Role of p53 in cell cycle regulation and apoptosis following exposure to proteasome inhibitors.
In this study, we explored what effect inhibitors of the 26S proteasome have on cell cycle distribution and induction of apoptosis in human skin fibroblasts and colon cancer cells differing in their p53 status. We found that proteasome inhibition resulted in nuclear accumulation of p53. This was surprising because it is thought that the degradation of p53 is mediated by cytoplasmic 26S proteasomes. Nuclear accumulation of p53 was accompanied by the induction of both p21WAF1 mRNA and protein as well as a decrease in cells entering S phase. Interestingly, cells with compromised p53 function showed a marked increase in the proportion of cells in the G2-M phase of the cell cycle and an attenuated induction of apoptosis after proteasome inhibition. Taken together, our results suggest that proteasome inhibition results in nuclear accumulation of p53 and a p53-stimulated induction of both G1 arrest and apoptosis.


Human immunodeficiency virus transmission at each step of the care continuum in the United States.
Human immunodeficiency virus (HIV) transmission risk is primarily dependent on behavior (sexual and injection drug use) and HIV viral load. National goals emphasize maximizing coverage along the HIV care continuum, but the effect on HIV prevention is unknown. To estimate the rate and number of HIV transmissions attributable to persons at each of the following 5 HIV care continuum steps: HIV infected but undiagnosed, HIV diagnosed but not retained in medical care, retained in care but not prescribed antiretroviral therapy, prescribed antiretroviral therapy but not virally suppressed, and virally suppressed. A multistep, static, deterministic model that combined population denominator data from the National HIV Surveillance System with detailed clinical and behavioral data from the National HIV Behavioral Surveillance System and the Medical Monitoring Project to estimate the rate and number of transmissions along the care continuum. This analysis was conducted January 2013 to June 2014. The findings reflect the HIV-infected population in the United States in 2009. Estimated rate and number of HIV transmissions. Of the estimated 1,148,200 persons living with HIV in 2009, there were 207,600 (18.1%) who were undiagnosed, 519,414 (45.2%) were aware of their infection but not retained in care, 47,453 (4.1%) were retained in care but not prescribed ART, 82,809 (7.2%) were prescribed ART but not virally suppressed, and 290,924 (25.3%) were virally suppressed. Persons who are HIV infected but undiagnosed (18.1% of the total HIV-infected population) and persons who are HIV diagnosed but not retained in medical care (45.2% of the population) were responsible for 91.5% (30.2% and 61.3%, respectively) of the estimated 45,000 HIV transmissions in 2009. Compared with persons who are HIV infected but undiagnosed (6.6 transmissions per 100 person-years), persons who were HIV diagnosed and not retained in medical care were 19.0% (5.3 transmissions per 100 person-years) less likely to transmit HIV, and persons who were virally suppressed were 94.0% (0.4 transmissions per 100 person-years) less likely to transmit HIV. Men, those who acquired HIV via male-to-male sexual contact, and persons 35 to 44 years old were responsible for the most HIV transmissions by sex, HIV acquisition risk category, and age group, respectively. Sequential steps along the HIV care continuum were associated with reduced HIV transmission rates. Improvements in HIV diagnosis and retention in care, as well as reductions in sexual and drug use risk behavior, primarily for persons undiagnosed and not receiving antiretroviral therapy, would have a substantial effect on HIV transmission in the United States.


Snoring and insomnia are not associated with subclinical atherosclerosis in the Northern Manhattan Study.
Sleep-disordered breathing is a risk factor for stroke, but its association with subclinical atherosclerosis remains controversial. Snoring and insomnia are frequently comorbid with sleep-disordered breathing and may contribute to stroke. Data on the relationship between snoring and insomnia with atherosclerotic disease are sparse. We investigated the relationship between markers of subclinical atherosclerosis, insomnia, snoring, and carotid intima-media thickness, in the Northern Manhattan Study. A group of 1605 participants (mean age 65 +/- 8 years; 40% men; 61% Hispanic, 19% black, 20% white) who had carotid intima-media thickness measurements performed was assessed for self-reported sleep habits. Habitual snoring was defined as self-reported snoring greater than four times per week. Presence of insomnia was based on three items extracted from the Hamilton Rating Scale for Depression. Carotid intima-media thickness was expressed as a mean composite measure of intima-media thickness in the carotid bifurcation, common, and internal carotid artery. Multivariate linear regression models were used to identify associations between snoring, insomnia, and carotid intima-media thickness. Habitual snoring was present in 29% of the subjects and insomnia in 26%. There was a higher prevalence of self-reported snoring (84%) and insomnia (66%) among Hispanics than non-Hispanics. The mean total carotid intima-media thickness was 0.95 +/- 0.09 mm; among those with self-reported snoring was 0.94 +/- 0.09 mm; and among those with insomnia was 0.95 +/- 0.08 mm. After controlling for age, gender, race-ethnicity, body mass index and cardiovascular risk factors, snoring (P=0.986) and insomnia (P=0.829) were not significantly associated with increased carotid intima-media thickness. Snoring and insomnia were not significantly associated with subclinical atherosclerosis in this population-based community cohort.


Comparative research on GaAs photocathodes before and after activation.
Obtaining higher quantum efficiency and more stability has been an important developing direction in the investigation of GaAs photocathodes. By solving the one-dimensional diffusion equation for no-equilibrium minority carriers of reflection-mode GaAs photocathode materials, we can get the equations of the surface photovoltage curve before activation and the spectral response curve after activation for uniform and exponential doping GaAs materials. Through experiments and fitting calculations for two doping structural materials designed by us, the parameters of the body materials are exactly measured by the surface photovoltage curves, and the curves for surface escape probability are also accurately fitted by the comparative research before and after activation. The differences for the fitting results of two doping structures are also well analyzed. This comparative research can form a closed-loop research for GaAs photocathodes and will help us to deeply study the varied doping structures and optimize Cs-O activation technology for GaAs photocathodes in the future.


Arterial blood pressure responses to graded transient arousal from sleep in normal humans.
During obstructive sleep apnea, transient arousal at the resumption of breathing is coincident with a substantial rise in blood pressure. To assess the hemodynamic effect of arousal alone, 149 transient stimuli were administered to five normal subjects. Two electroencephalograms (EEG), an electrooculogram, a submental electromyogram (EMG), and beat-to-beat blood pressure (Finapres, Ohmeda) were recorded in all subjects. Stimulus length was varied to produce a range of cortical EEG arousals that were graded as follows: 0, no increase in high-frequency EEG or EMG; 1, increased high-frequency EEG and/or EMG for < 10 s; 2, increased high-frequency EEG and/or EMG for > 10 s. Overall, compared with control values, average systolic pressure rose [nonrapid-eye-movement (NREM) sleep 10.0 +/- 7.69 (SD) mmHg; rapid-eye-movement (REM) sleep 6.0 +/- 6.73 mmHg] and average diastolic pressure rose (NREM sleep 6.1 +/- 4.43 mmHg; REM sleep 3.7 +/- 3.02 mmHg) over the 10 s following the stimulus (NREM sleep, P < 0.0001; REM sleep, P < 0.002). During NREM sleep, there was a trend toward larger blood pressure rises at larger grades of arousal (systolic: r = 0.22, 95% confidence interval 0.02-0.40; diastolic: r = 0.48, 95% confidence interval 0.31-0.62). The average blood pressure rise in response to the grade 2 arousals was approximately 75% of that during obstructive sleep apnea. Arousal stimuli that did not cause EEG arousal still produced a blood pressure rise (mean systolic rise 8.6 +/- 7.0 mmHg, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)


Controllable broadband nonlinear optical response of graphene dispersions by tuning vacuum pressure.
Nonlinear scattering, originating from laser induced solvent micro-bubbles and/or micro-plasmas, is regarded as the principal mechanism for nonlinear optical (NLO) response of graphene dispersions at ns timescale. In this work, we report the significant enhancement of NLO response of graphene dispersions by decreasing the atmospheric pressure, which has strong influence on the formation and growth of micro-bubbles and/or micro-plasmas. A modified open-aperture Z-scan apparatus in combination with a vacuum system was used to study the effect of vacuum pressure on the NLO property of graphene dispersions prepared by liquid-phase exfoliation technique. We show that the atmospheric pressure can be utilized to control and tune the nonlinear responses of the graphene dispersions for ns laser pulses at both 532 nm and 1064 nm. The lower the vacuum pressure was, the larger the NLO response was. In contrast, the NLO property of fullerene was found to be independent of the pressure change, due to its nature of nonlinear absorption. This work affords a simple method to distinguish the nonlinear scattering and absorption mechanisms for NLO nanomaterials.


Pattern of energy expenditure during simulated competition.
To determine how athletes spontaneously use their energetic reserves when the only instruction was to finish in minimal time, and whether experience from repeated performance changes the strategy of recreational athletes. Recreational road cyclists/speed skaters (N = 9) completed three laboratory time trials of 1500 m on a windload braked cycle. The pattern of energy use was calculated from total work and from the work attributable to aerobic metabolism, which allowed computation of anaerobic energy use. Regional level speed skaters (N = 8) also performed a single 1500-m time trial with the same protocol and measurements. The serial trials were completed in (mean +/- SD) 133.8 +/- 6.6, 133.9 +/- 5.8, 133.8 +/- 5.5 s (P > 0.05 among trials); and in 125.7 +/- 10.9 s in the skaters (P < 0.05 vs cyclists). The [OV0312]O(2peak) during the terminal 200 m was similar within trials (3.23 +/- 0.44, 3.34 +/- 0.44, 3.30 +/- 0.51 (P > 0.05)) versus 3.91 +/- 0.68 L.min-1 in the skaters (P < 0.05 vs cyclists). In all events, the initial power output and anaerobic energy use was high and decayed to a more or less constant value ( approximately 25% of peak) over the remainder of the event. Contrary to predictions based on an assumed "all out" starting strategy, the subjects reserved some of their ability to perform anaerobic work for a terminal acceleration. The total work accomplished was not different between trials (43.53, 43.78, and 47.48 kJ in the recreational athletes, or between the cyclists and skaters (47.79 kJ). The work attributable to anaerobic sources was not different between the rides (20.67, 20.53, and 21.12 kJ in the recreational athletes). In the skaters, the work attributable to anaerobic sources was significantly larger versus the cyclists (24.67 kJ). Energy expenditure during high-intensity cycling seems: 1) to be expended in a manner that allows the athlete to preserve an anaerobic energetic contribution throughout an event, 2) does not appear to have a large learning effect in already well trained cyclists, and 3) anaerobic energy expenditure may be the performance discriminating factor among groups of athletes.


