Single-neuron responses in the human nucleus accumbens during a financial decision-making task.
Linking values to actions and evaluating expectations relative to outcomes are both central to reinforcement learning and are thought to underlie financial decision-making. However, neurophysiology studies of these processes in humans remain limited. Here, we recorded the activity of single human nucleus accumbens neurons while subjects performed a gambling task. We show that the nucleus accumbens encodes two signals related to subject behavior. First, we find that under relatively predictable conditions, single neuronal activity predicts future financial decisions on a trial-by-trial basis. Interestingly, we show that this activity continues to predict decisions even under conditions of uncertainty (e.g., when the probability of winning or losing is 50/50 and no particular financial choice predicts a rewarding outcome). Furthermore, we find that this activity occurs, on average, 2 s before the subjects physically manifest their decision. Second, we find that the nucleus accumbens encodes the difference between expected and realized outcomes, consistent with a prediction error signal. We show this activity occurs immediately after the subject has realized the outcome of the trial and is present on both the individual and population neuron levels. These results provide human single neuronal evidence that the nucleus accumbens is integral in making financial decisions.


Rapid detection of synthetic cannabinoids in herbal highs using surface-enhanced Raman scattering produced by gold nanoparticle co-aggregation in a wet system.
Synthetic cannabinoids (SCs) are a major category of new psychoactive substances that are frequently distributed after addition to plants. To date, various SCs with small differences in their chemical structures have prevailed in the illegal drug market. Thus, the development of a method for rapid detection with high discrimination capability is critically important for the forensic field. Vibrational spectroscopy is a possible analytical technique for this purpose because it can sensitively reflect differences among chemical structures. In this study, we applied surface-enhanced Raman scattering (SERS) with gold nanoparticle co-aggregation in a wet system to plant samples containing SCs. The experimental protocol used was simple and involved only mixing of the sample with several other solutions. It was possible to detect SERS spectra from various stock solutions of SCs by this method. The method was then applied to street samples containing SCs. Some of the plant samples containing SCs did not produce significant SERS signals even though stock solutions of the same SCs did produce SERS spectra. We investigated the reason for this discrepancy and speculated that the solubility in aqueous solutions was a factor determining whether a significant SERS signal could be detected or not. According to this hypothesis, minimal sample pre-treatment methods were applied. This allowed for the detection of SERS spectra from the examined plant samples. The developed approach is a powerful method for screening analysis of SCs in plant fragments.


The Role of Organizational Factors in the Provision of Comprehensive Women's Health in the Veterans Health Administration.
Increasing numbers of women veterans present an organizational challenge to a health care system that historically has served men. Women veterans require comprehensive women's health services traditionally not provided by the Veterans Health Administration. Examine the association of organizational factors and adoption of comprehensive women's health care. Cross-sectional analysis of the 2007 Veterans Health Administration National Survey of Women Veterans Health Programs and Practices. Dependent measures included a) model of women's health care: separate women's health clinic (WHC), designated women's health provider in primary care (DWHP), both (WHC+DWHP), or neither and b) the availability of five women's health services: cervical cancer screening and evaluation and management of vaginitis, menstrual disorders, contraception, and menopause. Exposure variables were organizational factors drawn from the Greenhalgh model of diffusion of innovations including measures of structure, absorptive capacity, and system readiness for innovation. The organizational factors of a gynecology clinic, an academic affiliation with a medical school, a women's health representative on one or more high-impact committees, and a greater caseload of women veterans were more common at sites with WHCs and WHC+DWHPs, compared with sites relying on general primary care with or without a DWHP. Academic affiliation and high-impact committee involvement remained significant in multivariable analysis. Sites with WHCs or WHC+DWHPs were more likely to offer all five women's health services. Facilities with greater apparent absorptive capacity (academic affiliation and women's health representation on high-impact committees) are more likely to adopt WHCs. Facilities with separate WHCs are more likely to deliver a package of women's health services, promoting comprehensive care for women veterans.


Case Report: Two Novel Frameshift Mutations in SLC20A2 and One Novel Splice Donor Mutation in PDGFB Associated With Primary Familial Brain Calcification.
Primary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is characterized by bilateral and symmetric brain calcification in the basal ganglia (globus pallidus, caudate nucleus, and putamen), thalamus, subcortical white matter, and cerebellum. PFBC can be caused by loss-of-function mutations in any of the six known causative genes. The most common clinical manifestations include movement disorders, cognitive impairment, and neuropsychiatric signs that gradually emerge in middle-aged patients. To broaden the PFBC mutation spectrum, we examined nine members of a family with PFBC and two sporadic cases from clinical departments, and sequenced all PFBC-causative genes in the index case. Two novel frameshift mutations in SLC20A2 [NM_001257180.2; c.806delC, p.(Pro269Glnfs*49) and c.1154delG, p.(Ser385Ilefs*70)] and one novel splice donor site mutation (NM_002608.4, c.456+1G>C, r.436_456del) in PDGFB were identified in the patient cohort. c.806delC co-segregated with brain calcification and led to SLC20A2 haploinsufficiency among the affected family members. The c.456+1G>C mutation in PDGFB resulted in aberrant mRNA splicing, thereby forming mature transcripts containing an in-frame 21 base pair (bp) deletion, which might create a stably truncated protein [p.(Val146_Gln152del)] and exert a dominant negative effect on wild-type PDGFB. All three mutations were located in highly conserved regions among multiple species and predicted to be pathogenic, as evaluated by at least eight common genetic variation scoring systems. This study identified three novel mutations in SLC20A2 and PDGFB, which broadened and enriched the PFBC mutation spectrum.


Flightless-I governs cell fate by recruiting the SUMO isopeptidase SENP3 to distinct HOX genes.
Despite recent studies on the role of ubiquitin-related SUMO modifier in cell fate decisions, our understanding on precise molecular mechanisms of these processes is limited. Previously, we established that the SUMO isopeptidase SENP3 regulates chromatin assembly of the MLL1/2 histone methyltransferase complex at distinct HOX genes, including the osteogenic master regulator DLX3. A comprehensive mechanism that regulates SENP3 transcriptional function was not understood. Here, we identified flightless-I homolog (FLII), a member of the gelsolin family of actin-remodeling proteins, as a novel regulator of SENP3. We demonstrate that FLII is associated with SENP3 and the MLL1/2 complex. We further show that FLII determines SENP3 recruitment and MLL1/2 complex assembly on the DLX3 gene. Consequently, FLII is indispensible for H3K4 methylation and proper loading of active RNA polymerase II at this gene locus. Most importantly, FLII-mediated SENP3 regulation governs osteogenic differentiation of human mesenchymal stem cells. Altogether, these data reveal a crucial functional interconnection of FLII with the sumoylation machinery that converges on epigenetic regulation and cell fate determination.


Peptone Supplementation of Culture Medium Has Variable Effects on the Productivity of CHO Cells.
The optimization of cell culture conditions for growth and productivity of recombinant Chinese hamster ovary (CHO) cells is a critical step in biopharmaceutical manufacturing. In the present study, the effects of the timing and amount of peptone feeding of a recombinant CHO cell line grown in a basal medium in serum-free suspension culture were determined for eight peptones of different origin (plant and casein). The amino acid content and the average molecular weight of the peptones chosen were available. In optimized feeding strategies with single peptones, increase 100 % volumetric productivity and 40 % in cell number were achieved. In feeding strategies with two peptones, several combinations stimulated protein productivity more than either peptone alone, depending on the peptone concentration and time of feeding. Some peptones, which did not stimulate productivity when added alone proved to be effective when used in combination. The combined peptones feeding strategies were more effective with peptones of different origin. Our data support the notion that the origin of peptones provides some guidance in identifying the most effective feeding strategies for recombinant CHO cells.


Lasiodiplodia theobromae as a Causal Agent of Kumquat Dieback in Taiwan.
Kumquat (Fortunella margarita (Lour.) Swingle) is an important citrus fruit crop of Iland County in northeastern Taiwan. Fruit produced in this area are mainly for making preserves, which is a well-known product in Taiwan. Decline of kumquat was first noticed in 1990. Since 1995, it has become an important problem affecting ≈80% of kumquat orchards. The problem was especially serious after the passage of a typhoon. Some orchards were abandoned due to death of many declining trees. Initial symptoms were yellowing and browning of leaves on some branches of affected trees. Abscission of leaves and fruits occurred, subsequently resulting in the appearance of dieback of affected branches. Disease symptoms could progress to other branches of the same tree, gummosis on the trunk, and eventually death of the tree. Previously, Phytophthora citrophthora (Smith & Smith) Leonian was reported to be a causal organism of kumquat decline (1). Recently, isolations from declining kumquat trees in several orchards failed to recover P. citrophthora and instead we isolated Lasiodiplodia theobromae (Pat.) Griffon & Maubl. (syn. Botryodiplodia theobromae Pat.) from tissue taken from the margin of discolored bark and wood on symptomatic branches. The fungus produced grayish black colonies on V8 agar and black ostiolate pycnidia (125 to 650 μm in diameter) with ovoid to elongate conidia (20 to 32 × 12 to 16 μm) on autoclaved whole wheat grains that were placed on V8 agar. Young conidia were hyaline and nonseptate, whereas mature conidia were brown, one septate, and striate. Pathogenicity tests were carried out on healthy kumquat trees located at the Taiwan Agricultural Research Institute experimental farm. Three isolates of L. theobromae were cultured on wheat-oat medium. Colonized grains (≈5 g) were held against a wound made by lightly scrapping a branch (5 to 7 mm in diameter) 200 to 250 cm above the ground by wrapping a sheet of clear plastic around the branch (2). Eighteen branches were used for each isolate, and the same number of branches similarly inoculated with sterile grains as a control. Healthy branches inoculated with L. theobromae showed disease symptoms similar to those observed on naturally infected plants. Discoloration of leaves on inoculated branches occurred within 1 week. Subsequently, all the leaves fell and infected branches died. The numbers of inoculated branches killed by the three isolates of L. theobromae tested were 18, 9, and 14 after 1 month. All control branches remained disease free. L. theobromae was reisolated from symptomatic tissues, completing Koch's postulates. The same isolates were used to inoculate trunks of kumquat trees with the method described above. Six trunks were inoculated with each isolate, and the same number of trunks similarly inoculated with sterile grains was used as the control. Gummosis on inoculated trunks occurred in 1 week. The numbers of inoculated trunks showing gummosis induced by the three isolates of L. theobromae tested were 6, 5, and 6 after 1 month. L. theobromae was reisolated from symptomatic tissue. All control trunks remained free of gummosis. Our results show that in addition to P. citrophthora, L. theobromae can also cause a dieback on kumquat. To our knowledge, this is the first report of disease caused by L. theobromae on kumquat or on any species in the Rutaceae family in Taiwan. References: (1) P. J. Ann et al. Plant Pathol. Bull. (Taiwan) 6:198, 1997. (2) W. H. Ko et al. Plant Pathol. 35:254, 1986.


