Impact of the hypothalamic-pituitary-adrenal/gonadal axes on trajectory of age-related cognitive decline.
Life expectancies have increased substantially in the last century, dramatically amplifying the proportion of individuals who will reach old age. As individuals age, cognitive ability declines, although the rate of decline differs amongst the forms of memory domains and for different individuals. Memory domains especially impacted by aging are declarative and spatial memories. The hippocampus facilitates the formation of declarative and spatial memories. Notably, the hippocampus is particularly vulnerable to aging. Genetic predisposition and lifetime experiences and exposures contribute to the aging process, brain changes and subsequent cognitive outcomes. In this review, two factors to which an individual is exposed, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, will be considered regarding the impact of age on hippocampal-dependent function. Spatial memory can be affected by cumulative exposure to chronic stress via glucocorticoids, released from the HPA axis, and from gonadal steroids (estrogens, progesterone and androgens) and gonadotrophins, released from the HPG axis. Additionally, this review will discuss how these hormones impact age-related hippocampal function. We hypothesize that lifetime experiences and exposure to these hormones contribute to the cognitive makeup of the aged individual, and contribute to the heterogeneous aged population that includes individuals with cognitive abilities as astute as their younger counterparts, as well as individuals with severe cognitive decline or neurodegenerative disease.


The immunization and vaccine crisis in developing countries.
Health care research has shown that immunization can play a crucial role in fighting infectious diseases. A global effort was launched to decrease the incidence of infectious disease worldwide through immunization. This paper highlights many of the problems which have contributed to an immunization crisis, in which developing countries are not receiving the benefits of vaccines due to slow vaccine delivery systems; the increasing cost of vaccines; and vaccine and immunization program deficiencies. Consequences of the crisis, solutions, and the role of health care professionals in supporting immunization programs are presented.


High-resolution optical position encoder with large mounting tolerances.
A high-resolution optical position encoder is described that consists of a scale as encountered in a standard moiré-based system, a simple imaging system with stabilized magnification and a novel segmented phase detector integrated circuit. Compared with encoder systems of comparable resolution and accuracy, the encoder presented offers large mechanical tolerances in the alignment of the reading head to the scale, while an interpolation accuracy of better than 0.1 mum is preserved. The system is especially well suited for high-resolution linear encoders as well as for the cost-effective fabrication of compact high-resolution rotary encoders.


Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality: A Systematic Review and Meta-analysis.
As many as 10% of women experience natural menopause by the age of 45 years. If confirmed, an increased risk of cardiovascular disease (CVD) and all-cause mortality associated with premature and early-onset menopause could be an important factor affecting risk of disease and mortality among middle-aged and older women. To systematically review and meta-analyze studies evaluating the effect of age at onset of menopause and duration since onset of menopause on intermediate CVD end points, CVD outcomes, and all-cause mortality. Medical databases (ie, Medline, EMBASE, and Web of Science) until March 2015. Studies (ie, observational cohort, case-control, or cross-sectional) that assessed age at onset of menopause and/or time since onset of menopause as exposures as well as risk of cardiovascular outcomes and intermediate CVD end points in perimenopausal, menopausal, or postmenopausal women. Studies were sought if they were observational cohort, case-control, or cross-sectional studies; reported on age at onset of menopause and/or time since onset of menopause as exposures; and assessed associations with risk of CVD-related outcomes, all-cause mortality, or intermediate CVD end points. Data were extracted by 2 independent reviewers using a predesigned data collection form. The inverse-variance weighted method was used to combine relative risks to produce a pooled relative risk using random-effects models to allow for between-study heterogeneity. Cardiovascular disease outcomes (ie, composite CVD, fatal and nonfatal coronary heart disease [CHD], and overall stroke and stroke mortality), CVD mortality, all-cause mortality, and intermediate CVD end points. Of the initially identified references, 32 studies were selected that included 310 329 nonoverlapping women. Outcomes were compared between women who experienced menopause younger than 45 years and women 45 years or older at onset; the relative risks (95% CIs) were 1.50 (1.28-1.76) for overall CHD, 1.11 (1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19 (1.08-1.31) for CVD mortality, and 1.12 (1.03-1.21) for all-cause mortality. Outcomes were also compared between women between 50 and 54 years at onset of menopause and women younger than 50 years at onset; there was a decreased risk of fatal CHD (relative risk, 0.87; 95% CI, 0.80-0.96) and no effect on stroke. Time since onset of menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies with inconsistent results. The findings of this review indicate a higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause.


Reduced Emergency Department Length of Stay and Proportion of Patients Who Left Without Being Seen Following Implementation of an Interprofessional Vertical Flow Track With Pivot Triage: A Retrospective Pre-/Postintervention Evaluation.
Our objective was to assess change in length of stay and patients who left without being seen following implementation of a pivot triage and interprofessional vertical flow track process at a midwestern academic medical center emergency department. The intervention leveraged an existing interprofessional staffing model including a registered nurse and a paramedic to staff a vertical flow track daily from 1100 to 2300. Pre- and postintervention data were retrospectively abstracted from the electronic charting software. Outcomes included emergency department length of stay and percentage of patients leaving without being seen. Visits for patients during the postintervention period (May 10, 2019, to August 31, 2019) were compared with a corresponding preintervention time period 1 year prior (May 10, 2018, to August 31, 2018). The percentage of patients routed to the vertical flow track increased from 5% to 22% following the process intervention. Median emergency department length of stay decreased from 199 (interquartile range [IQR]: 129-282) to 159 (IQR: 98-232) min. The percentage of patients leaving without being seen decreased from 2.9% to 0.5%; between 1100 and 2300, these changes were more pronounced. Odds of a patient experiencing emergency department length of stay under 180 min increased nearly twofold (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.79-2.08) and odds that a patient stayed to be seen by a medical professional increased sixfold (OR: 5.94, 95% CI: 4.08-8.63). Overall, more than 20% of patients were routed through the vertical flow track following the process change. Implementation of an emergency department pivot triage approach with a dedicated interprofessional vertical flow track was associated with significantly shorter emergency department length of stay and reduced patients leaving without being seen.


Survey of symptoms, respiratory function, and immunology and their relation to glutaraldehyde and other occupational exposures among endoscopy nursing staff.
To find the nature and incidence of symptoms experienced by a large sample of hospital endoscopy nurses. To find whether nurses in endoscopy units develop asthma under current working conditions in endoscopy units. To obtain analytically reliable data on exposure concentrations of glutaraldehyde (GA) vapour in endoscopy units, and to relate them to individual hygiene and work practices. To characterise any exposure-response relations between airborne GA and the occurrence of work related symptoms (WRSs). Due to the growing concern about the perceived increase in WRSs among workers regularly exposed to biocides, all of whom work within a complex multiexposure environment, a cross sectional study was designed. Current endoscopy nurses (n=348) from 59 endoscopy units within the United Kingdom and ex-employees (who had left their job for health reasons (n=18) were surveyed. Symptom questionnaires, end of session spirometry, peak flow diaries, skin prick tests (SPTs) to latex and common aeroallergens, and measurements of total immunoglobulin E (IgE) and IgE specific to GA and latex were performed. Exposure measurements included personal airborne biocide sampling for peak (during biocide changeover) and background (endoscopy room, excluding biocide changeover) concentrations. All 18 ex-employees and 91.4% of the current nurses were primarily exposed to GA, the rest were exposed to a succinaldehyde-formaldehyde (SF) composite. Work related contact dermatitis was reported by 44% of current workers exposed to GA, 56.7% of those exposed to SF composite, and 44.4% of ex-employees. The prevalence of WRSs of the eyes, nose, and lower respiratory tract in current workers exposed to GA was 13.5%, 19.8%, and 8.5% respectively and 50%, 61.1%, and 66.6% in the ex-employees. The mean percentage predicted forced expired volume in 1 second (ppFEV(1)) for ex-employees (93.82, 95% confidence interval (95% CI) 88.53 to 99.11) was significantly lower (p<0.01) than that of current workers exposed to GA (104.08, 95% CI 102.35 to 105.73). Occupational peak flow diaries completed by current workers with WRSs of the lower respiratory tract showed no evidence of bronchial asthma (<15% variation). Six per cent of the population had positive latex SPTs. Positive indications of one GA specific IgE and 4.1% latex specific IgE occurred. There was no conformity between the latex specific IgE and positive SPTs. Positive SPTs to latex were associated with WRSs of dermatitis and ocular WRSs, but no other WRSs. Exposures were above the current maximum exposure limit (MEL) of 0.2 mg/m(3) (0.05 ppm) in eight of the units investigated. A significant relation existed between peak GA concentrations and work related chronic bronchitis and nasal symptoms (after adjustment for types of local ventilation) but not to other WRSs. Peak GA concentrations were significantly higher in units that used both negative pressure room and decontaminating unit ventilation. This study documents a significant level of symptoms reported in the absence of objective evidence of the physiological changes associated with asthma. Ex-employees and current workers with WRSs warrant further study to elucidate the cause and mechanisms for their symptoms. Ventilation systems used for the extraction of aldehydes from the work area may be less effective than expected and due to poor design may even contribute to high peak exposures.


Ventricular tachycardias induced by intracoronary administration of endothelin-1 in dogs.
In 12 anesthetized, open-chest mongrel dogs, endothelin-1 (ET-1) was infused into the left anterior descending coronary artery through an indwelling catheter at a dose of 30 pmol.min-1 for 30 min (n = 8). In four dogs the ET-1 dose was increased to 60 pmol/min for 10 min. Programmed electrical stimulation was used for electrophysiologic studies. Coronary blood flow was reduced by 32% on average without any ischemic ECG signs. QT time (186 +/- 3 ms vs. 218 +/- 6, p < 0.05, and 225 +/- 9, p < 0.05, p < 0.05). Ventricular irritability increased in all cases; ventricular extrasystoles, and nonsustained and sustained tachycardias occurred and, in 11 cases, ventricular fibrillation terminated the experiments. In two dogs, early afterdepolarization was recorded. Therefore, ET-1 is capable of inducing fatal ventricular arrythmias at least partly independent of its vasoconstrictor effect. QT prolongation appears to have a pathophysiologic role in this arrythmogenic effect.


