Optical advantages and function of multifocal spherical fish lenses.
The spherical crystalline lenses in the eyes of many fish species are well-suited models for studies on how natural selection has influenced the evolution of the optical system. Many of these lenses exhibit multiple focal lengths when illuminated with monochromatic light. Similar multifocality is present in a majority of vertebrate eyes, and it is assumed to compensate for the defocusing effect of longitudinal chromatic aberration. In order to identify potential optical advantages of multifocal lenses, we studied their information transfer capacity by computer modeling. We investigated four lens types: the lens of Astatotilapia burtoni, an African cichlid fish species, an equivalent monofocal lens, and two artificial multifocal lenses. These lenses were combined with three detector arrays of different spectral properties: the cone photoreceptor system of A. burtoni and two artificial arrays. The optical properties compared between the lenses were longitudinal spherical aberration curves, point spread functions, modulation transfer functions, and imaging characteristics. The multifocal lenses had a better balance between spatial and spectral information than the monofocal lenses. Additionally, the lens and detector array had to be matched to each other for optimal function.


Linear and curvilinear relationship between knee range of motion and physical functioning in people with knee osteoarthritis: a cross-sectional study.
Knee range of motion (KROM) is associated with the ability to perform daily activities in people with knee OA. However, this association is weak, possibly through the use of linear analyses. Curvilinear associations appear much more relevant, as these allow the determination of relevant clinical thresholds in KROM. The goal of this study is to assess the curvilinear association between KROM and daily activities (self-reported and observed) in people with knee osteoarthritis (OA). Demographic, functional and KROM (flexion and extension) data were collected from a convenience sample of people with knee OA awaiting total knee arthroplasty. Self-reported functioning was measured by use of the Knee Osteoarthritis Outcomes Scale and observed functioning with the timed up and go and six-minute walk test. The presence of curvilinear relationships between KROM and measures of functioning were tested by generalized additive modeling, piecewise regression modeling and receiver operated curves. Data from 110 participants (mean age ± standard deviation: 65 ± 9 and female: 54%) with knee OA were evaluated. Statistical modeling did not reveal linear nor curvilinear associations between KROM and self-reported or observed measures of functioning; except for statistical significant associations between reduced knee flexion and major difficulties standing (p<=0.01). However, further modeling did not provide convincing evidence for relevant clinical associations and thresholds. No clinically relevant relationship between KROM and self-reported or observed measures of physical functioning could be established, indicating that the limitations in range of motion in the affected knee OA alone do not contribute to poorer functional performance.


Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial remodeling.
Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood. To characterize atrial fibroblast inward-rectifier K(+) current (IK1) remodeling in CHF and its effects on fibroblast properties. Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and IK1. RMP was significantly increased by CHF (from -43.2±0.8 mV, control, to -55.5±0.9 mV). CHF upregulated IK1 (eg, at -90 mV from -1.1±0.2 to -2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52%) and protein (by 80%). Ba(2+) (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca(2+) entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced IK1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed IK1 and depolarized RMP. Overexpression of KCNJ2 increased Ca(2+) entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca(2+) entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated IK1. CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca(2+) entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.


Antagonistic growth regulation by Dpp and Fat drives uniform cell proliferation.
We use the Dpp morphogen gradient in the Drosophila wing disc as a model to address the fundamental question of how a gradient of a growth factor can produce uniform growth. We first show that proper expression and subcellular localization of components in the Fat tumor-suppressor pathway, which have been argued to depend on Dpp activity differences, are not reliant on the Dpp gradient. We next analyzed cell proliferation in discs with uniformly high Dpp or uniformly low Fat signaling activity and found that these pathways regulate growth in a complementary manner. While the Dpp mediator Brinker inhibits growth in the primordium primarily in the lateral regions, Fat represses growth mostly in the medial region. Together, our results indicate that the activities of both signaling pathways are regulated in a parallel rather than sequential manner and that uniform proliferation is achieved by their complementary action on growth.


Birth weight, weight at 1 y of age, and body composition in older men: findings from the Hertfordshire Cohort Study.
Size in early life is related to adult body mass index, and early environmental influences have been proposed to have lifelong consequences for obesity. However, body mass index also reflects fat-free mass, and few studies have examined the relation between size in early life and direct measures of body composition in older people. We investigated the associations of birth weight and weight at 1 y of age with body composition in older men. We carried out a retrospective cohort study in Hertfordshire, United Kingdom. Men who were born between 1931 and 1939 and for whom there were records of birth weight and weight at 1 y of age (n = 737) participated in the study. The main outcome measures were adult body mass index, fat-free mass, and fat mass. Birth weight was significantly and consistently positively associated with adult body mass index and fat-free mass but not with measures of adult fat mass. In contrast, weight at 1 y of age was associated with adult body mass index, fat-free mass, and fat mass. The consistently reported positive relation between birth weight and adult body mass index may reflect prenatal and maternal influences on fat-free mass rather than on fat mass in older people. The postnatal environment may be more influential than prenatal factors in the development of obesity in later life.


Vitamin K-dependent carboxylation of osteocalcin: friend or foe?
Osteocalcin originates from osteoblastic synthesis and is deposited into bone or released into circulation, where it correlates with histological measures of bone formation. The presence of 3 vitamin K-dependent γ carboxyglutamic acid residues is critical for osteocalcin's structure, which appears to regulate the maturation of bone mineral. In humans, the percentage of the circulating osteocalcin that is not γ-carboxylated (percent ucOC) is used as a biomarker of vitamin K status. In contrast, when ucOC is not corrected for total osteocalcin, the interpretation of this measure is confounded by osteoblastic activity, independent of vitamin K. Observational studies using percent ucOC have led to the conclusion that vitamin K insufficiency leads to age-related bone loss. However, clinical trials do not provide overall support for the suggestion that vitamin K supplementation of the general population will reduce bone loss or fracture risk. More recently, results from in vitro and in vivo studies using animal models indicate that ucOC is an active hormone with a positive role in glucose metabolism. By inference, vitamin K, which decreases ucOC, would have a detrimental effect. However, in humans this hypothesis is not supported by the limited data available, nor is it supported by what has been established regarding osteocalcin chemistry. In summary, the specific function of osteocalcin in bone and glucose metabolism has yet to be elucidated.


Effect of caudal epidural steroid or saline injection in chronic lumbar radiculopathy: multicentre, blinded, randomised controlled trial.
To assess the efficacy of caudal epidural steroid or saline injection in chronic lumbar radiculopathy in the short (6 weeks), intermediate (12 weeks), and long term (52 weeks). Multicentre, blinded, randomised controlled trial. Outpatient multidisciplinary back clinics of five Norwegian hospitals. Between October 2005 and February 2009, 461 patients assessed for inclusion (presenting with lumbar radiculopathy >12 weeks). 328 patients excluded for cauda equina syndrome, severe paresis, severe pain, previous spinal injection or surgery, deformity, pregnancy, ongoing breast feeding, warfarin therapy, ongoing treatment with non-steroidal anti-inflammatory drugs, body mass index >30, poorly controlled psychiatric conditions with possible secondary gain, and severe comorbidity. Subcutaneous sham injections of 2 mL 0.9% saline, caudal epidural injections of 30 mL 0.9% saline, and caudal epidural injections of 40 mg triamcinolone acetonide in 29 mL 0.9% saline. Participants received two injections with a two week interval. Primary: Oswestry disability index scores. Secondary: European quality of life measure, visual analogue scale scores for low back pain and for leg pain. Power calculations required the inclusion of 41 patients per group. We did not allocate 17 of 133 eligible patients because their symptoms improved before randomisation. All groups improved after the interventions, but we found no statistical or clinical differences between the groups over time. For the sham group (n = 40), estimated change in the Oswestry disability index from the adjusted baseline value was -4.7 (95% confidence intervals -0.6 to -8.8) at 6 weeks, -11.4 (-6.3 to -14.5) at 12 weeks, and -14.3 (-10.0 to -18.7) at 52 weeks. For the epidural saline intervention group (n = 39) compared with the sham group, differences in primary outcome were -0.5 (-6.3 to 5.4) at 6 weeks, 1.4 (-4.5 to 7.2) at 12 weeks, and -1.9 (-8.0 to 4.3) at 52 weeks; for the epidural steroid group (n=37), corresponding differences were -2.9 (-8.7 to 3.0), 4.0 (-1.9 to 9.9), and 1.9 (-4.2 to 8.0). Analysis adjusted for duration of leg pain, back pain, and sick leave did not change this trend. Caudal epidural steroid or saline injections are not recommended for chronic lumbar radiculopathy. Trial registration Current Controlled Trials ISRCTN No 12574253.