Network-based features enable prediction of essential genes across diverse organisms.
Machine learning approaches to predict essential genes have gained a lot of traction in recent years. These approaches predominantly make use of sequence and network-based features to predict essential genes. However, the scope of network-based features used by the existing approaches is very narrow. Further, many of these studies focus on predicting essential genes within the same organism, which cannot be readily used to predict essential genes across organisms. Therefore, there is clearly a need for a method that is able to predict essential genes across organisms, by leveraging network-based features. In this study, we extract several sets of network-based features from protein-protein association networks available from the STRING database. Our network features include some common measures of centrality, and also some novel recursive measures recently proposed in social network literature. We extract hundreds of network-based features from networks of 27 diverse organisms to predict the essentiality of 87000+ genes. Our results show that network-based features are statistically significantly better at classifying essential genes across diverse bacterial species, compared to the current state-of-the-art methods, which use mostly sequence and a few 'conventional' network-based features. Our diverse set of network properties gave an AUROC of 0.847 and a precision of 0.320 across 27 organisms. When we augmented the complete set of network features with sequence-derived features, we achieved an improved AUROC of 0.857 and a precision of 0.335. We also constructed a reduced set of 100 sequence and network features, which gave a comparable performance. Further, we show that our features are useful for predicting essential genes in new organisms by using leave-one-species-out validation. Our network features capture the local, global and neighbourhood properties of the network and are hence effective for prediction of essential genes across diverse organisms, even in the absence of other complex biological knowledge. Our approach can be readily exploited to predict essentiality for organisms in interactome databases such as the STRING, where both network and sequence are readily available. All codes are available at https://github.com/RamanLab/nbfpeg.


Localizing Spectral Interactions in the Resting State Network Using the Hilbert-Huang Transform.
Brain synchronizations are orchestrated from neuronal oscillations through frequency interactions, such as the alpha rhythm during relaxation. Nevertheless, how the intrinsic interaction forges functional integrity across brain segregations remains elusive, thereby motivating recent studies to localize frequency interactions of resting-state fMRI (rs-fMRI). To this point, we aim to unveil the fMRI-based spectral interactions using the time-frequency (TF) analysis; however, Fourier-based TF analyses impose restrictions on revealing frequency interactions given the limited time points in fMRI signals. Instead of using the Fourier-based wavelet analysis to identify the fMRI frequency of interests, we employed the Hilbert-Huang transform (HHT) for probing the specific frequency contribution to the functional integration, called ensemble spectral interaction (ESI). By simulating data with time-variant frequency changes, we demonstrated the Hilbert TF maps with high spectro-temporal resolution and full accessibility in comparison with the wavelet TF maps. By detecting amplitude-to-amplitude frequency couplings (AAC) across brain regions, we elucidated the ESI disparity between the eye-closed (EC) and eye-open (EO) conditions in rs-fMRI. In the visual network, the strength of the spectral interaction within 0.03-0.04 Hz was amplified in EC compared with that in EO condition, whereas a canonical connectivity analysis did not present differences between conditions. Collectively, leveraging from the instantaneous frequency of HHT, we firstly addressed the ESI technique to map the fMRI-based functional connectivity in a brand-new AAC perspective. The ESI possesses potential in elucidating the functional connectivity at specific frequency bins, thereby providing additional diagnostic merits for future clinical neuroscience.


A rare case of enchondromatosis of the knees and hands with involvement of Hoffa's fat pad and peri-articular soft-tissues.
We report a case of a 56-year old man with chronic pain in both knees for several years. This patient had already undergone surgery on his left knee in 2002 after an x-ray showed multiple lytic and well margined lesions in the distal femur and proximal tibia with ground-glass matrix, involving Hoffa's fat pad and the patellar ligament. Histology was consistent with an enchondroma. The most recent MRI examination showed enchondromatosis involving both knees with bilateral extension into Hoffa's fat pad and the patellar ligament. Subsequently, we performed an additional radiographic examination of the hands and feet, as well as an MRI of both hands to identify other possible enchondromas in the most common sites for this disease. Enchondromatosis with soft tissue involvement is extremely rare, and involvement of Hoffa's fat pad has not been reported in the scientific literature. The clinical presentation of this case and the general aspects of Enchondromatosis are discussed.


Diverse transcriptional programs associated with environmental stress and hormones in the Arabidopsis receptor-like kinase gene family.
The genome of Arabidopsis thaliana encodes more than 600 receptor-like kinase (RLK) genes, by far the dominant class of receptors found in land plants. Although similar to the mammalian receptor tyrosine kinases, plant RLKs are serine/threonine kinases that represent a novel signaling innovation unique to plants and, consequently, an excellent opportunity to understand how extracellular signaling evolved and functions in plants as opposed to animals. RLKs are predicted to be major components of the signaling pathways that allow plants to respond to environmental and developmental conditions. However, breakthroughs in identifying these processes have been limited to only a handful of individual RLKs. Here, we used a Syngenta custom Arabidopsis GeneChip array to compile a detailed profile of the transcriptional activity of 604 receptor-like kinase genes after exposure to a cross-section of known signaling factors in plants, including abiotic stresses, biotic stresses, and hormones. In the 68 experiments comprising the study, we found that 582 of the 604 RLK genes displayed a two-fold or greater change in expression to at least one of 12 types of treatments, thereby providing a large body of experimental evidence for targeted functional screens of individual RLK genes. We investigated whether particular subfamilies of RLK genes are responsive to specific types of signals and found that each subfamily displayed broad ranges of expression, as opposed to being targeted towards particular signal classes. Finally, by analyzing the divergence of sequence and gene expression among the RLK subfamilies, we present evidence as to the functional basis for the expansion of the RLKs and how this expansion may have affected conservation and divergences in their function. Taken as a whole, our study represents a preliminary, working model of processes and interactions in which the members of the RLK gene family may be involved, where such information has remained elusive for so many of its members.


Sodium Polystyrene Sulfonate and Cytomegalovirus-Associated Hemorrhagic Duodenitis: More than Meets the Eye.
BACKGROUND Hemorrhagic duodenitis is an exceptionally rare adverse event of sodium polystyrene sulfonate (SPS) treatment and is a common manifestation of cytomegalovirus (CMV) reactivation. SPS is known to cause marked inflammation in the lower gastrointestinal tract, including colonic necrosis, whereas involvement of the small bowel is uncommon. Although its effectiveness and safety has been disputed since its introduction, SPS remains widely used due to lack of alternatives. CMV infection and reactivation are well-known complications after solid-organ transplantation, particularly in seronegative recipients receiving organs from seropositive donors, and is associated with significant morbidity and mortality. The lower gastrointestinal tract is more commonly involved, but infections of all parts of the intestine are observed. CASE REPORT Here, we report the case of a 56-year-old man who presented with severe upper-gastrointestinal bleeding. Hemorrhagic duodenitis was initially attributed to the use of SPS, as abundant SPS crystals were detected in the duodenal mucosa but we found only 2 CMV-infected endothelial cells. Two weeks later, gastrointestinal bleeding recurred. However, this time, abundant CMV-infected cells were demonstrated in the duodenal biopsies. CONCLUSIONS Our case report highlights an uncommon adverse event after SPS use with a simultaneous CMV reactivation. The main difficulty was to differentiate between CMV reactivation and CMV as an "innocent bystander". This demonstrates the challenge of decision-making in patients with complex underlying diseases.


Managing the soils of sub-saharan Africa.
Many constraints to intensive food-crop production in tropical Africa are related to tropical soils. Improved technologies are available for different ecological regions. Important technological innovations include manual land clearing, mulch farming, conservation tillage and tiedridges, agroforestry, cover crops, mixed- and relay-cropping, and early sowing for improved and sustained productivity. Irrigation, animal traction or draft animals, and the use of chemical fertilizers are also important. Much of the agrarian stagnation in Africa is caused by neglect and misuse of the most basic of all resources, the soil. In fact, the root cause of the perpetual famine can be traced to the misuse of soil and water resources and issues related to their misuse. Substantial increases in food production are possible if the proven technologies can be effectively transferred and implemented. Priorities lie in both short-term development projects and in initiating long-term research to understand soil and water resources and how to manage them. The agrarian research must address the issue of improving the welfare of resource-poor farmers.


Profile of Nigerians with diabetes mellitus - Diabcare Nigeria study group (2008): Results of a multicenter study.
Diabetes Mellitus is the commonest endocrine-metabolic disorder in Nigeria similar to the experience in other parts of the world. The aim was to assess the clinical and laboratory profile, and evaluate the quality of care of Nigerian diabetics with a view to planning improved diabetes care. In a multicenter study across seven tertiary health centers in Nigeria, the clinical and laboratory parameters of diabetic out-patients were evaluated. Clinical parameters studied include type of diabetes, anthropometry, and blood pressure (BP) status, chronic complications of diabetes, and treatment types. Laboratory data assessed included fasting plasma glucose (FPG), 2-h post-prandial (2-HrPP) glucose, glycated hemoglobin (HbA1c), urinalysis, serum lipids, electrolytes, urea, and creatinine. A total of 531 patients, 209 (39.4%) males and 322 (60.6%) females enrolled. The mean age of the patients was 57.1 ± 12.3 years with the mean duration of diabetes of 8.8 ± 6.6 years. Majority (95.4%) had type 2 diabetes mellitus (DM) compared to type 1 DM (4.6%), with P < 0.001. The mean FPG, 2-HrPP glucose, and HbA1c were 8.1 ± 3.9 mmol/L, 10.6 ± 4.6 mmol/L, and 8.3 ± 2.2%, respectively. Only 170 (32.4%) and 100 (20.4%) patients achieved the ADA and IDF glycemic targets, respectively. Most patients (72.8%) did not practice self-monitoring of blood glucose. Hypertension was found in 322 (60.9%), with mean systolic BP 142.0 ± 23.7 mmHg, and mean diastolic BP 80.7 ± 12.7 mmHg. Diabetic complications found were peripheral neuropathy (59.2%), retinopathy (35.5%), cataracts (25.2%), cerebrovascular disease (4.7%), diabetic foot ulcers (16.0%), and nephropathy (3.2%). Most Nigerian diabetics have suboptimal glycemic control, are hypertensives, and have chronic complications of DM. Improved quality of care and treatment to target is recommended to reduce diabetes-related morbidity and mortality.


