Targeted large-scale analysis of protein acetylation.
Protein modifications are biologically important events that may be studied by mass spectrometry-based high-throughput proteome analyses. In recent years, several new technologies have emerged that have widened and deepened the targeted analysis of one important, albeit functionally ill-defined modification, namely protein acetylation. This modification can take place both co- and post-translationally by the transfer of acetyl groups under the catalysis of acetyltransferases. The acetyl group can modify either the α-amino group at the N-terminus, so-called N-terminal acetylation, or the ε-amino group on the side chain of lysine residues. Here, we review several emerging targeted technologies to chart both N-terminal acetylation as well as acetylation at the lysine side chain, on a proteome-wide scale, highlighting in particular studies that have expanded the biological knowledge on the appearance and function of these common but functionally still less investigated co- and post-translational modifications.


Implementation of an evidence-based depression treatment into social service settings: the relative importance of acceptability and contextual factors.
Listening Visits (LV), an empirically supported depression treatment delivered by non mental health specialists, were implemented into two distinctly structured programs. The relative importance of providers' views and organizational context on implementation were examined. Thirty-seven home visitors completed pre- and post-LV training surveys assessing their views toward implementing LV. Implementation rates markedly differed in the two organizations (73.9% vs. 35.7%). Logistic regression results showed that when predicting the implementation rate, the impact of the organizational setting outweighed home visitors' personal views. These results underscore the importance of organizational context in the implementation of empirically supported treatments.


Primary care physician-reported secondary and tertiary stroke prevention practices. A comparison between the United States and the United Kingdom.
Stroke is a major healthcare problem in both the United States (US) and the United Kingdom (UK). Little comparative data are available concerning how generalist physicians in the two countries approach the management of patients at high risk of stroke. Contemporaneous surveys of random samples of primary care physician-reported stroke prevention practices were performed in the US and UK from 1993 to 1994. The US National Survey of Physician Practices for the Secondary and Tertiary Prevention of Ischemic Stroke included 254 noninternist primary care physicians. The UK Survey of the Care of Patients With Stroke in General Practice obtained responses from 661 general practitioners. The two surveys used many of the same questions, allowing for direct comparisons of reported stroke prevention practices between American and British physicians. More than 80% of American physicians reported a variety of services (24-hour electrocardiography, echocardiography, brain CT scan, brain MR scan, carotid ultrasonography, cerebral angiography) as readily available. These same services were readily available to less than 10% of physicians in the UK (P < .001 for each comparison). Although physicians in the UK reported prescribing lower doses of aspirin for stroke prevention than physicians in the US, the proportions of physicians using aspirin were not different. In contrast, almost 70% of physicians in the US responded that they always or often anticoagulate patients with nonvalvular atrial fibrillation compared with 7% of British physicians (P < .001). Whereas 70% of American versus 14% of British physicians reported obtaining carotid ultrasound studies in patients with asymptomatic bruits (P < .001), physicians in the UK more commonly reported referring this type of patient to neurologists (46% versus 21%, P < .001). For patients with recent carotid-distribution transient ischemic attack or minor stroke, physicians in the US more commonly reported referral to neurologists (55% versus 45%, P = .022), referral to surgeons (39% versus 19%, P < .001), the performance of carotid ultrasonography (80% versus 11%, P < .001), echocardiography (45% versus 5%, P < .001), 24-hour electrocardiography (49% versus 4%, P < .001), brain CT scan (72% versus 3%, P < .001), and the prescription of anticoagulants (53% versus 4%, P < .001). These data show significant differences in stroke prevention practices as reported by primary care physicians practicing in the US and UK. Some of these differences may be related to the relative availability of specific services in the two countries, potentially leading to overutilization in the US and underutilization in the UK in certain circumstances.


Human Granulocytic Anaplasmosis as a COVID-19 Mimicker.
Human granulocytic anaplasmosis (HGA) is a tick-borne illness caused by the bacterium Anaplasma phagocytophilum. HGA has a widely variable clinical presentation and can be life-threatening. A 77-year-old man was transferred from an outside facility with altered mental status, a fever of up to 40.5°C, and shortness of breath. Laboratory analysis revealed a progressively worsening pro-inflammatory state and abnormalities in the patient's coagulation studies. With clinical and laboratory evidence concerning for potential COVID-19 infection, the patient was placed in isolation as a precaution. The results of two COVID-19 tests, given approximately 24 hours apart, were negative. The patient's spouse confirmed a bug bite to his upper extremity while working outdoors. His symptoms resolved completely after a 10-day course of empiric doxycycline. The diverse clinical presentations of HGA necessitate a broad differential diagnosis, including viral, bacterial and non-infectious aetiologies. In severe cases, a cytokine-mediated immune cascade can occur (namely, cytokine storm) leading to devastating downstream effects. This cytokine storm can be seen in many other diseases, but most recently it has been demonstrated in the novel coronavirus disease 2019 (COVID-19). Here we present a case of HGA in which diagnosis was delayed due to mimicry of COVID-19 infection. This case highlights the importance of taking clinical and social histories, seasonality and geography into account during diagnosis, and maintaining a broad differential with non-specific symptoms. Despite the current COVID-19 pandemic, we recommend that HGA remains in the differential diagnosis of a pro-inflammatory state with an atypical respiratory presentation. Human granulocytic anaplasmosis (HGA) has a widely variable clinical presentation and can be life-threatening.When presented with non-specific symptoms, it is critical to consider clinical and social histories, seasonality and geography while maintaining a broad differential.Cytokine storm can be seen in HGA and other diseases, but most recently it has been observed in the novel COVID-19. However, despite the prevalence of COVID-19, we recommend that HGA remain in the differential diagnosis of a pro-inflammatory state with an atypical respiratory presentation.


Detection of left ventricular hypertrophy by M-mode echocardiography. Anatomic validation, standardization, and comparison to other methods.
Because of its simplicity, widespread availability, relatively low cost, and lack of adverse effects, M-mode echocardiography has become the most widely used technique for measurement of human left ventricular mass. Necropsy comparison studies have yielded formulas for anatomically accurate estimation of left ventricular mass in patients with normally shaped ventricles using left ventricular measurements by either Penn or American Society of Echocardiography conventions, but M-mode methods are less accurate in abnormally shaped ventricles. The standard error of M-mode echocardiographic left ventricular mass measurements is approximately 40 g under difficult clinical recording conditions and 30 g or less for research studies of stable subjects. Interstudy variability of mass estimates appeared somewhat lower, resulting in 95% confidence limits for serial change up to 58 g for individual subjects and up to 10 g for study populations of 34 patients or more. The accuracy of M-mode echocardiography for measurement of left ventricular mass is similar to that of contrast angiography but may be exceeded by newer methods with greater cost or radiation exposure, including magnetic resonance imaging, cine-computed tomography, and three-dimensional echocardiographic reconstruction. Identification of left ventricular hypertrophy needs to take into account the influence of sex and body size, the variables that most influence normal ventricular mass, with provisional criteria for recognition of hypertrophy being left ventricular mass index over 134 g/m2 in men and above 110 g/m2 in women.


Cell Fate Specification Based on Tristability in the Inner Cell Mass of Mouse Blastocysts.
During development, interactions between transcription factors control the specification of different cell fates. The regulatory networks of genetic interactions often exhibit multiple stable steady states; such multistability provides a common dynamical basis for differentiation. During early murine embryogenesis, cells from the inner cell mass (ICM) can be specified in epiblast (Epi) or primitive endoderm (PrE). Besides the intracellular gene regulatory network, specification is also controlled by intercellular interactions involving Erk signaling through extracellular Fgf4. We previously proposed a model that describes the gene regulatory network and its interaction with Erk signaling in ICM cells. The model displays tristability in a range of Fgf4 concentrations and accounts for the self-organized specification process observed in vivo. Here, we further investigate the origin of tristability in the model and analyze in more detail the specification process by resorting to a simplified two-cell model. We also carry out simulations of a population of 25 cells under various experimental conditions to compare their outcome with that of mutant embryos or of embryos submitted to exogenous treatments that interfere with Fgf signaling. The results are analyzed by means of bifurcation diagrams. Finally, the model predicts that heterogeneities in extracellular Fgf4 concentration play a primary role in the spatial arrangement of the Epi/PrE cells in a salt-and-pepper pattern. If, instead of heterogeneities in extracellular Fgf4 concentration, internal fluctuations in the levels of expression of the transcription factors are considered as a source of randomness, simulations predict the occurrence of unrealistic switches between the Epi and the PrE cell fates, as well as the evolution of some cells toward one of these states without passing through the previous ICM state, in contrast to what is observed in vivo.


Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide and Peripheral Blood Stem Cell Grafts in Older Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome.
Many hematologic malignancies are diseases of aging, and the use of hematopoietic cell transplant (HCT) is growing rapidly among older adults. Modern post-transplant cyclophosphamide (PTCy) protocols with haploidentical (haplo) donors have dramatically expanded the donor pool for patients requiring HCT. Initial studies were performed with bone marrow grafts, which require the donor to undergo anesthesia during harvest. However, the use of mobilized peripheral blood stem cells (PBSCs) may be desirable, especially with older donors. However, data on PBSC haplo-HCT in older adults are lacking. To characterize the impact of age on outcomes in haplo-HCT, we identified all adult patients undergoing haplo-HCT with PTCy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at our institution from January 2009 to June 2016. Patients were grouped into 3 cohorts: Age 1 (≤55), Age 2 (55 to 65), and Age 3 (≥65). To characterize the impact of donor type on outcomes in older patients, we identified age- and disease risk index (DRI)-matched patient age ≥ 65 undergoing HLA-matched unrelated donor (MUD) HCT for AML or MDS during the same time frame. Patients were scored for disease risk and underlying comorbidities using the DRI and HCT-specific comorbidity index. Overall survival (OS) was analyzed using 3 different Cox proportional hazards models. We identified 112 haplo-HCT patients, 95 with AML and 17 with MDS. There were 61 patients in Age 1, 29 patients in Age 2, and 22 in Age 3. Median OS was 448, 397, and 147 days in Age 1, Age 2, and Age 3 patients (log-rank, P = .04). After adjusting for other risk factors, age ≥ 65 was associated with significantly worse OS after haplo-HCT (aHR, 2.16; 95% CI, 1.15 to 4.07). There was a trend toward increased relapse among older patients at 2 years (56%; 95% CI, 32% to 79%) versus Age 1 (41%; 95% CI, 28% to 54%) and Age 2 (31%; 95% CI, 12% to 50%) (P = .08). Among patients age ≥ 65, donor type (MUD versus haplo) did not impact OS (aHR, 1.03; 95% CI, .56 to 1.88) after adjusting for other risk factors. Prior allo-HCT (aHR, 4.95; 95% CI, 1.82 to 13.49) and myeloablative conditioning (aHR, 1.97; 95% CI, 1.04 to 3.73) were associated with inferior survival. Although age ≥ 65 was associated with inferior OS in our haplo-HCT cohort, no difference was seen in survival between MUD and haplo-HCT. Therefore, the use of haploidentical donors in older patients is a reasonable treatment option, especially if there is concern for clinical deterioration. A careful pretransplant evaluation and analysis of risks and benefits is warranted when offering this transplant modality to older adults, especially in patients with previous transplant or poor performance status. Strategies to reduce the risk of relapse and decrease nonrelapse mortality in older adults are areas of ongoing research, and prospective studies are needed.


Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study.
The authors sought to assess the relationship between candidate genes and two clinical outcomes, namely, symptomatic improvement and the occurrence of suicidal events, in a sample of treatment-resistant depressed adolescents. A subsample of depressed adolescents participating in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial, 155 of whom were of European origin, were genotyped with respect to 21 polymorphisms on 12 genes that have a reported association with depression, treatment response, or suicidal events. Participants had not responded to a previous adequate trial with an antidepressant and were randomized to receive either another selective serotonin reuptake inhibitor or venlafaxine, with or without cognitive-behavioral therapy (CBT). Single-nucleotide polymorphism (SNP) analyses were conducted using PLINK with permutation procedures. No relationship was observed between any polymorphism and response to treatment. The FKBP5 (which codes for a protein causing subsensitivity of the glucocorticoid receptor) rs1360780TT and rs3800373GG genotypes were associated with suicidal events (N=18), even after controlling for treatment effects and relevant covariates. These two SNPs were in significant linkage disequilibrium (r=0.91). The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity. These results are consistent with those of other studies linking alterations in the hypothalamic-pituitary-adrenal axis with suicidal behavior. The small number of events and lack of a placebo condition make these results preliminary. Replication with a larger sample and a placebo condition is needed to assess whether these events are related to treatment.


Influence of horizontal damage size of grating ridge on the optical properties of multilayer dielectric gratings.
Based on typical laser damage morphologies of multilayer dielectric gratings (MDGs), in this paper the influence of horizontal damage size of the grating ridge on optical properties of MDGs is analyzed by numerical calculations using the rigorous coupled wave analysis method. From simulation results, the optical performance of MDGs decreases with the increase in horizontal damage size of the grating ridge. But the maximum electric field value in the grating ridge and the multilayer enhances constantly with the increase in horizontal damage size, thus inducing further laser damage of MDGs. This paper provides the preliminary study for functional damage of MDGs.


The C-seal trial: colorectal anastomosis protected by a biodegradable drain fixed to the anastomosis by a circular stapler, a multi-center randomized controlled trial.
Anastomotic leakage is a major complication in colorectal surgery and with an incidence of 11% the most common cause of morbidity and mortality. In order to reduce the incidence of anastomotic leakage the C-seal is developed. This intraluminal biodegradable drain is stapled to the anastomosis with a circular stapler and prevents extravasation of intracolonic content in case of an anastomotic dehiscence.The aim of this study is to evaluate the efficacy of the C-seal in reducing anastomotic leakage in stapled colorectal anastomoses, as assessed by anastomotic leakage leading to invasive treatment within 30 days postoperative. The C-seal trial is a prospective multi-center randomized controlled trial with primary endpoint, anastomotic leakage leading to re-intervention within 30 days after operation. In this trial 616 patients will be randomized to the C-seal or control group (1:1), stratified by center, anastomotic height (proximal or distal of peritoneal reflection) and the intention to create a temporary deviating ostomy. Interim analyses are planned after 50% and 75% of patient inclusion. Eligible patients are at least 18 years of age, have any colorectal disease requiring a colorectal anastomosis to be made with a circular stapler in an elective setting, with an ASA-classification < 4. Oral mechanical bowel preparation is mandatory and patients with signs of peritonitis are excluded. The C-seal student team will perform the randomization procedure, supports the operating surgeon during the C-seal application and achieves the monitoring of the trial. Patients are followed for one year after randomization en will be analyzed on an intention to treat basis. This Randomized Clinical trial is designed to evaluate the effectiveness of the C-seal in preventing clinical anastomotic leakage.


Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer.
Although novel agents targeting the androgen-androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients. Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR. On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, χ(2)). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline ≥ 30% (P = 0.013, χ(2)) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression). AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC.


Concordant glucose induction of glucokinase, glucose usage, and glucose-stimulated insulin release in pancreatic islets maintained in organ culture.
Using cultured islets as the experimental system, this study established dosage-response and time-dependency curves of the inductive glucose effect on glucose-stimulated insulin release, glucose usage, and glucokinase activity. Glucose-stimulated insulin release in islets cultured for 1, 2, or 7 days was increased as a function of glucose concentration in the culture medium and as a function of time. Glucose usage in the cultured islets showed a close relationship with glucose concentration in the culture medium at both 2 and 7 days of culture. Glucokinase activity increased in islets cultured for 1, 2, or 7 days as a function of increasing glucose concentrations in the culture medium and as a function of time. The V(max) of glucokinase in islets cultured for 7 days in medium containing 30 mM glucose was twice the value of freshly isolated islets and was almost fivefold higher than that in islets cultured for 7 days in 3 mM glucose. The glucose induction of glucose-stimulated insulin release, of glucose usage, and of glucokinase activity were tightly correlated. The biochemical mechanisms of glucose induction of islet glucokinase were further studied. Immunoblotting with an antibody against C-terminal peptide of glucokinase showed that densities of a 52,000-kD protein band from tissue extracts of islets cultured for 7 days in 3, 12, and 30 mM glucose were 25, 44, and 270% compared with that of extract from freshly isolated islets (100%). RNA blot analysis of glucokinase mRNA demonstrated virtually the same levels in fresh islets and islets after 7 days of culture in 3 or 30 mM glucose. The adaptive response of glucokinase to glucose appears therefore to be occurring at a translational or posttranslational site in cultured islets. These data greatly strengthen the concept that glucose is the regulator that induces the activity of glucokinase, which in turn determines the rate change of glucose usage as well as glucose-stimulated insulin release from beta-cells. Thus, the hypothesis that glucokinase is the glucose sensor of beta-cells is strengthened further.


The impact of office neck ultrasonography on reducing unnecessary thyroid surgery in patients undergoing parathyroidectomy.
Some have suggested that thyroid disease is even more prevalent among patients with hyperparathyroidism (HPT) than in the general population. We sought to define the incidence and optimal management strategies of thyroid disease in patients undergoing surgery for HPT. Clinical characteristics were reviewed for 1200 consecutive HPT patients treated at two endocrine surgery referral centers from 1992-2003. Both centers practice bilateral neck exploration, and one routinely obtains preoperative neck ultrasound (US) performed by surgeons. Forty percent (477/1195) of HPT patients had coexisting thyroid disease, whether identified at parathyroidectomy (39%; 327/845) or by US (43%; 150/350). Colloid nodules/goiters accounted for nearly half of thyroid pathology, followed by follicular adenomas, papillary cancer, thyroiditis, and intrathyroidal parathyroids. Thyroid malignancy was found in 4.6% of HPT patients versus less than 1% in autopsy reports. Thyroid pathology was similar among single adenomas, multigland, and renal HPT. Unexpected thyroid disease first encountered at parathyroidectomy required partial or total thyroidectomy in 30% (257/845). US-detected thyroid nodules prompted fine-needle biopsy in 20%, which was cost effective in limiting concomitant thyroid surgery to fewer patients (6%; 21/350). Overall low incidence (<0.5%) of persistent/recurrent HPT, nerve injury, and neck hematoma was unaffected by thyroid abnormalities. The high prevalence of thyroid disease, especially malignancies, among HPT patients mandates vigilant diagnosis and preparation for possible simultaneous parathyroid-thyroid surgery. Without appropriate preoperative screening, focal explorations for HPT may be prone to delayed diagnosis of thyroid tumors. Ultrasound performed by surgeons or endocrinologists preoperatively is an excellent diagnostic tool and minimizes unnecessary thyroidectomy in patients with subclinical thyroid disease.


Involvement of AT2 receptors at NRVL in tonic baroreflex suppression by endogenous angiotensins.
We evaluated the role of endogenous angiotensin II and III (ANG II and ANG III) at the rostral nucleus reticularis ventrolateralis (NRVL) in the modulation of baroreceptor reflex (BRR) response and the subtype of angiotensin receptors involved in this process. Adult male Sprague-Dawley rats anesthetized and maintained with pentobarbital sodium were used. Exogenous application of ANG II or ANG III (10, 20, or 40 pmol) by bilateral microinjection into the NRVL significantly suppressed the BRR response to transient hypertension induced by phenylephrine (5 micrograms/kg i.v.). The suppressive effect of ANG II (20 pmol) was reversed by an equimolar dose (1.6 nmol) of its peptide antagonist, [Sar1, Ile8]ANG II, and the nonpeptide antagonists for AT1 and AT2 receptors, losartan and PD-123319, respectively. On the other hand, the inhibitory action of ANG III (20 pmol) was blunted by its peptide antagonist. [Ile7]ANG III or PD-123319, but not by losartan. Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NRVL of [Sar1, Ile8]ANG II, [Ile7]ANG III, or PD-123319 elicited an appreciable enhancement of the BRR response, whereas losartan produced minimal effect. These results suggest that, under physiological conditions, both endogenous ANG II and ANG III may exert a tonic inhibitory modulation on the BRR response by acting selectively on the AT2 receptors at the NRVL.


