Actionable driver DNA variants and fusion genes can be detected in archived cytological specimens with the Oncomine Dx Target Test Multi-CDx system in lung cancer.
Molecular testing is critical for identifying actionable variants in lung cancer for precision medicine. When tumor tissue samples are unavailable, archived cytological specimens (ACSs) can be used. The authors examined whether oncogenic variants could be accurately detected in ACSs versus paired formalin-fixed, paraffin-embedded (FFPE) tumor tissues with in vitro diagnostic tests. The authors collected 18 ACSs and 15 FFPE tissues from 15 patients with lung cancer and investigated genomic profiles with the Oncomine Dx Target Test Multi-CDx system, which is an integrated next-generation sequencing platform that comprehensively examines 4 companion diagnostic target genes (epidermal growth factor receptor [EGFR]; B-Raf proto-oncogene, serine/threonine kinase [BRAF]; anaplastic lymphoma kinase [ALK]; and ROS proto-oncogene 1, receptor tyrosine kinase [ROS1]). They compared the quantity and quality of extracted nucleic acids, the sequencing quality control (QC), and the detected variants between ACSs and FFPE tissues. The total amount of DNA and RNA obtained from 1 slide was higher in FFPE tissues than ACSs. The RNA integrity number was higher in ACSs. There were no differences in sequencing QC between ACSs and FFPE tissues. A total of 21 variants, including EGFR mutations and ALK and ROS1 fusion genes, were detected in both ACSs and FFPE tissues with 100% concordance. ACSs can be a feasible alternative with which to identify actionable mutations and fusion genes via the Oncomine Dx Target Test Multi-CDx system.


Characterization of an anterior segment organ culture model for open globe injuries.
Open-globe injuries have poor visual outcomes and have increased in frequency. The current standard of care is inadequate, and a therapeutic is needed to stabilize the injury until an ophthalmic specialist is reached. Unfortunately, current models or test platforms for open-globe injuries are insufficient. Here, we develop and characterize an open-globe injury model using an anterior segment organ-culture platform that allows therapeutic assessment for up to 72 h post-injury. Anterior segments maintained in organ culture were kept at physiological intraocular pressure throughout, and puncture injuries were created using a novel pneumatic-powered system. This system can create high-speed, military-relevant injuries up to 4.5 mm in diameter through the cornea. From intraocular pressure readings, we confirmed a loss of pressure across the 72 h after open-globe injury. Proof-of-concept studies with a Dermabond tissue adhesive were performed to show how this model system could track therapeutic performance for 72 h. Overall, the organ-culture platform was found to be a suitable next step towards modeling open-globe injuries and assessing wound closure over the critical 72 h post-injury. With improved models such as this, novel biomaterial therapeutics development can be accelerated, improving care, and, thus, improving the prognosis for the patients.


Microsatellite instability as a prognostic factor in resected colorectal cancer liver metastases.
Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are currently recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Untreated CRC hepatic metastases are incurable and are associated with a median survival of 4 to 12 months. Conversely, surgical resection in selected patients results in a 20% to 50% cure rate. The aim of this study was to investigate the prognostic importance of MSI-H in patients undergoing resection of hepatic CRC metastases. DNA was extracted from paraffin-embedded, resected metastatic CRC liver lesions and corresponding normal liver parenchyma from 190 patients. MSI-H status was determined by polymerase chain reaction-based evaluation of the noncoding mononucleotide repeats BAT-25 and BAT-26. MSI was detected in tumors from 5 (2.7%) of the 190 CRC patients. All MSI-H tumors were in patients with node-positive CRC primary tumors. The median survival after hepatic resection of MSI-H and non-MSI-H tumors was 67 and 61 months, respectively (P = .9). These data suggest that MSI-H is not a common feature in resected CRC liver metastases and do not suggest a role for MSI in stratifying good versus poor prognosis in these patients.


Efficient Biexciton Preparation in a Quantum Dot-Metal Nanoparticle System Using On-Off Pulses.
We consider a hybrid nanostructure composed by semiconductor quantum dot coupled to a metallic nanoparticle and investigate the efficient creation of biexciton state in the quantum dot, when starting from the ground state and using linearly polarized laser pulses with on-off modulation. With numerical simulations of the coupled system density matrix equations, we show that a simple on-off-on pulse-sequence, previously derived for the case of an isolated quantum dot, can efficiently prepare the biexciton state even in the presence of the nanoparticle, for various interparticle distances and biexciton energy shifts. The pulse durations in the sequence are obtained from the solution of a transcendental equation.


Distribution of laminin, a basement membrane glycoprotein in epithelial proliferations. A preliminary study in the breast, the lungs and uterine cervix.
Distribution of laminin, a basement membrane glycoprotein, was studied by an indirect immunofluorescence technique in benign, dysplastic and malignant lesions of breast, lungs and uterine cervix as compared with normal tissues. Laminin was present with a linear and continuous staining in epithelial and vascular basement membranes in normal tissues, benign and dysplastic lesions and in in situ carcinomas of the uterine cervix. By contrast, laminin was absent or very irregularly distributed around malignant infiltrating tumoral clusters. Of particular interest was the linear and disrupted labeling observed in intra-epithelial carcinomas of breast and bronchi. Loss of laminin in these conditions could be related to a potential tumoral invasion.