Calcium release and influx in yeast: TRPC and VGCC rule another kingdom.
Calcium is one of the most ubiquitous second messengers, in addition to being a fundamentally important cofactor for many proteins' functions. Thus, cells from fungi to plants to animals have evolved mechanisms for carefully controlling calcium concentrations in their organelles and cytosol. This perspective discusses the similarities and differences between yeast and animals in cation channels of two families: the transient receptor potential channels (TRPCs) and voltage-gated calcium channels (VGCCs). One of the key differences highlighted is in the channels implicated in the response of yeast and animal cells to depletion of calcium from intracellular stores, and the differences in localization of these channels between yeast and animal cells. Understanding the logic of fungal Ca(2+) channels, therefore, may provide new insights into the organization and regulation of cellular calcium signaling networks in animals.


Activation of PERK Contributes to Apoptosis and G2/M Arrest by Microtubule Disruptors in Human Colorectal Carcinoma Cells ‡.
Microtubule-targeting agents (MTAs) are widely used in cancer chemotherapy, but the therapeutic responses significantly vary among different tumor types. Protein kinase RNA-like endoplasmic reticular (ER) kinase (PERK) is an ER stress kinase, and the role of PERK in the anticancer effects of MTAs is still undefined. In the present study, taxol (TAX) and nocodazole (NOC) significantly induced apoptosis with increased expression of phosphorylated PERK (pPERK; Tyr980) in four human colon cancer cell lines, including HCT-15, COLO205, HT-20, and LOVO cells. Induction of G2/M arrest by TAX and NOC with increases in phosphorylated Cdc25C and cyclin B1 protein were observed in human colon cancer cells. Application of the c-Jun N-terminal kinase (JNK) inhibitors SP600125 (SP) and JNK inhibitor V (JNKI) significantly reduced TAX- and NOC-induced apoptosis and G2/M arrest of human colon cancer cells. Interestingly, TAX- and NOC-induced pPERK (Tyr980) protein expression was inhibited by adding the JNK inhibitors, SP and JNKI, and application of the PERK inhibitor GSK2606414 (GSK) significantly reduced apoptosis and G2/M arrest by TAX and NOC, with decreased pPERK (Tyr980) and pJNK, phosphorylated Cdc25C, and Cyc B1 protein expressions in human colon cancer cells. Decreased viability by TAX and NOC was inhibited by knockdown of PERK using PERK siRNA in COLO205 and HCT-15 cells. Disruption of the mitochondrial membrane potential and an increase in B-cell lymphoma-2 (Bcl-2) protein phosphorylation (pBcl-2; Ser70) by TAX and NOC were prevented by adding the PERK inhibitor GSK and JNK inhibitor SP and JNKI. A cross-activation of JNK and PERK by TAX and NOC leading to anti-CRC actions including apoptosis and G2/M arrest was first demonstrated herein.


Control of Hep G2-cell triacylglycerol and apolipoprotein B synthesis and secretion by polyunsaturated non-esterified fatty acids and insulin.
Non-esterified fatty acids (NEFAs) and insulin are important factors in the control of lipoprotein secretion, but the mechanism of action is unclear. The present study was undertaken to determine whether insulin and NEFAs modulated hepatic secretion of triacylglycerol and apolipoprotein B (apo-B) by regulation of hepatic intracellular apo-B content. The experiments were performed with the human hepatoblastoma cell line Hep G2, for periods of up to 72 h in the presence and absence of NEFAs and insulin. Higher concentrations of eicosapentanoate (EPA) sustained for 72 h decreased cellular protein content (at 250 microM) or caused cell death (at 750 microM), and this effect was not observed with the other NEFAs studied, whereas 75 microM-EPA did not affect cell viability. Compared with the absence of NEFA, 75 microM-EPA did not alter the intracellular triacylglycerol content, but decreased the intracellular content of apo-B by 47% (P < 0.01) and decreased secreted triacylglycerol and secreted apo-B by 13% (P < 0.05) and 21% (P < 0.01) respectively, after 72 h. However 250 microM-oleate increased the intracellular triacylglycerol by 36% (P < 0.01), intracellular apo-B by 22% (P < 0.05) and secreted triacylglycerol and apo-B by 20-30% (P < 0.05-0.01). Insulin decreased secreted triacylglycerol and apo-B in the presence of each NEFA studied by 20-30%. There was no correlation between the changes in intracellular triacylglycerol and the rate of secretion. However, when the secreted triacylglycerol or apo-B was plotted against intracellular apo-B content a significant correlation was observed (r = 0.89, P < 0.001 for both analyses). Apo-B mRNA levels did not change after 72 h incubation with oleate or EPA. These results demonstrate that EPA can be toxic to hepatocytes and that NEFAs and insulin control secretion of triacylglycerol and apo-B by regulation of the intracellular apo-B concentration, thus controlling assembly of apo-B with triacylglycerol to form lipoproteins.


One step forward, two steps back? The GMC, the common law and 'informed' consent.
Until 2008, if doctors followed the General Medical Council's (GMC's) guidance on providing information prior to obtaining a patient's consent to treatment, they would be going beyond what was technically required by the law. It was hoped that the common law would catch up with this guidance and encourage respect for patients' autonomy by facilitating informed decision-making. Regrettably, this has not occurred. For once, the law's inability to keep up with changing medical practice and standards is not the problem. The authors argue that while the common law has moved forward and started to recognise the importance of patient autonomy and informed decision-making, the GMC has taken a step back in their 2008 guidance on consent. Indeed, doctors are now required to tell their patients less than they were in 1998 when the last guidance was produced. This is an unfortunate development and the authors urge the GMC to revisit their guidance.


Volatile anesthetics improve survival after cecal ligation and puncture.
Sepsis remains a leading cause of death in intensive care units. There is growing evidence that volatile anesthetics have beneficial immunomodulatory effects on complex inflammation-mediated conditions. The authors investigated the effect of volatile anesthetics on the overall survival of mice in a sepsis model of cecal ligation and puncture (CLP). Mice (N = 12 per treatment group) were exposed to anesthetic concentrations of desflurane, isoflurane, and sevoflurane either during induction of sepsis or when the mice showed pronounced symptoms of inflammation. Overall survival, as well as organ function and inflammation was compared with the CLP group without intervention. With desflurane and sevoflurane conditioning (1.2 minimal alveolar concentration for 2 h immediately after induction of CLP) overall survival was improved to 58% and 83%, respectively, compared with 17% in the untreated CLP group. Isoflurane did not significantly affect outcome. Application of sevoflurane 24 h after sepsis induction significantly improved overall survival to 66%. Administration of the volatile anesthetics desflurane and sevoflurane reduced CLP-induced mortality. Anesthesia may be a critical confounder when comparing study data where different anesthesia protocols were used.


Application of mismatch equations in dynamic seating designs.
Anthropometry is critical for product and workplace design. Highly prevalent, office work is associated with sedentarism and physical discomfort due to prolonged sitting. Dynamic seating (alternating across sitting, perching, and standing) has been suggested as an alternative to overcome those problems. The current study tested a large sample of anthropometric data for mismatch levels against national and international office furniture standards using dynamic seating as a framework with traditional and perching mismatch equations, applied to three recommended dynamic seating components. Dimensions present in the standards used did not match the majority of the sample. For sitting, seat width and depth individually presented the lowest levels of match, as well as under cumulative fit of all office furniture dimensions. However, these were alleviated when incorporating adjustability. Perching was shown to be generally impeded given commercially-available chair height options. Limitations in state-of-the-art perching equations are discussed, and two new models are proposed as design alternatives. Further research should focus on testing the criteria presented in this research through discomfort and objective measures.


IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis.
Insertions and deletions (indels) have been implicated in dozens of human diseases through the radical alteration of gene function by short frameshift indels as well as long indels. However, the accurate detection of these indels from next-generation sequencing data is still challenging. This is particularly true for intermediate-size indels (≥50 bp), due to the short DNA sequencing reads. Here, we developed a new method that predicts intermediate-size indels using BWA soft-clipped fragments (unmatched fragments in partially mapped reads) and unmapped reads. We report the performance comparison of our method, GATK, PINDEL and ScanIndel, using whole exome sequencing data from the same samples. False positive and false negative counts were determined through Sanger sequencing of all predicted indels across these four methods. The harmonic mean of the recall and precision, F-measure, was used to measure the performance of each method. Our method achieved the highest F-measure of 0.84 in one sample, compared to 0.56 for GATK, 0.52 for PINDEL and 0.46 for ScanIndel. Similar results were obtained in additional samples, demonstrating that our method was superior to the other methods for detecting intermediate-size indels. We believe that this methodology will contribute to the discovery of intermediate-size indels associated with human disease.