AMPed-up adolescents: The role of age in the abuse of amphetamines and its consequences on cognition and prefrontal cortex development.
Adolescent use of amphetamine and its closely related, methylated version methamphetamine, is alarmingly high in those who use drugs for nonmedical purposes. This raises serious concerns about the potential for this drug use to have a long-lasting, detrimental impact on the normal development of the brain and behavior that is ongoing during adolescence. In this review, we explore recent findings from both human and laboratory animal studies that investigate the consequences of amphetamine and methamphetamine exposure during this stage of life. We highlight studies that assess sex differences in adolescence, as well as those that are designed specifically to address the potential unique effects of adolescent exposure by including groups at other life stages (typically young adulthood). We consider epidemiological studies on age and sex as vulnerability factors for developing problems with the use of amphetamines, as well as human and animal laboratory studies that tap into age differences in use, its short-term effects on behavior, and the long-lasting consequences of this exposure on cognition. We also focus on studies of drug effects in the prefrontal cortex, which is known to be critically important for cognition and is among the later maturing brain regions. Finally, we discuss important issues that should be addressed in future studies so that the field can further our understanding of the mechanisms underlying adolescent use of amphetamines and its outcomes on the developing brain and behavior.


The relationship between hip flexion/extension and the sagittal curves of the spine.
The objective of this study was to develop a finite element model (FEM) in order to study the relationship between hip flexion/extension and the sagittal curves of the spine. A previously developed FEM of the spine, rib cage and pelvis personalized to the 3D reconstructed geometry of a patient using biplanar radiographs was adapted to include the lower limbs including muscles. Simulations were performed to determine: the relationship between hip flexion / extension and lumbar lordosis / thoracic kyphosis, the mechanism of transfer between hip flexion / extension and pelvic rotation, and the influence that knee bending, muscle stiffness, and muscle mass have on the degree to which sagittal spinal curves are modified due to lower limb positioning. Preliminary results showed that the model was able to accurately reproduce published results for the modulation of lumbar lordosis due to hip flexion; which proved to linearly decrease 68% at 90 degrees of flexion. Additional simulations showed that the hamstrings and gluteal muscles were responsible for the transmission of hip flexion to pelvic rotation with the legs straight and flexed respectively, and the important influence of knee bending on lordosis modulation during lower limb positioning. The knowledge gained through this study is intended to be used to improve operative patient positioning.


Association between Single-Nucleotide Polymorphisms of the hOGG1,NEIL1,APEX1, FEN1,LIG1, and LIG3 Genes and Alzheimer's Disease Risk.
One of the factors that contribute to Alzheimer's disease (AD) is the DNA damage caused by oxidative stress and inflammation that occurs in nerve cells. It has been suggested that the risk of AD may be associated with an age-dependent reduction of the DNA repair efficiency. Base excision repair (BER) is, among other things, a main repair system of oxidative DNA damage. One of the reasons for the reduced efficiency of this system may be single-nucleotide polymorphisms (SNP) of the genes encoding its proteins. DNA for genotyping was obtained from the peripheral blood of 281 patients and 150 controls. In the present study, we evaluated the impact of 8 polymorphisms of 6 BER genes on the AD risk. We analyzed the following SNP: c.-468T>G and c.444T>G of APEX1, c.*50C>T and c.*83A>C of LIG3, c.977C>G of OGG1, c.*283C>G of NEIL1, c.-441G>A of FEN1, and c.-7C>T of LIG1. We showed that the LIG1 c.-7C>T A/A and LIG3 c.*83A>C A/C variants increased, while the APEX1 c.444T>G G/T, LIG1 c.-7C>T G/, LIG3 c.*83A>C C/C variants reduced, the AD risk. We also evaluated the relation between gene-gene interactions and the AD risk. We showed that combinations of certain BER gene variants such as c.977C>G×c.*50C>T CC/CT, c.444T>G×c.*50C>T GG/CT, c.-468T>G×c.*50C>T GG/CT, c.-441G>Ac.*50C>T×c.*50C>T GG/CT, c.*83A>C× c.*50C>T CT/AC, and c.-7C>T×c.*50C>T CT/GG can substantially positively modulate the risk of AD. In conclusion, we revealed that polymorphisms of BER genes may have a significant effect on the AD risk, and the presence of polymorphic variants may be an important marker for AD.


High ubiquitin-specific protease 44 expression induces DNA aneuploidy and provides independent prognostic information in gastric cancer.
Chromosomal instability (CIN), characterized by aneuploidy, is a major molecular subtype of gastric cancer. The deubiquitinase USP44 is an important regulator of APC activation in the spindle checkpoint and leads to proper chromosome separation to prevent aneuploidy. Aberrant expression of USP44 leads CIN in cells; however, the correlation between USP44 and DNA aneuploidy in gastric cancer is largely unknown. We analyzed USP44 expression in 207 patients with gastric cancer by immunohistochemistry and found that the proportion of USP44 expression was higher in gastric cancer tumors (mean, 39.6%) than in gastric normal mucosa (mean, 14.6%) (P < 0.0001). DNA aneuploidy was observed in 124 gastric cancer cases and high USP44 expression in cancer strongly correlated with DNA aneuploidy (P = 0.0005). The overall survival was significantly poorer in the high USP44 expression group compared with the low USP44 group (P = 0.033). Notably, USP44 expression had no prognostic impact in the diploid subgroup; however, high USP44 expression was a strong poor prognostic factor for progression-free survival (P = 0.018) and overall survival (P = 0.036) in the aneuploid subgroup. We also confirmed that stable overexpression of USP44 induced somatic copy-number aberrations in hTERT-RPE-1 cells (50.6%) in comparison with controls (6.6%) (P < 0.0001). Collectively, our data show USP44 has clinical impact on the induction of DNA aneuploidy and poor prognosis in the CIN gastric cancer subtype.


Migration to the medieval Middle East with the crusades.
During the 12th and 13th centuries thousands of people moved from Europe to the Middle East to fight, undertake pilgrimage, or settle and make a new life. The aim of this research is to investigate two populations from the Crusader kingdom of Jerusalem, by determining who was born in Europe and who came from the Middle East. Oxygen and strontium stable isotope analyses were conducted on the enamel of teeth from skeletal remains excavated from Crusader contexts. Twenty individuals from the coastal city of Caesarea (10 high status and 10 low status), and two local Near Eastern Christian farmers from the village of Parvum Gerinum (Tel Jezreel) were analyzed as a control sample. Results were compared with known geographic values for oxygen and strontium isotopes. The population of the city of Caesarea appears to have been dominated by European-born individuals (probably 19/20, but at least 13/20), with few locals. This was surprising as a much higher proportion of locals were expected. Both controls from the farming village of Parvum Gerinum had spent their childhood in the area of the village, which matches our understanding of limited mobility among poor Medieval farmers. This is the first time that stable isotope analysis has been applied to the study of the migration of peoples between Medieval Europe and the Middle East at the time of the crusades. In view of these findings, we must now rethink past estimations of population social structure in Levantine coastal Medieval cities during the Crusader period.


What every spine surgeon should know about transforaminal lumbar interbody fusion surgery for herniated discs.
The aim of this study is to report our experiences on managing large lumbar disc herniations with several symptoms by surgery with transforaminal lumbar interbody fusion (TLIF) and to shed light for spine surgeons about TLIF surgery. We retrospectively evaluated our database of patients with various lumbar spine pathologies who underwent TLIF surgery from 2014 to 2017. We separated 18 patients who had been operated on for extruded disc herniation, which causes severe pain and radicular symptoms. The pain was quantified by visual analog scores (VAS). The disability status were pre-operatively and post-operatively evaluated by the Oswestry Disability Index (ODI). We evaluated the patients for at least two years. Interbody fusion was detected by routine radiographs at six, 12, and 24 months after surgery. An ODI outcomes analysis demonstrated a statistically significant improvement in the six and 24-month mean scores compared with the pre-operative scores on the same scales. Patients' mobility improved significantly after surgery, as indicated by the decrease in the Oswestry Disability Index from 72 to 23 over two years (p < 0.001). Pain rapidly decreased in all patients and continued to decrease at the time of the latest follow-up. The mean pre-operative VAS scores for pain was 8.8; it had improved to 2.4 after surgery (p < 0.05). Within the follow-up period of two years, the ascertained mean VAS declined from 8.8 to 1.4 (p < 0.001). The average disc space height at the herniated levels was fairly well maintained. No patient had evidence of implant failure. Interbody fusion was graded as definitely solid in 100% of cases two years post-operatively. One patient displayed a superficial wound infection. Following appropriate debridement and antibiotics, the wound healed without sequelae. No major complications were observed, including permanent neurological deficit, pulmonary embolism, peri-operative cardiac event, or death. The findings of our study and those in the literature showed that primary herniated disc patients with radicular and chronic low back pain, degenerative changes, bi-radicular symptoms, and instability are required to have fusion after a discectomy. Being a heavy-duty worker is also a criterion for fusion surgery. TLIF is performed by a unilateral approach preserving the interlaminar surface on the contralateral side, which can be used as a site for additional fusion. As an effective results TLIF procedure should be chosen for fusion surgery.


Charting Our Course: Chaplain Documentation as a Performance Improvement Project.
This article presents the results of a 30-month process improvement initiative examining the spiritual assessment documentation patterns of staff chaplains as well as CPE residents and interns at an academic medical center. Preliminary examination of chaplain documentation patterns led to a multidimensional intervention to address perceived documentation limitations and enhance reliability. The intervention resulted in positive changes in documentation patterns as assessed by an expert panel of experienced chaplains. Results offer opportunities for the use of electronic medical record documentation in training of chaplains.