Association of Self-Reported Coping Strategies With Speech Recognition Outcomes in Adult Cochlear Implant Users.
To characterize the degree to which individual coping strategies may influence speech perception after cochlear implantation. Retrospective cohort study. Tertiary referral center. Adult, postlingually deaf cochlear implant recipients. The Coping Orientation to Problems Experience inventory, a validated, multidimensional self-reported coping scale, was administered preoperatively. Speech perception was measured using consonant-nucleus-consonant (CNC) phoneme and word scores, AzBio sentence accuracy in quiet and noise, and Hearing in Noise Test sentences in quiet preoperatively and at 1, 3, and 6 months postoperatively. Quality of life was measured with the Hearing Implant Sound Quality Index and the Nijmegen Cochlear Implant Questionnaire. Thirty-six patients were included in this study. Mean age at surgery was 70.7 ± 11.4 years. Acceptance was associated with a decreased AzBio in noise score in the 6 months after CI (regression coefficient b = -0.05; 95% confidence interval [CI], -0.07 to -0.03; p < 0.01). Denial was associated with a decreased AzBio in quiet score (b = -0.05; 95% CI, -0.09 to -0.01; p < 0.05), whereas humor was associated with an increased AzBio in quiet score (b = 0.02; 95% CI, 0.01 to 0.04; p < 0.05). Humor was also associated with an increased Hearing in Noise Test score (b = 0.05; 95% CI, 0.02 to 0.07; p < 0.05). Denial was associated with decreased CNC word (b = -0.04; 95% CI, -0.06 to -0.02; p < 0.01) and phoneme (b = -0.04; 95% CI, -0.07 to -0.02; p < 0.01) scores, whereas substance use was associated with increased CNC word (b = 0.03; 95% CI, 0.01 to 0.05, p < 0.01) and phoneme (b = 0.04; 95% CI, 0.02 to 0.06; p < 0.01) scores. Scores on self-reported quality of life measures were not significantly correlated with coping strategies. A variety of adaptive and maladaptive coping strategies are used by postlingually deaf adult cochlear implant users. Denial and acceptance may be more predictive of poor speech performance, whereas humor and substance use may be more predictive of improved speech performance.


α-Synuclein Seeding Assay Using Cultured Cells.
α-Synuclein, a presynaptic protein, is involved in synaptic vesicle dynamics in response to neuronal activity. Mutations of the α-synuclein gene and the neuronal deposition of α-synuclein, called Lewy bodies, are linked to the development of Parkinson's disease. α-Synuclein has a prion-like property that converts its physiological protein conformation to a pathogenic one, forming disease-causing fibrils. Aggregation of these fibrils and subsequent inclusion formation are suggested to interfere with vesicular trafficking and organelle function in neurons. Thus, detection of a prion-like property of α-synuclein and the evaluation of its modifying factors are required to understand the pathogenesis of Parkinson's disease and to develop new therapies. In this chapter, we describe a cell-based assay for detecting α-synuclein propagation.


Measuring functional outcomes in major trauma: can we do better?
There is relatively limited large scale, long-term unified evidence to describe how quality of life (QoL) and functional outcomes are affected after polytrauma. The aim of this study is to review validated measures available to assess QoL and functional outcomes and make recommendations on how best to assess patents after major trauma. PubMed and EMBASE databases were interrogated to identify suitable patient-reported outcome measures (PROMs) for use in major trauma, and current practice in their use globally. Overall, 81 papers met the criteria for inclusion and evaluation. Data from these were synthesised. A full set of validated PROMs tools were identified for patients with polytrauma, as well as critique of current tools available, allowing us to evaluate practice and recommend specific outcome measures for patients following polytrauma, and system changes needed to embed this in routine practice moving forward. To achieve optimal outcomes for patients with polytrauma, we will need to focus on what matters most to them, including their needs (and unmet needs). The use of appropriate PROMs allows evaluation and improvement in the care we can offer. Transformative effects have been noted in cases where they have been used to guide treatment, and if embedded as part of the wider system, it should lead to better overall outcomes. Accordingly, we have made recommendations to this effect. It is time to seize the day, bring these measures even further into our routine practice, and be part of shaping the future.


Two-photon absorption cross section of excited phthalocyanines by a femtosecond Ti-sapphire laser.
In the past few years, photodynamic therapy (PDT) has become a major treatment for neovascular age-related macular degeneration (AMD) in which there is abnormal growth of choroidal neovasculature (CNV) that eventually obscures central vision, leading to blindness. However, one of the main limitations of current PDT is the relatively low specificity of the photosensitizer (PS) and light for pathological tissue which may induce damage to adjacent healthy tissue. An alternative approach to circumvent the specificity limitation is to improve the irradiation process. In particular two photon (2-gamma) excitation promises a more precise illumination of the target tissue. PS are activated by the simultaneous absorption of 2-gamma delivered by ultra-fast pulses of near infrared light. In order to evaluate the efficiency of phthalocyanine (Pc) dyes for 2-gamma absorption we measured 2-gamma absorption cross sections (sigma(2)) of a number of metalated Pc (MPc) dyes at lambda(ex) = 800 nm using a femtosecond laser. The studied Pc molecules vary by the type of the central metal ion (Al or Zn) and the number of peripheral sulfo substituents (MPcS). Each MPc dye of our series shows an improved 2-gamma absorption sigma(2) as compared to that obtained for Photofrin (3.1 +/- 0.1 GM, with 1 GM = 10(-50) cm(4) s photon(-1) mol(-1)), the PS currently approved for 1-gamma PDT. Our data show an 2.5-fold enhancement for AlPcCl, AlPcS(2adj) and ZnPcS(3)C(9), up to 10-fold (28.6 +/- 0.72 GM) for the ZnPcS(4) dye relative to Photofrin. These findings confirm the efficiency of Pc for 2-gamma absorption processes and represent the first detailed comparison study of 2-gamma absorption sigma(2) between Photofrin and Pc dyes.