Clarithromycin and endoscopic sinus surgery for adults with chronic rhinosinusitis with and without nasal polyps: study protocol for the MACRO randomised controlled trial.
Chronic rhinosinusitis (CRS) is a common source of ill health; 11% of UK adults reported CRS symptoms in a worldwide population study. Guidelines are conflicting regarding whether antibiotics should be included in primary medical management, reflecting the lack of evidence in systematic reviews. Insufficient evidence to inform the role of surgery contributes to a fivefold variation in UK intervention rates. The objective of this trial is to establish the comparative effectiveness of endoscopic sinus surgery (ESS) or a prolonged course of antibiotics (clarithromycin) in adult patients with CRS in terms of symptomatic improvement and costs to the National Health Service compared with standard medical care (intranasal medication) at 6 months. A three-arm parallel-group trial will be conducted with patients who remain symptomatic after receiving appropriate medical therapy (either in primary or secondary care). They will be randomised to receive: (1) intranasal medication plus ESS, (2) intranasal medication plus clarithromycin (250 mg) or (3) intranasal medication plus a placebo. Intranasal medication (current standard medical care) is defined as a spray or drops of intranasal corticosteroids and saline irrigations. The primary outcome measure is the SNOT-22 questionnaire, which assesses disease-specific health-related quality of life. The study sample size is 600. Principal analyses will be according to the randomised groups irrespective of compliance. The trial will be conducted in at least 16 secondary or tertiary care centres with an internal pilot at six sites for 6 months. The potential cardiovascular side effects of macrolide antibiotics have been recently highlighted. The effectiveness of antibiotics will be established through this trial, which may help to reduce unnecessary usage and potential morbidity. If ESS is shown to be clinically effective and cost-effective, the trial may encourage earlier intervention. In contrast, if it is shown to be ineffective, then there should be a significant reduction in surgery rates. The trial results will feed into the other components of the MACRO research programme to establish best practice for the management of adults with CRS and design the ideal patient pathway across primary and secondary care. ISRCTN36962030 . Registered on 17 October 2018.


Family history and risk of hair loss.
The genetic basis of androgenetic alopecia (AGA) is well accepted in the medical community and among the general population. However, rigorous studies investigating the familial basis of AGA are lacking. The purpose of the current study was to explore the relationship between family history and expression of AGA in a sample of men from the general community. Hair loss was assessed by an independent observer trained by an expert dermatologist using the Norwood/Hamilton classification scale and a 7-point global description of hair loss. Men were classified into two groups, one as having little or no hair loss and the other having hair loss. The family history of hair loss in parents and grandparents was assessed by subject self-report. Adjusting for age, men whose fathers had hair loss were 2.5 times as likely to have had some level of hair loss compared to men whose fathers had no hair loss (95% CI: 1.3-4.9). Likewise, men whose fathers had hair loss were twice as likely to have hair loss than men whose fathers had no hair loss even after adjusting for age (OR = 2.1, 95% CI: 1.2-3.7 and OR = 2.5, 95% CI: 1.4-4.7 for Norwood/Hamilton and global description of hair loss assessments, respectively). Results suggest that the probability of male pattern hair loss is dependent on family history and age. Hair loss in a man's father also appears to play an important role in increasing a man's risk of hair loss, either in conjunction with a history of hair loss in the mother or hair loss in the maternal grandfather.


Deep-water kelp refugia as potential hotspots of tropical marine diversity and productivity.
Classic marine ecological paradigms view kelp forests as inherently temperate-boreal phenomena replaced by coral reefs in tropical waters. These paradigms hinge on the notion that tropical surface waters are too warm and nutrient-depleted to support kelp productivity and survival. We present a synthetic oceanographic and ecophysiological model that accurately identifies all known kelp populations and, by using the same criteria, predicts the existence of >23,500 km(2) unexplored submerged (30- to 200-m depth) tropical kelp habitats. Predicted tropical kelp habitats were most probable in regions where bathymetry and upwelling resulted in mixed-layer shoaling above the depth of minimum annual irradiance dose for kelp survival. Using model predictions, we discovered extensive new deep-water Eisenia galapagensis populations in the Galápagos that increased in abundance with increasing depth to >60 m, complete with cold-water flora and fauna of temperate affinities. The predictability of deep-water kelp habitat and the discovery of expansive deep-water Galápagos kelp forests validate the extent of deep-water tropical kelp refugia, with potential implications for regional productivity and biodiversity, tropical food web ecology, and understanding of the resilience of tropical marine systems to climate change.


Study protocol: systematic review of the burden of heart failure in low- and middle-income countries.
Setting priorities for the prevention and management of heart failure requires an empirical understanding of the pattern of disease burden. We aim to describe the methods for a systematic review of the literature on burden of heart failure in low- and middle-income countries (LMIC) and how this information will be synthesized to produce useful estimates that can inform policy and practice. We will conduct a comprehensive search strategy for articles published between 1995 and April 2012 related to incidence, prevalence and treatment of heart failure in LMIC. Populations will be coded as urban, rural, or combined and studies classified as national, sub-national, healthcare system-based, or community level. Details from eligible studies will be extracted independently by two reviewers using a pre-designed data extraction form that will cover information on demographics, diagnostic criteria including disease incidence and prevalence, medical history, medication history, and hospital- or community-based management and outcomes. We will assess the reporting and methodological quality of the included studies and conduct a quantitative summary of reported outcomes where appropriate. Currently, there are important gaps in our knowledge on the burden of heart failure in LMIC and this systematic review aims to provide useful information that improves our knowledge in this field. Results are expected to be publicly available in early 2013.


Nursing student voices: reflections on an international service learning experience.
For the past decade participation in service and experiential learning in higher education has increased. The purpose of this study was to explore the lived experience of BSN and MSN students participating in a multidisciplinary service-learning course in a rural, underserved village in Belize. Researchers analyzed student journals utilizing qualitative data analysis techniques. There were eight consistent themes found in the student journals. The findings indicate that international service learning opportunities increase students' awareness of their place in a global society and the potential contribution they can make in society. For the past decade, service and experiential learning in higher education, including nursing education, has become increasingly important. Simply put, service and experiential learning combine community service activities with a student's academic study for the sole purpose of enriching the academic experience. As faculty, we feel the goal of baccalaureate and graduate nursing education is to produce an educated professional who will become a responsible citizen.


Functional status and self-rated health in 2,262 nonagenarians: the Danish 1905 Cohort Survey.
To describe the functional capacity and self-rated health of a large cohort of nonagenarians. A cross-sectional survey of all Danes born in 1905 (92-93 years of age), carried out August to October 1998. Participants' homes. Two thousand two hundred and sixty-two nonagenarians, corresponding to a participation rate of 63% (of these, 20% participated by proxy). Activities of daily living (ADLs) and self-rated health were assessed by interview. Five items from Katz's ADLs (bathing, dressing, transfer, toileting, and eating) were used to construct a three-level five-item ADL scale (not disabled (no disabilities), moderately disabled (1-2 disabilities), severely disabled (3-5 disabilities)). From responses to a more extensive list of questions on ADLs (26 items), we identified scales of strength and agility by means of factor analysis. Furthermore, a 26-item ADL scale was made. Physical performance tests (chair stand, timed walk, lifting a 2.7 kg box, maximum grip-strength, and flexibility tests) were performed among nonproxy responders. According to the five-item ADL scale, 50% of the men and 41% of the women were categorized as not disabled, while 19% and 22%, respectively, were categorized as severely disabled. The five-item ADL scale correlated highly with the 26-item ADL scale (r = 0.83). The ADL scales showed moderate-to-good correlation with each other (r = 0.74-0.83), and with the physical performance tests (r = 0.31-0.58). Only 3.7% of the women and 6.3% of the men walked (normal pace) with a speed of at least 1 meter per second, which is the minimum walking speed required to cross signaled intersections in Denmark. A total of 56% considered their health to be excellent or good. Of the participants, 74% were always or almost always satisfied with their lives, even though only 45% reported that they "felt well enough to do what they wanted." The analyses showed that no single ADL item seemed to be of particular importance for how the participants rated their health. The Danish 1905 cohort survey is the largest and the only nationwide survey of a whole birth-cohort of nonagenarians. A total of 2,262 fairly nonselected nonagenarians participated. The level of both self-reported disability and functional limitations measured by physical performance tests among nonagenarians was high. Despite their lower mortality, women were more disabled than men and did not perform as well as men in the physical performance tests. Nevertheless, the majority of the participants considered their health to be good and were satisfied with their lives.