Typical Shape Differences in the Subtalar Joint Bones Between Subjects with Chronic Ankle Instability and Controls.
Bone shapes, particularly those defining the subtalar joint (STJ), have not received much attention yet as a risk factor for developing chronic ankle instability (CAI) after sustaining a lateral ankle sprain (LAS). This study aimed to compare three-dimensional (3D) shape variations in the STJ bones within individuals with CAI and healthy controls. 3D statistical shape models (SSMs) of the STJ bones were built to describe the bone shape variations observed within a population consisting of 26 individuals with unilateral CAI and 26 healthy controls. Using the SSMs and analysis of covariance test, age- and gender-adjusted shape variations in the bones were compared within individuals with CAI and healthy controls. The mean age of the CAI patients (14 males and 12 females) and healthy controls (12 males and 14 females) was 29 (standard deviation [SD] = 11) and 36 years (SD = 11), respectively. Tali and calcanei did not significantly vary between ipsilateral CAI and their contralateral ankle. Two shape modes, one for the talus (p = 0.015, variations in the curvature of the talar lateral process and the inclination angle of the talar neck relative to the body) and one for the calcaneus (p = 0.003, variations in the medial and lateral tuberosities, and the contour of the anterior articular surface), described significant shape differences between the CAI patients and healthy controls. The CAI patients generally had flatter talar joint surfaces and a flattened calcaneal ground-contact surface. These findings suggest that specific bone shapes may increase the risk of developing CAI after sustaining a LAS. © 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:1892-1902, 2019.


EPR Oximetry of Cetuximab-Treated Head-and-Neck Tumours in a Mouse Model.
Head and neck squamous cell carcinoma (HNSCC) tumours are associated with high mortality despite advances in therapy. The monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of advanced HNSCC. However, only a subset of HNSC patients receiving cetuximab actually responds to treatment, underlining the need for a means to tailor treatments of individual patients. The aim of the present study was to investigate the effect of cetuximab treatment on tumour growth, on tumour partial oxygen pressure as measured by LiPc electron paramagnetic resonance oximetry and on the expression of proteins involved in tumour growth, metabolism and hypoxia. Two HNSCC cell lines, UT-SCC-2 and UT-SCC-14, were used to generate xenografts on female BALB/c (nu/nu) nude mice. Mice with xenografts were given three injections of intraperitoneal cetuximab or phosphate-buffered saline, and the tumour volume was recorded continuously. After treatment the tumour partial oxygen pressure was measured by LiPc electron paramagnetic resonance oximetry and the expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, Ki-67, MCT1, MCT4, GLUT1, CAIX and HIF-1α were investigated by immunohistochemistry. In xenografts from both cell lines (UT-SCC-2 and UT-SCC-14) cetuximab had effect on the tumour volume but the effect was more pronounced on UT-SCC-14 xenografts. A higher tumour oxygenation was measured in cetuximab-treated tumours from both cell lines compared to untreated controls. Immunocytochemical staining after cetuximab treatment shows a significantly decreased expression of EGFR, pEGFR, Ki67, CAIX and nuclear HIF-1α in UT-SCC-14 tumours compared to untreated controls. MCT1 and GLUT1 were significantly decreased in tumours from both cell lines but more pronounced in UT-SCC-14 tumours. Taken together, our results show that cetuximab treatment decreases the tumour growth and increases the tumour partial oxygen pressure of HNSCC xenografts. Furthermore we found a potential connection between the partial oxygen pressure of the tumours and the expression of proteins involved in tumour growth, metabolism and hypoxia.


What Patients and Providers Want to Know About Complementary and Integrative Health Therapies.
We conducted a quality improvement project to determine (1) what information providers and patients most wanted to learn about complementary and integrative health (CIH) therapies and (2) in what format they wanted to receive this information. The overall aim was to develop educational materials to facilitate the CIH therapy decision-making processes. We used mixed methods to iteratively pilot test and revise provider and patient educational materials on yoga and meditation. We conducted semistructured interviews with 11 medical providers and held seven focus groups and used feedback forms with 52 outpatients. We iteratively developed and tested three versions of both provider and patient materials. Activities were conducted at four Veterans Administration medical facilities (two large medical centers and two outpatient clinics). Patients want educational materials with clearly stated basic information about: (1) what mindfulness and yoga are, (2) what a yoga/meditation class entails and how classes can be modified to suit different abilities, (3) key benefits to health and wellness, and (4) how to find classes at the hospital/clinic. Diverse media (videos, handouts, pocket guides) appealed to different Veterans. Videos should depict patients speaking to patients and demonstrating the CIH therapy. Written materials should be one to three pages with colors, and images and messages targeting a variety of patients. Providers wanted a concise (one-page) sheet in black and white font with no images listing the scientific evidence for CIH therapies from high-impact journals, organized by either type of CIH or health condition to use during patient encounters, and including practical information about how to refer patients. Providers and patients want to learn more about CIH therapies, but want the information in succinct, targeted formats. The information learned and materials developed in this study can be used by others to educate patients and providers on CIH therapies.


The psychosocial context of bipolar disorder: environmental, cognitive, and developmental risk factors.
In this article, we review empirical research on the role of individuals' current environmental contexts, cognitive styles, and developmental histories as risk factors for the onset, course, and expression of bipolar spectrum disorders. Our review is focused on the following over arching question: Do psychosocial factors truly contribute risk to the onset, course, or expression of bipolar disorders? As a secondary issue, we also address whether the psychosocial risks for bipolar disorders are similar to those for unipolar depression. We begin by discussing the methodological requirements for demonstrating a psychosocial risk factor and the challenges posed by bipolar spectrum disorders for psychosocial risk research. Next, we review the extant studies on the role of recent life events and supportive and non-supportive social interactions (current environment) in bipolar disorders, as well as psychosocial treatments designed to remediate these current environmental factors. We then review the role of cognitive styles featured as vulnerabilities in theories of unipolar depression as risk factors for bipolar disorder alone and in combination with life events, including studies of cognitive-behavioral therapies for bipolar disorder. Finally, we review studies of parenting and maltreatment histories in bipolar disorders. We conclude with an assessment of the state of the psychosocial risk factors literature in bipolar disorder with regard to our guiding questions.


Regulatory role of human AP-endonuclease (APE1/Ref-1) in YB-1-mediated activation of the multidrug resistance gene MDR1.
Human AP-endonuclease (APE1/Ref-1), a central enzyme involved in the repair of oxidative base damage and DNA strand breaks, has a second activity as a transcriptional regulator that binds to several trans-acting factors. APE1 overexpression is often observed in tumor cells and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to such agents. Because the involvement of APE1 in repairing the DNA damage induced by many of these drugs is unlikely, drug resistance may be linked to APE1's transcriptional regulatory function. Here, we show that APE1, preferably in the acetylated form, stably interacts with Y-box-binding protein 1 (YB-1) and enhances its binding to the Y-box element, leading to the activation of the multidrug resistance gene MDR1. The enhanced MDR1 level due to the ectopic expression of wild-type APE1 but not of its nonacetylable mutant underscores the importance of APE1's acetylation in its coactivator function. APE1 downregulation sensitizes MDR1-overexpressing tumor cells to cisplatin or doxorubicin, showing APE1's critical role in YB-1-mediated gene expression and, thus, drug resistance in tumor cells. A systematic increase in both APE1 and MDR1 expression was observed in non-small-cell lung cancer tissue samples. Thus, our study has established the novel role of the acetylation-mediated transcriptional regulatory function of APE1, making it a potential target for the drug sensitization of tumor cells.


Machine-Learning Classification of Bacteria Using Two-Dimensional Tandem Mass Spectrometry.
Biothreat detection has continued to gain attention. Samples suspected to fall into any of the CDC's biothreat categories require identification by processes that require specialized expertise and facilities. Recent developments in analytical instrumentation and machine learning algorithms offer rapid and accurate classification of Gram-positive and Gram-negative bacterial species. This is achieved by analyzing the negative ions generated from bacterial cell extracts with a modified linear quadrupole ion-trap mass spectrometer fitted with two-dimensional tandem mass spectrometry capabilities (2D MS/MS). The 2D MS/MS data domain of a bacterial cell extract is recorded within five s using a five-scan average after sample preparation by a simple extraction. Bacteria were classified at the species level by their lipid profiles using the random forest, k-nearest neighbor, and multilayer perceptron machine learning models. 2D MS/MS data can also be treated as image data for use with image recognition algorithms such as convolutional neural networks. The classification accuracy of all models tested was greater than 99%. Adding to previously published work on the 2D MS/MS analysis of bacterial growth and the profiling of sporulating bacteria, this study demonstrates the utility and information-rich nature of 2D MS/MS in the identification of bacterial pathogens at the species level when coupled with machine learning.


Are three weeks hypofractionated radiation therapy (HFRT) comparable to six weeks for newly diagnosed glioblastoma patients? Results of a phase II study.
The current standard of care for newly diagnosed glioblastoma (GBM) is surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT). The patients outcome is still poor. In this study we evaluated hypofractionated radiation therapy (HFRT), instead of standard fractionated radiation therapy, with concomitant and adjuvant TMZ chemotherapy, in terms of safety and effectiveness. Patients with newly diagnosed GBM, Karnofsky performance scale (KPS) ≥70, and tumor up to 10 cm underwent maximal feasible surgical resection were treated. HFRT consisted of 60 Gy, in daily fractions of 4 Gy given 5 days per week for 3 weeks. The primary endpoints were overall survival (OS), progression free survival (PFS), and incidence of radiation induced brain toxicity. Secondary endpoint was the evaluation of neurocognitive function. A total of 97 patients were included in this phase II study. The median age was 60.5 years (range 23-77 years). Debulking surgery was performed in 83.5% of patients, HFRT was completed in all 97 patients, concurrent and adjuvant TMZ in 93 (95.9%). The median number of TMZ cycles was six (range 1-12 cycles). No severe toxicity occurred and the neuropsychological evaluation remained stable. At a median follow up time of 15.2 months the median OS time, 1,2-year OS rate were 15.9 months (95% CI 14-18), 72.2% (95% CI 62.1-80) and 30.4% (95% CI 20.8-40.6). Age, KPS, MGMT methylation status, and extent of surgical resection were significant factors influencing the outcome. HFRT with concomitant and adjuvant TMZ chemotherapy is an effective and safe treatment.