AuAg nanocages/graphdiyne for rapid elimination and detection of trace pathogenic bacteria.
We prepared a biocompatible AuAg nanocages/graphdiyne @ polyethylene glycol (AuAg/GDY@PEG) composite. The combination of AuAg and GDY to obtain a synergistically enhanced photothermal effect, and the antibacterial effect of GDY and AuAg are used in combined anti-infective therapy. The in vitro antibacterial activity of AuAg/GDY@PEG was investigated, showing an impressive broad-spectrum antibacterial activity with the killing rate > 99.999%. Based on the photothermal conversion ability of AuAg/GDY@PEG, a simple photothermal immunoassay for pathogenic bacteria was successfully established. Sandwich immune response was performed on a microporous plate, the microplate containing the antibody binds specifically to the bacterium being tested, which then binds to the material with the antibody on its surface, and the signal was a change in temperature under 808 nm near-infrared light. The limit of detection (LOD) for S. typhimurium detection is 103 CFU mL-1, with a range of 103-107 CFU mL-1. This method is accurate, rapid and low-cost, which can be used for on-site detection of pathogenic bacteria in food.


Neurally adjusted ventilatory assist in neonates with congenital diaphragmatic hernia.
To measure short-term outcomes of neonates with congenital diaphragmatic hernia (CDH) while on Neurally Adjusted Ventilator Assist (NAVA), and to measure the impact of a congenitally abnormal diaphragm on NAVA ventilator indices. First, we conducted a retrospective-cohort analysis of 16 neonates with CDH placed on NAVA over a treatment period of 72 h. Second, we performed a case-control study comparing NAVA level and Edi between neonates with CDH and those without CDH. Compared to pre-NAVA, there were clinically meaningful improvements in PIP (p < 0.003), Respiratory Severity Score (p < 0.001), MAP (p < 0.001), morphine (p = 0.004), and midazolam use (p = 0.037). Compared to a 1:2 matched group without CDH, there was no meaningful difference in NAVA level (p = 0.286), Edi-Peak (p = 0.315), or Edi-Min (p = 0.266). The potential benefits of NAVA extend to neonates with CDH. There is minimal compensatory change in Edis, and higher/lower ventilator settings compared to neonates without CDH.


Redevelopment of hepatitis B surface antigen after renal transplantation.
A patient with chronic hepatitis B virus (HBV) and chronic renal failure received a renal transplantation. Hepatitis B surface antigen (HBsAg) disappeared, and antibodies to HBsAg appeared 10 months before transplantation. Liver tests showed no abnormality at transplantation. Six months later, chronic hepatitis reactivated, antibodies to HBsAg disappeared, and HBsAg reappeared. Hepatitis B virus DNA was demonstrated with polymerase chain reaction in the serum collected before transplantation. This observation suggests that low level HBV replication was present before transplantation despite the absence of detectable HBsAg and was reactivated under immunosuppressive therapy after transplantation.


[Topical application of tranexamic acid to prevent post-tonsillectomy haemorrhage].
Haemorrhage after tonsillectomy (TE) is a frequent and possibly major complication. The aim of the present study was to examine, if the rate of haemorrhage after tonsillectomy could be reduced by the topical application of Tranexamic acid (TXA) postoperatively. Between November 2011 and April 2013, all patients (n=246) received TXA postoperatively to prevent haemorrhage after TE. The patients were instructed to dilute 1 ampulla of TXA in 300 ml of tap water (concentration 0.2%) from postoperative day 5-10 and to gargle or spray the tonsillar fossae 5-6 times daily. The study group was compared retrospectively with a control group of patients undergoing TE with-out postoperative application of TXA from December 2010 to November 2011 (n=248). The overall rate of postoperative haemorrhage was 19% and 22% in the study and control group, respectively. The rate of postoperative bleeding that needed surgical intervention was at 8.9% and 11.3% in the study and control group, respectively. Topical application of TXA did not significantly reduce the rate of postoperative haemorrhage after TE. Topically applied TXA did not reduce postoperative haemorrhage after TE. However, a slight tendency to less bleeding which needed surgical intervention was found in pa-tients older than ≥ 12 years.


Ultrasound Imaging and Antithrombotic Effects of PLA-Combined Fe3O4-GO-ASA Multifunctional Nanobubbles.
PLA-combined ferroferric oxide-graphene oxide-aspirin (Fe3O4-GO-ASA) multifunctional nanobubbles were prepared using the double emulsion-solvent evaporation method. The obtained composite nanobubbles had a regular spherical shape, Zeta potential of (-36.5 ± 10.0) mV, and particle size distribution range of 200-700 nm. The experimental results showed that PLA-combined Fe3O4-GO-ASA nanobubbles could effectively improve the antithrombin parameters of PT, TT, APTT, and INR, and significantly inhibit thrombosis when the composite nanobubbles with a concentration of 80 mg·mL-1 interacted with the rabbit blood. The prepared composite nanobubbles could reach a significant ultrasonic imaging effect and good magnetic targeting under the magnetic field when the nanobubbles' concentration was only 60 mg·mL-1.