Short-term Effects of High-Dose Caffeine on Cardiac Arrhythmias in Patients With Heart Failure: A Randomized Clinical Trial.
The presumed proarrhythmic action of caffeine is controversial. Few studies have assessed the effect of high doses of caffeine in patients with heart failure due to left ventricular systolic dysfunction at high risk for ventricular arrhythmias. To compare the effect of high-dose caffeine or placebo on the frequency of supraventricular and ventricular arrhythmias, both at rest and during a symptom-limited exercise test. Double-blinded randomized clinical trial with a crossover design conducted at the heart failure and cardiac transplant clinic of a tertiary-care university hospital. The trial included patients with chronic heart failure with moderate-to-severe systolic dysfunction (left ventricular ejection fraction <45%) and New York Heart Association functional class I to III between March 5, 2013, and October 2, 2015. Caffeine (100 mg) or lactose capsules, in addition to 5 doses of 100 mL decaffeinated coffee at 1-hour intervals, for a total of 500 mg of caffeine or placebo during a 5-hour protocol. After a 1-week washout period, the protocol was repeated. Number and percentage of ventricular and supraventricular premature beats assessed by continuous electrocardiographic monitoring. We enrolled 51 patients (37 [74%] male; mean [SD] age, 60.6 [10.9] years) with predominantly moderate-to-severe left ventricular systolic dysfunction (mean [SD] left ventricular ejection fraction, 29% [7%]); 31 [61%] had an implantable cardioverter-defibrillator device. No significant differences between the caffeine and placebo groups were observed in the number of ventricular (185 vs 239 beats, respectively; P = .47) and supraventricular premature beats (6 vs 6 beats, respectively; P = .44), as well as in couplets, bigeminal cycles, or nonsustained tachycardia during continuous electrocardiographic monitoring. Exercise test-derived variables, such as ventricular and supraventricular premature beats, duration of exercise, estimated peak oxygen consumption, and heart rate, were not influenced by caffeine ingestion. We observed no increases in ventricular premature beats (91 vs 223 vs 207 beats, respectively) in patients with higher levels of plasma caffeine concentration compared with lower plasma levels (P = .91) or with the placebo group (P = .74). Acute ingestion of high doses of caffeine did not induce arrhythmias in patients with systolic heart failure and at high risk for ventricular arrhythmias. clinicaltrials.gov Identifier: NCT02045992.


Surface-enhanced Raman scattering of graphene with photo-assisted-synthesized gold nanoparticles.
This paper presents a convenient and reliable method to prepare gold nanoparticles (AuNPs) on graphene. Photo-assisted synthesis (PAS) was employed to grow AuNPs in AuCl(4)(-) electrolyte on graphene. The size of AuNPs could be as large as 130 nm. This optical method had a steady growth rate of AuNPs. The distribution of AuNPs was well controlled by focusing the laser for PAS. The minimum diameter of the distribution was approximately 1 μm. Surface-enhanced Raman scattering of graphene due to AuNPs was observed. Electrical fields near AuNPs calculated by the finite-difference time-domain algorithm ensured that the Raman enhancement was attributed to the localized surface plasmons of AuNPs.


Emodin and AZT synergistically inhibit the proliferation and induce the apoptosis of leukemia K562 cells through the EGR1 and the Wnt/β‑catenin pathway.
The aim of the present study was to investigate the synergistic antitumor effects of emodin and 3'‑azido‑3'‑deoxythymidine (AZT) on human chronic myeloid leukemia cells and to explore the possible underlying mechanisms. The K562 cells were treated with emodin and AZT, and the rates of cell inhibition and apoptosis were determined by MTT assay and flow cytometry, respectively. The mRNA expression of EGR1 was detected by reverse transcription‑polymerase chain reaction (RT‑PCR) analysis. The expression of EGR1 was silenced using siRNA, and then protein expression of β‑catenin was detected by western blotting. The results demonstrated that AZT enhanced the inhibitory effect of emodin in K562 cells. The IC50 of the emodin/AZT combination at 24, 48 or 72 h was 23.6/235.6, 10.2/101.6 or 5.9/58.5 µmol/l, respectively, which was significantly lower compared with the IC50 of emodin (all >32 µmol/l) or AZT (all >320 µmol/l) alone. There was a dose‑dependent response to the combined emodin and AZT treatment, and the calculation of the combination index yielded values <1, demonstrating the synergistic effect of the combined treatment compared with the control (P<0.05). Furthermore, the combination of emodin and AZT increased apoptosis in K562 cells (P<0.05). Apoptosis was higher in the combination group compared with that of either treatment alone or control groups. The expression of early growth response‑1 (EGR1) in K562 cells was upregulated in a time‑dependent manner. The expression of EGR1 was higher in the combination group compared with that in the emodin or AZT alone groups. The expression of the Wnt/β‑catenin signaling pathway in the combination group was lower compared with that in the emodin or AZT alone groups. The expression of the Wnt/β‑catenin signaling pathway was significantly increased following EGR1 siRNA transfection. These data suggest that treating K562 cells with a combination of emodin and AZT exhibits reduced toxicity and improves therapeutic efficacy, and that the growth, inhibition, apoptosis and regulation of the Wnt/β‑catenin signaling pathway in human chronic myeloid leukemia cells by emodin and AZT may be associated with the expression of EGR1.


Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia.
To evaluate the efficacy of oxcarbazepine (OXC) in the treatment of agitation and aggression in patients with Alzheimer's disease, vascular dementia or both. This is an 8-week, multicenter, randomized, double-blind, placebo-controlled trial carried out independently of the pharmaceutical industry. Changes in the agitation and aggression subscore of the Neuropsychiatric Inventory (NPI) were the primary outcomes. The secondary out- comes were the changes in the caregivers' total burden scores (measured by the NPI) and changes in the Brief Agitation Rating Scale (BARS). In total, 103 institutionalized patients at 35 sites were randomized to the trial. After 8 weeks, no statistically significant differences were found between the 2 groups for all outcomes. A trend was observed in favor of the OXC group in the reduction in the scores on the BARS (p = 0.07). This study found no significant effect of OXC in treatment of agitation and aggression in patients with dementia.


Simultaneous sinus floor elevation and implant placement using leukocyte- and platelet-rich fibrin as a sole graft material.
Sinus floor elevation (SFE) and simultaneous implant placement is predictable and reproducible. However, the graft material for the antral cavity remains a topic of debate. Considering the high osteogenic potential of the sinus membrane, most graft materials are generally accepted. This study aimed to assess the outcome of simultaneous SFE and implant placement, using leukocyte- and platelet-rich fibrin (LPRF) as a sole graft material. This study was designed as a single cohort prospective study. Clinical and radiographic measurements (cone beam computed tomography [CBCT]) were performed immediately after implant placement and at abutment connection (6 months later). The amount of newly formed bone was linearly recorded on cross-sectional images. Four measurements (mesial, distal, buccal, palatal) were registered with the axis of the implant as reference. Six lateral and 22 transalveolar SFEs were performed in 26 patients with simultaneous implant placement. Six months after surgery, 27/29 implants were clinically integrated. The mean vertical bone gain was 3.4 ± 1.2 mm and 5.4 ± 1.5 mm for transalveolar SFE and lateral SFE, respectively. The level of the new sinus floor was in all cases in continuation with the apex of the implant, and the peri-implant crestal bone height was stable. L-PRF as a sole graft material during simultaneous SFE and implant placement proved to be a practical, safe, and economical subsinus graft material, resulting in natural bone formation.


Covalent binding of cyclosporine inhibits irreversibly T-lymphocyte activation.
A diazirine derivative of cyclosporine (PL-CS) was used to photolabel recombinant human cyclophilin (rhCyp), the cytosolic receptor for the immunosuppressant cyclosporine. The affinity of PL-CS for rhCyp and the immunosuppressive activity were 10-fold reduced as compared to cyclosporine A. Whereas cyclosporine immunosuppression was fully reversible, UV cross-linking of PL-CS resulted in permanent inhibition of lymphocyte activation as shown by proliferation of anti-CD3 stimulated human peripheral lymphocyte, interleukin (IL)-2 gene transcription and IL-2 synthesis in the human T-leukemia cell line Jurkat. In vivo photolabeling of viable Jurkat cells revealed that a 21-kDa complex was the major radiolabeled product which was identified as a cyclophilin-cyclosporine complex. In addition, cyclophilin B (25 kDa) and proteins of an unidentified nature at 40, 46 and 60 kDa were observed in Jurkat cells. The cyclosporine-resistant human fibroblast cell line MRC5 displayed a different labeling pattern: cyclophilin B (25 kDa) and a 65-kDa protein were the major labeled products, while the 46- and 60-kDa components were not detectable and cyclophilin was only faintly labeled. In summary, covalent cyclosporine binding caused irreversible lymphocyte inactivation and revealed in addition to cyclophilin other specifically labeled proteins in lymphoid cells. The role and identity of these proteins is presently unknown.