The Multiple Sclerosis-Fatigue Self- Efficacy (MS-FSE) scale: initial validation.
To examine the validity and sensitivity to change of the Multiple Sclerosis-Fatigue Self-Efficacy scale. A validation study nested within a randomized controlled trial. Community setting. Adults with a clinically definite diagnosis of multiple sclerosis and significant fatigue taking part in a randomized controlled trial evaluating a group-based fatigue management programme (FACETS) for people with multiple sclerosis (N=164). The 9-item Multiple Sclerosis-Fatigue Self-Efficacy scale was completed at baseline, 1-, 4- and 12 months post intervention. Validity, internal consistency and sensitivity to change were examined using classical test theory and Rasch analysis. Item 3 was unanswered by 6% of respondents as they did not know any other people with multiple sclerosis; remaining analyses were carried out with this item deleted. All response choices were utilised, no floor or ceiling effects were evident and there were few missing responses. Cronbach's alphas were high (baseline, 0.89; follow-up 1, 0.93; follow-up 2, 0.94; follow-up 3, 0.90). The Multiple Sclerosis-Fatigue Self-Efficacy scale (8-item) demonstrated good sensitivity to change following attendance of the FACETS programme (within participant effect sizes 0.66 and 0.69 and 0.54 at 1, 4, and 12 months follow-up). Principal Components Analysis yielded one component. In the Rasch analysis two items with disordered thresholds were rescored. Item 8 displayed differential item functioning by disability and was combined into a testlet with item 4, resulting in a unidimensional scale. The sample was well targeted to the scale. At a scale level the Multiple Sclerosis-Fatigue Self-Efficacy scale is internally valid and has good sensitivity to change.


Efficacy of a virus-vectored vaccine against human and bovine respiratory syncytial virus infections.
Human respiratory syncytial virus (HRSV) is a major cause of lower respiratory tract disease in children and the elderly for which there is still no effective vaccine. We have previously shown that PanAd3-RSV, which is a chimpanzee adenovirus-vectored vaccine candidate that expresses a secreted form of the HRSV F protein together with the N and M2-1 proteins of HRSV, is immunogenic in rodents and nonhuman primates, and protects mice and cotton rats from HRSV challenge. Because the extent to which protection demonstrated in rodent models will translate to humans is unclear, we have exploited the calf model of bovine RSV (BRSV) infection, which mimics HRSV disease in children more closely than do experimental models of unnatural laboratory hosts, to evaluate the safety and efficacy of the PanAd3-RSV vaccine. We show that PanAd3-RSV alone and in combination with a modified vaccinia Ankara expressing the same HRSV antigens (MVA-RSV) induced neutralizing antibodies and cellular immunity in young seronegative calves and protected against upper and lower respiratory tract infection and pulmonary disease induced by heterologous BRSV challenge. There was no evidence either of enhanced pulmonary pathology or of enhanced respiratory disease in vaccinated calves after BRSV challenge. These findings support the continued evaluation of the vectored RSV vaccines in man.


The role of vulnerability in stress-related insomnia, social support and coping styles on incidence and persistence of insomnia.
Individuals who are more prone to experience situational insomnia under stressful conditions may also be at greater risk to develop subsequent insomnia. While cross-sectional data exist on the link between sleep reactivity (heightened vulnerability to stress-related insomnia) and insomnia, limited data exist on its predictive value. The aim of the study was to evaluate prospectively whether sleep reactivity was associated with increased risk of incident and persistent insomnia in a population-based sample of good sleepers. Social support and coping styles were also investigated as potential moderators. Participants were 1449 adults (Mage = 47.4 years, standard deviation = 15.1; 41.2% male) without insomnia at baseline and evaluated four times over 3 years. Sleep reactivity was measured using the Ford Insomnia Response to Stress Test (FIRST). Additional measures included depressive symptoms, the frequency and perceived impact of stressful life events, social support and coping styles. After controlling for prior sleep history, depressive symptoms, arousal predisposition, stressful life events and perceived impact, individuals with higher sleep reactivity had an odds ratio (OR) of 1.56 [95% confidence interval (CI): 1.13-2.16], 1.41 (95% CI: 0.87-2.30) and 2.02 (95% CI: 1.30-3.15) of developing insomnia symptoms, syndrome and persistent insomnia, respectively. Social support and coping styles did not moderate these associations. Results suggest that heightened vulnerability to insomnia is associated with an increased risk of developing new-onset subsyndromal and persistent insomnia in good sleepers. Knowledge of premorbid differences is important to identify at-risk individuals, as this may help to develop more targeted prevention and intervention strategies for insomnia.


Mechanical load inhibits IL-1 induced matrix degradation in articular cartilage.
Osteoarthritis is a disease process of cellular degradation of articular cartilage caused by mechanical loads and inflammatory cytokines. We studied the cellular response in native cartilage subjected to a mechanical load administered simultaneously with an inflammatory cytokine interleukin-1 (IL-1), hypothesizing that the combination of load and cytokine would result in accelerated extracellular matrix (ECM) degradation. Mature bovine articular cartilage was loaded for 3 days (stimulation) with 0.2 and 0.5 MPa stresses, with and without IL-1 (IL-1alpha, 10 ng/ml), followed by 3 days of no stimulation (recovery). Aggrecan and collagen loss were measured as well as aggrecan cleavage using monoclonal antibodies AF-28 and BC-3 for cleavage by aggrecanases (ADAMTS) and matrix metalloproteinases (MMPs), respectively. Incubation with IL-1 caused aggrecan cleavage by aggrecanases and MMPs during the 3 days of stimulation. A load of 0.5 MPa inhibited the IL-1-induced aggrecan loss while no inhibition was found for the 0.2 MPa stress. There was no collagen loss during the treatments but upon load and IL-1 removal proteoglycan and collagen loss increased. Load itself under these conditions was found to have no effect when compared to the unloaded controls. A mechanical load of sufficient magnitude can inhibit ECM degradation by chondrocytes when stimulated by IL-1. The molecular mechanisms involved in this process are not clear but probably involve altered mechanochemical signal transduction between the ECM and chondrocyte.


Colonoscopy: practice variation among 69 hospital-based endoscopists.
The medical profession, payers, and patients are interested increasingly in the quality of endoscopic procedures, including colonoscopy. The American Society for Gastrointestinal Endoscopy has recommended "report cards" by which endoscopists may keep track of certain key elements of their practice including indications, findings, duration, technical end points, complications, and patient satisfaction. The GI-Trac endoscopy reporting database includes many of the data points recommended by ASGE for report cards. Seven hospital centers in North America have been collecting data prospectively for varying periods since 1994. These data were aggregated and analyzed by individual endoscopist. A total of 69 endoscopists performed 17,868 colonoscopies. Twelve percent of the endoscopists reported that more than 20% of procedures they performed were completely normal. The average time taken by 27% of endoscopists was more than 40 minutes (without trainees involved), and only 55% achieved a cecal intubation rate of over 90%; for 9% the rate was less than 80%. Complication rates were too low for individual comparisons. These data provide an idea of colonoscopy performance by individual endoscopists in mainly academic centers. Incorporating all recommended data elements in future reporting databases will contribute to meaningful bench marking and to quality improvement efforts.


Low prospects and high risk: structural determinants of health associated with sexual risk among young African American women residing in resource-poor communities in the south.
African American women at increased risk of HIV/sexually transmitted infection (STI) may engage in risky sex as a coping mechanism for depressed economic conditions. This study examines the association between high-risk sexual behavior and structural determinants of sexual health among a sample of young African American women. 237 young African American women (16-19 years old) from economically disadvantaged neighborhoods in North Carolina were enrolled into a randomized trial testing the efficacy of an adapted HIV/STI prevention intervention. Logistic regression analyses predicted the likelihood that young women reporting lack of food at home, homelessness and low future prospects would also report sexual risk behaviors. Young women reporting a lack of food at home (22 %), homelessness (27 %), and low perceived education/employment prospects (19 %) had between 2.2 and 4.7 times the odds as those not reporting these risk factors of reporting multiple sex partners, risky sex partners including older men and partners involved in gangs, substance use prior to sex, and exchange sex. Self-reported structural determinants of sexual health were associated with myriad sexual risk behaviors. Diminished economic conditions among these young women may lead to sexual risk due to hopelessness, the need for survival or other factors.


Estimating DNA repair by sequential evaluation of head and neck tumor radiation sensitivity using the comet assay.
The alkaline comet assay is a microelectrophoretic technique for detecting single-strand DNA breaks, and may be used as an indirect measure of hypoxia by determining the radiation sensitivity of individual cells. To assess the ability of the comet assay to estimate the rate of DNA repair after irradiation in patients with head and neck cancer. The comet assay was used to evaluate DNA damage in fine-needle aspirates of lymph nodes containing metastatic squamous cell carcinoma in patients with head and neck cancer 1, 2, and 3 minutes after treatment with 500 rad (5 Gy) of irradiation. The amount of DNA damage (measured as the "tail moment" of the comet) is proportional to the number of DNA single-strand breaks after irradiation, which in turn depends on the oxygen concentration in each cell. The mean +/- SD of the median tail moment of the 1-minute postirradiation comets was 29.4 +/- 14.2 (n = 27). After 2 minutes, the mean median tail moment decreased to 25.4 +/- 13.6 (n = 25), representing a mean decrease of 11.9% in those patients with both 1- and 2-minute comet assays. Assuming a linear rate of repair, this decrease in DNA damage corresponds to a repair half-life of 4.2 minutes. A 3-minute assay was also performed on samples from a smaller number of patients (n = 9), with a mean value not significantly different from that of the 2-minute assay of the samples from this group. The comet assay is a promising tool for evaluating radiation sensitivity in individual cells. The rate of DNA repair early after irradiation is consistent with data in the literature.


