational facets of deficient flexibility contribute to the reliance of older adults on stereotypes compared with younger adults. However, this is only true when older adults process information about outgroup members, but not about ingroup members. Thus, the current research goes beyond previous results by providing direct evidence that ingroup-outgroup perception contributes to stereotyping among older participants.


Biomimetic Moth-eye Nanofabrication: Enhanced Antireflection with Superior Self-cleaning Characteristic.
Sub-wavelength antireflection moth-eye structures were fabricated with Nickel mold using Roll-to-Plate (R2P) ultraviolet nanoimprint lithography (UV-NIL) on transparent polycarbonate (PC) substrates. Samples with well replicated patterns established an average reflection of 1.21% in the visible light range, 380 to 760 nm, at normal incidence. An excellent antireflection property of a wide range of incidence angles was shown with the average reflection below 4% at 50°. Compared with the unpatterned ultraviolet-curable resin coating, the resulting sub-wavelength moth-eye structure also exhibited increased hydrophobicity in addition to antireflection. This R2P method is especially suitable for large-area product preparation and the biomimetic moth-eye structure with multiple performances can be applied to optical devices such as display screens, solar cells, or light emitting diodes.


Cytolytic factor in eggs of the sea hare Aplysia kurodai.
A cytolytic factor partially purified from eggs of the sea hare Aplysia kurodai was examined for cytolytic activity against various target cells. All kinds of tumor cells tested were lysed in vitro by the cytolytic factor in the range of 10-100 ng protein/ml. In contrast, normal spleen cells were lysed by 10 micrograms/ml of this factor and red cells were not lysed even at this higher concentration. Tumor lysis was time-dependent and was complete within 10 hr. This factor inhibited DNA and RNA syntheses of tumor cells but not protein synthesis. The cytolytic activity was lost on heat-treatment (60 degrees) and at pH 2, and was partially inhibited by treatment with 8M urea and at pH 12, but the factor was resistant to treatments with trypsin, periodate and 2-mercaptoethanol. Neutralizing activity was observed in vivo on pretreatment of MM46 and L1210 cells with the factor. This cytolytic factor also inhibited the growth of solid-type MH134 tumor and ascitic-type MM46 tumor. These results indicate that Aplysia eggs contain a novel cytolytic factor that lyses tumor cells in vitro and inhibits tumor growth in vivo.


Episodic idiopathic systemic capillary leak syndrome in a girl.
Episodic idiopathic systemic capillary leak syndrome is a rare disorder that presents with attacks of circulatory shock due to plasma leakage into the extravascular space. Reported here is the case of a girl who had recurrent circulatory shock. The diagnosis of episodic idiopathic systemic capillary leak syndrome was made following the fourth episode. The course was favorable following acute i.v. cristalloids and methylprednisolone.


Studies on the relationship between Yersinia enterocolitica IX and Brucella abortus agglutinins in naturally infected animals.
Attempts were made to define the Brucella abortus and Yersinia enterocolitica IX infection status of animal populations by means of selected agglutination tests. The Brucella abortus O, the Yersinia enterocolitica IX OH and the Y enterocolitica IX H agglutinin titres were measured in a large number of cattle, goat and pig sera In the goats and, to a much lesser extent, the pigs, the relationships between these titres suggested that Yersinia infection was common. In contrast, the results from the cattle sera were complex and tended to indicate the presence of both Yersinia infection and brucellosis.