Looming signals reveal synergistic principles of multisensory integration.
Multisensory interactions are a fundamental feature of brain organization. Principles governing multisensory processing have been established by varying stimulus location, timing and efficacy independently. Determining whether and how such principles operate when stimuli vary dynamically in their perceived distance (as when looming/receding) provides an assay for synergy among the above principles and also means for linking multisensory interactions between rudimentary stimuli with higher-order signals used for communication and motor planning. Human participants indicated movement of looming or receding versus static stimuli that were visual, auditory, or multisensory combinations while 160-channel EEG was recorded. Multivariate EEG analyses and distributed source estimations were performed. Nonlinear interactions between looming signals were observed at early poststimulus latencies (∼75 ms) in analyses of voltage waveforms, global field power, and source estimations. These looming-specific interactions positively correlated with reaction time facilitation, providing direct links between neural and performance metrics of multisensory integration. Statistical analyses of source estimations identified looming-specific interactions within the right claustrum/insula extending inferiorly into the amygdala and also within the bilateral cuneus extending into the inferior and lateral occipital cortices. Multisensory effects common to all conditions, regardless of perceived distance and congruity, followed (∼115 ms) and manifested as faster transition between temporally stable brain networks (vs summed responses to unisensory conditions). We demonstrate the early-latency, synergistic interplay between existing principles of multisensory interactions. Such findings change the manner in which to model multisensory interactions at neural and behavioral/perceptual levels. We also provide neurophysiologic backing for the notion that looming signals receive preferential treatment during perception.


The related causes in very early morning onset of stroke.
We investigated the influence of early awakening and related factors on onset of cerebrovascular disease (CVD). Totally 1199 stroke patients, in whom the onset time was known, at 3 reference hospitals were included in this study. The effects of demographic, medical, and pathophysiological factors on the circadian pattern of an unselected series of patients with ischemic stroke were analyzed. Nine-hundred seventeen CVD patients with cerebral infarction (CI), 240 patients with intracerebral hemorrhage (CH), and 42 patients with subarachnoid hemorrhage (SAH) were identified. The greatest portion of strokes (32.5%) occurred between 03:00 and 06:00 a.m. Nearly one half of the strokes in this series occurred in the very early- to mid-morning hours. This analysis of strokes provides strong evidence with a higher risk in the early morning hours (03:00 a.m. to 06:00 a.m.), and lower risk during the night time period (21:00 p.m. to midnight). Approximately 1 of every 3 strokes (1 of 3 ischemic strokes, 1 of 6 hemorrhagic strokes, and 1 of 8 subarachnoid hemorrhages) is attributable to the early morning excess. This difference tried to be explained by three ways: cold weather, religious factors, and physiological mechanisms.


Bistabilities and annihilation phenomena in electrophysiological cardiac models.
We have investigated the oscillatory behavior of cardiac cellular elements simulated by two electrophysiological models: the van Capelle and Durrer (VCD) model and the sinoatrial node cell model of Yanagihara, Noma, and Irisawa (YNI). The VCD model behavior was examined systematically by using continuation-bifurcation analysis. Bifurcation diagrams were constructed as a function of Qit1, an intrinsic parameter of the model, which sets both maximum diastolic potential and depolarization threshold of the cell. The existence of stable high amplitude oscillations was evidenced between two Hopf bifurcation points (HB). Near each HB, a zone of bistability was detected. Close to the HB that corresponded to high values of Qit1, a high amplitude periodic stable state coexisted with a stable steady state. Close to the other HB, in a narrow range of lower Qit1 values, a relatively high amplitude periodic stable state coexisted with a low amplitude periodic stable state. There was no stable steady state in the latter bistability zone. Through the use of phase-plane representations and the determination of separatrices between the different attractor basins, we could deduce the conditions of timing, polarity, and strength needed for a pulse perturbation to send the system from one state to another and vice versa. The YNI model was analyzed by numerical simulation, and the oscillatory behavior of the sinoatrial node cell was explored while applying a depolarizing bias current of various strengths. Results were similar to those obtained from the VCD model in that there were two bistability regions for two different ranges of applied bias current. Depending on current intensity, annihilation of pacemaker activity could be achieved in both zones. However, the coexistence of two oscillatory stable states was never observed in the YNI model. From the behavioral similarities of these different models, we can conclude that bistabilities and annihilation phenomena can be found in transitional zones between quiescence and rhythmic activity.


Sister Society Meeting on Global Education Development and Collaboration: Meeting Report.
To identify common barriers to teaching and training and to identify strategies that would be useful in developing future training programs in gynecologic oncology in low- and middle- income countries. There is a lack of overall strategy to meet the needs of education and training in gynecologic oncology in low- and middle- income countries, the leaderships of sister societies and global health volunteers met at the European Society of Gynecologic Oncology in October 23, 2015. The challenges of the training programs supported by gynecologic oncology societies, major universities and individual efforts were presented and discussed. Strategies to improve education and training were identified. Major challenges include language barriers, limited surgical equipment, inadequate internet access, lack of local support for sustainability in training programs, inadequate pathology and radiation oncology, finance and a global deficiency in identifying sites and personnel in partnering or developing training programs. The leaderships identified various key components including consultation with the local Ministry of Health, local educational institutions; inclusion of the program into existing local programs, a needs assessment, and the development of curriculum and regional centers of excellence. Proper preparation of training sites and trainers, the development of global curriculum, the establishment of centers of excellence, and the ability to measure outcomes are important to improve education and training in gynecologic oncology in low- and middle- income countries.


Effects of meal carbohydrate content on insulin requirements in type 1 diabetic patients treated intensively with the basal-bolus (ultralente-regular) insulin regimen.
In this study, we evaluated the effects of high-(55%) and low-(40%) carbohydrate diets on insulin requirements in nine type 1 diabetic subjects treated intensively with ultralente as basal insulin and regular insulin as premeal insulin adjusted to the carbohydrate content of meals. Nine subjects were randomized in a crossover design to follow two diets consecutively for a period of 14 days each. A 3-day food diary was completed for each diet with the amount of carbohydrate in the mixed meals ranging from 21 to 188 g. Preprandial (5.9 vs. 6.1 mmol/l) and postprandial (8 vs. 8.9 mmol/l) capillary glucose and fructosamine (310 vs. 316 mumol/l) were comparable on both the low- and high-carbohydrate diets. The assessment of meal carbohydrate content by the patients was excellent, with > 85% of cases falling within 15% of computer-assisted evaluation. When premeal regular insulin was prescribed in U/10 g of carbohydrate, the postprandial glycemic rise remained constant (2.4 +/- 2.8 mmol/l) over a wide range of carbohydrate ingested (21-188 g) and was not affected by the glycemic index, fiber, and caloric and lipidic content of the meals. This tight control was maintained during the low- and high-carbohydrate diet without any change in insulin requirements (breakfast, 1.5 vs. 1.5 U/10 g of carbohydrate; lunch, 1.0 vs. 1.0; supper, 1.1 vs. 1.2) and in basal ultralente insulin requirements (22.5 vs. 21.4 U/day). These results indicate that in type 1 diabetic subjects 1) increasing the amount of carbohydrate intake does not influence glycemic control if premeal regular insulin is adjusted to the carbohydrate content of the meals; 2) algorithms based on U/10 g of carbohydrate are effective and safe, whatever the amount of carbohydrate in the meal; 3) the glycemic index, fiber, and lipidic and caloric content of the meals do not affect premeal regular insulin requirements; 4) wide variations in carbohydrate intake do not modify basal (ultralente) insulin requirements; and, finally 5) the ultralente-regular insulin regimen allows dissection between basal and prandial insulin requirements, so that each can be adjusted accurately and independently.


Effects of Salidroside on Trabecular Meshwork Cell Extracellular Matrix Expression and Mouse Intraocular Pressure.
Excessive accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) reduces aqueous humor outflow, which likely contributes to elevation of IOP in primary open-angle glaucoma (POAG). Salidroside, a phenolic glycoside isolated from Rhodiola rosea is reported to prevent profibrotic responses by inhibiting Smad signaling pathway activated by TGF-β in liver, lung, and kidney tissues. We tested if salidroside can (1) inhibit TGF-β2-induced ECM expression in cultured human TM cells, and (2) lower TGF-β2-induced ocular hypertension in the mouse. Cultured human TM cells stimulated with 5 ng/mL TGF-β2 for 48 hours were treated with salidroside for 24 hours. The expressions of fibronectin (FN), collagen type IV (COL-IV), and laminin (LN) were evaluated by quantitative PCR, Western blot, and immunocytochemistry. BALB/cJ mice were injected intravitreally with an adenoviral vector encoding a bioactive mutant of TGF-β2 (Ad.hTGF-β2226/228) in one eye to induce ocular hypertension, with the uninjected contralateral or Ad.Empty-injected eyes serving as controls. Mice were treated with a daily intraperitoneal injection of 40 mg/kg salidroside. Conscious mouse IOP values were measured using a TonoLab rebound tonometer. In cultured human TM cells, treatment with TGF-β2 increased expressions of FN, COL-IV, and LN, as assessed by quantitative PCR, Western blotting, and immunocytochemistry, all of which were significantly and completely ameliorated by 30 μM salidroside. Daily intraperitoneal injections of salidroside (40 mg/kg), starting either at day 0 (same day as Ad.hTGF-β2226/228 injection) or at day 14, significantly lowered TGF-β2-induced ocular hypertension in the mouse. In contrast, salidroside did not affect IOP of control eyes. These results demonstrated that salidroside is capable of minimizing TGF-β2-induced ECM expression in cultured human TM cells. It also reduced TGF-β2-induced ocular hypertension in the mouse. These findings indicate that this phenolic glycoside may be useful as a novel treatment for POAG.