Development of a neonate lung reconstruction algorithm using a wavelet AMG and estimated boundary form.
Objective, non-invasive measures of lung maturity and development, oxygen requirements and lung function, suitable for use in small, unsedated infants, are urgently required to define the nature and severity of persisting lung disease, and to identify risk factors for developing chronic lung problems. Disorders of lung growth, maturation and control of breathing are among the most important problems faced by the neonatologists. At present, no system for continuous monitoring of neonate lung function to reduce the risk of chronic lung disease in infancy in intensive care units exists. We are in the process of developing a new integrated electrical impedance tomography (EIT) system based on wearable technology to integrate measures of the boundary diameter from the boundary form for neonates into the reconstruction algorithm. In principle, this approach could provide a reduction of image artefacts in the reconstructed image associated with incorrect boundary form assumptions. In this paper, we investigate the required accuracy of the boundary form that would be suitable to minimize artefacts in the reconstruction for neonate lung function. The number of data points needed to create the required boundary form is automatically determined using genetic algorithms. The approach presented in this paper is to assist quality of the reconstruction using different approximations to the ideal boundary form. We also investigate the use of a wavelet algebraic multi-grid (WAMG) preconditioner to reduce the reconstruction computation requirements. Results are presented that demonstrate a full 3D model is required to minimize artefact in the reconstructed image and the implementation of a WAMG for EIT.


Prevalence of child sexual abuse in Switzerland: a systematic review.
Although child sexual abuse (CSA) is considered to be a significant health risk, there is no systematic overview of studies that have investigated the prevalence of CSA in Switzerland. To conduct a systematic review of studies on the prevalence of CSA in Switzerland. A literature search was conducted using several online bibliographic databases. In addition, experts in the field in Switzerland were contacted to find studies that had not been published in academic journals. Studies were selected on the basis of predefined criteria. Because heterogeneity of studies did not allow meta-analytic calculations, data were suitably structured and summarised according to the most common types of CSA. Fifteen studies met inclusion criteria. Probably due to heterogeneity regarding definition and non-validated assessment of CSA, reported prevalence estimates varied greatly across studies. Prevalence rates were consistently higher for girls (up to 40%) than for boys (up to 11%). The most prevalent CSA with contact appears to be "perpetrator fondled victim", and the most common form of non-contact CSA was "exhibitionism". Due to inconsistent findings, conclusions that can be drawn are limited. However, results indicate that CSA prevalence rates in Switzerland are high and comparable to other European countries. In future, representative studies need to be conducted using a validated instrument based on internationally recognized definitions of CSA to obtain valid assessments of the prevalence of CSA in Switzerland.


Pediatric cardiovascular safety: challenges in drug and device development and clinical application.
Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic.


Optimal sampling in derivation studies was associated with improved discrimination in external validation for heart failure prognostic models.
The objective of the study was to identify determinants of external validity of prognostic models. We systematically searched for studies reporting prognostic models of heart failure (HF) and examined their performance for predicting 30-day death in a cohort of consecutive 3,452 acute HF patients. We applied published critical appraisal tools and examined whether bias or other characteristics of original derivation studies determined model performance. We identified 224 models from 6,354 eligible studies. The mean c-statistic in the cohort was 0.64 (standard deviation, 0.07). In univariable analyses, only optimal sampling assessed by an adequate and valid description of the sampling frame and recruitment details to collect the population of interest (total score range: 0-2, higher scores indicating lower risk of bias) was associated with high performance (standardized β = 0.25, 95% CI: 0.12 to 0.38, P < 0.001). It was still significant after adjustment for relevant study characteristics, such as data source, scale of study, stage of illness, and study year (standardized β = 0.24, 95% CI: 0.07 to 0.40, P = 0.01). Optimal sampling representing the gap between the population of interest and the studied population in derivation studies was a key determinant of external validity of HF prognostic models.


Locomotor sensory organization test: a novel paradigm for the assessment of sensory contributions in gait.
Feedback based balance control requires the integration of visual, proprioceptive and vestibular input to detect the body's movement within the environment. When the accuracy of sensory signals is compromised, the system reorganizes the relative contributions through a process of sensory recalibration, for upright postural stability to be maintained. Whereas this process has been studied extensively in standing using the Sensory Organization Test (SOT), less is known about these processes in more dynamic tasks such as locomotion. In the present study, ten healthy young adults performed the six conditions of the traditional SOT to quantify standing postural control when exposed to sensory conflict. The same subjects performed these six conditions using a novel experimental paradigm, the Locomotor SOT (LSOT), to study dynamic postural control during walking under similar types of sensory conflict. To quantify postural control during walking, the net Center of Pressure sway variability was used. This corresponds to the Performance Index of the center of pressure trajectory, which is used to quantify postural control during standing. Our results indicate that dynamic balance control during locomotion in healthy individuals is affected by the systematic manipulation of multisensory inputs. The sway variability patterns observed during locomotion reflect similar balance performance with standing posture, indicating that similar feedback processes may be involved. However, the contribution of visual input is significantly increased during locomotion, compared to standing in similar sensory conflict conditions. The increased visual gain in the LSOT conditions reflects the importance of visual input for the control of locomotion. Since balance perturbations tend to occur in dynamic tasks and in response to environmental constraints not present during the SOT, the LSOT may provide additional information for clinical evaluation on healthy and deficient sensory processing.


Multiple signals in anterior cingulate cortex.
Activity in anterior cingulate cortex (ACC) has been linked both to commitment to a course of action, even when it is associated with costs, and to exploring or searching for alternative courses of action. Here we review evidence that this is due to the presence of multiple signals in ACC reflecting the updating of beliefs and internal models of the environment and encoding aspects of choice value, including the average value of choices afforded by the environment ('search value'). We contrast this evidence with the influential view that ACC activity is better described as reflecting task difficulty. A consideration of cortical neural network properties explains why ACC may carry such signals and also exhibit sensitivity to task difficulty.


Increased visfatin concentrations in women with gestational diabetes mellitus.
The recently discovered adipocytokine visfatin has insulin-like properties. It lowers blood glucose and improves insulin sensitivity; however, clinical data on visfatin are limited. To evaluate the role of visfatin in GDM (gestational diabetes mellitus), we determined visfatin levels in women with GDM and in healthy pregnant controls. Furthermore, visfatin concentrations were investigated longitudinally during pregnancy and after delivery in a subgroup of women with GDM. Blood for measurement of visfatin and metabolic parameters was obtained from 64 women with GDM [median week of gestation, 34 (interquartile range, 27-36) weeks] and 30 healthy pregnant controls [median week of gestation, 34 (interquartile range, 28-36) weeks]. In a subgroup of 24 women with GDM, visfatin, leptin and metabolic parameters were investigated twice during pregnancy (28-30 and 38-40 weeks of gestation) and 2 weeks after delivery. In the cross-sectional analysis, median visfatin levels were significantly elevated in women with GDM [64.0 (interquartile range, 50.9-74.8) ng/ml] compared with controls [46.0 (interquartile range, 36.9-54.6) ng/ml; P<0.0001]. In women with GDM, visfatin correlated with week of gestation at the time of blood draw (R=0.35, P=0.005). No association with fasting glucose, insulin, homoeostasis model assessment-insulin resistance or body mass index was observed. According to the longitudinal analysis, visfatin increased during pregnancy (P=0.002) and rose further after delivery (P=0.014), whereas leptin and insulin levels decreased after parturition (both P<0.001). In conclusion, visfatin is elevated in women with GDM and increases during the course of pregnancy as well as after delivery. Furthermore, visfatin shows no association with insulin and leptin in women with GDM.


Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity.
Pemphigus is a life-threatening autoimmune disease in which antibodies specific for desmogleins (Dsgs) cause loss of keratinocyte cell adhesion and blisters. In order to understand how antibodies cause pathogenicity and whether there are commonalities among antibodies in different patients that could ultimately be used to target specific therapy against these antibodies, we characterized Dsg-specific mAbs cloned by phage display from 3 patients with pemphigus vulgaris and 2 with pemphigus foliaceus. Variable heavy chain gene usage was restricted, but similar genes were used for both pathogenic and nonpathogenic mAbs. However, the heavy chain complementarity-determining region 3 (H-CDR3) of most pathogenic, but not nonpathogenic, mAbs shared an amino acid consensus sequence. Randomization of the H-CDR3 and site-directed mutagenesis indicated that changes in this sequence could block pathogenicity but not necessarily binding. In addition, for 2 antibodies with longer H-CDR3s, a tryptophan was critical for pathogenicity but not binding, a result that is consistent with blocking the tryptophan acceptor site that is thought to be necessary for Dsg-mediated adhesion. These studies indicate that H-CDR3 is critical for pathogenicity of a human autoantibody, that a small region (even 1 amino acid) can mediate pathogenicity, and that pathogenicity can be uncoupled from binding in these antibodies.


Silica glass fiber photorefractometer.
We report a fiber-optic refractive-index sensor that is applicable to a long-distance measurement. The sensor consists of a silica glass fiber bent into a U shape with a bending radius of typically several hundred micrometers. The cladding at the tip of the sensor is stripped off. The sensing mechanism is based on the variation of the output intensity that is induced by radiation loss at the bend, which enables us to measure the refractive index of the outer medium. A fabrication method of fusing the sensor with a CO(2) laser and etching with HF is described. Multipoint measurements of optical-time-domain reflectometry are also described.