Bacteriophages as viral indicators for radiation processing of water: a chemical approach.
Inactivation of the bacteriophages PHI X 174 (somatic coliphage), MS2 (F-specific coliphage) and B40-8 (phage infecting Bacteroides fragilis) suspended in tap water was studied applying gamma and electron beam irradiation as well. PHI X 174 phage was found to be a suitable viral indicator for water disinfection by means of ionizing radiation. The nutrient broths introduced simultaneously with the bacteriophages into the water when it is spiked with the phages for the experiments did not significantly change the scavenging capacity of the water matrix. No dose rate effect was observed with MS2 and B40-8 phages but PHI X 174 phage showed a clear dose rate effect. It was found that in water MS2 phage is significantly more sensitive to ionizing radiation than Escherichia coli.


Comparative laminar distribution of various autoradiographic cholinergic markers in adult rat main olfactory bulb.
To provide anatomical information on the complex effects of acetylcholine (ACh) in the olfactory bulb (OB), the distribution of different cholinergic muscarinic and nicotinic receptor sub-types was studied by quantitative in vitro autoradiography. The muscarinic M1-like and M2-like sub-types, as well as the nicotinic bungarotoxin-insensitive (alpha 4 beta 2-like) and bungarotoxin-sensitive (alpha 7-like) receptors were visualized using [3H]pirenzepine, [3H]AF-DX 384, [3H]cytisine and [125I] alpha-bungarotoxin (BTX), respectively. In parallel, labelling patterns of [3H]vesamicol (vesicular acetylcholine transport sites) and [3H]hemicholinium-3 (high-affinity choline uptake sites), two putative markers of cholinergic nerve terminals, were investigated. Specific labelling for each cholinergic radioligand is distributed according to a characteristic laminar and regional pattern within the OB revealing the lack of a clear overlap between cholinergic afferents and receptors. The presynaptic markers, [3H]vesamicol and [3H]hemicholinium-3, demonstrated similar laminar pattern of distribution with two strongly labelled bands corresponding to the glomerular layer and the area around the mitral cell layer. Muscarinic M1-like and M2-like receptor sub-types exhibited unique distribution with their highest levels seen in the external plexiform layer (EPL). Intermediate M1-like and M2-like binding densities were found throughout the deeper bulbar layers. In the glomerular layer, the levels of muscarinic receptor subtypes were low, the level of M2-like sites being higher than M1. Both types of nicotinic receptor sub-types displayed distinct distribution pattern. Whereas [125I] alpha-BTX binding sites were mostly concentrated in the superficial bulbar layers, [3H]cytisine binding was found in the glomerular layers, as well as the mitral cell layer and the underlying laminae. An interesting feature of the present study is the visualization of two distinct cholinoceptive glomerular subsets in the posterior OB. The first one exhibited high levels of both [3H]vesamicol and [3H]hemicholinium-3 sites. It corresponds to the previously identified atypical glomeruli and apparently failed to express any of the cholinergic receptors under study. In contrast, the second subset of glomeruli is not enriched with cholinergic nerve terminal markers but displayed high amounts of [3H]cytisine/nicotinic binding sites. Taken together, these results suggest that although muscarinic receptors have been hypothesized to be mostly involved in cholinergic olfactory processing and short-term memory in the OB, nicotinic receptors, especially of the cytisine/ alpha 4 beta 2 sub-type, may have important roles in mediating olfactory transmission of efferent neurons as well as in a subset of olfactory glomeruli.


Filming the family: a documentary film to educate clinicians about family caregivers of patients with brain tumors.
The objective of this paper is to evaluate the educational value of a documentary film about family caregiving for patients with brain tumors. The method used in this study is a pre-post survey among neurosurgeons, neuro-oncologist, and other clinician viewers. Viewers evaluated the film highly and reported an intention to change their practice as a result of watching the film. Following viewing, participants felt more strongly that "all families of patients with brain cancers should meet with a social worker" (P = 0.01) and that "family caregivers greatly impact the health of patients" (P = 0.002), and they were less likely to believe that "supporting family caregivers is primarily someone else's job" (P = 0.009). A documentary film about family caregiving is an effective educational tool to increase awareness among neurosurgery/neuro-oncology clinicians about the importance and needs of family caregivers of patients with brain tumors.