Noninvasive external cardiac pacing for thallium-201 scintigraphy.
Improvements in noninvasive external cardiac pacing have led to a technique with reliable electrical capture and tolerable patient discomfort. To assess the use of this modality of pacing in combination with thallium scintigraphy as a noninvasive pacing stress test, we applied simultaneous noninvasive cardiac pacing, hemodynamic monitoring, and thallium-201 scintigraphy in 14 patients undergoing cardiac catheterization for chest pain syndromes. Two patients had normal coronary arteries, while the remaining 12 had significant coronary artery disease. Thallium scintigraphic responses to pacing were compared to routine exercise thallium stress testing in nine of these 14 patients. All patients were noninvasively paced to more than 85% of the age-predicted maximum heart rate. Twelve patients demonstrated reversible thallium defects, which corresponded in 11 cases to significant lesions seen on coronary angiography. Of nine patients who underwent both pacing and exercise thallium stress tests, comparable maximal rate-pressure products were achieved. Moreover, thallium imaging at peak pacing and during delayed views did not differ significantly from exercise thallium scintigraphy. A limiting factor associated with the technique was local patient discomfort, which occurred to some degree in all patients. We conclude that noninvasive external cardiac pacing together with thallium scintigraphy is capable of detecting significant coronary artery disease and may be comparable to routine exercise thallium stress testing. This new modality of stress testing could be useful in patients unable to undergo the exercise required for standard exercise tolerance testing, particularly if improvements in the technology can be found to reduce further the local discomfort.


Effects of Discontinuation of Paliperidone Long-Acting Injectable After Switching from Risperidone Long-Acting Injectable Switching.
Risperidone long-acting injection (RLAI) is increasingly being switched to paliperidone palmitate (PP) because of several benefits. However, this switching is not always successful. We examined patient profiles following discontinuation of PP after switching from RLAI. We collected the electronic records of 24 patients with schizophrenia who had switched from RLAI to PP treatment at our hospital between November 2013 and March 2014. Twelve patients continued PP injection for over 1 year (PP-continuers), the other 12 patients discontinued within 1 year (PP-discontinuers), and both groups were followed up until December 31, 2014. PP-discontinuers had significantly shorter RLAI-administration period (mean 73.1 ± 59.0 weeks versus 148.5 ± 75.0 weeks), and lower chlorpromazine (CP) equivalent mean doses (mean 553.5 ± 251.0 mg versus 1002.5 ± 529.3 mg) compared with PP-continuers. The CP equivalent mean dose of PP-discontinuers had increased at the time of discontinuation and their social status became significantly worse. Six PP-discontinuers (50%) re-switched to RLAI, and their social status was not significantly worse at the end of the observation period. On switching from RLAI to PP, we need to consider that some patients have had a shorter RLAI-administration period and may require lower amounts of antipsychotics.


Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres.
Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity. In glioblastoma, MGMT-methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception (<50%). The CpG methylation patterns were characteristic for each glioblastoma exhibiting 25% to 90% methylated CpGs of 28 sites interrogated. Furthermore, MGMT promoter methylation was associated with a nonpermissive chromatin status in accordance with very low MGMT transcript levels and undetectable MGMT activity. In MGMT-methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy.


Cost-effectiveness of targeting patients undergoing percutaneous coronary intervention for therapy with bivalirudin versus heparin monotherapy according to predicted risk of bleeding.
Although bivalirudin compared with unfractionated heparin with glycoprotein IIb/IIIa inhibitors reduces bleeding and hospitalization costs in patients undergoing percutaneous coronary intervention (PCI), little is known about the economic impact of bivalirudin versus heparin alone and at what threshold of procedural bleeding risk bivalirudin would be considered cost-effective. A validated model was used to predict risk of major bleeding for 81,628 National Cardiovascular Data Registry (NCDR) CathPCI Registry patients from 2004 to 2006 who received unfractionated heparin only. Costs were derived from multiple sources including wholesale acquisition costs (for drugs) and single-center data (for PCI-related complications). Based on ISAR-REACT 3, we assumed that bivalirudin would reduce the risk of major bleeding by 33% compared with unfractionated heparin alone. A Markov model was used to estimate lost life expectancy associated with a major bleed. Major bleeding was predicted to occur in 2.2% of patients. Bivalirudin for all patients was estimated to increase costs by $571 per patient, yielding cost-effectiveness ratios of $287,473 per bleeding event averted and $1,173,360 per quality-adjusted life-year gained. Bivalirudin was cost saving for patients with a predicted bleeding risk >20% (0.16% of CathPCI population). At willingness-to-pay thresholds of $50K and $100K per quality-adjusted life-year gained, bivalirudin was cost-effective for patients with a bleeding risk > or = 8% (2.5% patients) and > or = 5% (7.9% patients), respectively. This decision-analytic modeling study demonstrates that for patients undergoing PCI, substitution of bivalirudin for unfractionated heparin monotherapy is projected to increase costs for virtually all patients and would be considered cost-effective for only a minority of patients with a high bleeding risk. From a policy standpoint, studies such as this, aimed at identifying the appropriate risk threshold for initiating treatment, may help in the development of informed guidelines for the use of expensive therapies.


Personality and gastric cancer screening attendance: a cross-sectional analysis from the Miyagi Cohort Study.
To determine the associations between personality subscales and attendance at gastric cancer screenings in Japan. A total of 21,911 residents in rural Japan who completed a short form of the Eysenck Personality Questionnaire-Revised (EPQ-R) and a questionnaire on various health habits including the number of gastric cancer screenings attended were included in the primary analysis. We defined gastric cancer screening compliance as attendance at gastric cancer screening every year for the previous 5 years; all other patterns of attendance were defined as non-compliance. We defined gastric cancer screening visiting as attendance at 1 or more screenings during the previous 5 years; lack of attendance was defined as non-visiting. We used logistic regression to estimate the odds ratios (ORs) of gastric cancer screening compliance and visiting according to 4 score levels that corresponded to the 4 EPQ-R subscales (extraversion, neuroticism, psychoticism, and lie). Extraversion had a significant linear, positive association with both compliance and visiting (trend, P < 0.001 for both). Neuroticism had a significant linear, inverse association with compliance (trend, P = 0.047), but not with visiting (trend, P = 0.21). Psychoticism had a significant linear, inverse association with both compliance and visiting (trend, P < 0.001 for both). Lie had no association with either compliance or visiting. The personality traits of extraversion, neuroticism, and psychoticism were significantly associated with gastric cancer screening attendance. A better understanding of the association between personality and attendance could lead to the establishment of effective campaigns to motivate people to attend cancer screenings.


METRIC-EF: magnetic resonance enterography to predict disabling disease in newly diagnosed Crohn's disease-protocol for a multicentre, non-randomised, single-arm, prospective study.
Crohn's disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating disease, and subsequent surgical resection. Therapeutics are effective but associated with certain side-effects and relatively expensive. There is therefore an urgent need for robust methods to predict which newly diagnosed patients will develop disabling disease, to identify patients who are most likely to benefit from early, advanced therapies. We aim to determine if magnetic resonance enterography (MRE) features at diagnosis improve prediction of disabling CD within 5 years of diagnosis. We describe the protocol for a multicentre, non-randomised, single-arm, prospective study of adult patients with newly diagnosed CD. We will use patients already recruited to the METRIC study and extend their clinical follow-up, as well as a separate group of newly diagnosed patients who were not part of the METRIC trial (MRE within 3 months of diagnosis), to ensure an adequate sample size. Follow-up will extend for at least 4 years. The primary outcome is to evaluate the comparative predictive ability of prognostic models incorporating MRE severity scores (Magnetic resonance Enterography Global Score (MEGS), simplified MAgnetic Resonance Index of Activity (sMaRIA) and Lémann Index) versus models using standard characteristics alone to predict disabling CD (modified Beaugerie definition) within 5 years of new diagnosis. This study protocol achieved National Health Service Research Ethics Committee (NHS REC), London-Hampstead Research Ethics Committee approval (IRAS 217422). Our findings will be disseminated via conference presentations and peer-reviewed publications. ISRCTN76899103.


Resilience of Microbial Communities after Hydrogen Peroxide Treatment of a Eutrophic Lake to Suppress Harmful Cyanobacterial Blooms.
Applying low concentrations of hydrogen peroxide (H2O2) to lakes is an emerging method to mitigate harmful cyanobacterial blooms. While cyanobacteria are very sensitive to H2O2, little is known about the impacts of these H2O2 treatments on other members of the microbial community. In this study, we investigated changes in microbial community composition during two lake treatments with low H2O2 concentrations (target: 2.5 mg L-1) and in two series of controlled lake incubations. The results show that the H2O2 treatments effectively suppressed the dominant cyanobacteria Aphanizomenon klebahnii, Dolichospermum sp. and, to a lesser extent, Planktothrix agardhii. Microbial community analysis revealed that several Proteobacteria (e.g., Alteromonadales, Pseudomonadales, Rhodobacterales) profited from the treatments, whereas some bacterial taxa declined (e.g., Verrucomicrobia). In particular, the taxa known to be resistant to oxidative stress (e.g., Rheinheimera) strongly increased in relative abundance during the first 24 h after H2O2 addition, but subsequently declined again. Alpha and beta diversity showed a temporary decline but recovered within a few days, demonstrating resilience of the microbial community. The predicted functionality of the microbial community revealed a temporary increase of anti-ROS defenses and glycoside hydrolases but otherwise remained stable throughout the treatments. We conclude that the use of low concentrations of H2O2 to suppress cyanobacterial blooms provides a short-term pulse disturbance but is not detrimental to lake microbial communities and their ecosystem functioning.