Common perinatal mental disorders in northern Viet Nam: community prevalence and health care use.
To establish the prevalence of common perinatal mental disorders their determinants, and their association with preventive health care use among women in one rural and one urban province in northern Viet Nam. We conducted a cross-sectional survey of cohorts of pregnant women and mothers of infants recruited systematically in 10 randomly-selected communes. The women participated in psychiatrist-administered structured clinical interviews and separate structured interviews to assess sociodemographic factors, reproductive health, the intimate partner relationship, family violence and the use of preventive and psychiatric health care. Associations between these variables and perinatal mental disorders were explored through univariate analyses and multivariable logistic regression. Among women eligible for the study (392), 364 (93%) were recruited. Of these, 29.9% (95% confidence interval, CI: 25.20-34.70) were diagnosed with a common perinatal mental disorder (CPMD). The frequency of such disorders during pregnancy and in the postpartum period was the same. Their prevalence was higher among women in rural provinces (odds ratio, OR: 2.17; 95% CI: 1.19-3.93); exposed to intimate partner violence (OR: 2.11; 95% CI: 1.12-3.96); fearful of other family members (OR: 3.36; 95% CI: 1.05-10.71) or exposed to coincidental life adversity (OR: 4.40; 95% CI: 2.44-7.93). Fewer women with a CPMD used iron supplements than women without a CPMD, but the results were not statistically significant (P = 0.05). None of the women studied had ever received mental health care. Perinatal depression and anxiety are prevalent in women in northern Viet Nam. These conditions are predominantly determined by social factors, including rural residence, poverty and exposure to family violence. At present the needs of women with common perinatal mental disorders are unrecognized and not attended to and their participation in essential antenatal preventive care appears to be compromised.


Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake.
Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage I-IV) women from the Kaiser Division of Research Pathways Study and the Illumina GoldenGate methylation bead-array platform, we measured 1,413 autosomal CpG loci associated with 773 cancer-related genes and validated select CpG loci with Sequenom EpiTYPER. Tumor grade, size, estrogen and progesterone receptor status, and triple negative status were significantly (Q-values <0.05) associated with altered methylation of 209, 74, 183, 69, and 130 loci, respectively. Unsupervised clustering, using a recursively partitioned mixture model (RPMM), of all autosomal CpG loci revealed eight distinct methylation classes. Methylation class membership was significantly associated with patient race (P<0.02) and tumor size (P<0.001) in univariate tests. Using multinomial logistic regression to adjust for potential confounders, patient age and tumor size, as well as known disease risk factors of alcohol intake and total dietary folate, were all significantly (P<0.0001) associated with methylation class membership. Breast cancer prognostic characteristics and risk-related exposures appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns.


Deconvolution from wave front sensing using the frozen flow hypothesis.
Deconvolution from wave front sensing (DWFS) is an image-reconstruction technique for compensating the image degradation due to atmospheric turbulence. DWFS requires the simultaneous recording of high cadence short-exposure images and wave-front sensor (WFS) data. A deconvolution algorithm is then used to estimate both the target object and the wave front phases from the images, subject to constraints imposed by the WFS data and a model of the optical system. Here we show that by capturing the inherent temporal correlations present in the consecutive wave fronts, using the frozen flow hypothesis (FFH) during the modeling, high-quality object estimates may be recovered in much worse conditions than when the correlations are ignored.


Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment: Part VII: Insomnia.
OBJECTIVE : To present the seventh in a series of articles designed to deconstruct chronic low back pain (CLBP) in older adults. This article focuses on insomnia and presents a treatment algorithm for managing insomnia in older adults, along with a representative clinical case. METHODS : A modified Delphi process was used to develop the algorithm and supportive materials. A multidisciplinary expert panel representing expertise in health psychology and sleep medicine developed the algorithm and supporting documents that were subsequently refined through an iterative process of input from a primary care provider panel. RESULTS : We present an illustrative clinical case and an algorithm to help guide the care of older adults with insomnia, an important contributor to CLBP and disability. Multicomponent cognitive behavioral therapy for insomnia (CBTI) and similar treatments (e.g., brief behavioral treatment for insomnia [BBTI]) are the recommended first-line treatment. Medications should be considered only if BBTI/CBTI is suboptimal or not effective and should be prescribed at the lowest effective dose for short periods of time (< 90 days). CONCLUSIONS : Insomnia is commonly comorbid with CLBP in older adults and should be routinely evaluated and treated because it is an important contributor to pain and disability. The algorithm presented was structured to assist primary care providers in planning treatment for older adults with CLBP and insomnia.


Tension-Dependent Free Energies of Nucleosome Unwrapping.
Nucleosomes form the basic unit of compaction within eukaryotic genomes, and their locations represent an important, yet poorly understood, mechanism of genetic regulation. Quantifying the strength of interactions within the nucleosome is a central problem in biophysics and is critical to understanding how nucleosome positions influence gene expression. By comparing to single-molecule experiments, we demonstrate that a coarse-grained molecular model of the nucleosome can reproduce key aspects of nucleosome unwrapping. Using detailed simulations of DNA and histone proteins, we calculate the tension-dependent free energy surface corresponding to the unwrapping process. The model reproduces quantitatively the forces required to unwrap the nucleosome and reveals the role played by electrostatic interactions during this process. We then demonstrate that histone modifications and DNA sequence can have significant effects on the energies of nucleosome formation. Most notably, we show that histone tails contribute asymmetrically to the stability of the outer and inner turn of nucleosomal DNA and that depending on which histone tails are modified, the tension-dependent response is modulated differently.


Pedophilia, hebephilia, and the DSM-V.
The term pedophilia denotes the erotic preference for prepubescent children. The term hebephilia has been proposed to denote the erotic preference for pubescent children (roughly, ages 11 or 12-14), but it has not become widely used. The present study sought to validate the concept of hebephilia by examining the agreement between self-reported sexual interests and objectively recorded penile responses in the laboratory. The participants were 881 men who were referred for clinical assessment because of paraphilic, criminal, or otherwise problematic sexual behavior. Within-group comparisons showed that men who verbally reported maximum sexual attraction to pubescent children had greater penile responses to depictions of pubescent children than to depictions of younger or older persons. Between-groups comparisons showed that penile responding distinguished such men from those who reported maximum attraction to prepubescent children and from those who reported maximum attraction to fully grown persons. These results indicated that hebephilia exists as a discriminable erotic age-preference. The authors recommend various ways in which the DSM might be altered to accommodate the present findings. One possibility would be to replace the diagnosis of Pedophilia with Pedohebephilia and allow the clinician to specify one of three subtypes: Sexually Attracted to Children Younger than 11 (Pedophilic Type), Sexually Attracted to Children Age 11-14 (Hebephilic Type), or Sexually Attracted to Both (Pedohebephilic Type). We further recommend that the DSM-V encourage users to record the typical age of children who most attract the patient sexually as well as the gender of children who most attract the patient sexually.


The structure of a rigorously conserved RNA element within the SARS virus genome.
We have solved the three-dimensional crystal structure of the stem-loop II motif (s2m) RNA element of the SARS virus genome to 2.7-A resolution. SARS and related coronaviruses and astroviruses all possess a motif at the 3' end of their RNA genomes, called the s2m, whose pathogenic importance is inferred from its rigorous sequence conservation in an otherwise rapidly mutable RNA genome. We find that this extreme conservation is clearly explained by the requirement to form a highly structured RNA whose unique tertiary structure includes a sharp 90 degrees kink of the helix axis and several novel longer-range tertiary interactions. The tertiary base interactions create a tunnel that runs perpendicular to the main helical axis whose interior is negatively charged and binds two magnesium ions. These unusual features likely form interaction surfaces with conserved host cell components or other reactive sites required for virus function. Based on its conservation in viral pathogen genomes and its absence in the human genome, we suggest that these unusual structural features in the s2m RNA element are attractive targets for the design of anti-viral therapeutic agents. Structural genomics has sought to deduce protein function based on three-dimensional homology. Here we have extended this approach to RNA by proposing potential functions for a rigorously conserved set of RNA tertiary structural interactions that occur within the SARS RNA genome itself. Based on tertiary structural comparisons, we propose the s2m RNA binds one or more proteins possessing an oligomer-binding-like fold, and we suggest a possible mechanism for SARS viral RNA hijacking of host protein synthesis, both based upon observed s2m RNA macromolecular mimicry of a relevant ribosomal RNA fold.


Prognostic factors and response to fludarabine therapy in patients with Waldenström macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003).
Current information on Waldenström macroglobulinemia (WM) is based on retrospective or single-institution studies of patients requiring therapy. Between 1992 and 1998, 231 patients with WM were enrolled in a prospective observational multicenter clinical trial. Of these, 182 patients with symptomatic or progressive disease were treated with 4 to 8 cycles of therapy with a purine nucleoside analogue, fludarabine (FAMP; 30 mg/m(2) of body-surface area daily for 5 days every 28 days). A serum beta2-microglobulin (beta2M) level below 3 mg/L and a hemoglobin level of at least 120 g/L (12 g/dL) at presentation predicted a lower likelihood of requiring therapy. The overall rate of response to FAMP therapy was 36% (95% confidence interval, 29%-44%), with 2% complete remissions. Patients who were 70 years old or older had a substantially lower likelihood of response (odds ratio, 0.34; P =.004) than younger patients. On multivariate analysis, a serum beta2M level of 3 mg/L or higher, hemoglobin level below 120 g/L, and serum IgM level below 40 g/L [4 g/dL] were significant adverse prognostic factors for survival. We developed a simple staging system for WM by using these variables and identified 4 distinct subsets of patients with estimated 5-year overall survival rates of 87%, 64%, 53%, and 22%, and 5-year progression-free survival rates of 83%, 55%, 33%, and 12%. Prognosis in WM is highly variable and serum beta2M was the dominant predictor of a need for therapy and of survival. FAMP has activity against WM. Our staging system may provide guidance for a risk-based approach to the treatment of WM.