Inhibition of intravacuolar acidification by antisense RNA decreases osteoclast differentiation and bone resorption in vitro.
The role of proton transport and production in osteoclast differentiation was studied in vitro by inhibiting the transcription/translation of carbonic anhydrase II (CA II) and vacuolar H(+)-ATPase (V-ATPase) by antisense RNA molecules. Antisense RNAs targeted against CA II, or the 16 kDa or 60 kDa subunit of V-ATPase were used to block the expression of the specific proteins. A significant decrease in bone resorption rate and TRAP-positive osteoclast number was seen in rat bone marrow cultures and fetal mouse metacarpal cultures after antisense treatment. Intravacuolar acidification in rat bone marrow cells was also significantly decreased after antisense treatment. The CA II antisense RNA increased the number of TRAP-positive mononuclear cells, suggesting inhibition of osteoclast precursor fusion. Antisense molecules decreased the number of monocytes and macrophages, but increased the number of granulocytes in marrow cultures. GM-CSF, IL-3 and IL-6 were used to stimulate haematopoietic stem cell differentiation. The 16 kDa V-ATPase antisense RNA abolished the stimulatory effect of GM-CSF, IL-3 and IL-6 on TRAP-positive osteoclast formation, but did not affect the formation of monocytes and macrophages after IL-3 treatment, or the formation of granulocytes after IL-6 treatment. These results suggest that CA II and V-ATPase are needed, not only for the actual resorption, but also for osteoclast formation in vitro.


Xanthohumol inhibits colorectal cancer cells via downregulation of Hexokinases II-mediated glycolysis.
Deregulation of glycolysis is a common phenomenon in human colorectal cancer (CRC). In the present study, we reported that Hexokinase 2 (HK2) is overexpressed in human CRC tissues and cell lines, knockout of HK2 inhibited cell proliferation, colony formation, and xenograft tumor growth. We demonstrated that the natural compound, xanthohumol, has a profound anti-tumor effect on CRC via down-regulation of HK2 and glycolysis. Xanthohumol suppressed CRC cell growth both in vitro and in vivo. Treatment with xanthohumol promoted the release of cytochrome C and activated the intrinsic apoptosis pathway. Moreover, our results revealed that xanthohumol down-regulated the EGFR-Akt signaling, exogenous overexpression of constitutively activated Akt1 significantly impaired xanthohumol-induced glycolysis suppression and apoptosis induction. Our results suggest that targeting HK2 appears to be a new approach for clinical CRC prevention or treatment.


Evaluating the benefit of serology during potential Australian bat lyssavirus and rabies post-exposure prophylaxis.
Post-exposure prophylaxis (PEP) for potential lyssavirus exposures consists of wound management, rabies vaccination and may include rabies immunoglobulin (RIG). Rabies serology is sometimes indicated if there is risk of PEP failure. Evaluate the benefit of serology by indication. Chart review of potential lyssavirus exposures managed at a Public Health Unit (June 2015 - December 2022) where serology was requested was conducted. The proportion of non-therapeutic titres was compared by sex, age, Indigenous status, serology indication, and whether RIG was given. 46 notifications with serology were included. Males (5/19) and people over 40 (3/16) were more likely to demonstrate a non-therapeutic response. 2/3 of cases where vaccine doses were not given in the deltoid were non-therapeutic. The rate of non-therapeutic titres was similar for RIG given into the ipsilateral arm (2/11) and given excess RIG for weight (1/4). Although this small sample was inconclusive in isolation, it was also noted that all cases who did not receive RIG had therapeutic serology, whereas 6/35 of those receiving RIG had non-therapeutic serology. This study supports broader literature questioning the utility of systemic RIG administration as likely limited and potentially detrimental considering the increased risk of immune interference. Highlights a need to review Australian national guidelines to align with World Health Organization advice recommending local RIG administration only.


Opioid use disorder during pregnancy in Tennessee: expediency vs. science.
Methadone and buprenorphine are highly effective and commonly prescribed for the treatment of opioid use disorder. Both medications are also efficacious for the treatment of pregnant women with this disorder. In one third of states, however, Medicaid reimbursement will cover the cost of buprenorphine, but not methadone, to treat opioid use disorder in pregnant women. This commentary will explore the clinical and policy rational and consequences of this policy, with the opinion that this approach is guided by political expediency rather than sound clinical research. The commentary will focus on the pharmacological management of prescription opioid dependence during pregnancy in Tennessee, one of the states that restrict Medicaid coverage of pregnant women to buprenorphine. Tennessee is also relevant in that this state ranks second nationally in the rate of prescriptions written for opioid pain relievers; in contrast to injection opioid use in urban populations, opioid addiction in rural and southeastern regions of the US is characterized by use of non-injection prescription opioids. Until recently, most research-based recommendations for the management of opioid use disorder during pregnancy have derived from studies of women using opioids intravenously. The lack of research in non-injection opioid-using pregnant women may partially explain why policy rather than scientific evidence guides Medicaid reimbursement. It is hoped that future research in pregnant women addicted to prescription opioids will clarify which opioid addicted pregnant women have better outcomes with buprenorphine or methadone treatment and these findings, in turn, will inform Medicaid reimbursement.


New Pesticidal Diterpenoids from Vellozia gigantea (Velloziaceae), an Endemic Neotropical Plant Living in the Endangered Brazilian Biome Rupestrian Grasslands.
Vellozia gigantea is a rare, ancient, and endemic neotropical plant present in the Brazilian Rupestrian grasslands. The dichloromethane extract of V. gigantea adventitious roots was phytotoxic against Lactuca sativa, Agrostis stolonifera, and Lemna paucicostata, and showed larvicidal activity against Aedes aegypti. Phytotoxicity bioassay-directed fractionation of the extract revealed one new isopimaradiene, 8(9),15-isopimaradien-1,3,7,11-tetraone, and three new cleistanthane diterpenoids, 7-oxo-8,11,13-cleistanthatrien-3-ol, 3,20-epoxy-7-oxo-8,11,13-cleistanthatrien-3-ol, and 20-nor-3,7-dioxo-1,8,11,13-cleistanthatetraen-10-ol. These new structures are proposed based on interpretation of ¹H, 13C, COSY, NOESY, HSQC, and HMBC NMR data. 8(9),15-isopimaradien-1,3,7,11-tetraone was especially phytotoxic with an IC50 value (30 μM) comparable to those of commercial herbicides clomazone, EPTC, and naptalam. In addition, 7-oxo-8,11,13-cleistanthatrien-3-ol provided 100% mortality at a concentration of 125 ppm against one-day-old Ae. aegypti larvae. Our results show that ancient and unique plants, like the endangered narrowly endemic neotropical species V. gigantea present in the Rupestrian grasslands, should also be protected because they can be sources of new bioactive compounds.


Neurological study on the effect of CeNPs and/or La Cl3 on adult male albino rats.
Lanthanides are a group of 15 elements (8 heavy and 7 light) grouped for their proximity in the chemical and physical properties. Recently, this group of elements has received great attention because of their importance, and their entrance into many industrial technologies making the probability of the living organisms' exposure to it increase. The present study aims to study ability of cerium nanoparticles (CeNPs) or lanthanum (LaCl3) to cross the blood brain barrier also, investigate their neuro effect separately or together on some parameters in six brain areas (cortex, cerebellum, hippocampus, striatum, midbrain, and hypothalamus) of the adult male albino rats. The results showed the ability of both elements to distribute and accumulate in the different brain areas. Also, the results of CeNPs or LaCl3 treatment were in the same line where each element caused a significant decrease in norepinephrine (NE), dopamine (DA), serotonin (5-HT) and GABA accompanied with a significant increase in 5- hydroxyl indoleacetic acid (5-HIAA) glucose level. On the other hand, GSH and MDA showed a significant decrease after CeNPs treatment while, with LaCl3 treatment, MDA showed a significant increase in the different brain areas after 3 weeks of treatment. The coadministration of CeNPs and La Cl3 caused an ameliorating effect in all the tested parameters. In conclusion, from the previous studies the effects of lanthanides in the present study may be in part due to its effect on the release or turnover of neurotransmitters and insulin secretion. Finally, the ameliorative effect of CeNPs may be regarded as its high activity to scavenge the free radicals.


Dynamic Visualization and Fast Computation for Convex Clustering via Algorithmic Regularization.
Convex clustering is a promising new approach to the classical problem of clustering, combining strong performance in empirical studies with rigorous theoretical foundations. Despite these advantages, convex clustering has not been widely adopted, due to its computationally intensive nature and its lack of compelling visualizations. To address these impediments, we introduce Algorithmic Regularization, an innovative technique for obtaining high-quality estimates of regularization paths using an iterative one-step approximation scheme. We justify our approach with a novel theoretical result, guaranteeing global convergence of the approximate path to the exact solution under easily-checked non-data-dependent assumptions. The application of algorithmic regularization to convex clustering yields the Convex Clustering via Algorithmic Regularization Paths (CARP) algorithm for computing the clustering solution path. On example data sets from genomics and text analysis, CARP delivers over a 100-fold speed-up over existing methods, while attaining a finer approximation grid than standard methods. Furthermore, CARP enables improved visualization of clustering solutions: the fine solution grid returned by CARP can be used to construct a convex clustering-based dendrogram, as well as forming the basis of a dynamic path-wise visualization based on modern web technologies. Our methods are implemented in the open-source R package clustRviz, available at https://github.com/DataSlingers/clustRviz.


Thialkalivibrio halophilus sp. nov., a novel obligately chemolithoautotrophic, facultatively alkaliphilic, and extremely salt-tolerant, sulfur-oxidizing bacterium from a hypersaline alkaline lake.
A new chemolithoautotrophic, facultatively alkaliphilic, extremely salt-tolerant, sulfur-oxidizing bacterium was isolated from an alkaline hypersaline lake in the Altai Steppe (Siberia, Russia). According to 16S rDNA analysis and DNA-DNA hybridization, strain HL 17T was identified as a new species of the genus Thialkalivibrio belonging to the gamma subdivision of the Proteobacteria for which the name Thialkalivibrio halophilus is proposed. Strain HL 17T is an extremely salt-tolerant bacterium growing at sodium concentrations between 0.2 and 5 M, with an optimum of 2 M Na+. It grew at high concentrations of NaCl and of Na2CO3/NaHCO3 (soda). Strain HL 17T is a facultative alkaliphile growing at pH range 7.5-9.8, with a broad optimum between pH 8.0 and 9.0. It used reduced inorganic sulfur compounds (thiosulfate, sulfide, polysulfide, elemental sulfur, and tetrathionate) as energy sources and electron donors. In continuous culture under energy limitation, thiosulfate was stoichiometrically oxidized to sulfate. In sodium carbonate medium under alkaline conditions, the maximum growth rate was similar, while the biomass yield was lower as compared with the NaCl-grown culture. The maximum sulfur-oxidizing capacity measured in washed cells was higher in the soda buffer independent of the growth conditions. The compatible solute content of the biomass was higher in the sodium chloride-grown culture than in the sodium carbonate/bicarbonate-grown culture. The data suggest that the osmotic pressure differences between soda and NaCl solutions might be responsible for the difference observed in compatible solutes production. This may have important implications in overall energetic metabolism of high salt adaptation.