Association of disorganization of retinal inner layers with optical coherence tomography angiography features in branch retinal vein occlusion.
To examine the associations between the disorganization of the retinal inner layers (DRIL) and optical coherence tomography angiography characteristics and visual acuity (VA) outcomes in eyes with macular edema secondary to branch retinal vein occlusion (BRVO). In this single-center cross-sectional cohort study, the data of 43 patients with macular edema secondary to BRVO that received pro re nata anti-vascular endothelial growth factor therapy were analyzed. B-scan and en face angiographic images were obtained by swept-source-based wide-field optical coherence tomography angiography performed at a single visit 1 month after the anti-vascular endothelial growth factor therapy session and evaluated. Correlations between the vascular indices in macula-centered 3 × 3 and 12 × 12 mm2 areas and B-scan parameters, such as DRIL length and VA, were examined. The mean DRIL length (Rs = 0.588, p < 0.001) and the proportion of scans with DRIL out of five scans (Rs = 0.507, p = 0.001) were significantly correlated with the final best-corrected VA in patients with BRVO. DRIL length was associated with vascular density (VD) and vascular length in the macula (Rs = - 0.425, p = 0.006 and Rs = - 0.382, p = 0.013, respectively), but not with VD and vascular length in the larger areas (12 × 12 mm2). Multilinear regression analysis revealed that the extent of macular edema (p = 0.0016) and VD in the 3 × 3 mm2 area (p = 0.004) was significantly associated with the DRIL development. DRIL severity was correlated with VA and associated with the peri-macular perfusion status in eyes with BRVO. Macular edema and macular perfusion affected DRIL severity. These findings would help understand the pathogenesis of DRIL in eyes with BRVO.


Transvaginal color Doppler in the detection of external iliac vein thrombosis in pregnancy.
A case is described where transvaginal color Doppler was used to demonstrate upward external iliac vein extension of thrombus at 26 weeks' gestation. Normally, transabdominal color Doppler can visualize the iliac vessels, but in advanced pregnancy the uterus obstructs the view. This technique is useful in determining of there is a 'high' deep vein thrombosis in pregnancy, and may also prove useful in the obese patient.


High ETV6 Levels Support Aggressive B Lymphoma Cell Survival and Predict Poor Outcome in Diffuse Large B-Cell Lymphoma Patients.
The identification of prognostic factors for aggressive B-cell lymphomas still represents an unmet clinical need. We used forward phase protein arrays (FFPA) to identify proteins associated with overall survival (OS) from diagnostic formalin-fixed paraffin-embedded material of diffuse large B-cell lymphoma (DLBCL) patients (n = 47). Univariate Cox regression analysis identified numerous proteins, including immune check-point molecules (PDCD1, PDCD2 and PD1L2) and BCL2 to be significantly associated with OS. However, only ETV6 and PIM2 proteins persisted following multivariate Cox analysis. Independent validation studies by immunohistochemistry and analysis of public gene expression profiles of DLBCL confirmed a prognostic role for high ETV6 and ETV6/PIM2 ratios in DLBCL. ETV6 is a recurrently mutated/deleted gene in DLBCL for which its function in this disease entity is currently unknown. We find that ETV6 is upregulated during oncogenic transformation of germinal center B-cells and that it regulates DLBCL survival, as its acute loss results in marked apoptosis. Fluctuations in survivin (BIRC5) expression levels were associated with this phenomenon. Furthermore, an inverse correlation between ETV6 and BIRC5 expression levels was found and correlated with a response to the BIRC5 inhibitor, YM155. In conclusion, we present evidence for an oncogenic function of ETV6 in DLBCL.


Association between Intermountain Risk Score and long-term mortality with the transcatheter aortic valve implantation procedure.
Since its first introduction, the spectrum and frequency of use of transcatheter aortic valve implantation (TAVI) have increased throughout the world. Therefore, it is crucial to determine which patients are at high mortality risk with TAVI. The Intermountain Risk Score (IMRS) is a score calculated from laboratory parameters. This study aimed to determine the long-term mortality of TAVI patients using the IMRS and to compare it with traditional scoring systems. The study included a total of 133 patients undergoing TAVI at our hospital from 2010 to 2019. Demographic data, co-morbid diseases, echocardiographic and laboratory parameters were collected retrospectively. The performance of IMRS was assessed as compared to the mortality determined in the overall patient population. During the follow-up, 54.9% of patients (60 patients) (Group 1) survived; the mortality in Group 2 (60 patients) was 45.1%. The survival period had a mean of 1433 (±124) days. The mean IMRS was 1.67 (0.7) in Group 1 and 2.33 (0.72) in Group 2 (P <0.001). In multivariable analyses, only high risk of IMRS (hazard ratio [HR], 3.430; 95% confidence interval [CI], 1.537-7.653; P = 0.003) and EuroSCORE II (HR, 1.141; 95% CI, 1.011-1.288; P = 0.03) independently predicted long-term mortality. From the evaluation of all laboratory and echocardiography parameters, long-term mortality (>30 days) following the TAVI procedure can be said to be higher in patients with a high IMRS. The data from this study can be considered of value in demonstrating the clinical significance of IMRS calculation before the TAVI procedure.


Curcumin induces cell apoptosis in human chondrosarcoma through extrinsic death receptor pathway.
Chondrosarcoma is a soft tissue sarcoma with a poor prognosis that is unresponsive to conventional chemotherapy. Surgical treatment leads to severe disability with high rates of local recurrence and life threat. Curcumin, an active compound in turmeric and curry, has been proven to induce tumor apoptosis and inhibit tumor proliferation, invasion, angiogenesis, and metastasis of cancer cells. In this study, we investigated the anticancer effects of curcumin in human chondrosarcoma cells. Curcumin induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353) but not in primary chondrocytes. Curcumin induced upregulation of Fas, FasL, and DR5 expression in chondrosarcoma cells. Transfection of cells with Fas, FasL, or DR5 siRNA reduced curcumin-induced cell death. In addition, p53 involved in curcumin-mediated Fas, FasL, and DR5 expression and cell apoptosis in chondrosarcoma cells. Most importantly, animal studies revealed a dramatic 60% reduction in tumor volume after 21 days of treatment. Thus, curcumin may be a novel anticancer agent for the treatment of chondrosarcoma.