Current status of systemic chemotherapy for octogenarians with advanced urothelial cancer in Japan: a Japanese multi-institutional study (CURE study).
The standard regimen of systemic chemotherapy for patients with advanced urothelial cancer (UC) changed from methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) to gemcitabine and cisplatin (GC) in 2008 when the use of gemcitabine for UC began to be reimbursed by public health insurance in Japan. We examined its influence on the chemotherapy trend in elderly patients aged ≥80 years. Among 345 patients included in our previous multicenter retrospective cohort study (chemotherapy for urothelial carcinoma: renal function and efficacy study; CURE study), the outcome of 30 patients aged ≥80 years was reviewed before and after 2008 and compared with 315 young patients. There were only 7 (4.6 %) elderly individuals among all registered patients before 2008, whereas the number increased to 23 (12 %) after 2008. Before 2008, only one elderly patient received MVAC, while GC (whose rate was similar to the rate in young patients) was administered to 13 patients (56.5 %) after 2008. The chemotherapeutic effect and overall survival (OS) rate was not significantly different between young and elderly patients. In the elderly treated with the GC regimen, the renal impairment rate after the first cycle was significantly higher, and the presence of distant metastases and renal impairment were independent prognostic factors in a multivariate analysis. Since GC was approved as the standard regimen for first-line chemotherapy in UC, selected elderly patients have been able to safely receive systemic chemotherapy like young patients. The clinical response rate and OS rate were similar to the young, but we need to monitor changes in renal function more closely in the elderly treated with GC.


CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes.
Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fcγ receptors (FcγRs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the FcγRIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16- expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated β2-integrins and induced TNFα secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNFα-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFNγ, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.


Interactions between imprinting effects: summary and review.
Mice with uniparental disomies (uniparental duplications) for defined regions of certain chromosomes, or certain disomies, show a range of developmental abnormalities most of which affect growth. These defects can be attributed to incorrect dosages of maternal or paternal copies of imprinted genes lying within the regions involved. Combinations of certain partial disomies result in interactions between the imprinting effects that seemingly independently affect foetal and/or placental growth in different ways or modify neonatal and postnatal development. The findings are generally in accord with the 'conflict hypothesis' for the evolution of genomic imprinting but do not demonstrate common growth axes within which imprinted genes may interact. Instead, it would seem that any gene that favours embryonic/foetal development, at consequent cost to the mother, will have been subject to evolutionary selection for only paternal allele expression. Reciprocally, any gene that reduces embryonic/foetal growth to limit disadvantage to the mother will have been selected for only maternal allele expression. It is concluded that survival of the placenta is core to the evolution of imprinting.


Functional MRI correlates of lower limb function in stroke victims with gait impairment.
Although knowledge concerning cortical reorganization related to upper limb function after ischemic stroke is growing, similar data for lower limb movements are limited. Previous studies with hand movement suggested increasing recruitment of motor areas in the unlesioned hemisphere with increasing disability. We used ankle movement as a lower limb analog to test for similarities and differences in recovery patterns. Eighteen subjects were selected with chronic residual gait impairment due to a single subcortical ischemic stroke. Functional MRI scans were obtained at 3.0 T during active and passive ankle dorsiflexion in the patients (8 females, 10 males; mean age, 59.9+/-13.5 years; range, 32 to 74 years) and 18 age-matched healthy control subjects. We observed substantial neocortical activity associated with foot movement both in the patients with stroke and in the healthy control subjects. Our primary finding was increased cortical activation with increasing functional impairment. The extent of activation (particularly in the primary sensorimotor cortex and the supplementary motor area of the unlesioned hemisphere) increased with disability. The changes were most prominent with the active movement task. Using ankle movement, we observed increased activation in the unlesioned hemisphere associated with worse function of the paretic leg, consistent with studies on movement of paretic upper limbs. We interpret this finding as potentially adaptive recruitment of undamaged ipsilateral motor control pathways from the supplementary motor area and (possibly maladaptive) disinhibition of the ipsilateral sensorimotor cortex.


Comparing costs of illness of multiple sclerosis in three different years: A population-based study.
Little is known about changes in the costs of illness (COI) among multiple sclerosis (MS) patients during recent years. To compare the COI among MS patients and matched controls in 2006, 2009, and 2012, respectively, indicating the costs attributable to the MS disease. Three cross-sectional datasets were analyzed, including all MS patients in Sweden aged 20-60 years and five matched controls for each of them. The analyses were based on 10,531 MS patients and 52,655 matched controls for 2006, 11,722 and 58,610 individuals for 2009, and 12,789 and 63,945 for 2012. Nationwide registers, including prescription drug use, specialized healthcare, sick leave, and disability pension, were linked to estimate the prevalence-based COI. Adjusted for inflation, the average difference in COI between MS patients and matched controls were Swedish Krona (SEK) 243,751 (95% confidence interval: SEK 239,171-248,331) in 2006, SEK 238,971 (SEK 234,516-243,426) in 2009, and SEK 225,923 (SEK 221,630-230,218) in 2012. The difference in indirect costs were SEK 170,502 (SEK 166,478-174,525) in 2006, SEK 158,839 (SEK 154,953-162,726) in 2009, and SEK 141,280 (SEK 137,601-144,960) in 2012. The inflation-adjusted COI of MS patients was lower in 2012 than in 2006, in particular regarding indirect costs.


Karyotypic determinants of chromosome instability in aneuploid budding yeast.
Recent studies in cancer cells and budding yeast demonstrated that aneuploidy, the state of having abnormal chromosome numbers, correlates with elevated chromosome instability (CIN), i.e. the propensity of gaining and losing chromosomes at a high frequency. Here we have investigated ploidy- and chromosome-specific determinants underlying aneuploidy-induced CIN by observing karyotype dynamics in fully isogenic aneuploid yeast strains with ploidies between 1N and 2N obtained through a random meiotic process. The aneuploid strains exhibited various levels of whole-chromosome instability (i.e. chromosome gains and losses). CIN correlates with cellular ploidy in an unexpected way: cells with a chromosomal content close to the haploid state are significantly more stable than cells displaying an apparent ploidy between 1.5 and 2N. We propose that the capacity for accurate chromosome segregation by the mitotic system does not scale continuously with an increasing number of chromosomes, but may occur via discrete steps each time a full set of chromosomes is added to the genome. On top of such general ploidy-related effect, CIN is also associated with the presence of specific aneuploid chromosomes as well as dosage imbalance between specific chromosome pairs. Our findings potentially help reconcile the divide between gene-centric versus genome-centric theories in cancer evolution.


Interaction of oligonucleotide-conjugates with the dipeptide transporter system in Caco-2 cells.
Oligonucleotide-based therapies represent novel strategies for manipulating the expression and function of target proteins and are undergoing clinical evaluation for the treatment of viral diseases and malignancies. However, poor biological stability and cellular delivery represent potential limitations to the therapeutic development of oligonucleotides. Conjugation of oligonucleotides to lipophilic groups can improve delivery to cells but the enhanced cellular binding may also facilitate nonspecific interactions. In this report, we show that phosphorothioate oligonucleotides conjugated to lipophilic groups, either tocopherol (Vitamin E) or 2-Di-O-hexadecyl-3-glycerol, can significantly inhibit the functioning of the dipeptide transporter system (DTS) in cultured Caco-2 intestinal cells. Because the DTS mediates the binding and absorption of nutrient peptides and important drugs, such as the cephalosporin and penicillin antibiotics, this finding has important implications in relation to the potential toxicity of lipophilic conjugates in vivo. It also suggests a potential drug interaction with lipophilic oligonucleotide-conjugates if they were to be delivered orally.


Impact of co-morbidities on self-rated health in self-reported COPD: an analysis of NHANES 2001-2008.
Chronic Obstructive Pulmonary Disease (COPD) coexists with co-morbidities. While co-morbidity has been associated with poorer health status, it is unclear which conditions have the greatest impact on self-rated health. We sought to determine which, and how much, specific co-morbid conditions impact on self-rated health in current and former smokers with self-reported COPD. Using the 2001-2008 National Health and Nutrition Examination Survey we characterized the association between thirteen co-morbidities and health status among individuals self-reporting COPD. Adjusted odds ratios (ORs) were generated using ordinal logistic regression. Additionally we evaluated the impact of increasing number of co-morbidities with self-rated health. Eight illnesses had significant associations with worse self-rated health, however after mutually adjusting for these conditions, congestive heart failure (OR 3.07, 95% CI 1.69-5.58), arthritis (OR 1.69, 95% CI 1.13-2.52), diabetes (OR 1.63, 95% CI 1.01-2.64), and incontinence/prostate disease (OR 1.63, 95% CI 1.01-2.62) remained independent predictors of self-rated health. Each increase in co-morbidities was associated with a 43% higher chance of worse self-rated health (95% CI 1.27-1.62). Individuals with COPD have a substantial burden of co-morbidity, which is associated with worse self-rated health. CHF, arthritis, diabetes and incontinence/prostate disease have the most impact on self-rated health. Targeting these co-morbidities in COPD may result in improved self-rated health.