Crowding alone cannot account for cosolute effect on amyloid aggregation.
Amyloid fiber formation is a specific form of protein aggregation, often resulting from the misfolding of native proteins. Aimed at modeling the crowded environment of the cell, recent experiments showed a reduction in fibrillation halftimes for amyloid-forming peptides in the presence of cosolutes that are preferentially excluded from proteins and peptides. The effect of excluded cosolutes has previously been attributed to the large volume excluded by such inert cellular solutes, sometimes termed "macromolecular crowding". Here, we studied a model peptide that can fold to a stable monomeric β-hairpin conformation, but under certain solution conditions aggregates in the form of amyloid fibrils. Using Circular Dichroism spectroscopy (CD), we found that, in the presence of polyols and polyethylene glycols acting as excluded cosolutes, the monomeric β-hairpin conformation was stabilized with respect to the unfolded state. Stabilization free energy was linear with cosolute concentration, and grew with molecular volume, as would also be predicted by crowding models. After initiating the aggregation process with a pH jump, fibrillation in the presence and absence of cosolutes was followed by ThT fluorescence, transmission electron microscopy, and CD spectroscopy. Polyols (glycerol and sorbitol) increased the lag time for fibril formation and elevated the amount of aggregated peptide at equilibrium, in a cosolute size and concentration dependent manner. However, fibrillation rates remained almost unaffected by a wide range of molecular weights of soluble polyethylene glycols. Our results highlight the importance of other forces beyond the excluded volume interactions responsible for crowding that may contribute to the cosolute effects acting on amyloid formation.


A mouse model for the human lysosomal disease aspartylglycosaminuria.
Aspartylglycosaminuria (AGU), the most common disorder of glycoprotein degradation in humans, is caused by mutations in the gene encoding the lysosomal enzyme glycosylasparaginase (Aga). The resulting enzyme deficiency allows aspartylglucosamine (GlcNAc-Asn) and other glycoasparagines to accumulate in tissues and body fluids, from early fetal life onward. The clinical course is characterized by normal early development, slowly progressing to severe mental and motor retardation in early adulthood. The exact pathogenesis of AGU in humans is unknown and neither therapy nor an animal model for this debilitating and ultimately fatal disease exists. Through targeted disruption of the mouse Aga gene in embryonic stem cells, we generated mice that completely lack Aga activity. At the age of 5-10 months a massive accumulation of GlcNAc-Asn was detected along with lysosomal vacuolization, axonal swelling in the gracile nucleus and impaired neuromotor coordination. A significant number of older male mice had massively swollen bladders, which was not caused by obstruction, but most likely related to the impaired function of the nervous system. These findings are consistent with the pathogenesis of AGU and provide further data explaining the impaired neurological function in AGU patients.


A Culture-Based Family-Centered Health Navigation Intervention for Chronic Disease Management in Native Hawaiians.
Greater medical and psychological concerns coupled with disparities in income and education and experiences with cultural distress have created an unprecedented demand for health and mental health services for Native Hawaiians. With 75% of the healthcare system moving to a value-based system within the next 2 years, a low-cost workforce that brings added value will be in high demand. The addition of community health navigators to an existing integrated patient-centered medical home may result in a culturally congruent, preventive, and responsive model of wellness that promotes health equity. The purpose of this paper is to discuss the culturally-based navigation framework we used to implement a pilot program in an integrated primary care setting, describe the intervention that was used, and examine the lessons learned throughout the process. Outcomes will be provided at a later date. We believe that our model will not only redesign an existing clinical practice but also will provide a reproducible model that can be translated into other settings to increase the health care utilization among Native Hawaiians and lead to improved outcomes.


Output beam from a confocal resonator with a pinhole for mode selection.
An approximate expression for the output beam from a confocal resonator, into which a pinhole for mode selection is inserted at an arbitrary position near the mirror at one end, is studied experimentally. The output beam consists of the fundamental component, in which the diffraction from the pinhole edge is not considered, and a field of the higher order component including the diffraction. In the region of the pinhole aperture larger than the beam width of the confocal resonator before the insertion of the pinhole, the diffraction component can be neglected. The output beam then may be approximated by the beam of the fundamental component, which is expressed simply by the field of the confocal resonator with unequal-sized mirrors of Boyd and Kogelnik. These results are confirmed by both experimental and theoretical examinations.


Long-term effects of poultry litter, alum-treated litter, and ammonium nitrate on phosphorus availability in soils.
Alum (Al2(SO4)(3).14H2O) additions to poultry litter result in lower ammonia (NH3) volatilization and phosphorus (P) runoff; however, the long-term effects of alum on soil P behavior have been unknown. The objectives of this study were to evaluate the long-term effects of poultry litter, alum-treated litter, and ammonium nitrate (NH4NO3) on P availability in soils and P runoff. Two studies were initiated in 1995: a small plot (1.5x3.0 m) study and a paired watershed (0.405 ha) study. In the small plot study 13 treatments (control, four rates of normal litter, four rates of alum-treated litter, and four rates of NH4NO3) were applied to tall fescue (Festuca arundinacea Schreb.) plots. Results show that after 7 yr water-extractable P (WEP) in surface soil samples was greater with normal litter, but Mehlich III P was greater in surface soils fertilized with alum-treated litter. When soil samples were taken at depth intervals to 50 cm in Year 7, Mehlich III P was only greater in the surface 5 cm for soils fertilized with alum-treated litter. At lower depths Mehlich III P was greater with normal litter, and WEP was up to 288% greater when normal litter was used, indicating that alum significantly reduced P leaching. Uptake of P by fescue was not affected by alum. Results from the paired watershed study showed P loss in runoff was 340% greater for normal litter than for alum-treated litter. This research, combined with earlier work that shows alum use improves air and soil quality, supports the use of alum as a long-term solution to reducing P runoff and leaching.


Insertion Torques of Self-Drilling Mini-Implants in Simulated Mandibular Bone: Assessment of Potential for Implant Fracture.
Fracture of orthodontic mini-implants during insertion is a limiting factor for their clinical success. The purpose of this study was to determine the fracture potential of commonly used self-drilling orthodontic mini-implants when placed into simulated thick, dense mandibular bone. Six mini-implant systems were assessed for the potential for fracture (Aarhus, Medicon; Dual-Top, Jeil Medical; OrthoEasy, Forestadent; tomas-pin, Dentaurum; Unitek, 3M; and VectorTAS, Ormco). First, mini-implants were inserted manually, without predrilling, into bone substitutes (Sawbones) with a 3-mm-thick, dense (1.64 g/cm(3)) cortical layer. A custom-made insertion device was used for placement of mini-implants. A sixaxis force/torque transducer was secured at the base of the bone blocks to measure the maximum torque experienced during insertion. Measured insertion torques were compared with previously reported fracture torques, yielding a torque ratio (insertion torque as a percentage of fracture torque), which was used as an indicator of the potential for mini-implant fracture. Mini-implants that experienced torque ratios ≥ 75% upon insertion underwent further testing, following the manufacturer's recommendations for predrilling in thick, dense bone conditions. Significant differences in torque ratios were found among all mini-implants, except between OrthoEasy and Dual-Top, and OrthoEasy and VectorTAS. Overall, Aarhus had the highest torque ratio (91% ± 3%), with Unitek showing the lowest ratio (37% ± 3%). Aarhus and tomas-pin mini-implants displayed torque ratios ≥ 75% and experienced fracture upon insertion. When the manufacturer's specific predrilling recommendations were followed, no changes in torque ratio were found for Aarhus and tomas-pin. However, while Aarhus continued to fracture upon insertion, all tomas-pin mini-implants were inserted fully without fracture following predrilling. These findings support the safe use of Unitek, VectorTAS, Dual-Top, and OrthoEasy self-drilling mini-implants in areas of 3-mm-thick, 1.64 g/cm(3) dense cortical bone without predrilling. Following predrilling, fractures did not occur with tomas-pin. For implants that continued to fracture after predrilling, other strategies may be required, such as the use of larger-diameter mini-implants in thick, dense bone conditions.


Recruitment and retention in clinical trials in chronic kidney disease: report from national workshops with patients, caregivers and health professionals.
Slow recruitment and poor retention jeopardize the reliability and statistical power of clinical trials, delaying access to effective interventions and increasing costs, as commonly observed in nephrology trials. Involving patients in trial design, recruitment and retention is infrequent but potentially transformational. We conducted three workshops involving 105 patients/caregivers and 43 health professionals discussing patient recruitment and retention in clinical trials in chronic kidney disease. We identified four themes. 'Navigating the unknown'-patients described being unaware of the research question, confused by technical terms, sceptical about findings and feared the risk of harm. 'Wary of added burden'-patients voiced reluctance to attend additional appointments, were unsure of the commitment required or at times felt too unwell and without capacity to participate. 'Disillusioned and disconnected'-some patients felt they were taken for granted, particularly if they did not receive trial results. Participants believed there was no culture of trial participation in kidney disease and an overall lack of awareness about opportunities to participate. To improve recruitment and retention, participants addressed 'Building motivation and interest'. Investigators should establish research consciousness from the time of diagnosis, consider optimal timing for approaching patients, provide comprehensive information in an accessible manner, emphasize current and future relevance to them and their illness, involve trusted clinicians in recruitment and minimize the burden of trial participation. Participation in clinical trials was seen as an opportunity for people to give back to the health system and for future people in their predicament.


Construction of the active site of glutathione peroxidase on polymer-based nanoparticles.
A new nanoenzyme model with glutathione peroxidase-like active site was constructed on polystyrene nanoparticle (PN1) via microemulsion polymerization. In this model system, two functional monomers were designed: one is a tellurium-containing compound that was introduced on the surface of the nanoparticle and acts as a catalytic center, and the other one is an arginine-containing compound designed as a binding site for the complexation of the carboxyl group of substrate 3-carboxy-4-nitrobenzenethiol (ArSH, 1). As a new glutathione peroxidase (GPx) mimic, it demonstrated excellent catalytic activity and substrate specificity. In ArSH assay system, it was at least 316,000-fold more efficient than PhSeSePh for the reduction of cumene hydroperoxide (CUOOH) by ArSH. In contrast to model PN2, which lacks of substrate binding site, PN1 exhibits an obvious enhancement in catalytic activity. To further promote the catalytic efficiency, a substrate ArSH surface-imprinted nanoenzyme model (I-PN) was developed. By correctly incorporating and positioning the catalytic center tellurium and functional binding factor guanidinium, a continuative activity enhancement of 596,000-fold for the reduction of CUOOH by catalyst I-PN compared with diphenyl diselenide (PhSeSePh) was observed. The results clearly show that polymeric nanoparticle can be developed as an excellent model for combining most of catalytic factors of enzyme into one scaffold.


Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP. In a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar-arterial difference in oxygen concentration (A-aDo2) at week 24. In total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point - the change from baseline in the A-aDo2 at week 24 - improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (-12.8 mm Hg vs. -6.6 mm Hg; estimated treatment difference, -6.2 mm Hg; P = 0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George's Respiratory Questionnaire total score at week 24 (-12.4 points vs. -5.1 points; estimated treatment difference, -7.4 points; P = 0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group. In patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.).


Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients.
Bone fluoride content (BFC) was measured and histomorphometric analysis of undecalcified sections was performed in transiliac biopsy cores from 29 patients (16 men, 13 women, aged 51 +/- 17 years) suffering from skeletal fluorosis due to chronic exposure to fluoride. The origin of the exposure, known in 20 patients, was either hydric (endemic or sporadic) or industrial, or in a few cases iatrogenic. Measured on calcined bone using a specific ion electrode, BFC was significantly high in each specimen (mean +/- SD; 0.79 +/- 0.36% on bone ash). The radiologically evident osteosclerosis observed in each patient was confirmed by a significant increase in cancellous bone volume (40.1 +/- 11.2% vs. 19.0 +/- 2.8% in controls, p less than 0.0001). There were significant increases in cortical width (1292 +/- 395 mcm vs. 934 +/- 173 mcm, p less than 0.0001) and porosity (14.4 +/- 6.4% vs. 6.5 +/- 1.7%, p less than 0.002), but without reduction of cortical bone mass. Cancellous osteoid volume and perimeter, as well as width of osteoid seams, were significantly increased in fluorotic patients. The increase in cancellous osteoid perimeter was almost three-fold greater than that noted in cancellous eroded perimeter. In 15 patients doubly labeled with tetracycline, the mineral apposition rate was significantly decreased, mineralization lag time was significantly increased. The fluorotic group had a greater number of osteoblasts than controls with a very high proportion of flat osteoblasts. The ultrastructural characteristics reflecting the activity of the bone cells were clearly visible on electron microscopy. Bone formation rate and adjusted apposition rate were significantly decreased in skeletal fluorosis. On stained sections and microradiographs, bone tissue showed typical modifications for skeletal fluorosis (linear formation defects, mottled bone). The volume of cancellous interstitial mineralization defects and the proportion of mottled periosteocytic lacunae were markedly increased in skeletal fluorosis. These two parameters were significantly correlated together but neither of these was significantly correlated with BFC. Renal function did not significantly influence the changes in BFC and histomorphometry of fluorotic patients. Skeletal fluorosis is thus characterized by an unbalanced coupling in favor of bone formation, and a great number of osteoblasts with a high proportion of flat osteoblasts.(ABSTRACT TRUNCATED AT 400 WORDS)


Measles outbreak in a fully immunized secondary-school population.
An outbreak of measles occurred among adolescents in Corpus Christi, Texas, in the spring of 1985, even though vaccination requirements for school attendance had been thoroughly enforced. Serum samples from 1806 students at two secondary schools were obtained eight days after the onset of the first case. Only 4.1 percent of these students (74 of 1806) lacked detectable antibody to measles according to enzyme-linked immunosorbent assay, and more than 99 percent had records of vaccination with live measles vaccine. Stratified analysis showed that the number of doses of vaccine received was the most important predictor of antibody response. Ninety-five percent confidence intervals of seronegative rates were 0 to 3.3 percent for students who had received two prior doses of vaccine, as compared with 3.6 to 6.8 percent for students who had received only a single dose. After the survey, none of the 1732 seropositive students contracted measles. Fourteen of 74 seronegative students, all of whom had been vaccinated, contracted measles. In addition, three seronegative students seroconverted without experiencing any symptoms. We conclude that outbreaks of measles can occur in secondary schools, even when more than 99 percent of the students have been vaccinated and more than 95 percent are immune.


A new biomarker for subthalamic deep brain stimulation for patients with advanced Parkinson's disease--a pilot study.
Deep brain stimulation (DBS) has become the standard treatment for advanced stages of Parkinson's disease (PD) and other motor disorders. Although the surgical procedure has improved in accuracy over the years thanks to imaging and microelectrode recordings, the underlying principles that render DBS effective are still debated today. The aim of this paper is to present initial findings around a new biomarker that is capable of assessing the efficacy of DBS treatment for PD which could be used both as a research tool, as well as in the context of a closed-loop stimulator. We have used a novel multi-channel stimulator and recording device capable of measuring the response of nervous tissue to stimulation very close to the stimulus site with minimal latency, rejecting most of the stimulus artefact usually found with commercial devices. We have recorded and analyzed the responses obtained intraoperatively in two patients undergoing DBS surgery in the subthalamic nucleus (STN) for advanced PD. We have identified a biomarker in the responses of the STN to DBS. The responses can be analyzed in two parts, an initial evoked compound action potential arising directly after the stimulus onset, and late responses (LRs), taking the form of positive peaks, that follow the initial response. We have observed a morphological change in the LRs coinciding with a decrease in the rigidity of the patients. These initial results could lead to a better characterization of the DBS therapy, and the design of adaptive DBS algorithms that could significantly improve existing therapies and help us gain insights into the functioning of the basal ganglia and DBS.


Association between oral bisphosphonate use and dental implant failure among middle-aged women.
To investigate the association between the use of oral bisphosphonate therapy and dental implant failure. The case-control study involved 337 female patients, aged 40 years and older, who had 1181 implants placed at the Department of Periodontology and Implant Dentistry at New York University College of Dentistry between January 1997 and December 2004. Cases, defined as women with one or more implant failures, were identified from the departmental database. Controls were then randomly selected for each case. Adjusted odds ratios were estimated using logistic regression models fitted through generalized estimating equations. After adjusting for selected covariates, the odds of oral bisphosphonate use was 2.69 (95% confidence interval [CI], 1.49-4.86) times higher in women for whom implants failed compared with those for whom implants did not fail. Although no significant interaction was observed (p = 0.41), the stratified analyses suggest that the association between oral bisphosphonate use and dental implant failure was stronger in the maxilla (Odds Ratio [OR] = 2.60; 95% CI, 1.36-4.96) than in the mandible (OR = 1.38; 95% CI, 0.51-3.73). Findings from this study suggest that dental practitioners should be aware of the increased risk of implant failure associated with oral bisphosphonate use in the population.


Shock-induced collapse of surface nanobubbles.
The collapse of cavitation bubbles often releases high-speed liquid jets capable of surface damage, with applications in drug delivery, cancer treatment, and surface cleaning. Spherical cap-shaped surface nanobubbles have previously been found to exist on immersed substrates. Despite being known nucleation sites for cavitation, their collapsing dynamics are currently unexplored. Here, we use molecular dynamics simulations to model the shock-induced collapse of different surface nanobubble sizes and contact angles. Comparisons are made with additional collapsing spherical nanobubble simulations near a substrate, to investigate the differences in their jet formation and resulting substrate pitting damage. Our main finding is that the pitting damage in the surface nanobubble simulations is greatly reduced, when compared to the spherical nanobubbles, which is primarily caused by the weaker jets formed during their collapse. Furthermore, the pit depths for surface nanobubble collapse do not depend on bubble size, unlike in the spherical nanobubble cases, but instead depend only on their contact angle. We also find a linear scaling relationship for all bubble cases between the final substrate damage and the peak pressure impulse at the impact centre, which can now be exploited to assess the relative damage in other computational studies of collapsing bubbles. We anticipate the more controlled surface-damage features produced by surface nanobubble cavitation jets will open up new applications in advanced manufacturing, medicine, and precision cleaning.


Pathogenesis and phylogenetic analyses of canine distemper virus strain ZJ7 isolate from domestic dogs in China.
A new isolate of canine distemper virus (CDV), named ZJ7, was isolated from lung tissues of a dog suspected with CDV infection using MDCK cells. The ZJ7 isolate induced cytopathogenic effects of syncytia in MDCK cell after six passages. In order to evaluate pathogenesis of ZJ7 strain, three CDV sero-negative dogs were intranasally inoculated with its virus suspension. All infected dogs developed clinical signs of severe bloody diarrhea, conjunctivitis, ocular discharge, nasal discharge and coughing, fever and weight loss at 21 dpi, whereas the mock group infected with DMEM were normal. The results demonstrated that CDV-ZJ7 strain isolated by MDCK cell was virulent, and the nucleotide and amino acid sequences of strain ZJ7 had no change after isolation by MDCK cell when compared with the original virus from the fresh tissues. Molecular and phylogenetic analyses for the nucleocapsid (N), phosphoprotein (P) and receptor binding haemagglutinin (H) gene of the ZJ7 isolate clearly showed it is joins to the Asia 1 group cluster of CDV strains, the predominant genotype in China.


The non-operative treatment of anterior knee pain.
Anterior knee pain is a common presenting complaint, and in many cases no identifiable cause can be found. In these circumstances it is commonly known as anterior knee pain syndrome or patellofemoral pain syndrome. The management for this condition is most commonly non-operative. Treatment strategies include physiotherapy, pharmacotherapy, orthoses and combinations of the above. There are many described methods in the literature with a wide spectrum of outcomes, which in itself is testimony to the lack of any generally accepted gold standard of care for these patients. It is thus unclear to the health care professional treating these patients which is the best treatment to offer. In this review we aim to summarise historical and most up to date literature on the subject and in so doing allow the health care professional pick whichever treatment strategy they feel most beneficial and also provide a guide for appropriate patient education.