Quinacrine: mechanisms of antimalarial action.
Two new interesting modes of action of quinacrine have been discovered. The first concerns a dose-related inhibition of uptake of [8-(3)H] adenosine into host cells of parasitized blood. Second, the drug inhibits the incorporation of tritiated adenosine triphosphate primarily into RNA but also into DNA of the erythrocyte-free malarial parasite Plasmodium berghei.


Measuring depression in persons with spinal cord injury: a systematic review.
Depression has been studied extensively among people with spinal cord injury (SCI). However, basic questions persist regarding the reliability and validity of depression measurement in the context of SCI. The objective of this study was to evaluate the state of knowledge of depression measurement in persons with SCI. English-language peer-reviewed citations from MEDLINE, CINAHL, PsycINFO, ProQuest, Google Scholar, and Web of Science from 1980 to present. Two reviewers screened 377 abstracts on SCI and depression topics to identify 144 containing classifiable psychometric data. All 144 were reviewed by 6 reviewers. Twenty-four studies reporting psychometric data on 7 depression measures in SCI samples were identified, including 7 validity studies. Reliability data were limited to internal consistency and were consistently good to excellent across 19 studies. Validity data were limited to concurrent validity, construct validity, and/or clinical utility in 10 studies. Measures were comparable with respect to internal consistency, factor structure, and clinical utility. Results are limited to peer-reviewed, English literature, and studies were not judged for quality. Greater attention should be paid to the psychometric evaluation of established measures. Although existing evidence may not justify universal screening, we recommend depression screening in clinical practice when patients may be seen by nonpsychology personnel. There is insufficient evidence to recommend one screening measure over another. Therefore, selection of measures will depend on clinician preferences. Psychometric studies are needed to show test-retest reliability, criterion validity, and sensitivity to change to improve depression recognition and treatment.


LACTB is a filament-forming protein localized in mitochondria.
LACTB is a mammalian active-site serine protein that has evolved from a bacterial penicillin-binding protein. Penicillin-binding proteins are involved in the metabolism of peptidoglycan, the major bacterial cell wall constituent, implying that LACTB has been endowed with novel biochemical properties during eukaryote evolution. Here we demonstrate that LACTB is localized in the mitochondrial intermembrane space, where it is polymerized into stable filaments with a length extending more than a hundred nanometers. We infer that LACTB, through polymerization, promotes intramitochondrial membrane organization and micro-compartmentalization. These findings have implications for our understanding of mitochondrial evolution and function.


Influence of a distraction task on pelvic floor muscle contraction.
Attention may play a key role in the contraction of pelvic floor muscles in stressful situations, meaning that mental distraction may be involved in urinary incontinence. Informed consent was obtained from 20 healthy volunteers. The electromyographic (EMG) activity of the external anal sphincter (EAS) was recorded during voluntary contraction elicited by local stimulation. The trials were carried out twice: combined (or not) with a mental distraction task (PASAT), Paced auditory serial additional test. Reaction time, latency between the stimulus and maximum EAS EMG activity, duration of the contraction, maximum EAS EMG activity, and the area under the EAS EMG activity curve were measured. The mental distraction task led to a 3.98 times greater reaction time (RT), (P = 0.00001 Wilcoxon's test). The RT increased from 217 (IQR: 170-270) to 779 msec (IQR: 550-1,025, P < 0.0001) when the EAS contraction was combined with PASAT. However, the maximum EAS EMG activity was weaker during PASAT than in the absence of a mental distraction task: 0.0850 mv versus 0.0701 mv, that is, 1.21 times weaker (P = 0.00077, Wilcoxon's test). Finally, when the two conditions (respectively with and without the mental distraction task) were compared, no significant difference was found in the area under the EAS EMG activity curve (0.0157 mv sec vs. 0.0162 mv sec, ratio 1.01, P = 0.52). The mental distraction task altered voluntary contraction of the pelvic floor muscles.


Reaching out to the lost generation of adults with early-treated phenylketonuria (PKU).
Many adult patients with phenylketonuria (PKU) are no longer receiving treatment for their disorder despite mounting evidence that elevated blood phenylalanine levels are associated with impairments of brain function manifested by neurocognitive deficits and psychiatric symptoms. An outreach program was established in a single PKU clinic with the goal of bringing "wayward" adults back into treatment. In a clinic with 152 active patients, another 162 records were identified of patients who had been previously treated and had not transferred to another clinic. 47 of these patients could not be located. Of the remaining 115, a total of 63 were re-engaged and received education, either through individual telephone encounters or attendance at adult educational programs. Thus far, 21 patients have returned to treatment. Obstacles to treatment for many patients include inadequate insurance coverage and lack of understanding of the significance of the diagnosis of PKU among patients off treatment for many years. The social, emotional and psychiatric symptoms of the disorder itself are perhaps the greatest barrier to successful re-introduction to treatment. This experience confirms that there are large numbers of adult patients with PKU who are not currently receiving any care for their disorder. Reaching them and re-engaging them in treatment will be a significant challenge and will require a multifaceted effort.


In situ generation of layered single- or double-hydroxide inorganic platelets (LSH and LDH) assisted by bola amphiphiles.
A novel preparation route for layered hydroxide based hybrid phases has been investigated combining the polyol route with the in situ generation of inorganic platelets, in the presence of an amphiphilic polymer as well as bola-amphiphiles. The polyol route consists of hydrolysis in an alcoholic medium containing acetate metal cations as precursor(s), to yield an LDH Zn2Al cation composition or LSH-Zn (layered single hydroxide). A bola amphiphile is described as hydrophobic polymer segment-telechelic-chains terminated by two anionic hydrophilic end groups, using volatile ammonium cations as counter ions. The impact of both process conditions as well as the chosen system with regard to the metal hydroxide framework on the morphology of the obtained hybrid phases is scrutinized by X-ray diffraction (XRD), small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM), and compared to that of the corresponding physical mixture. For the ex situ approach, the diffusion of large cumbersome polymers or amphiphilic bolas between the inorganic platelets was found to be efficient, mostly driven by an anion exchange reaction between interleaved acetate anions and carboxylate functions of the molecular backbones, and keeping intact the inner sheet integrity through a topotactic process. In particular with LSH-Zn, a multi-stratified assembly has been observed combining an acetate pristine structure and a partly bola diffused structure, leading to a biphasic structure, aggregated and intercalated. To the best of our knowledge, observation of LSH-Zn single platelets has never been reported, making the combined process polyol/in situ an interesting new route to reach exfoliation. Indeed, it leads to the generation of either LSH or LDH platelets of lateral size ranging from 10 up to 200 nm. However, the platelets were found to be porous; it is considered as a drawback for barrier properties. It is our belief that such porosity may open new insights in "tectonic" architecture by intertwining 2D and 1D-type fillers. Rather counterintuitively, the ex situ approach based on a topotactic exchange reaction matches the in situ templating reaction in many cases as a function of the dispersion state regardless of the polymer or bolas as well as the platelet cation composition.


Single amino acid substitutions confer the antiviral activity of the TRAF3 adaptor protein onto TRAF5.
The TRAF [tumor necrosis factor receptor-associated factor] family of cytoplasmic adaptor proteins link cell-surface receptors to intracellular signaling pathways that regulate innate and adaptive immune responses. In response to activation of RIG-I (retinoic acid-inducible gene I), a component of a pattern recognition receptor that detects viruses, TRAF3 binds to the adaptor protein Cardif [caspase activation and recruitment domain (CARD) adaptor-inducing interferon-β (IFN-β)], leading to induction of type I IFNs. We report the crystal structures of the TRAF domain of TRAF5 and that of TRAF3 bound to a peptide from the TRAF-interacting motif of Cardif. By comparing these structures, we identified two residues located near the Cardif binding pocket in TRAF3 (Tyr(440) and Phe(473)) that potentially contributed to Cardif recognition. In vitro and cellular experiments showed that forms of TRAF5 with mutation of the corresponding residues to those of TRAF3 had TRAF3-like antiviral activity. Our results provide a structural basis for the critical role of TRAF3 in activating RIG-I-mediated IFN production.


Ethnic differences in in-hospital place of death among older adults in California: effects of individual and contextual characteristics and medical resource supply.
: Substantial ethnic differences have been reported in the probability that death will occur in a hospital setting rather than at home, in a hospice, or in a nursing home. To date, no study has investigated the role of both individual characteristics and contextual characteristics, including local health care environments, to explain ethnic differentials in end-of-life care. : The study purpose is to examine ethnic differences in the association between death as a hospital in-patient and individual and contextual characteristics, as well as medical resource supply. : This study employed a secondary data analysis. : We used data from the California Death Statistical Master file for the years 1999-2001, which included 472,382 complete cases. These data were geocoded and linked to data from the US Census Bureau and the American Hospital Association. : Death as an in-patient was most common for Asian (54%) and Hispanic immigrants (49%) and least common for non-Hispanic whites (36%) and US-born Asians (41%). Medical resource supply variables are of considerable importance in accounting for ethnic differentials in the probability of dying in a hospital. Residual differences in in-hospital site of death were largest for immigrant populations. : There are sizeable ethnic differentials in the probability that a death will occur in a hospital in California. These differences are substantially mediated by sociodemographic characteristics of the decedent and local medical care supply. One implication of these findings is that variation exists in the efficiency and quality of end of life care delivered to ethnic minorities.