Pesticide vapor sensing using an aptamer, nanopore, and agarose gel on a chip.
A pesticide vapor sensor was developed using an agarose gel-based chip containing a nanopore sensing system. Vaporized omethoate was detected by the absorption into the gel, the complex formation with a DNA aptamer, and its obstruction at the nanopore. This strategy is applicable to other vapors, expanding the versatility of nanopore sensors.


A review of quality surveillance projects on cosmetics in Taiwan.
The Food and Drug Administration in Taiwan is responsible for the quality regulation and control of cosmetics. In order to have a clear understanding of the trends in the product quality monitoring outcomes and the regulatory control measures over the past years, this study has put together the reports of nine cosmetic surveillance projects conducted between 1982 and 2012. The findings can be used as a reference in developing a more solid quality monitoring plan and management system for cosmetic products. Results show that permanent wave products, hair dye products, and phthalate esters in cosmetic products have the highest average noncompliance rates at 39.2%, 14.2%, and 11.2%, respectively. These are followed by the average noncompliance rates of mercury in products, sunscreen products, and microorganisms in products, at 8.5%, 7.1%, and 5.5%, respectively, and the remaining three projects averaging below 4.1%. Since 1997, when new standards were announced and assistance to manufacturers was reinforced, the noncompliance rates of permanent wave products decreased annually, until 2007, when it was fully qualified for the standards. Overall, the study showed that the noncompliance rates of permanent wave products and for levels of phthalate esters, mercury, and hydroquinone in cosmetic products have all decreased in the previous years. The results of surveillance projects conducted after 2005 revealed only one noncompliance sample with lead, arsenic, and cadmium, whereas the surveillance projects on permanent wave products and chloroform- and 1,4-dioxane-containing products revealed full compliance with regulation standards. However, the noncompliance rates for microorganisms in cosmetics and the ingredients in hair dye products and sunscreen products were still high. These high-risk products must be monitored. These surveillance projects are conducted to ensure the safety of cosmetics in the market.


Sleep Quality but Not Quantity Altered With a Change in Training Environment in Elite Australian Rules Football Players.
To assess the effects of a change in training environment on the sleep characteristics of elite Australian Rules football (AF) players. In an observational crossover trial, 19 elite AF players had time in bed (TIB), total sleep time (TST), sleep efficiency (SE), and wake after sleep onset (WASO) assessed using wristwatch activity devices and subjective sleep diaries across 8-d home and camp periods. Repeated-measures ANOVA determined mean differences in sleep, training load (session rating of perceived exertion [RPE]), and environment. Pearson product-moment correlations, controlling for repeated observations on individuals, were used to assess the relationship between changes in sleep characteristics at home and camp. Cohen effect sizes (d) were calculated using individual means. On camp TIB (+34 min) and WASO (+26 min) increased compared with home. However, TST was similar between home and camp, significantly reducing camp SE (-5.82%). Individually, there were strong negative correlations for TIB and WASO (r = -.75 and r = -.72, respectively) and a moderate negative correlation for SE (r = -.46) between home and relative changes on camp. Camp increased the relationship between individual s-RPE variation and TST variation compared with home (increased load r = -.367 vs .051, reduced load r = .319 vs -.033, camp vs home respectively). Camp compromised sleep quality due to significantly increased TIB without increased TST. Individually, AF players with higher home SE experienced greater reductions in SE on camp. Together, this emphasizes the importance of individualized interventions for elite team-sport athletes when traveling and/or changing environments.


Determination of primary particle size distributions from time-resolved laser-induced incandescence measurements.
For a polydisperse nanoparticle ensemble the evaluation of time-resolved laser-induced incandescence (LII) measurements yields a weighted average value for the primary nanoparticle size. Although this value is sufficient for narrow size distributions, a comprehensive characterization of a particle-evolution process requires the reconstruction of the size distribution. An easy-to-use online approach is presented to evaluate the LII signal regarding higher moments of the distribution. One advantage of this approach is that the size distribution results in a deceleration of the LII signal decay with time after the laser pulse. Therefore LII signal-decay curves are evaluated in two different time intervals after the laser pulse, providing information about the desired distribution parameters that has been tested successfully with experimental curves taken in different soot-formation processes.


A corepressor participates in LexA-independent regulation of error-prone polymerases in Acinetobacter.
The DNA damage response of the multidrug-resistant pathogen Acinetobacter baumannii, which induces mutagenic UmuD'2C error-prone polymerases, differs from that of many bacteria. Acinetobacter species lack a LexA repressor, but induce gene transcription after DNA damage. One regulator, UmuDAb, binds to and represses the promoters of the multiple A. baumannii ATCC 17978 umuDC alleles and the divergently transcribed umuDAb and ddrR genes. ddrR is unique to the genus Acinetobacter and of unknown function. 5' RACE (rapid amplification of cDNA ends) PCR mapping of the umuDAb and ddrR transcriptional start sites revealed that their -35 promoter elements overlapped the UmuDAb binding site, suggesting that UmuDAb simultaneously repressed expression of both genes by blocking polymerase access. This coordinated control of ddrR and umuDAb suggested that ddrR might also regulate DNA damage-inducible gene transcription. RNA-sequencing experiments in 17 978 ddrR- cells showed that ddrR regulated approximately 25 % (n=39) of the mitomycin C-induced regulon, with umuDAb coregulating 17 of these ddrR-regulated genes. Eight genes (the umuDC polymerases, umuDAb and ddrR) were de-repressed in the absence of DNA damage, and nine genes were uninduced in the presence of DNA damage, in both ddrR and umuDAb mutant strains. These data suggest ddrR has multiple roles, both as a co-repressor and as a positive regulator of DNA damage-inducible gene transcription. Additionally, 57 genes were induced by mitomycin C in the ddrR mutant but not in wild-type cells. This regulon contained multiple genes for DNA replication, recombination and repair, transcriptional regulators, RND efflux, and transport. This study uncovered another regulator of the atypical DNA damage response of this genus, to help describe how this pathogen acquires drug resistance through its expression of the error-prone polymerases under DdrR and UmuDAb control.


Introduction: personality psychology and the case study.
This article introduces the Journal of Personality's special issue on the life voyage of Dodge Morgan who, in 1986 at the age of 54, sailed solo around the world in 150 days. Before the voyage, Morgan agreed to participate in an intensive psychological case study, the data for which provide the focus for this special issue. William Nasby and Nancy W. Read have organized the vast array of psychological data obtained from Morgan and produced a complex and illuminating interpretation of his life, drawing liberally from the five-factor trait model of personality and the life-story model of adult identity. This introduction provides a historical and intellectual context for Nasby and Read's study by considering the various ways in which personality psychologists have employed the case study in research and examining the many conceptual and methodological problems and possibilities that arise in the psychological study of the single case.


Preconditioning with death ligands FasL and TNF-alpha protects the cirrhotic mouse liver against ischaemic injury.
Ischaemic preconditioning is the preemptive proven strategy to reduce ischaemic injury in the liver, but it can be harmful in the elderly or in patients with liver diseases. Ischaemic preconditioning induces a protective effect via activation of oxidative stress. We hypothesised that Fas ligand and tumour necrosis factor alpha can induce a similar response. Therefore, we tested if death ligands could mimic ischaemic preconditioning. Ischaemia was maintained for 60 min in cirrhotic mice. Death ligands were given 40 min before ischaemia. Ischaemic injury was assessed by histology and biochemical assays. To elucidate the mechanism, we used zinc protophorphyrin, an inhibitor of haem oxygenase-1 (HO-1), and gadolinium chloride, an inhibitor of Kupffer cells. Compared with the control group, death ligand preconditioning strongly reduced all markers of injury: serum transaminase levels, necrosis and apoptosis. Preconditioning caused an upregulation of HO-1, predominantly in macrophages. When zinc protophorphyrin or gadolinium chloride was applied prior to preconditioning, the beneficial effect of preconditioning was lost. These results demonstrate that ischaemic preconditioning can be replaced by death ligand preconditioning in the cirrhotic liver to prevent ischaemic injury. The protective mechanism depends on HO-1 induction in macrophages. These results open doors for novel hepato-protective strategies in liver surgery and transplantation.


Stress exposure and psychological stress responses are related to glucose concentrations during pregnancy.
The role of stress in the development of gestational diabetes mellitus (GDM) has so far been neglected. We investigated the impact of stress exposure (pregnancy-related and pregnancy-unrelated major life events), psychological stress responses (perceived stress, subjective experience of stress, anxiety, depression, sleep), and physiological stress responses (salivary cortisol, plasma copeptin levels) on glucose concentrations during pregnancy. Cross-sectional study, including 203 pregnant women at the maternity department of a Swiss university hospital. All women underwent routine screening for GDM with a 75-g oral glucose-tolerance test at 24-30 weeks of gestation. Pregnancy-related and pregnancy-unrelated major life events, perceived stress, general psychological distress, anxiety, depression, and amount of sleep were assessed by validated self-report questionnaires. Cortisol was measured using fasting and bedtime saliva samples, and copeptin using fasting plasma. All data were collected before communication of the screening test results. Significant positive associations were found between the number of pregnancy-related major life events and fasting glucose, while there was no association with pregnancy-unrelated major life events. More anxiety and depressive symptoms, a higher general level of distress, and a shorter duration of sleep were related to fasting glucose, although the latter two were no longer significant when age and BMI were controlled for. However, physiological stress responses were not associated with glucose concentrations. When testing for unique associations with fasting glucose, more general distress and shorter duration of sleep independently accounted for higher fasting glucose levels. Finally, when comparing women with and without GDM, we found that women who subsequently received the diagnosis of GDM reported more pregnancy-related life events. Some indicators of stress exposure and psychological stress responses were associated with fasting glucose concentrations in pregnant women, thus representing important risk factors for GDM development. Statement of contribution What is already known on this subject? Only approximately half of women with gestational diabetes mellitus (GDM) report any known risk factors. Women after GDM diagnosis reported more major life events compared to healthy pregnant controls. What does this study add? Stress exposure and psychological stress responses were associated with fasting glucose concentrations in pregnant before women were aware of their GDM diagnosis. These represent important risk factors for GDM development and potential targets for intervention.