Activation of the epithelial sodium channel by the metalloprotease meprin β subunit.
The Epithelial Na(+) Channel (ENaC) is an apical heteromeric channel that mediates Na(+) entry into epithelial cells from the luminal cell surface. ENaC is activated by proteases that interact with the channel during biosynthesis or at the extracellular surface. Meprins are cell surface and secreted metalloproteinases of the kidney and intestine. We discovered by affinity chromatography that meprins bind γ-ENaC, a subunit of the ENaC hetero-oligomer. The physical interaction involves NH(2)-terminal cytoplasmic residues 37-54 of γ-ENaC, containing a critical gating domain immediately before the first transmembrane domain, and the cytoplasmic COOH-terminal tail of meprin β (residues 679-704). This potential association was confirmed by co-expression and co-immunoprecipitation studies. Functional assays revealed that meprins stimulate ENaC expressed exogenously in Xenopus oocytes and endogenously in epithelial cells. Co-expression of ENaC subunits and meprin β or α/β in Xenopus oocytes increased amiloride-sensitive Na(+) currents approximately two-fold. This increase was blocked by preincubation with an inhibitor of meprin activity, actinonin. The meprin-mediated increase in ENaC currents in oocytes and epithelial cell monolayers required meprin β, but not the α subunit. Meprin β promoted cleavage of α and γ-ENaC subunits at sites close to the second transmembrane domain in the extracellular domain of each channel subunit. Thus, meprin β regulates the activity of ENaC in a metalloprotease-dependent fashion.


Conflicts of interest in research: is clinical decision-making compromised? An opinion paper.
Lack of transparency in funded research can compromise clinical decision-making in an evidence-based practice. Transparency can be defined as full disclosure of all financial assistance and support to authors and investigators. There is a perception that ethical principles are eroding and that research data can be biased due to conflicts of interest. These research outcomes biased or not, are used for clinical decision-making in the evidence-based practice. One suggested solution to this common ethical dilemma is to continue the dialogue on transparency in research and to create oversight bodies which include representatives from business and industry, private practice, academia, and research. There is increasing evidence of the need for more ethics education at all levels.


Up-regulation of inflammatory signalings by areca nut extract and role of cyclooxygenase-2 -1195G>a polymorphism reveal risk of oral cancer.
Because the mRNA expression of cyclooxygenase-2 (COX-2) is up-regulated by arecoline in human gingival fibroblasts, as shown in our previous study, we further investigated the mRNA expression level of COX-2 and its upstream effectors in three oral epithelial carcinoma cell lines (KB, SAS, and Ca9-22) by using areca nut extract (ANE) and saliva-reacted ANE (sANE). A case-control study of 377 oral squamous cell carcinoma (OSCC) patients and 442 controls was conducted to evaluate the gene-environment interaction between COX-2 promoter polymorphisms and substance use of alcohol, betel quid, and cigarettes (ABC) in risk of OSCC. The heterogeneous characteristics of the oral site and the COX-2 -1195G>A polymorphism in these cell lines showed diverse inflammatory response (KB>>Ca9-22>SAS) after 24-hour ANE/sANE treatments, and the COX-2 up-regulation might be mostly elicited from alternative nuclear factor-kappaB activation. In the case-control study, betel chewing [adjusted odds ratios (aOR), 42.2] posed a much higher risk of OSCC than alcohol drinking and cigarette smoking (aORs, 2.4 and 1.8, respectively), whereas the COX-2 -1195A/A homozygote presented a potential genetic risk (OR, 1.55). The strongest joint effect for OSCC was seen in betel chewers with -1195A/A homozygote (aOR, 79.44). In the non-betel chewing group, the -1195A/G and A/A genotypes together with the combined use of alcohol and cigarettes increased risk to 15.1-fold and 32.1-fold, respectively, compared with the G/G genotype without substance use. Taken together, these findings illustrate a valuable insight into the potential role of the COX-2 promoter region in contributing to the development of betel-related OSCC, including ANE/sANE-induced transcriptional effects and enhanced joint effects of COX-2 -1195A allele with substance use of ABC.


Anterior perforations in lumbar discectomies. A report of four cases of vascular complications and a CT study of the prevertebral lumbar anatomy.
Four cases of vascular complications to anterior perforations during discectomy prompted a CT study to measure lumbar disc diameters and to evaluate the prevertebral anatomy. Fifty young adults who had been referred for low-back pain and/or sciatica but had not undergone operation were included. In five additional patients, prone versus supine CT examinations were compared. Six typical configurations of the vascular anatomy could be classified to explain the type of vascular complications occurring at the L3-4 and L4-L5 disc levels. The sagittal diameter of the three lowest lumbar discs varied from 33 to 56 mm, indicating the importance of this parameter as an intraoperative guideline for the spine surgeon. Air-filled intestines were observed anterior to the L5-S1 disc predominantly in the prone position. The possible relationship between this finding and postoperative discitis is discussed.