Breathing during sleep.
The depth, rate, and regularity of breathing change following transition from wakefulness to sleep. Interactions between sleep and breathing involve direct effects of the central mechanisms that generate sleep states exerted at multiple respiratory regulatory sites, such as the central respiratory pattern generator, respiratory premotor pathways, and motoneurons that innervate the respiratory pump and upper airway muscles, as well as effects secondary to sleep-related changes in metabolism. This chapter discusses respiratory effects of sleep as they occur under physiologic conditions. Breathing and central respiratory neuronal activities during nonrapid eye movement (NREM) sleep and REM sleep are characterized in relation to activity of central wake-active and sleep-active neurons. Consideration is given to the obstructive sleep apnea syndrome because in this common disorder, state-dependent control of upper airway patency by upper airway muscles attains high significance and recurrent arousals from sleep are triggered by hypercapnic and hypoxic episodes. Selected clinical trials are discussed in which pharmacological interventions targeted transmission in noradrenergic, serotonergic, cholinergic, and other state-dependent pathways identified as mediators of ventilatory changes during sleep. Central pathways for arousals elicited by chemical stimulation of breathing are given special attention for their important role in sleep loss and fragmentation in sleep-related respiratory disorders.


Endocrine profiles and fertility status of human menstrual cycles of varying follicular phase length.
Assessment of the relationship between ovarian endocrine function and follicular phase length was made in 48 patients (51 cycles) with spontaneous ovular cycles of varying length. On the basis of follicular phase length when measured from the first day of menstruation to, and including, the day of the luteinizing hormone (LH) peak, cycles were grouped into short (less than 21 days), medium (12 to 16 days), and long (more than 6 days). Daily serum LH, androstenedione, 17 beta-estradiol, progesterone, and 17 alpha-hydroxyprogesterone concentrations were determined in the periovular period. The overall pattern of serum steroid concentrations in medium and long cycles was similar to that previously described for normal women. However, cycles with a short follicular phase had lower mean concentrations of androstenedione and estradiol. In order to assess the fertility potential of cycles with follicular phases of varying length, the prior 265 cycles of 92 consecutive patients who conceived with artificial insemination by donor (AID) were studied. In all cases, insemination occurred on day 0 and day + 1 with respect to the LH peak, and all cycles were assumed to have equal fertility potential. Statistical analysis revealed no significant difference in fertility potential among cycles with follicular phases of differing length.


Association between Estimated Cardiorespiratory Fitness and Abnormal Glucose Risk: A Cohort Study.
Cardiorespiratory fitness (CRF) is a predictor of chronic disease that is impractical to routinely measure in primary care settings. We used a new estimated cardiorespiratory fitness (eCRF) algorithm that uses information routinely documented in electronic health care records to predict abnormal blood glucose incidence. Participants were adults (17.8% female) 20-81 years old at baseline from the Aerobics Center Longitudinal Study between 1979 and 2006. eCRF was based on sex, age, body mass index, resting heart rate, resting blood pressure, and smoking status. CRF was measured by maximal treadmill testing. Cox proportional hazards regression models were established using eCRF and CRF as independent variables predicting the abnormal blood glucose incidence while adjusting for covariates (age, sex, exam year, waist girth, heavy drinking, smoking, and family history of diabetes mellitus and lipids). Of 8602 participants at risk at baseline, 3580 (41.6%) developed abnormal blood glucose during an average of 4.9 years follow-up. The average eCRF of 12.03 ± 1.75 METs was equivalent to the CRF of 12.15 ± 2.40 METs within the 10% equivalence limit. In fully adjusted models, the estimated risks were the same (HRs = 0.96), eCRF (95% CIs = 0.93-0.99), and CRF (95% CI of 0.94-0.98). Each 1-MET increase was associated with a 4% reduced risk. Higher eCRF is associated with a lower risk of abnormal glucose. eCRF can be a vital sign used for research and prevention.


Knockdown of long non-coding RNA XIST increases blood-tumor barrier permeability and inhibits glioma angiogenesis by targeting miR-137.
Antiangiogenic therapy plays a significant role in combined glioma treatment. However, poor permeability of the blood-tumor barrier (BTB) limits the transport of chemotherapeutic agents, including antiangiogenic drugs, into tumor tissues. Long non-coding RNAs (lncRNAs) have been implicated in various diseases, especially malignant tumors. The present study found that lncRNA X-inactive-specific transcript (XIST) was upregulated in endothelial cells that were obtained in a BTB model in vitro. XIST knockdown increased BTB permeability and inhibited glioma angiogenesis. The analysis of the mechanism of action revealed that the reduction of XIST inhibited the expression of the transcription factor forkhead box C1 (FOXC1) and zonula occludens 2 (ZO-2) by upregulating miR-137. FOXC1 decreased BTB permeability by increasing the promoter activity and expression of ZO-1 and occludin, and promoted glioma angiogenesis by increasing the promoter activity and expression of chemokine (C-X-C motif) receptor 7b (CXCR7). Overall, the present study demonstrates that XIST plays a pivotal role in BTB permeability and glioma angiogenesis, and the inhibition of XIST may be a potential target for the clinical management of glioma.