Inter-comparison of the potentially active prokaryotic communities in the halocline sediments of Mediterranean deep-sea hypersaline basins.
The sediment microbiota of the Mediterranean deep-sea anoxic hypersaline basins (DHABs) are understudied relative to communities in the brines and halocline waters. In this study, the active fraction of the prokaryotic community in the halocline sediments of L' Atalante, Urania, and Discovery DHABs was investigated based on extracted total RNA and 454 pyrosequencing of the 16S rRNA gene. Bacterial and archaeal communities were different in the sediments underlying the halocline waters of the three habitats, reflecting the unique chemical settings of each basin. The relative abundance of unique operational taxonomic units (OTUs) was also different between deep-sea control sediments and sediments underlying DHAB haloclines, suggesting adaptation to the steep DHAB chemical gradients. Only a few OTUs were affiliated to known bacterial halophilic and/or anaerobic groups. Many OTUs, including some of the dominant ones, were related to aerobic taxa. Archaea were detected only in few halocline samples, with lower OTU richness relative to Bacteria, and were dominated by taxa associated with methane cycling. This study suggests that, while metabolically active prokaryotic communities appear to be present in sediments underlying the three DHABs investigated, their diversity and activity are likely to be more reduced in sediments underlying the brines.


Enhancement of bone formation during distraction osteogenesis: pediatric applications.
Delayed bone healing during distraction osteogenesis negatively affects clinical outcome. In addition to autologous bone grafting, several mechanical, chemical, biologic, and external treatment modalities may be employed to promote bone growth during distraction osteogenesis in the pediatric patient. Mechanical approaches include compressive loading of the distraction regenerate, increased frequency of small increments of distraction, and compression-distraction. Intramedullary nailing and submuscular plating can reduce the time in external fixation; however, these techniques are associated with technical difficulties and complications. Exogenous application of low-intensity pulsed ultrasound or pulsed electromagnetic fields may shorten the duration of external fixation. Other promising modalities include diphosphonates, physician-directed use (off-label use) of bone morphogenetic proteins, and local injection of bone marrow aspirate and platelet gel at the osteotomy site. Well-designed clinical studies are needed to establish safe and effective guidelines for various modalities to enhance new bone formation during distraction osteogenesis in children.


Vaginal bleeding during pregnancy and preterm birth.
This study investigated the relation between self-reported vaginal bleeding during pregnancy and preterm birth in a prospective cohort of 2,829 pregnant women enrolled from prenatal clinics between 1995 and 2000 in central North Carolina. The overall association between vaginal bleeding and preterm birth was modest (risk ratio (RR) = 1.3, 95% confidence interval (CI): 1.1, 1.6). Bleeding in the first trimester only was associated with earlier preterm birth (< or =34 weeks' gestation) (RR = 1.6, 95% CI: 1.1, 2.4) and preterm birth due to preterm premature rupture of the membranes (PPROM) (RR = 1.9, 95% CI: 1.1, 3.3). Bleeding in both trimesters was associated with preterm birth due to preterm labor (RR = 3.6, 95% CI: 1.9, 6.8). Bleeding of multiple episodes, on multiple days, and with more total blood loss was associated with an approximate twofold increased risk of earlier preterm birth, PPROM, and preterm labor. In contrast, bleeding in the second trimester only, of a single episode, on a single day, and with less total blood loss was not associated with any category of preterm birth. Vaginal bleeding was not associated with preterm birth among African Amercians (RR = 1.2, 95% CI: 0.9, 1.7). This study indicates that more intense but not less intense bleeding is associated with earlier preterm birth and spontaneous preterm birth presenting as PPROM or preterm labor, and it suggests that bleeding is less predictive of preterm birth among African-American compared with White women.


Comprehensive screening reveals strong and broadly directed human immunodeficiency virus type 1-specific CD8 responses in perinatally infected children.
Advances in antiviral therapy have dramatically shifted the demographics of pediatric human immunodeficiency virus type 1 (HIV-1) infection in the developed world, and a growing proportion of perinatally HIV-1-infected children are now entering their second or even third decade of life. Although cellular immune responses to HIV are known to be weak in early infancy, the magnitude, breadth, and specificity of responses later in childhood have not been characterized in detail. We performed a comprehensive characterization of HIV-1-specific CD8 responses in 18 perinatally infected children (age range, 6 to 17 years), most of whom were on antiviral therapy, using both previously defined HIV-1 epitopes and overlapping peptides spanning all HIV-1 proteins. Multispecific responses were detected in all subjects and accounted for a median of 0.25 to 0.3% of all peripheral blood mononuclear cells that was similar to the magnitude seen in HIV-infected adults. CD8 responses were broadly directed at an average of 11 epitopes (range, 2 to 27 epitopes) and targeted nearly all HIV-1 proteins, with the highest proportion in Gag. Responses were readily detected even in those children with suppressed viremia on highly active antiretroviral therapy, although the breadth (P = 0.037) and the magnitude (P = 0.021) were significantly lower in these subjects. Each child recognized only a small minority of the HIV-1 optimal epitopes defined for his or her class I HLA alleles. Together, these data indicate that perinatally infected children who survive infancy mount a robust HIV-1-specific CD8 response that is much stronger than previously thought and is comparable in magnitude and breadth to that of adults. Moreover, this response has the potential to be broadened to target more epitopes, making these children attractive candidates for immunotherapeutic interventions.


Characterization of graphene layers using super resolution polarization parameter indirect microscopic imaging.
We report on the development of super-resolution polarization (parameter) indirect microscopic imaging (PIMI) and its application to visualizing and quantifying graphene layer's morphological and structural features. The PIMI system was built by modifying a conventional optical microscopy such that the variation of the polarization status of incident light can be precisely controlled, imaging was subsequently acquired by analyzing the dependence of the optical intensity transmitted through (or reflected from) the samples on the incident light polarization status. Measurements on the thickness as well as other structural features of graphene samples which had been prepared by different methods were performed. The results which were highly consistent to those measured by Raman spectroscopy indicate that the PIMI system is capable of characterizing graphene's dimensional and structural features with super resolution.


Psychological stress level detection based on electrodermal activity.
This paper presents a method for detecting psychological stress levels. It aims to explore the feasibility of using a single physiological signal to create a more practical alternative for detecting stress in people than current multiple physiological signals approaches involve. In particular, the approach explored uses linear discriminant analysis (LDA) based on the electrodermal activity (EDA) signal which aims at discriminating between three stress levels: low, medium and high. We used the MIT Media lab 'stress database' from which we selected eleven 'foot' based EDA data sets for our experiments. Using this eighteen EDA features were extracted from (sixty-six) five-minutes data segments equating to three driving conditions: at rest, on the open road (highway) and city driving. After that, Fisher projection and Linear discriminant analysis (LDA) were used to classify the stress levels with feature vectors, that included both leaving one out and test cross-validation strategy. The results showed that these methods achieved recognition rate of 81.82% which we argue, while less that multiple signal systems, may be a better balance between recognition performance and computational load, that could be a promising line of research for the development of practical personal stress monitors.


Oligomeric interactions maintain active-site structure in a noncooperative enzyme family.
The evolutionary benefit accounting for widespread conservation of oligomeric structures in proteins lacking evidence of intersubunit cooperativity remains unclear. Here, crystal and cryo-EM structures, and enzymological data, demonstrate that a conserved tetramer interface maintains the active-site structure in one such class of proteins, the short-chain dehydrogenase/reductase (SDR) superfamily. Phylogenetic comparisons support a significantly longer polypeptide being required to maintain an equivalent active-site structure in the context of a single subunit. Oligomerization therefore enhances evolutionary fitness by reducing the metabolic cost of enzyme biosynthesis. The large surface area of the structure-stabilizing oligomeric interface yields a synergistic gain in fitness by increasing tolerance to activity-enhancing yet destabilizing mutations. We demonstrate that two paralogous SDR superfamily enzymes with different specificities can form mixed heterotetramers that combine their individual enzymological properties. This suggests that oligomerization can also diversify the functions generated by a given metabolic investment, enhancing the fitness advantage provided by this architectural strategy.


Mediterranean diet- and exercise-induced improvement in age-dependent vascular activity.
The aging effect on microvascular integrity, marked by endothelial dysfunction and reduction in exercise tolerance, is a major cause of CVD (cardiovascular disease). Improved dietary habits, known to reduce morbidity and mortality, are also known to attenuate those aging effects. The present study investigated the effects of combined MD (Mediterranean diet) and exercise intervention on lower- and upper-limb cutaneous microvascular functions in an older healthy population. A total of 22 sedentary healthy participants (age, 55±4 years) underwent cardiopulmonary exercise tolerance test, and were assessed for their upper- and lower-limb vascular endothelial CVC (cutaneous vascular conductance) using LDF (laser Doppler fluximetry) with endothelium-dependent [ACh (acetylcholine chloride)] and -independent [SNP (sodium nitroprusside)] vasodilation. Participants were then randomized into two groups: MD and non-MD, and followed an 8-week intervention programme, which included discontinuous treadmill running based on each individual's exertion, twice per week. Exercise training improved CVC in both groups (e.g. 0.42±0.19 compared with 1.50±1.05 and 0.47±0.26 compared with 1.15±0.59 at 1000 μCb for MD and non-MD respectively; P<0.001). This was also combined by improvement in the exercise tolerance indicated by increased VT (ventilatory threshold) in both groups [12.2±2.8 compared with 14.8±2.8 ml·(kg of body weight)(-1)·min(-1) and 11.7±2.7 compared with 14.6±3.2 ml·(kg of body weight)(-1)·min(-1) for MD and non-MD groups respectively; P<0.05]. However, the MD group showed greater improvement in endothelium-dependent vasodilation than non-MD [ANCOVA (analyses of co-variance), P=0.02]. The results of the present study suggest that compliance with MD, combined with regular moderate exercise, improves age-provoked microcirculatory endothelial dysfunction and increases exercise tolerance, both responsible for reducing cardiovascular risk in this age group.


Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis.
Depression and substance abuse are common and costly disorders that frequently co-occur, but controversy about effective treatment for patients with both disorders persists. To conduct a systematic review and meta-analysis to quantify the efficacy of antidepressant medications for treatment of combined depression and substance use disorders. PubMed, MEDLINE, and Cochrane database search (1970-2003), using the keywords antidepressant treatment or treatment depressed in conjunction with each of the following alcohol dependence, benzodiazepine dependence, opiate dependence, cocaine dependence, marijuana dependence, and methadone; a search of bibliographies; and consultation with experts in the field. Among inclusion criteria used for study selection were prospective, parallel group, double-blind, controlled clinical trials with random assignment to an antidepressant medication or placebo for which trial patients met standard diagnostic criteria for current alcohol or other drug use and a current unipolar depressive disorder. Of the more than 300 citations extracted, 44 were placebo-controlled clinical trials, 14 of which were selected for this analysis and included 848 patients: 5 studies of tricyclic antidepressants, 7 of selective serotonin re-uptake inhibitors, and 2 from other classes We independently screened the titles and abstracts of each citation, identified placebo-controlled trials of patients with both substance dependence and depression, applied the inclusion criteria, and reached consensus. Data on study methods, sample characteristics, and depression and substance use outcomes were extracted. The principal measure of effect size was the standardized difference between means on the Hamilton Depression Scale (HDS). For the HDS score, the pooled effect size from the random-effects model was 0.38 (95% confidence interval, 0.18-0.58). Heterogeneity of effect on HDS across studies was significant (P <.02), and studies with low placebo response showed larger effects. Moderator analysis suggested that diagnostic methods and concurrent psychosocial interventions influenced outcome. Studies with larger depression effect sizes (>0.5) demonstrated favorable effects of medication on measures of quantity of substance use, but rates of sustained abstinence were low. Antidepressant medication exerts a modest beneficial effect for patients with combined depressive- and substance-use disorders. It is not a stand-alone treatment, and concurrent therapy directly targeting the addiction is also indicated. More research is needed to understand variations in the strength of the effect, but the data suggest that care be exercised in the diagnosis of depression-either by observing depression to persist during at least a brief period of abstinence or through efforts by clinical history to screen out substance-related depressive symptoms.


The atypical antipsychotics quetiapine, risperidone and ziprasidone do not increase insulin release in vitro.
In the light of the recent finding that the atypical antipsychotics clozapine and olanzapine have a stimulatory effect on basal insulin release in vitro, the influence on insulin release of three other atypical agents; quetiapine, risperidone and ziprasidone, was examined. The effect of each atypical antipsychotic in a concentration of 10(-6) M was investigated on both basal and glucose-stimulated insulin release from isolated rat pancreatic islets. No difference in effect on insulin release was found for any of the three atypical antipsychotic substances compared to controls without antipsychotics, either in basal or in glucose-stimulated insulin release. This study demonstrates that the main compounds of quetiapine, risperidone and ziprasidone do not increase insulin release from isolated pancreatic islets, which stands in clear contrast to what has been found previously for clozapine and olanzapine. Thus, atypical antipsychotics seem to differ in their effect on insulin release in vitro.


Paraincisional subcutaneous infusion of ropivacaine after open abdominal vascular surgery shows significant advantages.
Opiates are widely used for postoperative pain relief. Unfortunately, their side effects such as inhibited gastrointestinal motility and respiratory depression may compromise or delay postoperative recovery after laparotomy. We used paraincisional subcutaneous catheters (PSCs) and applied 0.25% ropivacaine infusion to improve pain relief and decrease postoperative morphine consumption in patients after open surgery for aortic aneurysm. A retrospective single-center study including 58 patients treated by open surgery for aortic aneurysm between October 2006 and June 2012. Overall, 28 patients (control group) received standard postoperative pain management including opiates, and 30 patients (PSC group) were treated with paraincisional continuous local analgesia with 0.25% ropivacaine administrated via bilateral subcutaneous catheters along with additional ad libitum opiates administration, at first intravenously and then orally. Patients characteristics as well as perioperative and postoperative outcomes were comparable between the groups during the first 5 days after surgery. Patients of the PSC group received significantly less morphine, although the patients in both groups reported a similar pain intensity. Neither wound-healing disorder nor catheter-associated subcutaneous infection was reported. High serum concentration of ropivacaine was detected in 2 patients (6%) with end-stage renal disease, who developed temporary neurologic symptoms. Length of intensive care unit (ICU) stay was significantly shorter in the PSC group (2 [0-23] vs. 4.5 [0-32] ICU days). This is the first report about PSCs for analgesia after laparotomy. This case/control study shows that continuous paraincisional subcutaneous infusion of 0.25% ropivacaine after open surgery for aortic aneurysm repair is a feasible method of postoperative analgesia. This technique allows sustained pain relief with significant reduction of opiate requirement and faster recovery after surgery. Prospective randomized controlled trial is necessary for the assessment of safety and efficacy of this method.


COPD care delivery pathways in five European Union countries: mapping and health care professionals' perceptions.
COPD is among the leading causes of chronic morbidity and mortality in the European Union with an estimated annual economic burden of €25.1 billion. Various care pathways for COPD exist across Europe leading to different responses to similar problems. Determining these differences and the similarities may improve health and the functioning of health services. The aim of this study was to compare COPD patients' care pathway in five European Union countries including England, Ireland, the Netherlands, Greece, and Germany and to explore health care professionals' (HCPs) perceptions about the current pathways. HCPs were interviewed in two stages using a qualitative, semistructured email interview and a face-to-face semistructured interview. Lack of communication among different health care providers managing COPD and comorbidities was a common feature of the studied care pathways. General practitioners/family doctors are responsible for liaising between different teams/services, except in Greece where this is done through pulmonologists. Ireland and the UK are the only countries with services for patients at home to shorten unnecessary hospital stay. HCPs emphasized lack of communication, limited resources, and poor patient engagement as issues in the current pathways. Furthermore, no specified role exists for pharmacists and informal carers. Service and professional integration between care settings using a unified system targeting COPD and comorbidities is a priority. Better communication between health care providers, establishing a clear role for informal carers, and enhancing patients' engagement could optimize current care pathways resulting in a better integrated system.


Safety at work: a meta-analytic investigation of the link between job demands, job resources, burnout, engagement, and safety outcomes.
In this article, we develop and meta-analytically test the relationship between job demands and resources and burnout, engagement, and safety outcomes in the workplace. In a meta-analysis of 203 independent samples (N = 186,440), we found support for a health impairment process and for a motivational process as mechanisms through which job demands and resources relate to safety outcomes. In particular, we found that job demands such as risks and hazards and complexity impair employees' health and positively relate to burnout. Likewise, we found support for job resources such as knowledge, autonomy, and a supportive environment motivating employees and positively relating to engagement. Job demands were found to hinder an employee with a negative relationship to engagement, whereas job resources were found to negatively relate to burnout. Finally, we found that burnout was negatively related to working safely but that engagement motivated employees and was positively related to working safely. Across industries, risks and hazards was the most consistent job demand and a supportive environment was the most consistent job resource in terms of explaining variance in burnout, engagement, and safety outcomes. The type of job demand that explained the most variance differed by industry, whereas a supportive environment remained consistent in explaining the most variance in all industries.


Multifeatural shape processing in rats engaged in invariant visual object recognition.
The ability to recognize objects despite substantial variation in their appearance (e.g., because of position or size changes) represents such a formidable computational feat that it is widely assumed to be unique to primates. Such an assumption has restricted the investigation of its neuronal underpinnings to primate studies, which allow only a limited range of experimental approaches. In recent years, the increasingly powerful array of optical and molecular tools that has become available in rodents has spurred a renewed interest for rodent models of visual functions. However, evidence of primate-like visual object processing in rodents is still very limited and controversial. Here we show that rats are capable of an advanced recognition strategy, which relies on extracting the most informative object features across the variety of viewing conditions the animals may face. Rat visual strategy was uncovered by applying an image masking method that revealed the features used by the animals to discriminate two objects across a range of sizes, positions, in-depth, and in-plane rotations. Noticeably, rat recognition relied on a combination of multiple features that were mostly preserved across the transformations the objects underwent, and largely overlapped with the features that a simulated ideal observer deemed optimal to accomplish the discrimination task. These results indicate that rats are able to process and efficiently use shape information, in a way that is largely tolerant to variation in object appearance. This suggests that their visual system may serve as a powerful model to study the neuronal substrates of object recognition.


Psychotherapy in historical perspective.
This article will briefly explore some of the ways in which the past has been used as a means to talk about psychotherapy as a practice and as a profession, its impact on individuals and society, and the ethical debates at stake. It will show how, despite the multiple and competing claims about psychotherapy's history and its meanings, historians themselves have, to a large degree, not attended to the intellectual and cultural development of many therapeutic approaches. This absence has the potential consequence of implying that therapies have emerged as value-free techniques, outside of a social, economic and political context. The relative neglect of psychotherapy, by contrast with the attention historians have paid to other professions, particularly psychiatry, has also underplayed its societal impact. This article will foreground some of the instances where psychotherapy has become an object of emerging historical interest, including the new research that forms the substance of this special issue of History of the Human Sciences.