Angiotensin-(1-7) does not affect vasodilator or TPA responses to bradykinin in human forearm.
Studies in isolated vessels and rat models of hypertension suggest that angiotensin (Ang)-(1-7) potentiates the vasodilator effect of bradykinin, possibly through ACE inhibition. We therefore tested the hypothesis that Ang-(1-7) potentiates the vasodilator or tissue plasminogen activator (TPA) response to bradykinin in the human forearm vasculature. Graded doses of Ang-(1-7) (10, 100, and 300 pmol/min), bradykinin (47, 94, and 189 pmol/min), and Ang I (1, 10, and 30 pmol/min) were administered through the brachial artery to 8 normotensive subjects in random order. Thirty minutes after initiation of a constant infusion of Ang-(1-7) (100 pmol/min), bradykinin and Ang I infusions were repeated. There were no systemic hemodynamic effects of the agonists. Bradykinin significantly increased forearm blood flow (P<0.001, from 3.8+/-0.5 to 13.9+/-3.1 mL/min per 100 mL at 189 pmol/min) and net TPA release (P=0.007, from 1.1+/-1.0 to 23.6+/-6.2 ng/min per 100 mL at 189 pmol/min), whereas Ang I caused vasoconstriction (P=0.003, from 3.3+/-0.4 to 2.5+/-0.3 mL/min per 100 mL at 30-pmol/min dose). There was no effect of Ang-(1-7) on either forearm blood flow (P=0.62, 3.3+/-0.4 to 3.5+/-0.4 mL/min per 100 mL at 300 pmol/min) or TPA release (P=0.52, from 0.7+/-0.8 to 1.0+/-0.7 ng/min/100 mL at 300 pmol/min). Moreover, there was no effect of 100 pmol/min Ang-(1-7) on the vasodilator [P=0.46 for Ang-(1-7) effect] or TPA [P=0.82 for Ang-(1-7) effect] response to bradykinin or the vasoconstrictor response to Ang I [P=0.62 for Ang-(1-7) effect]. These data do not support a role of Ang-(1-7), given at supraphysiological doses, in the regulation of human peripheral vascular resistance or fibrinolysis.


Use of Smart Technology for the Early Diagnosis of Complications After Cardiac Surgery: The Box 2.0 Study Protocol.
Atrial fibrillation (AF), sternal wound infection, and cardiac decompensation are complications that can occur after cardiac surgery. Early detection of these complications is clinically relevant, as early treatment is associated with better clinical outcomes. Remote monitoring with the use of a smartphone (mobile health [mHealth]) might improve the early detection of complications after cardiac surgery. The primary aim of this study is to compare the detection rate of AF diagnosed with an mHealth solution to the detection rate of AF diagnosed with standard care. Secondary objectives include detection of sternal wound infection and cardiac decompensation, as well as assessment of quality of life, patient satisfaction, and cost-effectiveness. The Box 2.0 is a study with a prospective intervention group and a historical control group for comparison. Patients undergoing cardiac surgery at Leiden University Medical Center are eligible for enrollment. In this study, 365 historical patients will be used as controls and 365 other participants will be asked to receive either The Box 2.0 intervention consisting of seven home measurement devices along with a video consultation 2 weeks after discharge or standard cardiac care for 3 months. Patient information will be analyzed according to the intention-to-treat principle. The Box 2.0 devices include a blood pressure monitor, thermometer, weight scale, step count watch, single-lead electrocardiogram (ECG) device, 12-lead ECG device, and pulse oximeter. The study started in November 2018. The primary outcome of this study is the detection rate of AF in both groups. Quality of life is measured with the five-level EuroQol five-dimension (EQ-5D-5L) questionnaire. Cost-effectiveness is calculated from a society perspective using prices from Dutch costing guidelines and quality of life data from the study. In the historical cohort, 93.9% (336/358) completed the EQ-5D-5L and patient satisfaction questionnaires 3 months after cardiac surgery. The rationale and design of a study to investigate mHealth devices in postoperative cardiac surgery patients are presented. The first results are expected in September 2020. ClinicalTrials.gov NCT03690492; http://clinicaltrials.gov/show/NCT03690492. DERR1-10.2196/16326.


The role of negative urgency and expectancies in problem drinking and disordered eating: testing a model of comorbidity in pathological and at-risk samples.
The aim of this study was to test hypotheses derived from a model that explains both the comorbidity of problem drinking and eating disorder symptoms and the difference in risk process between the two disorders. In Study One, the authors examined four personality constructs typically associated with rash action (sensation seeking, lack of planning, lack of persistence, and negative urgency) and disorder-specific expectancies in samples of women with eating disorders, substance dependence disorders, comorbid conditions, and no symptoms (N = 104). Negative urgency, the tendency to act rashly when distressed, differentiated the disordered groups from the control group. In contrast, learned expectancies differentiated among clinical groups. Women with eating disorders endorsed high levels of eating and dieting expectancies and women with substance use disorders endorsed high levels of alcohol expectancies, while comorbid women endorsed high levels of both. In Study Two, this pattern of findings was replicated in a sample of fifth grade girls (N = 905). Girls who had engaged in binge eating, alcohol use, or both had higher levels of negative urgency than asymptomatic girls, and the pattern of outcome expectancy endorsement was disorder specific. Negative urgency may represent a general, personality influence on both eating disordered behaviors and symptoms of alcohol dependence, which, when combined with learned, behavior-specific expectancies, leads to specific addictive behavior patterns.


The function of loud calls in black howler monkeys (Alouatta pigra): food, mate, or infant defense?
Loud calling (i.e., howling) is the single most distinctive behavioral attribute of the social system of howler monkeys (Alouatta spp.), yet no general consensus exists regarding its main function. During a 28-month study of five groups of black howler monkeys (Alouatta pigra) at Palenque National Park, Mexico, we examined whether howling mainly functioned in the defense of food resources, mates, or infants vulnerable to infanticide. We recorded 602 howling bouts. Howling occurred more frequently when monkeys were feeding, particularly on fruits, and less frequently when they were resting than would be expected by chance. Furthermore, howling was concentrated in areas of the home range in which major feeding sites were located. Howling did not occur more frequently when vulnerable infants or potentially fertile females were present versus absent, nor did the howling rate increase with an increasing number of vulnerable infants or potentially fertile females in the group. Howling bouts lasted on average 14.4 ± SE 0.5 min, and call duration was not influenced by the presence of vulnerable infants or potentially fertile females. The duration of spontaneous calls, however, was positively correlated to the percentage of feeding time in the vicinity of howling locations. In addition, vocal displays lasted longer when neighboring groups and extragroup males were within visual contact compared with spontaneous calls and calls in response to nearby calls in which there was no visual contact between callers. Our findings suggest that loud calls in black howler monkeys are multifunctional, but most frequently occur in the defense of major feeding sites. These calls also may function in the defense of infants and mates during encounters with extragroup males.


Does duration of spousal caregiving affect risk of depression onset? Evidence from the Health and Retirement Study.
To assess the association of current and long-term spousal caregiving with risk of depression in a nationally (U.S.) representative sample of older adults. We studied married and depression-free Health and Retirement Study respondents aged 50 years and older (n = 9,420) at baseline from 2000 to 2010. Current (≥14 hours per week of help with instrumental/activities of daily living for a spouse in the most recent biennial survey) and long-term caregiving (care at two consecutive surveys) were used to predict onset of elevated depressive symptoms (≥3 on a modified Centers for Epidemiologic Studies Depression scale) with discrete-time hazards models and time-updated exposure and covariate information. Current caregiving was associated with significant elevations in risk of depression onset (hazard ratio: 1.64; Wald χ(2), 1 df: 28.34; p <0.0001). Effect estimates for long-term caregiving were similar (hazard ratio: 1.52, Wald χ(2), 1 df: 3.63; p = 0.06). Current spousal caregiving significantly predicted onset of depression; the association was not exacerbated by longer duration of caregiving.


Risk Factors, Clinical Consequences, Prevention, and Treatment of Childhood Obesity.
Obesity might adversely affect the health and well-being of children and their families. Childhood obesity has crucial implications for health, both during childhood and as they age. It is highly associated with many acute problems and is commonly present during childhood, making visits and hospital admissions polarized in this group of children. The problems that may affect these children can be medical, such as asthma, chronic inflammation, orthopedic abnormalities, liver disease, diabetes mellitus or dyslipidemia. Long-term consequences of cardiovascular risk factors, the persistence of obesity and premature mortality are common among adults who had obesity during their early lives. Additionally, they could also suffer from psychological issues, such as low self-esteem, which puts them at risk of a much more serious psychosocial problem that may lead to depression, as well as a disruption in educational achievements and social relationships. A healthy diet, physical activity, adequate sleep, and limited screen time are all preventive measures that should be implemented at the family and community levels, preferably through well-structured programs. Furthermore, pharmacological management of childhood obesity is limited and only used after non-pharmacological interventions have failed or in the late stages of obesity. However, recent guidelines advocate the early use of medical interventions. Approved pharmacotherapeutic options include orlistat, phentermine/topiramate combination and liraglutide. There are several other options approved primarily for other specific forms of obesity or for other indications, including setmelanotide, metformin, lisdexamfetamine, zonisamide and fluoxetine. Bariatric surgery is a safe and effective option in cases with extreme obesity and comorbidities considering the need for long-term monitoring and support for cases and their families post-surgery. This review aims to discuss and highlight the recent evidence regarding risk factors, clinical consequences, prevention, and treatment of childhood obesity.