[Computer-assisted diagnostic procedure for multislice computed tomography for assessment of the pulmonary arterial circulation. Clinical relevance].
A recently developed CAD software which highlights intravascular thrombotic structures from multislice computed tomography (MSCT) data was tested regarding feasibility, interobserver reliability and effect on radiology reports. The CAD system ImageChecker® CT-Lung was tested in a randomized double-blinded study on 160 MSCT datasets (standardized technical conditions) performed for suspected pulmonary embolism (PE). The CAD data and images were analyzed by three radiologists in an independent and blinded fashion. The data from all 160 cases could be analyzed and 604 CAD prompts were set. Using the CAD analysis significantly more PEs were found in the peripheral pulmonary arterial circulation than described in the initial report. In 38 cases the 3 radiologists in consensus scored the images with the CAD adjunct as PE positive in peripheral vessels, which were initially reported as negative. Despite differences in the evaluation between two radiologists the amended assessment of the imaging data using the CAD softwear was reliable. There was a significant correlation between D-dimer values and the number of embolic structures detected by the CAD analysis. The recently developed CAD system is a useful adjunct as second reader to detect subtle emboli in peripheral vessels of MSCT datasets.


Molecular cloning and functional analysis of duck Toll-like receptor 5.
Toll-like receptor 5 (TLR5) is responsible for the recognition of bacterial flagellin in vertebrates. In this study, we cloned the single-exon TLR5 gene of the Maya breed of Common Shelduck (Tadorna tadorna). The TLR5 open reading frame is 2580 bp in length and encodes an 859-amino acid protein. The putative amino acid sequence of duck TLR5 consisted of a signal peptide sequence, 11 leucine-rich repeat domains, a leucine-rich repeat C-terminal domain, a transmembrane domain, and an intracellular Toll-interleukin-1 receptor domain. The duck TLR5 gene was highly expressed in the lung, bone marrow, spleen, and liver; moderately expressed in kidney, small intestine, large intestine, and brain. A plasmid expressing duck TLR5 was constructed and transfected into HEK293T cells, and expression was confirmed by indirect immunofluorescence assay. HEK293T cells transfected with duck TLR5- and NF-κB-luciferase-containing plasmids significantly responded to flagellin from Salmonella typhimurium, indicating that it is a functional TLR5 homolog.


Reduced cellular susceptibility to in vitro HIV infection is associated with CD4+ T cell quiescence.
HIV preferentially establishes productive infection in activated CD4+ T cells. Since proportions of activated CD4+ T cells vary between individuals, this study aimed to determine if individuals with a greater proportion of activated CD4+ T cells would be more susceptible to in vitro HIV infection. Unstimulated peripheral blood mononuclear cells (PBMC) from various donors were inoculated with HIV(ML1956)in vitro. HIV replication was evaluated by HIV p24 ELISA of culture supernatants and intracellular staining for HIV p24, which was detected by flow cytometry. Baseline T cell phenotypes and infected cell phenotypes were also evaluated by flow cytometry. Ex vivo phenotyping at the time of blood draw showed that elevated T cell activation and reduced Tregs were associated with increased cellular susceptibility to in vitro infection. Furthermore, the infected CD4+ T cell population was enriched for activated cells. These data suggest that CD4+ T cell quiescence provides an environment less conducive to the establishment of HIV infection by limiting the pool of activated target cells.


Changing nurse licensing examinations: media analysis and implications of the Canadian experience.
This study examines perceptions of the implementation of National Council Licensing Examination in Canada through a content analysis of articles in the media. Public opinions of nursing in the media have been acknowledged as important for the profession, specifically in relation to their portrayal of nursing. The Canadian Council of Registered Nurse Regulators began using the US-based National Council Licensing Examination as entry examination (also known widely as NCLEX) for Canada's registered nurses, discontinuing the previous Canadian Registered Nurse Examination in 2015. A qualitative content analysis was conducted of media reports that emerged following adoption of the National Council Licensing Examination in Canada, and highlight the image of nursing portrayed in the media during this key regulatory policy change. Release of the examination results for the first three quarters of 2015 identified a much lower overall Canadian pass rate than with the previous exam. Media reports highlight differences in perception of the examination between Canadian regulators and other stakeholders in the context of the examination experiences reported and test results. Issues around applicability of the examination to Canadian nursing practice, curriculum alignment, language translation concerns and stakeholder engagement were identified. The implementation of the National Council Licensing Examination in Canada highlighted lack of communication among nursing stakeholders in the country. Most of the media reporting has been negative and poses a reputational risk to the Canadian nursing profession. This change in the licensing requirement has significant policy implications for nursing in Canada and globally. Issues such as appropriate examination translation, access to appropriate test preparation materials, assurance that the examination reflects distinctive aspects of a country's healthcare system and the need for stakeholder engagement were identified.