Late-Pregnancy Salivary Cortisol Concentrations of Ghanaian Women Participating in a Randomized Controlled Trial of Prenatal Lipid-Based Nutrient Supplements.
High circulating cortisol is associated with miscarriage, preterm birth, and low birth weight. Research in nonpregnant individuals suggests that improved nutrition may lower cortisol concentrations. It is unknown whether nutritional supplementation during pregnancy lowers cortisol. Our objective was to determine whether women receiving a lipid-based nutrient supplement (LNS) throughout pregnancy would have lower salivary cortisol at 36 wk gestation compared with women receiving other nutrient supplements. We conducted a randomized controlled trial in 1320 pregnant Ghanaian women at ≤20 wk gestation who were assigned to receive daily throughout pregnancy: 1) 60 mg iron + 400 μg folic acid (IFA), 2) multiple micronutrients (MMNs), or 3) 20 g LNS (containing 118 kcal, 22 micronutrients, and protein). Morning salivary cortisol was collected from a subsample at baseline and at 28 and 36 wk gestation. A total of 758 women had cortisol measurements at 28 or 36 wk gestation. Salivary cortisol at 36 wk gestation did not differ between groups and was (mean ± SE) 7.97 ± 0.199 in the IFA group, 7.84 ± 0.191 in the MMN group, and 7.77 ± 0.199 nmol/L in the LNS group, when adjusted for baseline cortisol, time of waking, and time between waking and saliva collection (P = 0.67). There was an interaction between supplementation group and women's age (continuous variable, P-interaction = 0.03); and when age was dichotomized by the median, significant differences in salivary cortisol concentrations between groups were seen in women ≤26 y of age (IFA = 8.23 ± 0.284 nmol/L, MMN = 8.20 ± 0.274 nmol/L, and LNS = 7.44 ± 0.284 nmol/L; P = 0.03) but not in women >26 y old (IFA = 7.71 ± 0.281 nmol/L, MMN = 7.50 ± 0.274 nmol/L, and LNS = 8.08 ± 0.281 nmol/L; P = 0.13). We conclude that supplementation with LNSs or MMNs during pregnancy did not affect the cortisol concentration in the study population as a whole, in comparison with IFA, but that LNS consumption among younger women may lead to lower cortisol at 36 wk gestation. This trial was registered at clinicaltrials.gov as NCT00970866.


Plasmodium serine hydroxymethyltransferase: indispensability and display of distinct localization.
Serine hydroxymethyltransferase (SHMT), a pyridoxal phosphate-dependent enzyme, plays a vital role in the de novo pyrimidine biosynthesis pathway in malaria parasites. Two genes have been identified in Plasmodium spp. encoding a cytosolic SHMT (cSHMT) and putative mitochondria SHMT (mSHMT), but their roles have not been fully investigated. The presence of Plasmodium SHMT isoforms in the intra-erythrocytic stage was assessed based on their gene expression using reverse transcription PCR (RT-PCR). Localization studies of Plasmodium SHMT isoforms were performed by transfection of fluorescent-tagged gene constructs into P. falciparum and expressions of fluorescent fusion proteins in parasites were observed using a laser scanning confocal microscope. Genetic targeting through homologous recombination was used to study the essentiality of SHMT in Plasmodium spp. Semi-quantitative RT-PCR revealed the expression of these two genes throughout intra-erythrocytic development. Localization studies using P. falciparum expressing fluorescent-tagged SHMT showed that PfcSHMT-red fluorescent fusion protein (PfcSHMT-DsRed) is localized in the cytoplasm, while PfmSHMT-green fluorescent fusion protein (PfmSHMT-GFP) co-localized with Mitotracker™-labelled mitochondria as predicted. The essentiality of plasmodial cSHMT was inferred from transfection experiments where recovery of viable knock-out parasites was not achieved, unless complemented with a functional equivalent copy of shmt. Distinct compartment localizations of PfSHMT were observed between cytoplasmic and mitochondrial isoforms, and evidence was provided for the indispensable role of plasmodial cSHMT indicating it as a valid target for development of novel anti-malarials.


Impact of breed and sex on porcine endocrine transcriptome: a bayesian biometrical analysis.
Transcriptome variability is due to genetic and environmental causes, much like any other complex phenotype. Ascertaining the transcriptome differences between individuals is an important step to understand how selection and genetic drift may affect gene expression. To that end, extant divergent livestock breeds offer an ideal genetic material. We have analyzed with microarrays five tissues from the endocrine axis (hypothalamus, adenohypophysis, thyroid gland, gonads and fat tissue) of 16 pigs from both sexes pertaining to four extreme breeds (Duroc, Large White, Iberian and a cross with SinoEuropean hybrid line). Using a Bayesian linear model approach, we observed that the largest breed variability corresponded to the male gonads, and was larger than at the remaining tissues, including ovaries. Measurement of sex hormones in peripheral blood at slaughter did not detect any breed-related differences. Not unexpectedly, the gonads were the tissue with the largest number of sex biased genes. There was a strong correlation between sex and breed bias expression, although the most breed biased genes were not the most sex biased genes. A combined analysis of connectivity and differential expression suggested three biological processes as being primarily different between breeds: spermatogenesis, muscle differentiation and several metabolic processes. These results suggest that differences across breeds in gene expression of the male gonads are larger than in other endocrine tissues in the pig. Nevertheless, the strong presence of breed biased genes in the male gonads cannot be explained solely by changes in spermatogenesis nor by differences in the reproductive tract development.


Isolation of human NURF: a regulator of Engrailed gene expression.
The modification of chromatin structure is an important regulatory mechanism for developmental gene expression. Differential expression of the mammalian ISWI genes, SNF2H and SNF2L, has suggested that they possess distinct developmental roles. Here we describe the purification and characterization of the first human SNF2L-containing complex. The subunit composition suggests that it represents the human ortholog of the Drosophila nucleosome-remodeling factor (NURF) complex. Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth.


Scope of practice of family medicine graduates who completed a rural versus urban program.
In Canada, rural-based family medicine residency programs were established largely in response to a shortage of rural physicians and the perception that urban-based training programs were not meeting the needs of rural populations. Examinations of practice patterns of physicians trained in rural and urban programs are lacking. The purpose of this study was to compare the scope of practice of family medicine graduates who completed a rural versus an urban residency program, by practice location. This was a cross-sectional, mail-out, questionnaire survey of 651 graduates who had completed the family medicine residency program at the University of Alberta or the University of Calgary, Alberta, Canada during 2006-2011. Rural program graduates lived and trained in regional settings and spent a considerable amount of time in smaller rural and remote communities for their clinical experience. The training of urban program graduates was primarily based in large urban settings and family medicine clinical experience was based in the community. Practice location (rural, urban) was classified by population size of the town/city at which physicians practiced. Scope of practice was ascertained through four domains of care: types of care, clinical procedures, practice settings and specific populations. Items within each domain were rated on a five-point scale (1='not part of practice', 5='element of core practice'). Mean rating scores for items in the domains of care were compared between urban and rural program graduates using ANOVA. A total of 307 (47.2%) graduates responded to the survey, of whom 173 were categorized as urban program graduates and 59 as rural program graduates. Overall, rural program graduates exhibited a broader scope of practice in providing postnatal care, intrapartum care/deliveries, palliative care, office-based and in-hospital clinical procedures, emergency care, in-hospital care, home visits, long-term care, and caring for rural and Aboriginal populations. Irrespective of program completed, those in a rural practice location had a broader scope of practice than those in urban practice. Urban and rural program graduates in rural locations tended to have a similar scope of practice. In urban locations, rural program graduates were more likely to include intrapartum care/deliveries as part of their clinical practice. Rural program graduates were more likely to practice in rural locations than urban program graduates. A combination of site of training (rural or urban program) and location of practice appear to work together to influence scope of practice of family physicians. A conceptual framework that summarizes the factors that have been reported to be associated with the scope of family practice is proposed.


Person-centred integrative diagnosis: conceptual bases and structural model.
To review the conceptual bases of Person-centred Integrative Diagnosis (PID) as a component and contributor to person-centred psychiatry and medicine and to outline its design and development. An analysis was conducted of the historical roots of person-centred psychiatry and medicine, tracing them back to ancient Eastern and Western civilizations, to the vicissitudes of modern medicine, to recent clinical and conceptual developments, and to emerging efforts to reprioritize medicine from disease to patient to person in collaboration with the World Medical Association, the World Health Organization, the World Organization of Family Doctors, the World Federation for Mental Health, and numerous other global health entities, and with the coordinating support of the International Network for Person-centered Medicine. One of the prominent endeavours within the broad paradigmatic health development outlined above is the design of PID. This diagnostic model articulates science and humanism to obtain a diagnosis of the person (of the totality of the person's health, both ill and positive aspects), by the person (with clinicians extending themselves as full human beings), for the person (assisting the fulfillment of the person's health aspirations and life project), and with the person (in respectful and empowering relationship with the person who consults). This broader and deeper notion of diagnosis goes beyond the more restricted concepts of nosological and differential diagnoses. The proposed PID model is defined by 3 keys: broad informational domains, covering both ill health and positive health along 3 levels: health status, experience of health, and contributors to health; pluralistic descriptive procedures (categories, dimensions and narratives); and evaluative partnerships among clinicians, patients, and families. An unfolding research program is focused on the construction of a practical guide and its evaluation, followed by efforts to facilitate clinical implementation and training. PID is aimed at appraising overall health through pluralistic descriptions and evaluative partnerships, and leading through a research program to more effective, integrative, and person-centred health care.