Subjective responses to display bezel characteristics.
High quality flat panel computer displays (FPDs) with high resolution screens are now commonplace, and black, grey, white, beige and silver surrounds ('bezels'), matt or glossy, are in widespread use. It has been suggested that bezels with high reflectance, or with a high gloss, could cause eyestrain, and we have investigated this issue. Twenty office workers (unaware of the study purpose) used six different FPDs, for a week each, at their own desk. These displays were identical apart from the bezel colour (black, white or silver) and shininess (matt or glossy). Participants completed questionnaires about their visual comfort at the end of each week, and were fully debriefed in lunch-time focus groups at the end of the study. For the white and the silver bezels, the glossiness of the bezel was not an issue of concern. The participants were significantly less content with the glossy black surround than with the matt black surround, and in general the glossy black bezel was the least-liked of all those used. With the possible exception of this surround, there was no evidence of significantly increased visual discomfort, indicative of eyestrain, as a result of high or low bezel reflectance, or of high glossiness.


Development of a crosswalk for pain interference measured by the BPI and PROMIS pain interference short form.
To help researchers in multiple sclerosis (MS) take advantage of the measurement properties of the PROMIS Pain Interference instrument while maintaining continuity with previous research, we developed and tested a crosswalk table to transform Brief Pain Inventory pain interference scale (BPI-PI) scores to PROMIS-PI short form (PROMIS-PI SF) scores. The BPI-PI and the PROMIS-PI SF were administered in two studies that included persons with MS. One sample of 369 participants served as a developmental calibration sample, and a separate sample of 360 served as a validation sample. The crosswalk development included dimensionality assessment, item-level parameter estimation, and assessment of accuracy. BPI-PI and PROMIS-PI T scores were obtained from participants' item responses, and using the crosswalk table, PROMIS-PI T scores were derived from responses to the BPI-PI items. Differences between observed and crosswalked T scores were compared in both samples. For BPI-PI summary scores ranging from 0 to 10, corresponding T scores ranged from 38.6 to 81.2. The mean difference between observed and crosswalked T scores was 0.51 (SD = 3.9) in the calibration sample and -1.47 (SD = 4.2) in the validation sample. Approximately 80 % of crosswalked scores in the calibration sample were within four score points of the observed PROMIS-PI SF scores, and 70 % were within four points in the validation sample. In both samples, the largest differences were at lower levels of the pain interference continuum. Crosswalked pain interference scores adequately approximated observed PROMIS-PI SF scores in both the calibration and validation samples. MS researchers and clinicians interested in adopting the PROMIS instruments can use this table to transform BPI-PI scores to enable comparisons with other studies and to maintain continuity with previous research.


Review: Precision Cut Liver Slices for the Evaluation of Fatty Liver and Fibrosis.
Ethanol metabolism in the liver results in oxidative stress, altered cytokine production and fat accumulation in the liver. Thus, it is thought that the accumulation of benign fat into the liver in conjunction with a second hit leads to liver failure. However, we have recently developed the use of precision-cut liver slices (PCLSs) as an in vitro culture model in which to investigate the pathophysiology of alcohol-induced liver injury. In this review, these studies will be discussed and newer data presented. Original investigations into the use of PCLS were obtained from chow fed rats (200-300g). PCLSs were cultured 24-96h in media, 25 mM ethanol, or 25 mM ethanol and 0.5 mM 4- methylpyrazole (4-MP). PCLSs were examined for at different times and evaluated for glutathione (GSH) levels, extent of lipid peroxidation (TBARS assay), cytokine production (ELISA and RT-PCR) and myofibroblast activation. Age-matched rats were fed high fat diets for 13 months, PCLSs were prepared, and evaluated as outlined above. In recently, human and mouse PCLSs were cut, equilibrated, and evaluated using the methods outlined as above. In these studies, it was shown that the PCLSs from rats, mice and human livers retained excellent viability over a 96 hour period of incubation. During this time period, alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P4502E1 levels were viable. After 24 hours of ethanol exposure, fatty livers and fibrogenic responses developed and could be prevented/reversed with the 4-MP. In a separate study using overly obese rats, ethanol metabolism was decreased in PCLSs as compared to age-matched controls (AMC). However, higher levels of triglycerides and lipid peroxidation were found in PCLSs from obese rats compared to AMC. Also, increased concentrations of the proinflammatory cytokines (TNF-α and IL-6) were found in the culture supernatants. In contrast, decreased levels of reduced glutathione (GSH) and heme oxygenase I (HO-1) levels were detected. Within 24h of incubation, ethanol metabolism by PCLSs initiates fat accumulation in the liver at which point there is an activation of myofibroblasts. Thus, fatty liver is the first response to ethanol and sensitizes the liver to other products of oxidative stress that result in inflammation and the start of liver failure ending in cirrhosis. Thus, from these studies it appears that PCLSs can be utilized to determine the mechanisms(s) by which ethanol exposure leads to the development and/or progression of alcoholic liver disease (ALD).


The somatic genomic landscape of chromophobe renal cell carcinoma.
We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.


A novel method of obtaining prostate tissue for gene expression profiling.
Gene expression profiling by DNA microarray analysis is a technique with great promise in cancer biology. The multifocality and heterogeneity of many prostate cancers makes the collection of adequate biological samples for such profiling particularly challenging. Current methods, such as laser capture microdissection, are not widely available and can have significant limitations. In this article, a novel method of prostatic sampling, which does not affect the histopathological assessment of the surgical specimen and provides adequate RNA yield for microarray analysis is described. This method is simple, inexpensive, easily reproducible, and has been validated as having >95% sensitivity and 99% specificity for histological prediction of tissue obtained. This method can be adopted by other investigators to perform DNA microarray analysis on prostate tumors.


An experimental investigation of thought suppression.
An experiment investigating the hypothesis that trying to suppress a thought will lead to an immediate and/or delayed increase in its occurrence is reported. Normal subjects listened to a taped story and then verbalized their stream of consciousness during two consecutive time periods. During the first period, one group (suppression) were asked not to think about the tape while two other groups (controls) were asked to think about anything or think about anything including the tape. During the second period, all three groups were instructed to think about anything. Results from the first period failed to support the immediate enhancement hypothesis as the suppression group reported less thoughts about the tape than the controls. However, results from the second period supported the delayed (rebound) hypothesis as subjects who had previously suppressed reported more thoughts about the tape than subjects who had not. The theoretical, methodological, and clinical implications of these results are discussed.


The major stressful life events and cancer: stress history and cancer.
The objective of this study was to analyze the extent of stressful life events' etiology and to compare socio-demographic and medical characteristics of the presence and absence of stress in Turkish cancer patients. Patients with cancer who attended ambulatory patient care units answered the questionnaires. Medical information was reviewed from chart data. The study population comprised 465 women (60.5%) and 303 men (39.5%), in total 768 cases. The median age was 53 years, ranging between 18 and 94. Three-hundred and twenty patients (41.7%) had at least one type of stress since last year of the time of initial diagnosis. Among patients had stress, the median number of stress modalities presented was 1 (range 1-6). Death, lack of livelihood, quarrel, illness, and debt almost always consisted of stress types. History of stress within last year was found more in women (66.3% vs. 56.5%, P = 0.006) and overweight patients (57.5% vs. 47.2%, P = 0.005). Similarly, among cancer types, only patients with breast cancer (41.9% vs. 31.7%, P = 0.04) had lived more stressful situation. However, the married patients (72.2% vs. 80.6%, P = 0.03) had less stress. Patients with gastric cancer had more frequent debt (29.0%, P < 0.001) and lack of livelihood history (21.4%, P = 0.001). Additionally, in lung cancer patients, their rate of livelihood difficulty was highly less than average (2.4%, P = 0.003). We found that overweight patients had more illness history (68.9% vs. 51.6%, P = 0.004), patients who were not working had more death history (89.7% vs. 78%, P = 0.01), and female patients had more quarrel history (78.2% vs. 60.5%, P = 0.002). Likewise, history of debt in patients who is a member of large family (56.2% vs. 27.4%, P = 0.01) was more frequent. Additionally, the lack of livelihood was prominent in urban patients (92.8% vs. 78.6%, P = 0.002) and in patients with low income (48.5% vs. 66.7%, P = 0.004). The question of whether or not psychological factors originated from stressful life events have an influence on cancer initiation and progression is still unanswered after several decades of research. Future studies might benefit from better well-designed articulated hypotheses, prospective design, and large study populations to ensure adequate knowledge.


PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals.
The PCP effector gene Inturned regulates planar cell polarity (PCP) and wing hair formation in Drosophila wings. In order to understand the roles for Inturned in mammalian embryonic development, we generated a null mutant allele for the mouse homologue of Inturned (Intu) via gene-targeting in ES cells. Mouse Intu null mutants are homozygous lethal at midgestation, exhibiting multiple defects including neural tube closure defects, abnormal dorsal/ventral patterning of the central nervous system and abnormal anterior-posterior patterning of the limbs resulting in severe polydactyly (7-9 digits each limb). The developmental processes affected by the Intu mutation are under the control of Hh signaling through Gli-family transcription factors. We found that in Intu mutant embryos the expression of Gli1 and Ptch1, two direct transcriptional targets of Hh signaling, is down-regulated, and the proteolytic processing of Gli3 is compromised. We further demonstrate that Intu plays significant roles in the formation of primary cilia both during embryonic development and in cultured fibroblasts. Finally, a cytoplasmic GFP-Intu fusion protein efficiently rescues the ciliogenic defects in Intu mutant cells. In conclusion, we show that PCP effector gene Intu is an important regulator of cilia formation, Hh signal transduction, and embryonic development in mammals.