Advances in Retinal Laser Therapy.
Since the 1960s, laser therapies have played a critical role in the treatment of numerous retinal diseases. Significant advances have been made in laser technology and the molecular understanding of laser-tissue interactions over the past 55 years to maximize the therapeutic effect while minimizing side-effects. While pharmacologic therapies (e.g., anti-vascular endothelial growth factor or anti-VEGF) are playing a larger role, laser therapy remains an important treatment modality for proliferative diabetic retinopathy (PDR), diabetic macular edema (DME), sickle cell retinopathy, retinal vein occlusions, central serous chorioretinopathy, tumors, polypoidal choroidal vasculopathy, and retinal tears. With the development new laser technologies such as selective retinal therapy, subthreshold micropulse laser, nanosecond laser, photomediated ultrasound therapy, and navigated laser, the risk of adverse events has been significantly reduced. This review summarizes the latest developments in retinal laser therapy.


Cancer cell response to nanoparticles: criticality and optimality.
A stochastic variation in size and electrical parameters is common in nanoparticles. Synthesizing gold nanoparticles with a varying range of size and zeta potential, we show that there is clustering at certain regions of hydrodynamic diameter and zeta potentials that can be classified using k-clustering technique. A cluster boundary was observed around 50 nm, a size known for its optimal response to cells. However, neither size nor zeta potential alone determined the optimal cellular response (e.g., percentage cell survival) induced by such nanoparticles. A complex interplay prevails between size, zeta potential, nature of surface functionalization, and extent of adhesion of the cell to a solid matrix. However, it follows that the ratio of zeta potential to surface area, which scales as the electrical field (by Gaussian law), serves as an appropriate indicator for optimal cellular response. The phase plot spanned by fractional survival and effective electric field (charge density) indicates a positive correlation between mean cell survival and the magnitude of the electric field. The phase plot spanned by fractional survival and effective electric field (charge density) associated with the nanosurface shows a bifurcation behavior. Wide variation of cell survival response is observed at certain critical values of the surface charge density, whereas in other ranges the cellular response is well behaved and more predictable. Existence of phase points near the critical region corresponds to wide fluctuation of nanoparticle-induced response, for small changes in the nanosurface property. Smaller nanoparticles with low zeta potential (e.g., those conjugated with arginine) can have such an attribute (i.e., higher electrical field strength), and eventually they cause more cell death. The study may help in optimal design of nanodrugs.


Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.
Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.


Prior knowledge is essential for the beneficial effect of targeted memory reactivation during sleep.
Prior knowledge speeds up system consolidation and accelerates integration of newly acquired memories into existing neocortical knowledge networks. By using targeted memory reactivations, we demonstrate that prior knowledge is also essential for successful reactivation and consolidation of memories during sleep, both on the behavioral and oscillatory level (i.e., theta and fast spindle activity). Thus, prior knowledge is a prerequisite for new memories to enter processes of system consolidation during sleep.


Diversification, disparification and hybridization in the desert shrubs Encelia.
There are multiple hypotheses for the spectacular plant diversity found in deserts. We explore how different factors, including the roles of ecological opportunity and selection, promote diversification and disparification in Encelia, a lineage of woody plants in the deserts of the Americas. Using a nearly complete species-level phylogeny based on double-digest restriction-aided sequencing along with a broad set of phenotypic traits, we estimate divergence times and diversification rates, identify instances of hybridization, quantify trait disparity and assess phenotypic divergence across environmental gradients. We show that Encelia originated and diversified recently (mid-Pleistocene) and rapidly, with rates comparable to notable adaptive radiations in plants. Encelia probably originated in the hot deserts of North America, with subsequent diversification across steep environmental gradients. We uncover multiple instances of gene flow between species. The radiation of Encelia is characterized by fast rates of phenotypic evolution, trait lability and extreme disparity across environments and between species pairs with overlapping geographic ranges. Encelia exemplifies how interspecific gene flow in combination with high trait lability can enable exceptionally fast diversification and disparification across steep environmental gradients.


A virtual hair cell, II: evaluation of mechanoelectric transduction parameters.
The virtual hair cell we have proposed utilizes a set of parameters related to its mechanoelectric transduction. In this work, we observed the effect of such channel gating parameters as the gating threshold, critical tension, resting tension, and Ca(2+) concentration. The gating threshold is the difference between the resting and channel opening tension exerted by the tip link assembly on the channel. The critical tension is the tension in the tip link assembly over which the channel cannot close despite Ca(2+) binding. Our results show that 1), the gating threshold dominated the initial sensitivity of the hair cell; 2), the critical tension minimally affects the peak response, (I), but considerably affects the time course of response, I(t), and the force-displacement, F-X, relationship; and 3), higher intracellular [Ca(2+)] resulted in a smaller fast adaptation time constant. Based on the simulation results we suggest a role of the resting tension: to help overcome the viscous drag of the hair bundle during the oscillatory movement of the bundle. Also we observed the three-dimensional bundle effect on the hair cell response by varying the number of cilia forced. These varying forcing conditions affected the hair cell response.


Cash transfers before pregnancy and infant health.
We estimate the impact of a cash transfer targeting new mothers on their subsequent children's health outcomes at birth. We exploit the unexpected introduction of a generous, universal child benefit in Spain in 2007. Using population-wide, individual-level, high-quality administrative data from birth records and a regression discontinuity approach, we find that women who received the benefit were much less likely to have low-birth-weight children in the future (while their subsequent fertility was unaffected). The overall effect is driven by poor women, unmarried women, and women with low education, and by births taking place relatively soon after the benefit receipt. The €2500 transfer led to a 0.7 percentage-point decline in the fraction of children born under 1500 g in poorer households in the following five years, an 83% reduction. We explore the underlying channels, and find evidence supporting faster intrauterine growth, possibly driven by better maternal health, nutrition, and behaviors. Gestation length, family structure, and parental employment do not seem to play a role. Recent research suggests that targeting pregnant women may be more effective than later interventions (such as cash transfers to families with children), given the strong persistence of fetal health effects. Our results suggest that the impact may be stronger if women are targeted even earlier, before conception.


Mutations in chronic lymphocytic leukemia and how they affect therapy choice: focus on NOTCH1, SF3B1, and TP53.
Chronic lymphocytic leukemia (CLL) is characterized by a relatively small number of recurrent genetic defects. These can be evaluated by clinically available methods such as fluorescent in situ hybridization and targeted sequencing approaches to provide data that can be very helpful in prognostication and planning of treatment. Acquired defects in the p53 pathway, activating mutations of NOTCH1, and dysfunctional mutations of SF3B1 and BIRC3 identify patients with higher risk of progressive disease, poorer responses to conventional chemoimmunotherapy, and shorter survival. Risk stratification using these data can identify patients with aggressive CLL who require careful monitoring and are unlikely to have durable responses to chemoimmunotherapy at disease progression. Patients with defective DNA damage repair mechanisms because of p53 dysfunction should be considered for non-chemotherapy-based regimens including tyrosine kinase inhibitors, BCL2 inhibitors, monoclonal antibodies, and immunological therapies including allogeneic transplantation and chimeric antigen receptor-targeted T cells. Conversely, patients with no high-risk mutations can usually be monitored for a prolonged time and are likely to have durable responses to chemoimmunotherapy at disease progression. New technologies for genetic analysis such as targeted next-generation sequencing have the potential to make these analyses cheaper, faster, and more widely available. Comprehensive genetic analysis of patients both at diagnosis and before treatment for progressive disease could become an integral component of care for CLL.


Oral ill-health in a general dental practice in south Wales.
To establish and report oral health status data by measuring social impact in conjunction with clinical impact. Oral health status encompassed functional, experiential and psychosocial impact measures in addition to clinical measures. Registered dental patients over 18 years of age attending for routine care at a general dental practice. A self-complete questionnaire based on the work of Locker was administered to consecutive patients as an ongoing survey evaluating service delivery and outcome. In addition clinical data were taken from the clinical examination and patient record card. Between December 1994 and June 1995, 997 patients provided a stratified sample representing the population studied. 96.7% were dentate leaving only 3.3% edentulous. A total of 15.1% were unable to chew one or more foods, 43.3% reported oral or facial pain in the previous four weeks and 62.9% experienced one or more other symptoms. Problems with eating and communication/social interaction were reported by 47.5%, 45% worried a great deal about their oral health and 26.3% were dissatisfied with some aspect of their oral health status. There is merit in using social impact measures in conjunction with clinical impact measures. Clinical outcome measures exceed national oral health targets set for 2002 by the Welsh Office. Social impact is weighted differently in different groups within the practice; for the elderly edentulous physical disability is the main burden whereas discomfort is the main problem for the younger dentate patients. Regular attenders benefit from regular care.