Deep-reef fish assemblages of the Great Barrier Reef shelf-break (Australia).
Tropical mesophotic and sub-mesophotic fish ecology is poorly understood despite increasing vulnerability of deeper fish assemblages. Worldwide there is greater fishing pressure on continental shelf-breaks and the effects of disturbances on deeper fish species have not yet been assessed. Difficult to access, deeper reefs host undocumented fish diversity and abundance. Baited Remote Underwater Video Stations (BRUVS) with lights were used to sample deeper habitats (54-260 m), in the Great Barrier Reef (GBR), Australia. Here we describe fish biodiversity, relative abundance and richness, assessing the prediction that depth would drive assemblage structure in the GBR. Distinct groups of fishes were found with depth whilst overall richness and abundance decreased steeply between 100 and 260 m. Commercially-valuable Lutjanidae species from Pristipomoides and Etelis genera, were absent from shallower depths. Few fish species overlapped between adjacent depth strata, indicating unique assemblages with depth. We also detected new location records and potential new species records. The high biodiversity of fish found in shelf-break environments is poorly appreciated and depth is a strong predictor of assemblage composition. This may pose a challenge for managers of commercial fisheries as distinct depth ranges of taxa may translate to more readily targeted habitats, and therefore, an inherent vulnerability to exploitation.


Radiation protection and dose monitoring in medical imaging: a journey from awareness, through accountability, ability and action…but where will we arrive?
Radiation awareness and protection of patients have been the fundamental responsibilities in diagnostic imaging since the discovery of x-rays late in 1895 and the first reports of radiation injury in 1896. In the ensuing years, there have been significant advancements in equipment that uses either x-rays to form images, such as fluoroscopy or computed tomography (CT), or the types of radiation emitted during nuclear imaging procedures (e.g., positron emission tomography [PET]). These advancements have allowed detailed and indispensable evaluation of a vast array of disorders. In fact, in 2001, CT and MRI were cited by physicians as the most significant medical innovations in the previous 3 decades. Rapid technological advancements in the last decade with CT, especially, have required imaging professionals to keep pace with increasingly complex technology to derive the maximum benefits of improved image acquisition and display techniques, in essence, the improved quality of the examination. It has also been challenging to fulfill the fundamental responsibilities of safety during this period of rapid growth (e.g., radiation protection, management of the risk of additional interventions driven by incidental findings, performing studies that were not indicated). The purpose of this paper is to define critical issues pertinent to ensuring patient safety through the appropriate assessment, recording, monitoring, and reporting of the radiation dose from CT.


Surface molecular view of colloidal gelation.
We investigate the phase behavior of surface-functionalized silica colloids at both the molecular and macroscopic levels. This investigation allows us to relate collective properties such as aggregation, gelation, and aging directly to molecular interfacial behavior. By using surface-specific vibrational spectroscopy, we reveal dramatic changes in the conformation of alkyl chains terminating submicrometer silica particles. In fluid suspension at high temperatures, the interfacial molecules are in a liquid-like state of conformational disorder. As the temperature is lowered, the onset of gelation is identified by macroscopic phenomena, including changes in turbidity, heat release, and diverging viscosity. At the molecular level, the onset of this transition coincides with straightening of the carbon-carbon backbones of the interfacial molecules. In later stages, their intermolecular crystalline packing improves. It is the increased density of this ordered boundary layer that increases the van der Waals attraction between particles, causing the colloidal gas to aggregate. The approach presented here can provide insights into phase transitions that occur through surface modifications in a variety of colloidal systems.


Virulence and Genomic Feature of a Virulent Klebsiella pneumoniae Sequence Type 14 Strain of Serotype K2 Harboring blaNDM-5 in China.
The objective of this study was to reveal the molecular mechanism involved in carbapenem resistance and virulence of a K2 Klebsiella pneumoniae clinical isolate 24835. The virulence of the strain was determined by in vitro and in vivo methods. The de novo whole-genome sequencing technology and molecular biology methods were used to analyze the genomic features associated with the carbapenem resistance and virulence of K. pneumoniae 24835. Strain 24835 was highly resistant to carbapenems and belonged to ST14, exhibited hypermucoviscous and unique K2-aerobactin-kfu-rmpA positive phenotype. As the only carbapenemase gene in strain 24835, blaNDM-5 was located on a 46-kb IncX3 self-transmissible plasmid, which is a very close relation of pNDM-MGR194 from India. Genetic context of blaNDM-5 in strain 24835 was closely related to those on IncX3 plasmids in various Enterobacteriaceae species in China. The combination of multiple virulence genes may work together to confer the relative higher virulence in K. pneumoniae 24835. Significantly increased resistance to serum killing and mice mortality were found in the virulent New Delhi metallo-β-lactamase (NDM)-producing K. pneumoniae strain compared to the other NDM-producing K. pneumoniae strain. Our study provides basic information of phenotypic and genomic features of K. pneumoniae 24835, a strain displaying carbapenem resistance and relatively high level of virulence. These findings are concerning for the potential of NDM-like genes to disseminate among virulent K. pneumoniae isolates.


[The early medical textbooks in Korea: medical textbooks published at Je Joong Won-Severance Hospital Medical School].
Kwang Hye Won(Je Joong Won), the first western hospital in Korea, was founded in 1885. The first western Medical School in Korea was open in 1886 under the hospital management. Dr. O. R. Avison, who came to Korea in 1893, resumed the medical education there, which was interrupted for some time before his arrival in Korea. He inaugurated translating and publishing medical textbooks with the help of Kim Pil Soon who later became one of the first seven graduates in Severance Hospital Medical School. The first western medical textbook translated into Korean was Henry Gray's Anatomy. However, these twice-translated manuscripts were never to be published on account of being lost and burnt down. The existing early anatomy textbooks, the editions of 1906 and 1909, are not the translation of Gray's Anatomy, but that of Japanese anatomy textbook of Gonda. The remaining oldest medical textbook in Korean is Inorganic Materia Medica published in 1905. This book is unique among its kind that O. R. Avison is the only translator of the book and it contains the prefaces of O. R. Avison and Kim Pil Soon. The publication of medical textbook was animated by the participation of other medical students, such as Hong Suk Hoo and Hong Jong Eun. The list of medical textbooks published includes almost all the field of medicine. The medical textbooks in actual existence are as follows: Inorganic Materia Medica (1905), Inorganic Chemistry (1906), Anatomy I (1906), Physiology (1906), Diagnostics I (1906), Diagnostics II (1907), Obstetrics (1908), Organic Chemistry (1909), Anatomy (1909), and Surgery (1910).


End-of-life care content in postgraduate critical care nursing programs: Structured telephone interviews to evaluate content-informing practice.
The provision of end-of-life care remains a significant component of work for clinicians in critical care settings. Critical care nurses report that this area of practice receives limited attention in education and training. The objective of this study was to identify and describe the end-of-life care content in postgraduate critical care nursing programs in Australia. Using a descriptive exploratory research design, an Internet search was undertaken in August 2015, identifying 17 education providers offering postgraduate critical care nursing programs. Thirteen individuals agreed to participate in a structured telephone interview regarding end-of-life content in their postgraduate program. Descriptive statistics were calculated to summarise the data obtained. Twelve participants reported that end-of-life care content was explicitly addressed in their postgraduate critical care nursing programs, yet variation in actual content areas covered was evident. The majority of programs addressed content related to organ donation (92%) and legal and ethical issues (77%). However, content least commonly identified as covered pertained to the work of the nurse in providing direct clinical care to the patient at the end of life and his or her family, including the physical changes experienced by the dying patient (31%), respiratory management encompassing withdrawal of ventilation and symptom management (23%), emotional support of family (23%), care of the body after death (23%), and the process of withdrawing life-sustaining treatment (15%). Participants (92%) agreed that end-of-life content was important in postgraduate critical care nursing programs, with 77% of participants agreeing that more time should be allocated to end-of-life content. This study provides preliminary evidence of the variation in end-of-life content in postgraduate critical care nursing programs in Australia. Addressing gaps in end-of-life care content in formal education, including clinical care of the dying patient, is urgently needed to address the complexity of this phase of care that is so frequently provided in critical care units.


ER Adaptor SCAP Translocates and Recruits IRF3 to Perinuclear Microsome Induced by Cytosolic Microbial DNAs.
Stimulator of interferon genes (STING, also known as MITA, ERIS or MPYS) induces the activation of TBK1 kinase and IRF3 transcription factor, upon sensing of microbial DNAs. How IRF3 is recruited onto the STING signalosome remains unknown. We report here that silencing of the ER adaptor SCAP markedly impairs the IRF3-responsive gene expression induced by STING. Scap knockdown mice are more susceptible to HSV-1 infection. Interestingly, SCAP translocates from ER, via Golgi, to perinuclear microsome in a STING-dependent manner. Mechanistically, the N-terminal transmembrane domain of SCAP interacts with STING, and the C-terminal cytosolic domain of SCAP binds to IRF3, thus recruiting IRF3 onto STING signalosome. Mis-localization of SCAP abolishes its antiviral function. Collectively, this study characterizes SCAP as an essential adaptor in the STING signaling pathway, uncovering a critical missing link in DNAs-triggered host antiviral responses.


One-visit RCT of Maxillary Incisors with Extensive Inflammatory Root Resorption and Periradicular Lesions: A Case Report.
Inflammatory external root resorption (IERR) is a pathological phenomenon of microbial origin. This study reports a case of external apical inflammatory root resorption of maxillary incisors associated with periradicular lesions in a 22 year old female, which was successfully treated by one-visit root canal therapy (RCT). Radiographic investigation revealed periapical radiolucencies in the upper incisors associated with varying degrees of external inflammatory root resorption of teeth 12, 21 and 22. One-visit RCT of all involved teeth was carried out. Access cavities were permanently restored after 1 week. Clinical and radiographic examinations at 1 day, 1 week and 14 month follow-up demonstrated complete resolution of patient's signs/symptoms. The incisors were fully functional, and complete bone healing of the apical radiolucencies had taken place. The treatment outcomes demonstrated that IERR associated with periradicular lesions can respond successfully to one-visit RCT when conducted with adequate disinfection and a satisfactory coronal seal. Hence, one-visit RCT may be a good alternative to multiple-visit RCT involving intra-canal medicaments.