Education-to-job mismatch and the risk of work injury.
To examine the association between education-to-job mismatch and work injury. Cross-sectional data from the 2003 and 2005 Canadian Community Health Surveys (n=63,462) were used to examine the relationship between having an educational level that is incongruent with occupational skills requirements and the risk of sustaining a work injury requiring medical attention or a work-related repetitive movement injury (RMI). The effect on injury of the interaction of overeducation with recent immigrant status was also examined. Models were stratified by sex and adjusted for possible confounders. Occupational physical demands were conceptualised as a potential mediating variable. After adjustment for covariates, over-education was associated with work injury and RMI for both sexes. Adjustment for occupational demands attenuated the impact on work injury but did not eliminate the effect on RMI among men. The interaction of over-education and recent immigrant status resulted among men in a fourfold increase in the odds of work injury compared with non-recent immigrants who were not over-educated. After adjustment for occupational demands, over-educated recent immigrant men still had more than a twofold increase in the odds of injury. The risk of sustaining a work injury is higher among those whose education exceeds that of job requirements. These findings highlight the need to address barriers to suitable employment, particularly among recent immigrants.


An audit of diagnostic coding in genitourinary medicine clinics. Trent Region Genitourinary Medicine Audit Group.
The KC60 diagnostic code information provides an epidemiological monitor of sexually transmitted infection (STI) and a means of standardizing clinical workload in genitourinary medicine (GUM) departments. We aimed to assess the coding process and its uniformity within the Trent region by means of a confidential self-administered coding exercise with simulated case presentations. The correct coding for STIs ranged from 59.4% to 100% in different scenarios. Difficulty was identified in the coding of vulvitis and balanitis where no organism was isolated, as represented by a wide range of codes. HIV pre-test counselling without testing was coded by only 57.8% of respondents. Over 95% indicated correctly the first hepatitis B vaccine dose but 21% failed to code once only for the course. Coding practice also varied within individual sites with a 21-100% discordance. In parts diagnostic accuracy was good but there were areas of non-uniformity both within sites and cross-regionally. Regional discussions have resulted in increased training opportunities and guidelines have been developed to increase uniformity and achieve consensus in uncertain areas.


Prevalence of elevated glycated hemoglobin concentrations in the polycystic ovary syndrome: anthropometrical and metabolic relationship in amazonian women.
To determine the prevalence of elevated glycated hemoglobin (HbA1c) and to examine its relationship with other carbohydrate metabolic parameter among Brazilian women with polycystic ovary syndrome (PCOS). A cross-sectional study including 288 PCOS patients was conducted. Anthropometrical, clinical, biochemical and endocrine parameters were evaluated. The mean age was 26.92 ± 5.51 years. HbA1c mean concentration was 5.83±1.34%. In 38.54% of patients, HbA1c was ≥ 5.7%. HbA1c was positively correlated with body weight (r = 0.142, P = 0.017), body mass index (P = 0.000), waist:hip ratio (P = 0.000), fat mass (P = 0.000), conicity index (P = 0.000), triglyceride (P = 0.001), C-peptide (P = 0.000), total testosterone (P = 0.003), free testosterone (P = 0.000), free androgen index (P = 0.006) and fasting insulin (P = 0.025). Using the oral glucose tolerance test, HbA1c showed positive correlation with glucose concentrations at any point in time (P < 0.05). HbA1c was elevated in nearly 40% of PCOS patients and it showed positive correlation with several anthropometric and metabolic factors and androgen levels. The current study provides further evidence that HbA1C is higher in PCOS patients and may have a potential role in the prediction of dysglycemic disease in these women.


Tinnitus among airline pilots: prevalence and effects of age, flight experience, and other noise.
Frequent or constant tinnitus can be a problem for pilots because it can be distracting and/or interfere with communications in the cockpit. We studied tinnitus in a population of airline pilots to determine its prevalence and identify predictors. A total of 418 male and 42 female pilots on duty in a Swedish airline returned a completed tinnitus questionnaire (response rate 79%). Multiple logistic regression analysis was performed; variables retained in the model included age, smoking, exposure to loud impulse noise during leisure time, previous work as a military pilot, years of employment as a commercial pilot, and type of aircraft. When available, the pilots' most recent routine audiometric test (N = 388) was used to study the association between hearing impairment and tinnitus. A total of 40% of respondents had experienced tinnitus for more than 5 min during the past year, 18% reported constant or severe tinnitus, and 12% had at some time visited a doctor for problems related to tinnitus. There were associations between tinnitus and age, impulse noise, and hearing impairment at 3, 4, and 6 kHz. There was no association with aircraft type or work as a military pilot. Pilots with tinnitus were more likely to report themselves disturbed by noise in the cockpit. These results show that tinnitus is relatively common among pilots and can create problems with sensitivity to noise. The frequency of tinnitus is most closely related to age, gender, exposure to high impulse noise during leisure time, and hearing impairment.


De novo synthesis of pyrimidine nucleotides; emerging interfaces with signal transduction pathways.
The de novo biosynthesis of pyrimidine nucleotides provides essential precursors for multiple growth-related events in higher eukaryotes. Assembled from ATP, bicarbonate and glutamine, the uracil and cytosine nucleotides are fuel for the synthesis of RNA, DNA, phospholipids, UDP sugars and glycogen. Over the past 2 decades considerable progress has been made in elucidating the mechanisms by which cellular pyrimidines are modulated to meet the needs of the cell. Recent studies demonstrate that CAD, a rate-limiting enzyme in the de novo synthesis of pyrimidines, is regulated through reversible phosphorylation, Myc-dependent transcriptional changes and caspase-mediated degradation. These studies point to increasing evidence for cooperation between key cell signaling pathways and basic elements of cellular metabolism, and suggest that these events have the potential to determine distinct cellular fates, including growth, differentiation and death. This review highlights some of the recent advances in the regulation of pyrimidine synthesis by growth-factor-stimulated signaling pathways.


Bruton's tyrosine kinase is involved in p65-mediated transactivation and phosphorylation of p65 on serine 536 during NFkappaB activation by lipopolysaccharide.
Bruton's tyrosine kinase (Btk) has recently been shown to participate in the induction of nuclear factor kappaB (NFkappaB)-dependent gene expression by the lipopolysaccharide (LPS) receptor Toll-like receptor-4 (TLR4). In this study we have examined the mechanism whereby Btk participates in this response. Treatment of the murine monocytic cell line Raw264.7 with LFM-A13, a specific Btk inhibitor, blocked LPS-induced NFkappaB-dependent reporter gene expression but not IkappaB alpha degradation. Transient transfection of HEK293 cells with Btk had no effect on NFkappaB-dependent reporter gene expression but strongly promoted transactivation of a reporter gene by a p65-Gal4 fusion protein. IkappaB alpha degradation activated by LPS was intact in macrophages from X-linked immunodeficiency (Xid) mice, which contain inactive Btk. Transfection of cells with a dominant negative form of Btk (BtkK430R) inhibited LPS-driven p65 mediated transactivation. Additionally LFM-A13 impaired phosphorylation of serine 536 on p65 induced by LPS in HEK293-TLR4 cells, and in Xid macrophages this response was impaired. This study therefore reveals a novel function for Btk. It is required for the signaling pathway activated by TLR4, which culminates in phosphorylation of p65 on serine 536 promoting transactivation by NFkappaB.


Smoking behaviours of Hong Kong Chinese hospitalised patients and predictors of smoking abstinence after discharge: a cross-sectional study.
Patients admitted to hospitals represent an excellent teachable moment for smoking cessation, as they are required to abstain from tobacco use during hospitalisation. Nevertheless, smoking behaviours of hospitalised patients, and factors that lead to smoking abstinence thereafter, remain relatively underexplored, particularly in a Hong Kong Chinese context. This study aimed to examine the smoking behaviours of hospitalised patients and explore factors leading to their abstaining from cigarette use after being hospitalised. A cross-sectional design was employed. This study was conducted in three outpatient clinics in different regions in Hong Kong. A total of 382 recruited Chinese patients. The patients were asked to complete a structured questionnaire that assessed their smoking behaviours before, during and after hospitalisation. The results indicated 23.6% of smokers smoked secretly during their hospital stay, and about 76.1% of smokers resumed smoking after discharge. Multivariate logistic regression analysis found that number of days of hospitalisation admission in the preceding year (OR 1.02; 95% CI 1.01 to 1.27; p=0.036), patients' perceived correlation between smoking and their illness (OR 1.08; 95% CI 1.01 to 1.17; p=0.032), withdrawal symptoms experienced during hospitalisation (OR 0.75; 95% CI 0.58 to 0.97; p=0.027) and smoking cessation support from healthcare professionals (OR 1.18; 95% CI 1.07 to 1.36; p=0.014) were significant predictors of smoking abstinence after discharge. The results of this study will aid development of appropriate and innovative smoking cessation interventions that can help patients achieve more successful smoking abstinence and less relapse. NCT02866760.


The role of the theta isoform of protein kinase C (PKC) in activity-dependent synapse elimination: evidence from the PKC theta knock-out mouse in vivo and in vitro.
PKC plays a critical role in competitive activity-dependent synapse modification at the neuromuscular synapse in vitro and in vivo. This action involves a reduction of the strength of inactive inputs to muscle cells that are activated by other inputs. A decrease of postsynaptic responsiveness and a loss of postsynaptic acetyl choline receptors account for the heterosynaptic loss in vitro. The loss is not seen in preparations in which PKC has been blocked pharmacologically. Here, we show that the loss does not occur in in vitro preparations made from animals genetically modified to lack the theta isoform of PKC. Synapse elimination in the newborn period in vivo is delayed but is eventually expressed in knock-out animals. PKC-dependent synapse reduction is suppressed in heterologous cultures combining normal nerve and PKC theta-deficient muscle, as might be expected from the postsynaptic locus of the changes that underlie the activity-dependent plasticity. Preparations in which PKC theta-deficient neurons innervated normal muscle also exhibited a marked deficit in PKC-deficient synapse reduction. The presynaptic action of PKC theta implied by this observation is blocked by TTX, and we propose that activity-related synapse strengthening is decreased by presynaptic PKC theta. Thus, PKC theta in both presynaptic and postsynaptic elements plays a critical role in activity-dependent synapse modulation and loss. We provide a model for activity-dependent synapse loss incorporating these findings.