Divergent Proteome Reactivity Influences Arm-Selective Activation of Pharmacological Endoplasmic Reticulum Proteostasis Regulators.
Pharmacological activation of the activating transcription factor 6 (ATF6) arm of the Unfolded Protein Response (UPR) has proven useful for ameliorating proteostasis deficiencies in a variety of etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino- p -cresol substructure affording a quinone methide, which then covalently modifies a subset of ER protein disulfide isomerases (PDIs). Intriguingly, another compound identified in this screen, AA132, also contains a 2-amino- p -cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent PDI modification. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. Paradoxically, activated AA132 reacts slower with PDIs, indicating it is less reactive than activated AA147. This suggests that the higher labeling of PDIs observed with activated AA132 can be attributed to its lower reactivity, which allows this activated compound to persist longer in the cellular environment prior to quenching by endogenous nucleophiles. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and allows for selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.


Molded arthroplasty and transfer of the extensor hallucis brevis tendon. A modification of the Keller-Lelievre operation.
The Keller-Lelievre technique for hallux valgus correction was modified by detaching the extensor hallucis brevis tendon from the proximal phalanx, and reattaching it on the medial sesamoid. Thirty-five consecutive patients were assigned randomly to 1 of 2 groups. Patients in Group 1 received the modified operation, and the original Keller-Lelievre technique was used for the control group. The only significant radiographic difference at 6 months was the distance between the first and the fifth metatarsal heads. There were only slightly significant differences in function and in pain relief between the 2 groups at the 6th postoperative month. At 3 years, these differences were greater, with the group treated by the modification described herein, retaining significant correction and showing better functional results.


Removal of excess activated sludge by aerobic mineralization.
The removal of excess activated sludge from biological purification plant treating crude oil refining wastewaters by the method of aerobic digestion was studied. In stationary system 58% of excess sludge was removed within 32 days. In semicontinvous system (with daily addition of sludge) 85--64% of the sludge was removed, depending on amount of excess activated sludge added. Enrichment of the aerating air in oxygen (10% v/v) increased the efficiency of sludge digestion by about 10%.


Antibody staining of the central nervous system in adult Drosophila.
The Drosophila nervous system provides a valuable model for studying various aspects of brain development and function. The postembryonic Drosophila brain is especially useful, because specific neuron types derive from specific progenitors at specific times. Elucidating the means by which diverse neuron types derive from a limited number of progenitors can contribute significantly to our understanding of the genetic and molecular mechanisms involved in developmental neurobiology. Antibody-labeling techniques are particularly useful for examining the Drosophila brain. These methods generally use primary antibodies specific to a protein or a structure of interest and a fluorescently labeled or enzyme-coupled secondary antibody to detect the primary antibodies. Immunofluorescence methods allow for simultaneous probing for multiple antigens using different fluorophores, as well as high-resolution confocal examination of deep structures. This protocol describes general procedures for antibody labeling of neural tissue from Drosophila, as well as visualization techniques for fluorescent and enzyme-linked probes.


Human corpses as time capsules: new perspectives in the study of past mass disasters.
Looking at the corpses of past natural catastrophes can change completely the conception of how to study human bone remains. The recovery of the Herculaneum victims of the 79 AD Vesuvius eruption was an opportunity for me to adopt a new approach in the study of human skeletons and their context of discovery. During two years of field work, my first aim was to investigate the effects of pyroclastic surges on people and things. The conservation of skeletons and their replacement by fiberglass casts were also provided. This "field laboratory" has developed into a palaeoforensic investigation of the mass disaster caused by the 79 AD natural event. Field and laboratory research, later extended to Pompeii plaster-cast corpses, were also carried out on the victims' remains, footprints, huts and objects found in the sites buried by the prehistoric "Avellino pumices" eruption (3780 ± 100 BP). The new results obtained from the study of the causes of death of people hit by pyroclastic surges produced by past Vesuvius eruptions have proved essential in hazard evaluation in the Neapolitan district and other volcanic areas.