Interaction between CD8 and major histocompatibility complex (MHC) class I mediated by multiple contact surfaces that include the alpha 2 and alpha 3 domains of MHC class I.
The cell surface glycoprotein CD8 functions as a coreceptor with the TCR on cytotoxic T lymphocytes. Mutational analysis of the binding site of CD8 for MHC class I predicted that distinct surfaces of CD8 would interact with both the alpha 2 and alpha 3 domains of class I. Using a cell-cell adhesion assay, we identified three residues Q115, D122, and E128 in the alpha 2 domain of class I critical for interaction with CD8. The side chains of these residues point towards a cavity formed by the alpha 1/alpha 2 platform, the alpha 3 domain and beta 2-microglobulin (beta 2m) of class I. These residues were predicted to contact CD8 based on a bivalent model of interaction between one CD8 alpha/alpha homodimer and two MHC class I molecules. These results therefore provide support for the model.


Cultural influences on HIV testing among Latino youth.
Young Latinos aged 13-24 years in the USA are disproportionately impacted upon by HIV. Despite the elevated risk, lower rates of HIV testing have been documented among Latino youth relative to other racial/ethnic groups. The objective of the current study was to examine the influence of acculturation and cultural values on HIV testing among Latino youth. The study consisted of 51 sexually experienced young Latinos aged 13-16 years from a major city in the Southeastern USA. Participants completed a survey on HIV testing history, cultural orientation and Latino cultural values. Results indicate that 21.6% of the young people had been tested for HIV. The number of times tested ranged from one to four (M = 1.9 ± 1.0). HIV testing was associated with US American cultural orientation and familism (and emphasis on strong family commitment, family support and emotional closeness). Participants with greater orientation to US American culture were more likely, whereas those who endorsed higher familism value were less likely, to have had an HIV test. For participants scoring high on familism, the desire to maintain family honour may serve as a deterrent to testing. Incorporating culturally relevant strategies, such as promoting sexual communication and conversations on HIV prevention within the family, may enhance testing and narrow the gap in HIV infection between Latino youth and other ethnic groups.


Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappaB.
Upon interleukin 1 (IL-1) stimulation, the IL-1-receptor (IL-1R)-associated kinase (IRAK) is rapidly recruited to the IL-1R complex and undergoes phosphorylation. Here we demonstrate that recombinant wild-type IRAK (IRAK-WT), but not a kinase-defective mutant with Asp340 replaced by an asparagine residue (IRAK-Asp340Asn), is highly phosphorylated and is capable of auto-phosphorylation in vitro. Overexpression of both IRAK-WT and IRAK-Asp340Asn caused activation of nuclear factor kappaB, suggesting that the kinase activity of IRAK is not required outside of the IL-1R complex.


Resistance training restores metabolic alterations induced by monosodium glutamate in a sex-dependent manner in male and female rats.
Despite resistance exercises being associated with health outcomes, numerous issues are still unresolved and further research is required before the exercise can faithfully be prescribed as medicine. The goal of this study was to investigate whether there are sex differences in resistance training effects on metabolic alterations induced by monosodium glutamate (MSG), a model of obesity, in male and female rats. Male and female Wistar rats received MSG (4 g/kg body weight/day, s.c.) from postnatal day 1 to 10. After 10 days from MSG administration, the rats were separated into two groups: MSG-sedentary and MSG-exercised. At postnatal day 60, the animals started a resistance training protocol in an 80 degrees inclined vertical ladder apparatus and performed it for 7 weeks. Control rats received saline solution and were divided in saline-sedentary and saline-exercised. Resistance training restored all plasma biochemical parameters (glucose, cholesterol, triglycerides, aspartate aminotransferase, and alanine aminotransferase) increased in male and female rats treated with MSG. The MSG administration induced hyperglycemia associated with a decrease in the skeletal muscle glucose transporter 4 (GLUT4) levels and accompanied by deregulation in proteins, G-6Pase, and tyrosine aminotransferase, involved in hepatic glucose metabolism of male and female rats. MSG induced dyslipidemia and lipotoxicity in the liver and skeletal muscle of male rats. Regarding female rats, lipotoxicity was found only in the skeletal muscle. The resistance training had beneficial effects against metabolic alterations induced by MSG in male and female rats, through regulation of proteins (GLUT2, protein kinase B, and GLUT4) involved in glucose and lipid pathways in the liver and skeletal muscle.


Effects of acquired immunity and mating strategy on the genetic structure of parasite populations.
Although it may have profound effects on how researchers seek to tackle many infectious diseases, little is known of the genetic structure of many pathogen populations. Previous models have suggested that if levels of cross-protection are high, parasite populations may be structured into discrete strains with nonoverlapping antigenic repertoires, even among populations that reproduce sexually. Here, I consider a discrete model of the coevolution of parasites with host-acquired immunity. In this model, if the effective recombination rate is low, strain structure can be maintained for very high levels of cross-protection. However, if the effective recombination rate is higher, this strain structure can no longer be maintained. The effective recombination rate is affected by the actual recombination rate between immunologically selected loci, the proportion of individuals that reproduce sexually, whether recombination occurs inside or outside of the host or vector, and the level of cross-protection. The model predicts that for Plasmodium falciparum, where reproduction occurs inside of a vector, we expect to see strain structure in areas of low transmission but not in areas of high transmission. Strain structure is unlikely to be seen in parasites that reproduce outside of a host or vector, such as Strongyloides ratti.


Lack of Exposure in a First-in-Man Study Due to Aldehyde Oxidase Metabolism: Investigated by Use of 14C-microdose, Humanized Mice, Monkey Pharmacokinetics, and In Vitro Methods.
Inclusion of a microdose of 14C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regard to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to metabolites in safety testing guidance and also when additional metabolism-related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis. Parallel accelerator mass spectrometry analysis revealed that the low exposure was almost exclusively attributable to extensive metabolism. The metabolism observed in humans was mediated via a human specific metabolic pathway, whereas an equivalent extent of metabolism was not observed in preclinical species. In vitro, incubation studies in human liver cytosol revealed involvement of aldehyde oxidase (AO) in the biotransformation of Lu AF09535. In vivo, substantially lower plasma exposure of Lu AF09535 was observed in chimeric mice with humanized livers compared with control animals. In addition, Lu AF09535 exhibited very low oral bioavailability in monkeys despite relatively low clearance after intravenous administration in contrast to the pharmacokinetics in rats and dogs, both showing low clearance and high bioavailability. The in vitro and in vivo methods applied were proved useful for identifying and evaluating AO-dependent metabolism. Different strategies to integrate these methods for prediction of in vivo human clearance of AO substrates were evaluated.


Degeneration of vestibular neurons in late embryogenesis of both heterozygous and homozygous BDNF null mutant mice.
The generation of mice lacking specific neurotrophins permits evaluation of the trophic requirements of particular neuronal populations throughout development. In the present study, we examined the developing vestibulocochlear system to determine the time course of neurotrophin dependence and to determine whether competition occurred among developing cochlear or vestibular neurons for available amounts of either brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5 (NT-4/5). Both cochlear and vestibular neurons were present in mice lacking NT-4/5. In contrast, vestibular neurons decreased in number beginning at mid-stages of inner ear development, in mice lacking BDNF. Early in development (E12.5-13), the size of the vestibular ganglion was normal in bdnf -/- mice. Decreased innervation to vestibular sensory epithelia was detected at E13.5-15, when progressive loss of all afferent innervation to the semicircular canals and reduced innervation to the utricle and saccule were observed. At E16.5-17, there was a reduction in the number of vestibular neurons in bdnf -/- mice. A further decrease in vestibular neurons was observed at P1 and P15. Compared to bdnf -/- mice, mice heterozygous for the BDNF null mutation (bdnf +/-) showed an intermediate decrease in the number of vestibular neurons from E16.5-P15. These data indicate a late developmental requirement of vestibular neurons for BDNF and suggest competition among these neurons for limited supplies of this factor.


Application of a toxicity test battery integrated index for a first screening of the ecotoxicological threat posed by ports and harbors in the southern Adriatic Sea (Italy).
Ports and harbors may represent a threat for coastal ecosystems due to pollutant inputs, especially those derived from maritime activities. In this study, we report a first assessment of the ecotoxicological threat posed by six ports and harbors of opposite coastal regions, Apulia and Albania, in the southern Adriatic Sea (Italy). A bioassay battery consisting of four different species representing different trophic levels, algae Dunaliella tertiolecta, bacteria Vibrio fischeri, crustacean Artemia salina, and echinoids Paracentrotus lividus, has been used to assess sediment elutriates, pore waters, and sediment suspensions. Two different approaches of toxicity data integration, worst case and integrated index, have been used to determine the most appropriate procedure for the investigated sites. All sites with the worst case approach showed high toxicity levels. The chronic test with algae was the most sensitive identifying the highest effects in the battery. This effect can be attributable to contaminants derived from antifouling paints. The sediments, evaluated with V. fischeri test, often showed toxicity not found in the aqueous matrices of the same sites and that can be mainly linked to organic compounds. The test battery used in this study allowed us to perform a preliminary screening of the ecotoxicological risk of the studied area. In fact, the species utilized for toxicity tests responded differently to the investigated samples, showing different sensitivity. The test battery integrated index did not allow highlighting the differences among the sites and showed a general high ecotoxicological risk. A larger number of tests with higher sensitivity together with a tailored attribution of weights to endpoints and matrices will improve the final site evaluation.


Bacteria from the gut of Australian termites.
The major gut bacteria of the worker caste of nine species of Australian termites, belonging to four families, were isolated and identified to generic level. All species were either facultative anaerobes or strict aerobes. A correlation appears to exist between the major gut bacterium and the family to which the termite belongs. The major bacterium from the two lowest termites, Mastotermes darwiniensis (family Mastotermitidae) and Cryptotermes primus (family Kalotermitidae), was Streptococcus; from four species belonging to the Rhinotermitidae (Heterotermes ferox, Coptotermes acinaciformis, C. lacteus, Schedorhinotermes intermedius intermedius) it was Enterobacter; and from three species of the Termitidae (Nasutitermes exitiosus, N. graveolus, N. walkeri) it was Staphylococcus. Enterobacter was a minor symbiont of M. darwiniensis, C. primus, and N. graveolus; Streptococcus was a minor symbiont of H. ferox, C. lacteus, S. intermedius intermedius, and N. exitiosus; and Bacillus was a minor symbiont of C. acinaciformis and S. intermedius intermedius. M. darwiniensis possessed another minor symbiont tentatively identified as Flavobacterium. C. acinaciformis from three widely separated locations possessed a similar microbiota, indicating some form of control on the composition of the gut bacteria. Bacteria, capable of growth on N-free medium in the presence of nitrogen gas, were isolated from all termites, except N. exitiosus and N. walkeri, and were identified as Enterobacter. No cellulose-degrading bacteria were isolated.