Plastic synaptic networks of the amygdala for the acquisition, expression, and extinction of conditioned fear.
The last 10 years have witnessed a surge of interest for the mechanisms underlying the acquisition and extinction of classically conditioned fear responses. In part, this results from the realization that abnormalities in fear learning mechanisms likely participate in the development and/or maintenance of human anxiety disorders. The simplicity and robustness of this learning paradigm, coupled with the fact that the underlying circuitry is evolutionarily well conserved, make it an ideal model to study the basic biology of memory and identify genetic factors and neuronal systems that regulate the normal and pathological expressions of learned fear. Critical advances have been made in determining how modified neuronal functions upon fear acquisition become stabilized during fear memory consolidation and how these processes are controlled in the course of fear memory extinction. With these advances came the realization that activity in remote neuronal networks must be coordinated for these events to take place. In this paper, we review these mechanisms of coordinated network activity and the molecular cascades leading to enduring fear memory, and allowing for their extinction. We will focus on Pavlovian fear conditioning as a model and the amygdala as a key component for the acquisition and extinction of fear responses.


The interaction in vivo of transferrin and asialotransferrin with liver cells.
Rat transferrin or asialotransferrin doubly radiolabelled with 59Fe and 125I was injected into rats. A determination of extrahepatic and hepatic uptake indicated that asialotransferrin delivers a higher fraction of the injected 59Fe to the liver than does transferrin. In order to determine in vivo the intrahepatic recognition sites for transferrin and asialotransferrin, the liver was subfractionated into parenchymal, endothelial and Kupffer cells by a low-temperature cell isolation procedure. High-affinity recognition of transferrin (competed for by an excess of unlabelled transferrin) is exerted by parenchymal cells as well as endothelial and Kupffer cells with a 10-fold higher association (expressed per mg of cell protein) to the latter cell types. In all three cell types iron delivery occurs, as concluded from the increase in cellular 59Fe/125I ratio at prolonged circulation times of transferrin. It can be calculated that parenchymal cells are responsible for 50-60% of the interaction of transferrin with the liver, 20-30% is associated with endothelial cells and about 20% with Kupffer cells. For asialotransferrin a higher fraction of the injected dose becomes associated with parenchymal cells as well as with endothelial and Kupffer cells. Competition experiments in vivo with various sugars indicated that the increased interaction of asialotransferrin with parenchymal cells is specifically inhibited by N-acetylgalactosamine whereas mannan specifically inhibits the increased interaction of asialotransferrin with endothelial and Kupffer cells. Recognition of asialotransferrin by galactose receptors from parenchymal cells or mannose receptors from endothelial and Kupffer cells is coupled to active 59Fe delivery to the cells. It is concluded that, as well as parenchymal cells, liver endothelial and Kupffer cells are also quantitatively important intrahepatic sites for transferrin and asialotransferrin metabolism, an interaction exerted by multiple recognition sites on the various cell types.


Update of the position paper on arterial hypertension and erectile dysfunction.
: Sexual health is an integral part of overall health, and an active and healthy sexual life is an essential aspect of a good life quality. Cardiovascular disease and sexual health share common risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, obesity, and smoking) and common mediating mechanisms (endothelial dysfunction, subclinical inflammation, and atherosclerosis). This generated a shift of thinking about the pathophysiology and subsequently the management of sexual dysfunction. The introduction of phosphodiesterase type 5 inhibitors revolutionized the management of sexual dysfunction in men. This article will focus on erectile dysfunction and its association with arterial hypertension. This update of the position paper was created by the Working Group on Sexual Dysfunction and Arterial Hypertension of the European Society of Hypertension. This working group has been very active during the last years in promoting the familiarization of hypertension specialists and related physicians with erectile dysfunction, through numerous lectures in national and international meetings, a position paper, newsletters, guidelines, and a book specifically addressing erectile dysfunction in hypertensive patients. It was noted that erectile dysfunction precedes the development of coronary artery disease. The artery size hypothesis has been proposed as a potential explanation for this observation. This hypothesis seeks to explain the differing manifestation of the same vascular condition, based on the size of the vessels. Clinical presentations of the atherosclerotic and/or endothelium disease in the penile arteries might precede the corresponding manifestations from larger arteries. Treated hypertensive patients are more likely to have sexual dysfunction compared with untreated ones, suggesting a detrimental role of antihypertensive treatment on erectile function. The occurrence of erectile dysfunction seems to be related to undesirable effects of antihypertensive drugs on the penile tissue. Available information points toward divergent effects of antihypertensive drugs on erectile function, with diuretics and beta-blockers possessing the worst profile and angiotensin receptor blockers and nebivolol the best profile.


Edible coatings for enhancing microbial safety and extending shelf life of hard-boiled eggs.
Hard-boiled eggs were coated with chitosan-lysozyme (CL), whey protein isolate (WPI), or Bake sheen (BS), inoculated with Listeria monocytogenes or Salmonella enterica Ser. Enteritidis at 10(4) CFU/g, and stored for 4 wk at 10 degrees C. Microbial populations were enumerated weekly. Two nonchallenge studies were also conducted with hard-boiled eggs: coated shell-on eggs packaged in plastic containers or peeled eggs coated and vacuum-packaged. Total plate counts (TPC), coliforms, yeasts, molds, weight loss, pH, and color of eggs were determined during the 10-wk storage at 10 degrees C. Uncoated eggs served as controls. All the coatings were not effective in inhibiting the growth of L. monocytogenes, but CL coating controlled the growth of S. Enteritidis. At the end of 4-wk storage, the numbers of S. enteritidis on CL-coated eggs were about 4-log(10) CFU/g less than that of the controls. Coatings reduced (P < 0.05) the populations of coliforms and TPC, and completely inhibited mold growth during the 10-wk storage. Coatings also reduced (P < 0.05) the weight loss of eggs, 4.1% to 4.8% on coated eggs compared with 7.5% in uncoated ones at the end of 10-wk storage. The pH of CL-coated eggs remained stable throughout the storage period, while the control eggs increased from 7.6 to 8.6. Color changes in CL- and WPI-coated eggshells were less (P < 0.05) than those of BS-coated and the control. The CL coating effectively suppressed the numbers of TPC, coliforms, yeasts, and molds on peeled eggs during the 6-wk storage (P < 0.05). The results suggest that CL coating on hard-boiled eggs can control the growth of S. Enteritidis and reduce undesirable changes in the interior quality of eggs.


Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.
Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, gamma-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.


T cell defect in patients with epidermodysplasia verruciformis due to human papillomavirus type 3 and 5.
Most of the patients with epidermodysplasia verruciformis (EV) were anergic to sensitization to dinitrochlorobenzene (DNCB) and were shown to have a decreased number of T lymphocytes and reduced lymphocyte PHA responsiveness. Preserved cell-mediated immunity (CMI) was found only in the abortive cases of EV infected with human papillomavirus type 3 (HPV-3). CMI was impaired to the same extent in patients with EV induced by HPV-3 and HPV-5, and in EV cases with combined infection with both viruses. In contrast to this, malignant transformation, i.e. of Bowen's carcinoma type, was observed only in the 7 patients infected with HPV-5. This could indicate that malignancy in EV is related rather to the oncogenic potential of HPV-5 type than to the extent of T cell defect that was similar in both EV varieties due to HPV-3 and HPV-5.


PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling.
The adipose-derived hormone, leptin, was discovered over 10 years ago, but only now are we unmasking its downstream pathways which lead to reduced energy intake (feeding) and increased energy expenditure (thermogenesis). Recent transgenic models have challenged the long-standing supposition that the hypothalamic arcuate nucleus (Arc) is omnipotent in the central response to leptin, and research focus is beginning to shift to examine roles of extra-arcuate sites. Dhillon et al. (2006) demonstrated that targeted knock out of the signaling form of the leptin receptor (lepr-B) in steroidogenic factor 1 (SF-1) cells of the hypothalamic ventromedial nucleus (VMN) produces obesity of a similar magnitude to the pro-opiomelanocortin (POMC)-driven lepr-B deleted mouse, via a functionally distinct mechanism. These findings reveal that SF-1 cells of the VMN could be equally as important as POMC cells in mediating leptin's anti-obesity effects. However, the identification of molecular and cellular correlates of this relationship remains tantalizingly unknown. Here, we have shown that mRNA expression of the VMN-expressed neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is regulated according to energy status and that it exerts catabolic effects when administered centrally to mice. Furthermore, we have shown that SF-1 and PACAP mRNAs are colocalized in the VMN, and that leptin signaling via lepr-B is required for normal PACAP expression in these cells. Finally, blocking endogenous central PACAP signaling with the antagonist PACAP(6-38) markedly attenuates leptin-induced hypophagia and hyperthermia in vivo. Thus, it appears that PACAP is an important mediator of central leptin effects on energy balance.


An insight into the effects of transition metals on the thermal expansion of complex perovskite compounds: an experimental and density functional theory investigation.
ABO3 perovskite-type LaCoO3, LaCo0.5Fe0.5O3, LaCo0.5Ni0.5O3, and LaCo0.5Mn0.5O3 complex oxides were synthesized using the sol-gel method. The microstructure and the thermal expansion behavior of the oxides were investigated. Insights into phonon dispersion and the effects of doped transition metals on thermal expansion were obtained by first-principles calculations based on density functional theory. Thermal expansion coefficients (TECs) at finite temperatures were obtained by quasi harmonic approximation. B-site doping was found to reduce the size of the crystalline grains and the TECs of perovskite compounds. The average TECs of LaCoO3, LaCo0.5Fe0.5O3, LaCo0.5Ni0.5O3, and LaCo0.5Mn0.5O3 were 25 × 10-6 K-1, 11 × 10-6 K-1, 12.5 × 10-6 K-1, and 5 × 10-6 K-1, respectively, in the 0-1000 K temperature range. In addition, the TECs of LaCo0.5Fe0.5O3 and LaCo0.5Ni0.5O3 matched well with those of some common electrolytes.


Dramatic difference in diversity between Plasmodium falciparum and Plasmodium vivax reticulocyte binding-like genes.
Malaria parasite proteins involved in erythrocyte invasion are considered important vaccine targets. Members of the reticulocyte binding-like (RBL) family of Plasmodium merozoite proteins are found in human, simian, and rodent malaria parasites and function in the initial steps of erythrocyte selection and invasion. The RBL genes are large, ranging in size from 7.7 to 10 kb, and the extent of any sequence diversity in parasite populations is unknown. We present the first assessment of sequence diversity within RBL genes from the two major human malaria parasites: Plasmodium falciparum and P. vivax. Polymorphism within the RBL genes is generally limited, except for P. vivax reticulocyte binding protein 2 (PvRBP2), which has nucleotide diversity levels 25-fold higher than the other RBL genes. The PvRBP2 haplotypes appear to fall into two distinct classes of alleles, suggesting large-scale dimorphism in this gene. Polymorphisms were frequently clustered, suggesting that different RBL domains may be evolving under different selection and functional pressures.