Psychiatric medication use among Manhattan residents following the World Trade Center disaster.
To assess medication use in New York after the September 11th attacks, a telephone survey was conducted in October 2001 (N = 1,008). The prevalence of psychiatric medication use 30 days before the disaster was 8.9 and 11.6% 30 days after, a small but significant increase. The most important factor predicting postdisaster use was predisaster use--92% of those who used medications postdisaster used them predisaster. In addition, 3.3% used psychiatric medications 30 days postdisaster, but not 30 days before. Those who had panic attacks, posttraumatic stress disorder (PTSD), and insurance coverage, were the most likely medicated (26.5%). However, among those who used postdisaster medications (n = 129), new users tended to be those with panic attacks (44.1%) and those with panic attacks and PTSD (69.2%).


Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB.
The ventrobasal nucleus of thalamus (VB) is considered to be intimately involved in the genesis of experimental absence-like seizures. Bilateral microinfusion of gamma-hydroxybutyric acid (GHB) into VB or systemic administration of gamma-butyrolactone, the pro-drug of GHB, induces generalized absence-like seizures in rats. In the present study, the basal and K(+)-evoked extracellular output of endogenous gamma-aminobutyric acid (GABA) and glutamate (GLU) in behaving rat VB nucleus was characterized 1) during unilateral GHB perfusion into VB and 2) during the course of generalized absence-like seizures induced by GHB. Although the basal extracellular release of GABA was inhibited by GHB (250-1500 microM) in a concentration-dependent manner, basal GLU levels remained unaltered. However, K(+)-evoked release of both GABA and GLU was significantly attenuated by GHB. During GHB-induced absence-like seizures, a similar decrease in basal GABA or K(+)-evoked GABA and GLU levels was observed. These effects of GHB were partially reversed by the specific GHB receptor antagonist NCS 382. (-)-Baclofen (10-50 microM) also produced a concentration-dependent decrease in basal and K(+)-evoked levels of GABA and GLU in this thalamic nucleus. The effects of either (-)-baclofen or GHB on the release of GABA and GLU were selectively antagonized by the GABAB receptor antagonists phaclofen (0.75-2 mM) and CGP 35348 (50-200 microM), respectively. These results suggest that by selectively modulating the basal and K(+)-evoked release of GABA and GLU, GHB induces, in the thalamic ventrobasal relay nucleus, an optimal "excitatory" environment conducive to the generation of absence seizures. Moreover, the data raise the possibility that a presynaptic GHB/GABAB receptor complex occurs in VB.


Cognitive Appraisals Mediate Affective Reactivity in Affiliative Extraversion.
Extraversion is comprised of two main components of affiliation and agency. Affiliative and agentic extraversion have been found to predict positive activation in response to appetitive stimuli, and affiliative extraversion also predicts warmth-affection in response to affiliative stimuli. The aim of this study was to test whether cognitive appraisals could account for these personality-emotion relationships. In an online experiment, 192 participants completed affiliative and appetitive imagery tasks, and reported their affect before and after each task. Participants also reported on how they appraised the imagined events. Affiliative extraversion was positively associated with warmth-affection following the affiliative imagery, and this relationship was mediated by appraisals of intrinsic pleasantness and compatibility with internal standards. Affiliative extraversion also predicted positive activation following the affiliative imagery, and this relationship was mediated by appraisals of importance. Neither agentic nor affiliative extraversion predicted any other form of affect following either the affiliative or appetitive imagery tasks. These results suggest that cognitive appraisals may be one mechanism that mediate affective reactivity in affiliative extraversion, although future confirmatory studies are required to further test this hypothesis.


Hollow-shelled nanoreactors endowed with high catalytic activity.
Hollow-shelled nanoreactors have emerged as efficient structures to maximize the potential of nanoparticles in the field of catalysis. In this Concept article, we underline the importance of both the morphology of the active nanoparticles as well as the composition and porosity of the shell for the catalytic performance of the overall nanocomposite. Different configurations are discussed, with a focus on preparative methods and applications in organic synthesis. Perspectives on future designs that may offer new opportunities to improve the selectivity of the catalyzed transformations and add additional features are also addressed, in order to illustrate the potential of these unique nanostructures.


Zebrafish assessment of cognitive improvement and anxiolysis: filling the gap between in vitro and rodent models for drug development.
Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-chamber task for learning and memory was shown to be sensitive to the cognitive enhancing effects of nicotine and has been useful in helping to determine neural mechanisms crucial for nicotinic-induced cognitive enhancement. The novel tank diving test was shown to be a valid and efficient test of stress response. It is sensitive to the reduction in stress-related behaviors due to the amxiolytic drugs diazepam and buspirone but not chlordiazepoxide. Nicotine also causes stress alleviating effects which can be interpreted as anxiolytic effects. Zebrafish models of behavioral pharmacology can be useful to efficiently screen test compounds for drug development and can be useful in helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments.


Developmental amnesia associated with early hypoxic-ischaemic injury.
We recently reported on three young patients with severe impairments of episodic memory resulting from brain injury sustained early in life. These findings have led us to hypothesize that such impairments might be a previously unrecognized consequence of perinatal hypoxic-ischaemic injury. Neuropsychological and quantitative magnetic resonance investigations were carried out on five young patients, all of whom had suffered hypoxic-ischaemic episodes at or shortly after birth. All five patients showed severe impairments of episodic memory (memory for events), with relative preservation of semantic memory (memory for facts). However, none had any of the major neurological deficits that are typically associated with hypoxic-ischaemic injury, and all attended mainstream schools. Quantitative magnetic resonance investigations revealed severe bilateral hippocampal atrophy in all cases. As a group, the patients also showed bilateral reductions in grey matter in the regions of the putamen and the ventral part of the thalamus. On the basis of their clinical histories and the pattern of magnetic resonance findings, we attribute the patients' pathology and associated memory impairments primarily to hypoxic-ischaemic episodes sustained very early in life. We suggest that the degree of hypoxia-ischaemia was sufficient to produce selective damage to particularly vulnerable regions of the brain, notably the hippocampi, but was not sufficient to result in the more severe neurological and cognitive deficits that can follow hypoxic-ischaemic injury. The impairments in episodic memory may be difficult to recognize, particularly in early childhood, but this developmental amnesia can have debilitating consequences, both at home and at school, and may preclude independent life in adulthood.


Vertical distribution and characterization of aerobic phototrophic bacteria at the Juan de Fuca Ridge in the Pacific Ocean.
The vertical distribution of culturable anoxygenic phototrophic bacteria was investigated at five sites at or near the Juan de Fuca Ridge in the Pacific Ocean. Twelve similar strains of obligately aerobic phototrophic bacteria were isolated in pure culture, from depths ranging from 500 to 2,379 m below the surface. These strains appear morphologically, physiologically, biochemically, and phylogenetically similar to Citromicrobium bathyomarinum strain JF-1, a bacterium previously isolated from hydrothermal vent plume waters. Only one aerobic phototrophic strain was isolated from surface waters. This strain is morphologically and physiologically distinct from the strains isolated at deeper sampling locations, and phylogenetic analysis indicates that it is most closely related to the genus Erythrobacter. Phototrophs were cultivated from three water casts taken above vents but not from two casts taken away from active vent sites. No culturable anaerobic anoxygenic phototrophs were detected. The photosynthetic apparatus was investigated in strain JF-1 and contains light-harvesting I and reaction center complexes, which are functional under aerobic conditions.


Motion correspondence in the Ternus display shows feature bias in spatiotopic coordinates.
How is the visual system able to maintain object identity as the objects or the eyes move? While many early studies have shown small or no influence of feature information on this correspondence process, more recent studies have shown large feature effects. Here we investigated if this incongruity might be due to the distance over which the feature influence has an effect. We used a variation of the Ternus display (Ternus, 1926), an ambiguous apparent motion display, in which two sets of three discs are presented and one can perceive either three discs moving together (group motion) or one disc jumping across the other two discs (element motion). We biased the percept toward element motion by matching the features of some of the discs. In Experiment 1, with the three discs aligned and moving vertically, we added a horizontal offset between the two sets of discs and found a strong bias toward element motion that decreased with increasing spatial offset. In Experiment 3 participants had to make horizontal saccades across the same Ternus displays so that the two Ternus frames were horizontally offset on the retina, but not in spatiotopic coordinates. We found that the bias showed a similar spatial range, but now it was clear that the range was set in spatial coordinates independently of the retinal position. These results show that feature information contributes to correspondence over a limited spatial range (Experiment 1) and that the range is imposed in spatial, not retinal, coordinates (Experiment 2).