ETV6/RUNX1 fusion at diagnosis and relapse: some prognostic indications.
This study was undertaken in order to compare the interphase and metaphase cytogenetics of 28 patients with ETV6/RUNX1 positive acute lymphoblastic leukemia, at diagnosis and relapse. The median time to relapse was 26 months. The significant fusion positive population heterogeneity revealed at interphase by a commercial probe for ETV6/RUNX1 fusion has not been described before. Six diagnostic samples had a single abnormal population; others had up to five each, which differed in the numbers of RUNX1 signals, and in the retention or loss of the second ETV6 signal. In contrast, the number of fusion signals was more constant. At relapse, there were fewer populations; the largest or unique clone was sometimes a re-emergence of a minor, diagnostic one, with a retained copy of ETV6 and the most RUNX1 signals. Abnormal, fusion negative clones were identified in bone marrow samples at extra-medullary relapse. Variant three or four-way translocations, which involved chromosomes 12 and 21, were prominent among the complex rearrangements revealed by metaphase FISH. The frequency of their occurrence at diagnosis and reappearance at relapse, sometimes accompanied by minor clonal evolution, was another new observation. Other recurrent cytogenetic features included a second copy of the fusion signal in six cases, partial duplication of the long arm of the X chromosome in two cases, and trisomy 10 in three cases. In comparing our data with previously reported cases, a picture is beginning to emerge of certain diagnostic features, which may provide circumstantial evidence of an increased risk of relapse.


Experimental and computational investigation of the role of stress fiber contractility in the resistance of osteoblasts to compression.
The mechanical behavior of the actin cytoskeleton has previously been investigated using both experimental and computational techniques. However, these investigations have not elucidated the role the cytoskeleton plays in the compression resistance of cells. The present study combines experimental compression techniques with active modeling of the cell's actin cytoskeleton. A modified atomic force microscope is used to perform whole cell compression of osteoblasts. Compression tests are also performed on cells following the inhibition of the cell actin cytoskeleton using cytochalasin-D. An active bio-chemo-mechanical model is employed to predict the active remodeling of the actin cytoskeleton. The model incorporates the myosin driven contractility of stress fibers via a muscle-like constitutive law. The passive mechanical properties, in parallel with active stress fiber contractility parameters, are determined for osteoblasts. Simulations reveal that the computational framework is capable of predicting changes in cell morphology and increased resistance to cell compression due to the contractility of the actin cytoskeleton. It is demonstrated that osteoblasts are highly contractile and that significant changes to the cell and nucleus geometries occur when stress fiber contractility is removed.


Ultrafast dynamics of exciton formation in semiconductor nanowires.
The dynamics of free electron-hole pairs and excitons in GaAs-AlGaAs-GaAs core-shell-skin nanowires is investigated using femtosecond transient photoluminescence spectroscopy at 10 K. Following nonresonant excitation, a bimolecular interconversion of the initially generated electron-hole plasma into an exciton population is observed. This conducting-to-insulating transition appears to occur gradually over electron-hole charge pair densities of 2-4 × 10(16) cm(-3) . The smoothness of the Mott transition is attributed to the slow carrier-cooling during the bimolecular interconversion of free charge carriers into excitons and to the presence of chemical-potential fluctuations leading to inhomogeneous spectral characteristics. These results demonstrate that high-quality nanowires are model systems for investigating fundamental scientific effects in 1D heterostructures.


An alternative transcription start site yields estrogen-unresponsive Kiss1 mRNA transcripts in the hypothalamus of prepubertal female rats.
The importance of the Kiss1 gene in the control of reproductive development is well documented. However, much less is known about the transcriptional regulation of Kiss1 expression in the hypothalamus. Critical for these studies is an accurate identification of the site(s) where Kiss1 transcription is initiated. Employing 5'-RACE PCR, we detected a transcription start site (TSS1) used by the hypothalamus of rats, mice, nonhuman primates and humans to initiate Kiss1 transcription. In rodents, an exon 1 encoding 5'-untranslated sequences is followed by an alternatively spliced second exon, which encodes 5'-untranslated regions of two different lengths and contains the translation initiation codon (ATG). In nonhuman primates and humans, exon 2 is not alternatively spliced. Surprisingly, in rat mediobasal hypothalamus (MBH), but not preoptic area (POA), an additional TSS (TSS2) located upstream from TSS1 generates an exon 1 longer (377 bp) than the TSS1-derived exon 1 (98 bp). The content of TSS1-derived transcripts increased at puberty in the POA and MBH of female rats. It also increased in the MBH after ovariectomy, and this change was prevented by estrogen. In contrast, no such changes in TSS2-derived transcript abundance were detected. Promoter assays showed that the proximal TSS1 promoter is much more active than the putative TSS2 promoter, and that only the TSS1 promoter is regulated by estrogen. These differences appear to be related to the presence of a TATA box and binding sites for transcription factors activating transcription and interacting with estrogen receptor-α in the TSS1, but not TSS2, promoter.


Effect of coffee on distal colon function.
Ninety nine healthy young volunteers (58 men, 34 women, aged 17-27 years) answered a questionnaire concerning their bowel habit with particular reference to the effects of beverages. Twenty nine per cent (63% women) claimed that coffee induced a desire to defecate. The rectosigmoid motor responses to black, unsweetened coffee were then investigated by multiport manometry in 14 healthy-subjects (12 men, two women, eight of whom claimed coffee caused a desire to defecate (responders). Results revealed an increase in motility index within four minutes after ingestion of both regular and decaffeinated coffee (p less than 0.05) in the eight responders, but not in the six non-responders. The increase in rectosigmoid motility induced by coffee lasted at least 30 minutes. There was no increase in the motility index in any subject after a drink of hot water. These results suggest that drinking coffee can stimulate a motor response of the distal colon in some normal people.


Minimal contribution of ERK1/2-MAPK signalling towards the maintenance of oncogenic GNAQQ209P-driven uveal melanomas in zebrafish.
Mutations affecting Gαq proteins are pervasive in uveal melanoma (UM), suggesting they 'drive' UM pathogenesis. The ERK1/2-MAPK pathway is critical for cutaneous melanoma development and consequently an important therapeutic target. Defining the contribution of ERK1/2-MAPK signalling to UM development has been hampered by the lack of an informative animal model that spontaneously develops UM. Towards this end, we engineered transgenic zebrafish to express oncogenic GNAQQ209P in the melanocyte lineage. This resulted in hyperplasia of uveal melanocytes, but with no evidence of malignant progression, nor perturbation of skin melanocytes. Combining expression of oncogenic GNAQQ209P with p53 inactivation resulted in earlier onset and even more extensive hyperplasia of uveal melanocytes that progressed to UM. Immunohistochemistry revealed only weak immunoreactivity to phosphorylated (p)ERK1/2 in established uveal tumours-in contrast to strong immunoreactivity in oncogenic RAS-driven skin lesions-but ubiquitous positive staining for nuclear Yes-associated protein (YAP). Moreover, no changes were observed in pERK1/2 levels upon transient knockdown of GNAQ or phospholipase C-beta (PLC-β) inhibition in the majority of human UM cell lines we tested harbouring GNAQ mutations. In summary, our findings demonstrate a weak correlation between oncogenic GNAQQ209P mutation and sustained ERK1/2-MAPK activation, implying that ERK1/2 signalling is unlikely to be instrumental in the maintenance of GNAQQ209P-driven UMs.


Maintenance Therapies for Hodgkin and Non-Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT.
Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naïve high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naïve FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.


Relationship between decayed teeth and metabolic syndrome: data from 4716 middle-aged male Japanese employees.
Epidemiological findings regarding the relationship between decayed teeth (DT) and metabolic syndrome (MetS) are scarce. We evaluated the relationship of DT with MetS, obesity, and MetS components in early middle-aged male Japanese employees. We cross-sectionally analyzed dental and medical health checkup results from a total of 4716 participants aged 42 or 46 years. Logistic regression models were employed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) after adjustment for age, breakfast consumption frequency, drinking habits, smoking status, and physical activity. Significant differences in the prevalence of MetS, obesity determined by body mass index, and the components of MetS between participating men with and without DT were detected (all P < 0.01). The adjusted OR of MetS was 1.41 (95% CI, 1.14-1.74) for those with 1 or 2 DT, and 1.66 (95% CI, 1.28-2.16) for those with ≥3 DT (P for trend = 0.01), and this significant relationship was observed even in those without periodontal pocket formation (P for trend = 0.03) or missing teeth (P for trend = 0.02). DT was significantly related to overweight/obesity and the MetS components of hypertension, dyslipidemia, and hyperglycemia, with adjusted ORs of 1.35 (95% CI, 1.19-1.53), 1.22 (95% CI, 1.07-1.39), 1.18 (95% CI, 1.03-1.34), and 1.33 (95% CI, 1.13-1.56), respectively. In addition, even in non-overweight/non-obese men, DT was found to be related to dyslipidemia and hyperglycemia, though with marginal significance (P < 0.05). Our findings suggest that having DT is related to MetS in early middle-aged Japanese men directly and through obesity and is independent of health behaviors, periodontal condition, and tooth loss.


An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients.
With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.