An immunohistochemical study of the nerve growth factor receptor in developing rats.
Nerve growth factor (NGF) receptor expression was studied in rats between embryonic day 11 (E11) to postnatal day 10 (PND10) by using a monoclonal antibody, 192-IgG, that specifically recognizes rat NGF receptor. Sympathetic ganglia were lightly stained by 192-IgG for NGF receptor immunoreactivity (NGFRI) (E11-PND10). Neural crest-derived sensory ganglia were moderately to densely stained (E11-PND10). Areas in CNS innervated by the central processes of these ganglia were also stained. Parasympathetic ciliary ganglion showed some detectable staining (E16-PND6). Placode-derived sensory ganglia were stained more densely than that of neural crest-derived sensory ganglia. The most densely stained tissue for NGFRI was found in all peripheral nerves. Basal forebrain cholinergic neurons were NGFRI positive from E15 throughout the period examined. Motoneurons in both spinal cord and brain stem were positive for NGFRI between E15 and PND10. NGFRI staining was seen in a variety of sensory pathways and related structures, such as olfactory tract and glomerular layer of olfactory bulb; retina, optic nerve and tract, lateral geniculate nucleus, medial terminal nucleus of the accessory optic tract, and olivary pretectal nucleus; ventral cochlear nucleus and to a lesser degree in dorsal cochlear nucleus, superior olive, and nucleus of lateral lemniscus; solitary tract; cuneate nucleus, gracile nucleus, and ventroposterior thalamic nucleus. The specific staining was also found in some other CNS structures, including brain-stem reticular formation; amygdala; medial nucleus of inferior olive but not the rest of inferior olive, external granule cell layer and Purkinje's cells of cerebellum, and deep cerebellar nuclei. Some non-neuronal tissues such as meninges and dental tissue showed very distinctive staining. Limb buds and somites were NGFRI positive starting at E11, and the staining on muscle tissue became very dense at E15-E18 and largely disappeared around PND10. Embryonic thymus was positive for NGFRI. The adventitia surrounding blood vessels was very densely stained. The changes in NGFRI staining seen in this study suggest that NGF may have broader effects during development than previously thought.


Detection of changes in intrathoracic fluid in man using electrical impedance tomography.
1. The Sheffield electrical impedance tomography system produces information on changes in the distribution of resistivity within tissue. We report on the assessment of electrical impedance tomography in monitoring changes in lung resistivity during a fluid challenge in normal man. 2. Eight normal subjects were studied. Electrical impedance tomography recordings were made at three different lung volumes before, during and after the intravenous infusion of 1 litre of 0.9% NaCl (saline). 3. The mean fall in lung resistivity during the infusion was -22% at total lung capacity (range -10% to -28%), -24% at tidal breathing (-15% to -37%) and -11% at residual volume (-5% to -19%) (P < 0.05 mean pre-infusion resistivity compared with the nadir value after infusion, Wilcoxon). 4. These changes in lung resistivity were probably due to a combination of a fall in haematocrit and an expansion of pulmonary blood volume.


Role of allied health care professionals in goals-of-care discussions with hospitalized patients and perceived barriers: a cross-sectional survey.
Allied health care professionals can contribute meaningfully to goals-of-care discussions with seriously ill hospitalized patients and their families. We sought to explore the perspective of hospital-based allied health care professionals on their role in goals-of-care discussions and to identify barriers to their participation. We surveyed allied health care professionals (social workers, physiotherapists, occupational therapists, registered dietitians, speech-language pathologists and pharmacists) on internal medicine, hematology-oncology, medical oncology and radiation oncology wards at 2 tertiary care hospitals in Hamilton, Ontario, from April 2013 to May 2014. We modified a validated questionnaire originally designed to assess barriers to discussing goals of care from the perspective of nurses, residents and staff physicians on hospital medical wards. Respondents rated the questionnaire items on a 7-point Likert scale. Of the 47 allied health care professionals invited, 32 (68%) participated: 9 physiotherapists, 7 social workers, 6 occupational therapists, 4 registered dietitians, 3 pharmacists and 2 speech-language pathologists; in 1 case, the profession was unknown. The greatest perceived barriers to engaging in goals-of-care discussions were lack of patient decision-making capacity (mean rating 5.9 [standard error (SE) 0.3]), lack of awareness of patients' previous discussions with other team members (mean rating 5.7 [SE 0.3]) and family members' difficulty accepting a poor prognosis (mean rating 5.6 [SE 0.2]). Although the respondents felt it was most acceptable for staff physicians, residents and advanced practice nurses to exchange information and reach a final decision during goals-of-care discussions, they felt it was acceptable for a broader range of allied health care professionals to initiate discussions (mean rating 4.7-5.8) and to act as decision coaches (clarifying values, weighing options) with patients and families (mean rating 5.3-6.1). Allied health care professionals are willing to initiate goals-of-care discussions and to act as a decision coach with seriously ill hospitalized patients and their families. By improving interprofessional collaboration, we can engage the entire health care team in this process.


Decreasing PICU catheter-associated bloodstream infections: NACHRI's quality transformation efforts.
Despite the magnitude of the problem of catheter-associated bloodstream infections (CA-BSIs) in children, relatively little research has been performed to identify effective strategies to reduce these complications. In this study, we aimed to develop and evaluate effective catheter-care practices to reduce pediatric CA-BSIs. Our study was a multi-institutional, interrupted time-series design with historical control data and was conducted in 29 PICUs across the United States. Two central venous catheter-care practice bundles comprised our intervention: the insertion bundle of pediatric-tailored care elements derived from adult efforts and the maintenance bundle derived from the Centers for Disease Control and Prevention recommendations and expert pediatric clinician consensus. The bundles were deployed with quality-improvement teaching and methods to support their adoption by teams at the participating PICUs. The main outcome measures were the rate of CA-BSIs from January 2004 to September 2007 and compliance with each element of the insertion and maintenance bundles from October 2006 to September 2007. Average CA-BSI rates were reduced by 43% across 29 PICUs (5.4 vs 3.1 CA-BSIs per 1000 central-line-days; P < .0001). By September 2007, insertion-bundle compliance was 84% and maintenance-bundle compliance was 82%. Hierarchical regression modeling showed that the only significant predictor of an observed decrease in infection rates was the collective use of the insertion and maintenance bundles, as demonstrated by the relative rate (RR) and confidence intervals (CIs) (RR: 0.57 [95% CI: 0.45-0.74]; P < .0001). We used comparable modeling to assess the relative importance of the insertion versus maintenance bundles; the results showed that the only significant predictor of an infection-rate decrease was maintenance-bundle compliance (RR: 0.41 [95% CI: 0.20-0.85]; P = .017). In contrast with adult ICU care, maximizing insertion-bundle compliance alone cannot help PICUs to eliminate CA-BSIs. The main drivers for additional reductions in pediatric CA-BSI rates are issues that surround daily maintenance care for central lines, as defined in our maintenance bundle. Additional research is needed to define the optimal maintenance bundle that will facilitate elimination of CA-BSIs for children.


Clinical Trials of Therapeutics for the Prevention of Congenital Zika Virus Disease: Challenges and Potential Solutions.
Zika virus (ZIKV) infection in pregnancy is associated with adverse fetal outcomes, such as microcephaly and other congenital malformations. No therapeutic options are available to pregnant women with ZIKV infection to prevent these effects. Drug trials in pregnancy raise several scientific, ethical, and logistic challenges, which are compounded further in ZIKV because of limited knowledge of the disease pathophysiology and a product development pipeline in its infancy. We evaluate the major challenges in choosing therapeutics to prevent congenital ZIKV disease and conducting clinical trials of these treatments, with a focus on preventing congenital central nervous system malformations. These challenges must be characterized and planned for now so that clinical trials can progress expediently and effectively in the future.


Antibiotic prophylaxis and clinical outcomes among older adults with recurrent urinary tract infection: cohort study.
clinical guidelines recommend antibiotic prophylaxis for preventing recurrent urinary tract infections (UTIs), but there is little evidence for their effectiveness in older adults. this was a retrospective cohort study of health records from 19,696 adults aged ≥65 with recurrent UTIs. We used prescription records to ascertain ≥3 months' prophylaxis with trimethoprim, cefalexin or nitrofurantoin. We used random effects Cox recurrent event models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of clinical recurrence (primary outcome), acute antibiotic prescribing and hospitalisation. of 4,043 men and 15,653 women aged ≥65 with recurrent UTIs, 508 men (12.6%) and 2,229 women (14.2%) were prescribed antibiotic prophylaxis. In men, prophylaxis was associated with a reduced risk of clinical recurrence (HR, 0.49; 95% CI, 0.45-0.54), acute antibiotic prescribing (HR, 0.54; 95% CI, 0.51-0.57) and UTI-related hospitalisation (HR, 0.78; 95% CI, 0.64-0.94). In women, prophylaxis was also associated with a reduced risk of clinical recurrence (HR, 0.57; 95% CI, 0.55-0.59) and acute antibiotic prescribing (HR, 0.61; 95% CI, 0.59-0.62), but estimates of the risk of UTI-related hospitalisation were inconsistent between our main analysis (HR, 1.16; 95% CI, 1.05-1.28) and sensitivity analysis (HR, 0.82; 95% CI, 0.72-0.94). antibiotic prophylaxis was associated with lower rates of UTI recurrence and acute antibiotic prescribing in older adults. To fully understand the benefits and harms of prophylaxis, further research should determine the frequency of antibiotic-related adverse events and the impact on antimicrobial resistance and quality of life.