Anti-intrusion effect of Lorazepam: an experimental study.
Easy triggering of trauma-related episodic memory fragments caused by perceptual cues is tied to strong perceptual priming in the implicit memory system. And among benzodiazepines, only lorazepam has been consistently reported to have an atypical suppression effect on perceptual priming processes. The aim of this study was to investigate the effects of single doses of lorazepam, diazepam, and a placebo on intrusive memories after exposure to a distressing videotape and to explore whether the anti-intrusive effect of lorazepam is acquired as a result of the suppression of perceptual but not conceptual priming processes. Under prospective, randomized, and double-blind conditions, we compared the anti-intrusion effect of a single dose of lorazepam (n=22) with that of diazepam (n=22) and a placebo (n=21) in young healthy Korean college students following exposure to a traumatic videotape. We present the first finding for an anti-intrusion effect of lorazepam. One day after the medication, lorazepam, rather than diazepam or the placebo, significantly reduced the extent of intrusion and data-driven processing of the traumatic information. There were no differences among the three conditions in state anxiety, depression, and an arousal scale throughout the experiment. Results from this study suggest the possibility of lorazepam as a candidate anti-intrusion drug, as well as the cautious use of diazepam in the treatment of PTSD patients. The anti-intrusive effect of lorazepam is directly related to its atypical inhibitory effect on implicit perceptual priming processes. The present study provides support for the enhanced perceptual priming hypothesis of PTSD.


Morphological and molecular differentiation of invasive freshwater species of the genus Corbicula (Bivalvia, corbiculidea) suggest the presence of three taxa in French rivers.
Asiatic Clams are common in brackish and fresh water in Asia, and they were introduced into North America in 1924 and have now spread throughout the continent. During the last two decades they have been reported in Europe, but the number of species here is uncertain. Populations of Corbicula from France and the Netherlands were analysed morphologically and genetically to quantify the degree of species and/or population differentiation. The morphological and genetic data, based on allozymes and mitochondrial sequences, were in full agreement. They indicate that there are two distinct species, identified as C. fluminalis and C. fluminea, in the two countries. Analyses of the mitochondrial COI gene revealed an unexpected divergent population of Corbicula in the Rhône. All these individuals were morphologically identified as C. fluminea, but had a COI sequence different from the two previous species. This population may, therefore, be a more ancient population, or a distinct species introduced via a different colonization route.


Succinylacetone as primary marker to detect tyrosinemia type I in newborns and its measurement by newborn screening programs.
Tyrosinemia type I (TYR I) is caused by autosomal recessive fumarylacetoacetate hydrolase deficiency and is characterized by development of severe liver disease in infancy and neurologic crises. If left untreated, most patients die of liver failure in the first years of life. Intervention with medication is effective when initiated during the first month of life. This improvement in the treatment of TYR I patients influenced the decision to include TYR I in the US Secretary of the Department of Health and Human Services' (HHS) Recommended Uniform Screening Panel. However, while tyrosine is routinely measured in newborn screening (NBS) by tandem mass spectrometry (MS/MS), elevated tyrosine levels are not specific to TYR I. To improve the specificity of NBS for TYR I, several assays were developed to measure succinylacetone (SUAC) in dried blood spots (DBS). SUAC is a pathognomonic marker of TYR I, and its detection by NBS MS/MS is possible. This review of the current status of NBS for TYR I in the US is the result of discussions at the HHS Secretary's (Discretionary) Advisory Committee on Heritable Disorders in Newborns and Children about the inconsistent implementation of effective NBS for TYR I in the US. We sought to understand the different TYR I screening practices in US NBS programs. Results indicate that 50 out of 51 NBS programs in the US screen for TYR I, and a successful SUAC performance evaluation scheme is available from the Centers for Disease Control and Prevention. Programmatic and methodological barriers were identified that prevent widespread adoption of SUAC measurements in NBS laboratories. However, since SUAC detection is currently the best approach to NBS for TYR I, a further delay of the addition of SUAC measurement into NBS procedures is discouraged. SUAC measurement should improve both the false positive and false negative rate in NBS for TYR I thereby yielding the desired benefits for affected patients at no expense to the overall population served.


Identification of HIV inhibitors guided by free energy perturbation calculations.
Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.


A single dose of cannabidiol modulates medial temporal and striatal function during fear processing in people at clinical high risk for psychosis.
Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.


Endoscopic and Clinicopathological Features of Superficial Non-Ampullary Duodenal Tumor Based on the Mucin Phenotypes.
We aimed to clarify the endoscopic/clinicopathological features of superficial non-ampullary duodenal epithelial tumors (SNADETs) based on their mucin phenotypes. We analyzed 62 SNADET lesions and classified them based on mucin phenotypic expression. Endoscopic and clinicopathological findings were compared according to mucin phenotypes. Eleven lesions had the gastric phenotype (GP) and 43 lesions had the intestinal phenotype (IP). All GP lesions were located in the first portion of the duodenum, while most IP lesions (72.1%) were located in the second portion (p < 0.01). Tumor size was significantly larger in the GP than in the IP group (14.4 mm vs. 10.2 mm, p < 0.05). Reddish color (72.7% in GP vs. 37.2% in IP, p < 0.05), type 0-I (72.7% vs. 11.6%, p < 0.01), lobular/granular pattern (81.8% vs. 4.7%, p < 0.01), and category 4/5 in Vienna classification (81.8% vs. 30.2%, p < 0.01) were observed significantly more often in the GP than in the IP group. Regarding findings of magnifying endoscopy with narrow-band imaging (M-NBI), white opaque substance (22.2% in GP vs. 89.7% in IP, p < 0.01) and light blue crest (0% vs. 43.6%, p < 0.05) were significantly less frequently observed in the GP group. Oval-shaped marginal epithelium (66.7% vs. 17.9%, p < 0.01), dense pattern (55.6% vs. 2.6%, p < 0.01), and dilatation of the intervening part (100% vs. 12.8%, p < 0.01) were more frequently observed in the GP group. SNADETs showed distinct endoscopic/clinicopathological features according to the mucin phenotype. Tumor location, coloration, macroscopic type, and endoscopic findings including M-NBI are useful to distinguish the mucin phenotypes of SNADETs.


Parental family history of dementia in relation to subclinical brain disease and dementia risk.
To determine the association of parental family history with risk of dementia by age at onset and sex of affected parent in a population-based cohort. From 2000 to 2002, we assessed parental history of dementia in participants without dementia of the Rotterdam Study. We investigated associations of parental history with risk of dementia until 2015, adjusting for demographics, cardiovascular risk factors, and known genetic risk variants. Furthermore, we determined the association between parental history and markers of neurodegeneration and vascular disease on MRI. Of 2,087 participants (mean age 64 years, 55% female), 407 (19.6%) reported a history of dementia in either parent (mean age at diagnosis 79 years). During a mean follow-up of 12.2 years, 142 participants developed dementia. Parental history was associated with risk of dementia independently of known genetic risk factors (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.12-2.48), in particular when parents were diagnosed at younger age (<80 years: HR 2.58, 95% CI 1.61-4.15; ≥80 years: HR 1.01, 95% CI 0.58-1.77). Accordingly, age at diagnosis in probands was highly correlated with age at diagnosis in their parents <80 years (r = 0.57, p = 0.001) but not thereafter (r = 0.17, p = 0.55). Among 1,161 participants without dementia with brain MRI, parental history was related to lower cerebral perfusion and higher burden of white matter lesions and microbleeds. Dementia risk and MRI markers were similar for paternal and maternal history. Parental history of dementia increases risk of dementia, primarily when age at parental diagnosis is <80 years. Unexplained heredity may be attributed in part to cerebral hypoperfusion and small vessel disease. We found no evidence of preferential maternal compared to paternal transmission.


Clinicopathologic characteristics of patients with tuberculosis and schizophrenia.
The clinicopathologic characteristics of patients with tuberculosis (TB) and schizophrenia are unclear. In order to facilitate early diagnosis and prompt treatment, a retrospective study was conducted in China. Subjects were 54 consecutive patients who were seen between October 2006 and December 2015. Data on demographic characteristics, underlying diseases, clinical features, and outcomes were collected from medical records using a standardized data collection form. Acid-fast bacilli were detected at a rate of 26.9%, a mycobacterial culture was positive at a rate of 35.4%, and a real-time polymerase chain reaction was positive for TB at a rate of 35%. Of the 54 patients, i) 44 (81.5%) had symptoms for at least 2 weeks; ii) 10 (18.5%) were transferred from a local psychiatric hospital, and 23 (42.6%) were transferred at least twice before arriving at this Hospital. Unfortunately, the outcome was not successful in these patients, 18 patients (33.3%) had to be retreated, 7 patients (13.0%) had their care interrupted because their schizophrenia worsened. The current study found that the management of TB in patients with schizophrenia poses several challenges. These include delays in diagnosis and treatment of TB, inefficient strategies for control of TB transmission in psychiatric hospitals, the need for a psychiatrist to be involved in care, and a high rate of retreatment.


Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis.
Morbidity and mortality in cystic fibrosis (CF) are due not only to abnormal epithelial cell function, but also to an abnormal immune response. We have shown previously that macrophages lacking CF transmembrane conductance regulator (CFTR), the gene mutated in CF, contribute significantly to the hyperinflammatory response observed in CF. In this study, we show that lack of functional CFTR in murine macrophages causes abnormal TLR4 subcellular localization. Upon LPS stimulation, CFTR macrophages have prolonged TLR4 retention in the early endosome and reduced translocation into the lysosomal compartment. This abnormal TLR4 trafficking leads to increased LPS-induced activation of the NF-κB, MAPK, and IFN regulatory factor-3 pathways and decreased TLR4 degradation, which affects downregulation of the proinflammatory state. In addition to primary murine cells, mononuclear cells isolated from CF patients demonstrate similar defects in response to LPS. Moreover, specific inhibition of CFTR function induces abnormal TLR4 trafficking and enhances the inflammatory response of wild-type murine cells to LPS. Thus, functional CFTR in macrophages influences TLR4 spatial and temporal localization and perturbs LPS-mediated signaling in both murine CF models and patients with CF.