Identification of a functional antioxidant response element within the eighth intron of the human ABCC3 gene.
The ATP-binding cassette (ABC) family of transporters, including ABCC3, is a large family of efflux pumps that plays a pivotal role in the elimination of xenobiotics from the body. ABCC3 has been reported to be induced during hepatic stress conditions and through the progression of some forms of cancer. Several lines of evidence have implicated the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this induction. However, although rodent models have been investigated, a functional antioxidant response element (ARE) in the human ABCC3 gene has not been identified. The purpose of this study was to identify and characterize the ARE(s) responsible for mediating the Nrf2-dependent induction of the human ABCC3 gene. A high-throughput chromatin immunoprecipitation-sequencing analysis performed in A549 cells revealed a specific interaction between Nrf2 and the eighth intron of the human ABCC3 gene rather than the more prototypical flanking region of the gene. Subsequent in silico analysis of the intron identified two putative ARE elements that contained the core consensus ARE sequence commonly found in several Nrf2-responsive genes. Functional characterization of these two AREs using luciferase-reporter constructs with ARE mutant constructs revealed that one of these putative AREs is functionally active. Finally, DNA pull-down assays confirmed specific binding of these intronic AREs by Nrf2 in vitro. Our findings identify a functional Nrf2 response element within the eighth intron of the ABCC3 gene, which may provide mechanistic insight into the induction of ABCC3 during antioxidant response stimuli.


Training the Next Generation of African Pathologists.
Quality patient care requires correct and timely evidence-based diagnoses. Pathology and laboratory medicine training varies significantly across the continent, but is inadequate to serve the needs of the population. This article summarizes the current state of pathology workforce and training in sub-Saharan Africa; discusses challenges to recruitment and retention; and outlines the necessary elements for training and sustaining a robust workforce in pathology and laboratory medicine. The authors provide several case studies of institutions around the continent that include expansion of existing programs, a de novo program, South-South collaborations, and skill building for the existing workforce.


An iron(II) complex featuring κ(3) and labile κ(2)-bound PNP pincer ligands - striking differences between CH2 and NH spacers.
Treatment of anhydrous FeCl2 with 2 equiv. of the pincer ligand PNP-Ph afforded the diamagnetic cationic octahedral complex [Fe(κ(3)-P,N,P-PNP)(κ(2)-P,N-PNP)Cl](+) featuring a κ(2)-P,N-bound PNP ligand. Preliminary reactivity studies revealed that the κ(2)-P,N-bound PNP ligand is labile reacting with CO to afford trans-[Fe(PNP-Ph)(CO)2Cl](+).


Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival.
The abilities of mutated active RAS proteins to modulate cell survival following exposure to ionizing radiation and small molecule kinase inhibitors were examined. Homologous recombination in HCT116 cells to delete the single allele of K-RAS D13 resulted in a cell line that exhibited an approximately 75% reduction in basal extracellular signal-regulated kinase 1/2, AKT, and c-jun-NH2-kinase 1/2 activity. Transfection of cells lacking K-RAS D13 with H-RAS V12 restored extracellular signal-regulated kinase 1/2 and AKT activity to basal levels but did not restore c-jun-NH2-kinase 1/2 phosphorylation. In cells expressing H-RAS V12, radiation caused prolonged intense activation of AKT. Inhibition of H-RAS V12 function, blockade of phosphatidylinositol 3-kinase (PI3K) function using small interfering RNA/small-molecule inhibitors, or expression of dominant-negative AKT abolished radiation-induced AKT activation, and radiosensitized these cells. Inhibition of PI3K function did not significantly radiosensitize parental HCT116 cells. Inhibitors of the AKT PH domain including perifosine, SH-(5, 23-25) and ml-(14-16) reduced the plating efficiency of H-RAS V12 cells in a dose-dependent fashion. Inhibition of AKT function using perifosine enhanced radiosensitivity in H-RAS V12 cells, whereas the SH and ml series of AKT PH domain inhibitors failed to promote radiation toxicity. In HCT116 H-RAS V12 cells, PI3K, PDK-1, and AKT were membrane associated, whereas in parental cells expressing K-RAS D13, only PDK-1 was membrane bound. In H-RAS V12 cells, membrane associated PDK-1 was phosphorylated at Y373/376, which was abolished by the Src family kinase inhibitor PP2. Inhibition of PDK-1 function using the PH domain inhibitor OSU-03012 or using PP2 reduced the plating efficiency of H-RAS V12 cells and profoundly increased radiosensitivity. OSU-03012 and PP2 did not radiosensitize and had modest inhibitory effects on plating efficiency in parental cells. A small interfering RNA generated against PDK1 also radiosensitized HCT116 cells expressing H-RAS V12. Collectively, our data argue that molecular inhibition of AKT and PDK-1 signaling enhances the radiosensitivity of HCT116 cells expressing H-RAS V12 but not K-RAS D13. Small-molecule inhibitory agents that blocked stimulated and/or basal PDK-1 and AKT function profoundly reduced HCT116 cell survival but had variable effects at enhancing tumor cell radiosensitivity.


High-resolution microscopy for biological specimens via cathodoluminescence of Eu- and Zn-doped Y2O3 nanophosphors.
High-resolution microscopy for biological specimens was performed using cathodoluminescence (CL) of Y(2)O(3):Eu, Zn nanophosphors, which have high CL intensity due to the incorporation of Zn. The intensity of Y(2)O(3):Eu nanophosphors at low acceleration voltage (3 kV) was increased by adding Zn. The CL intensity was high enough for imaging even with a phosphor size as small as about 30 nm. The results show the possibility of using CL microscopy for biological specimens at single-protein-scale resolution. CL imaging of HeLa cells containing laser-ablated Y(2)O(3):Eu, Zn nanophosphors achieved a spatial resolution of a few tens of nanometers. Y(2)O(3):Eu, Zn nanophosphors in HeLa cells were also imaged with 254 nm ultraviolet light excitation. The results suggest that correlative microscopy using CL, secondary electrons and fluorescence imaging could enable multi-scale investigation of molecular localization from the nanoscale to the microscale.


Functional landscape of SARS-CoV-2 cellular restriction.
A deficient interferon (IFN) response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated as a determinant of severe coronavirus disease 2019 (COVID-19). To identify the molecular effectors that govern IFN control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human IFN-stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of endoplasmic reticulum (ER)/Golgi-resident ISGs inhibiting viral assembly/egress. These included broad-acting antiviral ISGs and eight ISGs that specifically inhibited SARS-CoV-2 and SARS-CoV-1 replication. Among the broad-acting ISGs was BST2/tetherin, which impeded viral release and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/SARS-CoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.


Just pretty pictures? What diffusion tractography can add in clinical neuroscience.
Diffusion tractography uses non-invasive brain imaging data to trace fibre bundles in the human brain in vivo. This raises immediate possibilities for clinical application but responsible use of this approach requires careful consideration of the scope and limitations of the technique. To illustrate the potential for tractography to provide new information in clinical neuroscience we review recent studies in three broad areas: use of tractography for quantitative comparisons of specific white matter pathways in disease; evidence from tractography for the presence of qualitatively different pathways in congenital disorders or following recovery; use of tractography to gain insights into normal brain anatomy that can aid our understanding of the consequences of localised pathology, or guide interventions. Diffusion tractography opens exciting new possibilities for exploring features of brain anatomy that previously were not visible to us in vivo.


Assessing the benefits of multisensory audiotactile stimulation for overweight individuals.
We report an experiment designed to examine whether individuals who are overweight would perform differently when trying to detect and/or discriminate auditory, vibrotactile, and audiotactile targets. The vibrotactile stimuli were delivered either to the participant's abdomen or to his hand. Thirty-six young male participants were classified into normal, underweight, or overweight groups based on their body mass index. All three groups exhibited a significant benefit of multisensory (over the best of the unisensory) stimulation, but the magnitude of this benefit was modulated by the weight of the participant, the task, and the location from which the vibrotactile stimuli happened to be presented. For the detection task, the overweight group exhibited a significantly smaller benefit than the underweight group. In the discrimination task, the overweight group showed significantly more benefits than the other two groups when the vibrotactile stimuli were delivered to their hands, but not when the stimuli were delivered to their abdomens. These results might raise some interesting questions regarding the mechanisms underlying audiotactile information processing and have applied relevance for the design of the most effective warning signal (e.g., for drivers).


Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review.
Biomarkers of infection, namely C-reactive protein and procalcitonin (PCT), are potentially useful in the diagnosis of infection as well as in the assessment of its response to antibiotic therapy. C-reactive protein variations overtime appears to have a good performance for the diagnosis of infection. Procalcitonin shows a better correlation with clinical severity. In addition, to overcome the worldwide problem of antibiotic overuse as well as misuse, biomarker guidance of antibiotic stewardship represents a promising new approach. In several randomized, controlled trials, including adult critically ill patients, PCT guidance was repeatedly associated with a decrease in the duration of antibiotic therapy. However, these trials present several limitations, namely high rate of patients' exclusion, high rate of algorithm overruling, long duration of antibiotic therapy in the control group, disregard the effect of renal failure on PCT level, and above all a possible higher mortality and higher late organ failure in the PCT arm. In addition, some infections (e.g., endocarditis) as well as frequent nosocomial bacteria (e.g., Pseudomonas aeruginosa) are not suitable to be assessed by PCT algorithms. Therefore, the true value of PCT-guided algorithm of antibiotic stewardship in assisting the clinical decision-making process at the bedside remains uncertain. Future studies should take into account the issues identified in the present review.