Neuroaxonal dystrophy in a litter of papillon pups.
A litter of five 14-week-old papillon puppies was referred for investigation of pelvic limb ataxia. Clinical examination revealed signs of ataxia, hypermetria and depressed postural reflexes affecting all four limbs. The severity of these signs varied between members of the litter. The condition became progressively worse and by 19 weeks of age all but the least severely affected pup (the single male of the litter) had deteriorated to the point that euthanasia was indicated on humane grounds. Pathological examination revealed widespread changes in both white and grey matter of the neuraxis caudal to the forebrain, particularly involving the dorsolateral white matter of the spinal cord, which were characterised by axonal swellings typical of neuroaxonal dystrophy.


Liquid-phase mega-electron-volt ultrafast electron diffraction.
The conversion of light into usable chemical and mechanical energy is pivotal to several biological and chemical processes, many of which occur in solution. To understand the structure-function relationships mediating these processes, a technique with high spatial and temporal resolutions is required. Here, we report on the design and commissioning of a liquid-phase mega-electron-volt (MeV) ultrafast electron diffraction instrument for the study of structural dynamics in solution. Limitations posed by the shallow penetration depth of electrons and the resulting information loss due to multiple scattering and the technical challenge of delivering liquids to vacuum were overcome through the use of MeV electrons and a gas-accelerated thin liquid sheet jet. To demonstrate the capabilities of this instrument, the structure of water and its network were resolved up to the 3 rd hydration shell with a spatial resolution of 0.6 Å; preliminary time-resolved experiments demonstrated a temporal resolution of 200 fs.


Copper sludge from printed circuit board production/recycling for ceramic materials: a quantitative analysis of copper transformation and immobilization.
The fast development of electronic industries and stringent requirement of recycling waste electronics have produced a large amount of metal-containing waste sludge. This study developed a waste-to-resource strategy to beneficially use such metal-containing sludge from the production and recycling processes of printed circuit board (PCBs). To observe the metal incorporation mechanisms and phase transformation processes, mixtures of copper industrial waste sludge and kaolinite-based materials (kaolinite and mullite) were fired between 650 and 1250 °C for 3 h. The different copper-hosting phases were identified by powder X-ray diffraction (XRD) in the sintered products, and CuAl2O4 was found to be the predominant hosting phase throughout the reactions, regardless of the strong reduction potential of copper expected at high temperatures. The experimental results indicated that CuAl2O4 was generated more easily and in larger quantities at low-temperature processing when using the kaolinite precursor. Maximum copper transformations reached 86% and 97% for kaolinite and mullite systems, respectively, when sintering at 1000 °C. To monitor the stabilization effect after thermal process, prolonged leaching tests were carried out using acetic acid with an initial pH value of 2.9 to leach the sintered products for 20 days. The results demonstrated the decrease of copper leachability with the formation of CuAl2O4, despite different sintering behavior in kaolinite and mullite systems. This study clearly indicates spinel formation as the most crucial metal stabilization mechanism when sintering copper sludge with aluminosilicate materials, and suggests a promising and reliable technique for reusing metal-containing sludge as ceramic materials.


Memory performance of geriatric and nongeriatric chronic schizophrenic patients: a cross-sectional study.
Memory functioning has been studied extensively in nongeriatric schizophrenic patients, leading to the suggestion that schizophrenic patients manifest a "subcortical" pattern of memory deficits. Few previous studies examined very poor outcome patients with a chronic course of hospitalization. This study examined the association of age and global cognitive dysfunction with verbal and spatial learning and delayed recall, as well as examining differential impairments in delayed recall as compared to delayed recognition memory. Sixty-six chronic schizophrenic patients were studied, with 30 of these patients over the age of 65. Verbal (California Verbal Learning Test) and spatial (Biber Figure Learning Test) serial learning and delayed memory tests were administered. All aspects of memory functioning were correlated with estimates of global cognitive status. When global cognitive status was controlled, age effects were still found for the majority of the memory measures. Delayed recognition memory was not spared, being performed as poorly as delayed recall. In contrast to previous studies of better-outcome patients with schizophrenia, geriatric patients with chronic schizophrenia performed more poorly than nongeriatric patients. The lack of sparing of delayed recognition memory suggests that previous findings of specific recall memory deficit and a subcortical profile of memory impairments may apply to schizophrenic patients with less severe global cognitive impairments. These data suggest that poor-outcome patients may have a pattern of memory impairments that has some features in common with cortical dementia.


Intravenous regional anaesthesia with ketamine.
Ketamine, 40 ml 0.5% solution, was used in the technique of intravenous regional anaesthesia in 14 patients undergoing upper limb surgery. Satisfactory analgesia was obtained in 12 of the patients. The method is limited by the fact that all patients became unconscious within a few minutes of tourniquet release, and that this could not be prevented by naloxone.


Endovascular micro-arterial stenting for arterial pseudoaneurysm after pancreatic surgery.
Although arterial pseudoaneurysm is one of the most serious complications after pancreatic surgery, the best practice with maximum efficacy and minimum adverse effects to overcome such a serious situation has not yet been elucidated. We performed endovascular micro-arterial stenting (EMAS) to manage this serious situation while preserving a sufficient hepatic arterial flow, and herein report the technical details and challenges of the procedure. Dilation of the stent using a balloon catheter to adhere to the parent artery, and embolization of the surrounding artery to prevent type I and type II endo-leaks are the most important points for ensuring a successful procedure. We applied this technique to 6 cases of hepatic arterial pseudoaneurysm, with a mean size of 6.5 ± 1.3 mm. The mean time of the procedure was 81 ± 22 min, without adverse events, including hepatic necrosis or arterial bleeding. EMAS may be the ideal procedure for treating pseudoaneurysm after pancreatic surgery while preserving the hepatic arterial inflow.


Comparison of G-to-A mutation frequencies induced by APOBEC3 proteins in H9 cells and peripheral blood mononuclear cells in the context of impaired processivities of drug-resistant human immunodeficiency virus type 1 reverse transcriptase variants.
APOBEC3 proteins can inhibit human immunodeficiency virus type 1 (HIV-1) replication by inducing G-to-A mutations in newly synthesized viral DNA. However, HIV-1 is able to overcome the antiretroviral activity of some of those enzymes by the viral protein Vif. We investigated the impact of different processivities of HIV-1 reverse transcriptases (RT) on the frequencies of G-to-A mutations introduced by APOBEC3 proteins. Wild-type RT or the M184V, M184I, and K65R+M184V RT variants, which are increasingly impaired in their processivities, were used in the context of a vif-deficient molecular HIV-1 clone to infect H9 cells and peripheral blood mononuclear cells (PBMCs). After two rounds of infection, a part of the HIV-1 env gene was amplified, cloned, and sequenced. The M184V mutation led to G-to-A mutation frequencies that were similar to those of the wild-type RT in H9 cells and PBMCs. The frequencies of G-to-A mutations were increased after infection with the M184I virus variant. This effect was augmented when using the K65R+M184V virus variant (P < 0.001). Overall, the G-to-A mutation frequencies were lower in PBMCs than in H9 cells. Remarkably, 38% +/- 18% (mean +/- standard deviation) of the env clones derived from PBMCs did not harbor any G-to-A mutation. This was rarely observed in H9 cells (3% +/- 3%). Our data imply that the frequency of G-to-A mutations induced by APOBEC3 proteins can be influenced by the processivities of HIV-1 RT variants. The high number of nonmutated clones derived from PBMCs leads to several hypotheses, including that additional antiretroviral mechanisms of APOBEC3 proteins other than their deamination activity might be involved in the inhibition of vif-deficient viruses.


Evolutionary transformation of mouthparts from particle-feeding to piercing carnivory in Viper copepods: Review and 3D analyses of a key innovation using advanced imaging techniques.
Novel feeding adaptations often facilitate adaptive radiation and diversification. But the evolutionary origins of such feeding adaptations can be puzzling if they require concordant change in multiple component parts. Pelagic, heterorhabdid copepods (Calanoida) exhibit diverse feeding behaviors that range from simple particle feeding to a highly specialized form of carnivory involving piercing mouthparts that likely inject venom. We review the evolutionary history of heterorhabdid copepods and add new high-resolution, 3D anatomical analyses of the muscular system, glands and gland openings associated with this remarkable evolutionary transformation. We examined four heterorhabdid copepods with different feeding modes: one primitive particle-feeder (Disseta palumbii), one derived and specialized carnivore (Heterorhabdus subspinifrons), and two intermediate taxa (Mesorhabdus gracilis and Heterostylites longicornis). We used two advanced, high-resolution microscopic techniques - serial block-face scanning electron microscopy and two-photon excitation microscopy - to visualize mouthpart form and internal anatomy at unprecedented nanometer resolution. Interactive 3D graphical visualizations allowed putative homologues of muscles and gland cells to be identified with confidence and traced across the evolutionary transformation from particle feeding to piercing carnivory. Notable changes included: a) addition of new gland cells, b) enlargement of some (venom producing?) glands, c) repositioning of gland openings associated with hollow piercing fangs on the mandibles, d) repurposing of some mandibular-muscle function to include gland-squeezing, and e) addition of new muscles that may aid venom injection exclusively in the most specialized piercing species. In addition, live video recording of all four species revealed mandibular blade movements coupled to cyclic contraction of some muscles connected to the esophagus. These behavioral and 3D morphological observations revealed a novel injection system in H. subspinifrons associated with piercing (envenomating?) carnivory. Collectively, these results suggest that subtle changes in mandibular tooth form, and muscle and gland form and location, facilitated the evolution of a novel, piercing mode of feeding that accelerated diversification of the genus Heterorhabdus. They also highlight the value of interactive 3D animations for understanding evolutionary transformations of complex, multicomponent morphological systems.