Novel and programmatic improvements to the workflow associated with the AccuBoost breast brachytherapy procedure.
While the noninvasive breast brachytherapy (NIBB) treatment procedure, known as AccuBoost, for breast cancer patients is well established, the treatment quality can be improved by the efficiency of the workflow delivery. A formalized approach evaluated the current workflow through failure modes and effects analysis and generated insight for developing new procedural workflow techniques to improve the clinical treatment process. AccuBoost treatments were observed for several months while gathering details on the multidisciplinary workflow. A list of possible failure modes for each procedure step was generated and organized by timing within the treatment process. A team of medical professionals highlighted procedural steps that unnecessarily increased treatment time, as well as introduced quality deficiencies involving applicator setup, treatment planning, and quality control checks preceding brachytherapy delivery. Procedural improvements and their impact on the clinical workflow are discussed. The revised clinical workflow included the following key procedural enhancements. Prepatient arrival: Improvement of prearrival preparation requires advance completion of dose calculation documentation with patient-specific setup data. Patient arrival pretreatment: Physicists carry out dwell time calculations and check the plan, while the therapist concurrently performs several checks of the ensuing hardware configuration. An electronic method to export the associated HDR brachytherapy paperwork to the electronic medical record system with electronic signatures and captured approvals was generated. Posttreatment: The therapist confirms the applicators were appropriately positioned, and treatment was delivered as expected. The procedural improvements reduced the overall treatment time, improved consistency across users, and eased performance of this special procedure for all participants.


Airplane pilot mental health and suicidal thoughts: a cross-sectional descriptive study via anonymous web-based survey.
The Germanwings Flight 9525 crash has brought the sensitive subject of airline pilot mental health to the forefront in aviation. Globally, 350 million people suffer from depression-a common mental disorder. This study provides further information on this important topic regarding mental health especially among female airline pilots. This is the first study to describe airline pilot mental health-with a focus on depression and suicidal thoughts-outside of the information derived from aircraft accident investigations, regulated health examinations, or identifiable self-reports, which are records protected by civil aviation authorities and airline companies. This is a descriptive cross-sectional study via an anonymous web-based survey administered between April and December 2015. Pilots were recruited from unions, airline companies, and airports via convenience sampling. Data analysis included calculating absolute number and prevalence of health characteristics and depression scores. One thousand eight hundred thirty seven (52.7%) of the 3485 surveyed pilots completed the survey, with 1866 (53.5%) completing at least half of the survey. 233 (12.6%) of 1848 airline pilots responding to the Patient Health Questionnaire 9 (PHQ-9), and 193 (13.5%) of 1430 pilots who reported working as an airline pilot in the last seven days at time of survey, met depression threshold-PHQ-9 total score ≥ 10. Seventy-five participants (4.1%) reported having suicidal thoughts within the past two weeks. We found a significant trend in proportions of depression at higher levels of use of sleep-aid medication (trend test z = 6.74, p < 0.001) and among those experiencing sexual harassment (z = 3.18, p = 0.001) or verbal harassment (z = 6.13, p < 0.001). Hundreds of pilots currently flying are managing depressive symptoms perhaps without the possibility of treatment due to the fear of negative career impacts. This study found 233 (12.6%) airline pilots meeting depression threshold and 75 (4.1%) pilots reporting having suicidal thoughts. Although results have limited generalizability, there are a significant number of active pilots suffering from depressive symptoms. We recommend airline organizations increase support for preventative mental health treatment. Future research will evaluate additional risk factors of depression such as sleep and circadian rhythm disturbances.


[Upper urinary tract video-urodynamics. Current indications].
Upper urinary tract videourodynamic studies were first described in the second half of the 20th century (years 60-70). The antegrade pyelogram with constant pressure and controlled flow received the name of its author, "Vela Navarrete test" (1982), who currently refers to it as video-urodynamic study of the upper urinary tract. It is the simultaneous study of pressure, flow, and dynamic x-ray of the upper urinary tract and it keeps same indications than the original design, in spite of the appearance of new dynamic and static imaging techniques (ultrasound, CT scan, MRI, radioisotope studies). The continued practice of video urodynamic study of the upper urinary tract in the FJD prompted an update of the procedure reviewing its current indications. Patient is positioned in the prone decubitus on an x-ray table with video. After punctioning renal cavities with fine needle, video urodynamic tests are performed: pyelomanometry, basal pyelic pressure (basic urodynamics study), pressure changes after induced diuresis, and pressure-flow studies. 10-20 ml of urine are obtained for biochemical tests (creatinine, electrolytes, osmolarity,...), which give information about the functional viability of the renal unit, cytology or microbiological tests. Finally, the study concludes with an antegrade pyelogram, a fluoroscopic study of the radiological anatomy which provides morphologic and dynamic data of the upper urinary tract. In the Urodynamics Unit of the FJD, urologists perform 30-40 studies per year. We analyzed retrospectively all studies performed over the last five years (1999-2005) for various pathological entities of kidney dilation. (Table I). Structural and dynamic data obtained by the studies offered conclusive information in most of them facilitating the decision for surgery or observation (Table II). The interpretation of the upper urinary tract video-urodynamic study is based on radiological and dynamic findings. Flow-controlled pyelogram enables determining the existence of obstruction, dilation volume, and ureteral peristaltic behaviour. Constant pressure enables quantification of obstruction. The video urodynamic study of the upper urinary tract is easy to perform, well tolerated and may be repeated as many times as required, mainly if nephrostomy tube is placed for more prolonged evaluations. It offers excellent anatomical, dynamic, and etiological information about the upper urinary tract, and furthermore conclusive, with minimal risk.


Surgical treatment of peripheral neuropathy: outcomes from 100 consecutive decompressions.
Since 1992 it has been reported that patients with diabetes mellitus recover sensibility and obtain relief of pain from neuropathy symptoms by decompression of lower-extremity peripheral nerves. None of these reports included a series with more than 36 diabetic patients with lower-extremity nerves decompressed, and only recently has a single report appeared of the results of this approach in patients with nondiabetic neuropathy. No previous report has described a change in balance related to restoration of sensibility. A prospective study was conducted of 100 consecutive patients (60 with diabetes and 40 with idiopathic neuropathy) operated on by a single surgeon, other than the originator of this approach, and with the postoperative results reviewed by someone other than these two surgeons. Each patient had neurolysis of the peroneal nerve at the knee and the dorsum of the foot, and the tibial nerve released in the four medial ankle tunnels. After at least 1 year of follow-up, 87% of patients with preoperative numbness reported improved sensation, 92% with preoperative balance problems reported improved balance, and 86% whose pain level was 5 or greater on a visual analog scale from 0 (no pain) to 10 (the most severe pain) before surgery reported an improvement in pain. Decompression of compressed lower-extremity nerves improves sensation and decreases pain, and should be recommended for patients with neuropathy who have failed to improve with traditional medical treatment.


Pathologic response after neoadjuvant therapy is the major determinant of survival in patients with esophageal cancer.
Esophageal cancer remains a malignancy with high morbidity and mortality despite improvements to diagnosis, staging, chemotherapy, radiation, and surgery. Neoadjuvant therapy (NT) may improve oncologic outcome in many patients, however the degree to which patients benefit remains unclear. We examined the relationship between pathologic response to NT and magnitude of benefit in patients with esophageal cancer. Using a comprehensive esophageal cancer database, we identified patients who underwent esophagectomy between 1994 and 2008. Pathologic response was denoted as complete (pCR), partial (pPR), and nonresponse (NR). Clinical and pathologic data were compared using Fisher's exact and chi-square when appropriate, while Kaplan-Meier estimates were used for survival analysis. We identified 347 patients who underwent esophagectomy, and 262 (75.5%) were treated with NT. The median age was 66 years (28-86 years) with median follow-up of 20 months (1-177 months). There were 106 (40.5%) patients exhibiting pCR, 95 (36.3%) with pPR, and 61 (23.3%) with NR. The rate of R0 resections was higher amongst pCR (100%) compared with 94.7% in pPR (P = 0.02) and 87.5% in NR (P = 0.0007). There were 15 (14.2%) recurrences in pCR, 22 (23.7%) in pPR, and 17 (28.8%) in NR (P = 0.04). Patients achieving pCR had 5-year disease-free survival (DFS) and overall survival (OS) of 52% and 52%, respectively, compared with 36% and 38% in pPR and 22% and 19% in NR (P < 0.0001, P < 0.0001). Esophageal cancer patients frequently succumb to their disease. However, patients treated with neoadjuvant therapy who achieve pCR have a higher rate of R0 resections, fewer recurrences, and improved 5-year OS and DFS.