NAD supplementation improves mitochondrial performance of cardiolipin mutants.
Cardiolipin (CL) deficiency causes mitochondrial dysfunction and aberrant metabolism that are associated in humans with the severe disease Barth syndrome (BTHS). Several metabolic abnormalities are observed in BTHS patients and model systems, including decreased oxidative phosphorylation, reduced tricarboxylic acid (TCA) cycle flux, and accumulated lactate and D-β-hydroxybutyrate, which strongly suggests that nicotinamide adenine dinucleotide (NAD) redox metabolism may be altered in CL-deficient cells. In this study, we identified abnormal NAD+ metabolism in multiple BTHS model systems and demonstrate that supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) improves mitochondrial function. Improved mitochondrial function in the Drosophila model was associated with restored exercise endurance, which suggests a potential therapeutic benefit of NAD+ precursor supplementation in the management of BTHS patients.


Alphoid variant-specific FISH probes can distinguish autosomal meiosis I from meiosis II non-disjunction in human sperm.
Over the past few years, several groups have used fluorescence in situ hybridization (FISH) to study aneuploidy in human sperm. Several important observations have derived from these studies, including the demonstration of chromosome-specific variation in non-disjunction frequencies, and the possible association of aneuploidy with environmental agents and with increasing paternal age. However, an important technical limitation of these studies has been the inability to distinguish between autosomal non-disjunction occurring at meiosis I and meiosis II. In the present report, we describe a simple FISH-based approach designed to overcome this limitation. Using oligonucleotide probes capable of distinguishing subtle differences in the alpha satellite sequences of chromosome 17, we demonstrate that (in appropriate heterozygotes) it is possible to simultaneously identify disomic sperm and to determine the meiotic stage of origin of the additional chromosome. This novel approach has important implications for future FISH sperm studies, since the ability to distinguish between meiosis I and meiosis II non-disjunction will make it possible to determine whether putative etiological agents affect chromosome segregation at both, or only one, of the two meiotic stages.


A large-scale clinical field study to evaluate the efficacy and safety of an oral formulation of the amino-acetonitrile derivative ( AAD ), monepantel , in sheep in New Zealand.
To evaluate the efficacy and safety of an oral formulation of the novel anthelmintic, monepantel (AAD 1566), in sheep, in comparison with some other anthelmintics currently registered in New Zealand. A study was conducted on 18 farms located throughout the North and South Islands of New Zealand. On each farm, sheep naturally infected with the target nematodes were randomly assigned to groups, which were then treated with either monepantel, at a minimum dose rate of 2.5 mg/kg, or one of five other anthelmintics encompassing the range of single-entity and combination formulations that are commercially available in New Zealand, or left untreated as controls. Faecal samples were collected from all sheep pre-treatment (1-3 weeks before treatment), at the time of treatment, and approximately 1, 2 and 3 weeks after treatment (Days 7, 14 and 21). Faecal nematode egg counts (FEC) were measured in all samples, and the efficacy of treatments, as indicated by reductions in FEC, calculated. All sheep were inspected at least daily, to check for any adverse effects of treatment. On all 18 farms, on Days 7, 14 and 21 (54 test points), the efficacy of the monepantel solution was >95%. At Days 7 and 14 post-treatment, efficacies>99% were recorded in 15 flocks. At Day 21 post-treatment, efficacies>98% were recorded in 13 flocks. Monepantel was as effective, or more effective, than the registered anthelmintics with which it was compared. Moreover, it was effective against strains of nematodes resistant to one or more of the currently available broad-spectrum anthelmintics. The monepantel solution used in this study was well tolerated by the sheep, and no adverse events could be attributed to its use. When administered as an oral formulation under field conditions, at a minimum dose rate of 2.5 mg/kg, monepantel appeared to be highly effective against all the major genera of gastrointestinal nematodes of sheep, including Haemonchus, Teladorsagia (=Ostertagia), Trichostrongylus, Cooperia, Nematodirus, Chabertia and Oesophagostomum. This included strains resistant to the currently available broad-spectrum anthelmintics. Monepantel is the first compound from the recently discovered amino-acetonitrile derivative (AAD) class of anthelmintics to be developed for use in sheep.


PVA and BSA stabilized silver nanoparticles based surface-enhanced plasmon resonance probes for protein detection.
To perform biosensing using nanoparticles in solution, silver particles were coated with bovine serum albumin (BSA) and polyvinyl alcohol (PVA) as control stabilizer. The plasmon resonance (420 nm) of the silver nanoparticles in solution was shifted slightly to longer wavelength (443 nm) when they were coated with BSA. The biointeractions of these engineered nanoparticles were studied using a mouse model. No significant changes in behavior or toxicity were observed. The nanoparticles were detected in all tissues including the brain. Antibody recognition was monitored via the change in light absorption which accompanied binding, indicating that the particles can be used as a biosensor to gain more insight into cellular mechanisms governing the function of organs in general, and the blood brain barrier (BBB) and brain in particular.


Estimating acceptable exposure time for bioaerosols emission in a wastewater treatment plant by reverse quantitative microbial risk assessment based on various risk benchmarks.
Populations exposed to bioaerosols over time in wastewater treatment plants (WWTPs) will be infected. Then, the reverse quantitative microbial risk assessment (QMRA) provides a quantitative framework for the estimation of acceptable exposure time to protect people from excessive exposure and then manage their health risk. In this study, the acceptable exposure time for staffs and visiting researchers exposed to S. aureus or E. coli bioaerosols emitted from aeration ponds in WWTPs was estimated and analyzed by Monte Carlo simulation-based reverse QMRA (using the 1E-4 pppy suggested by the US EPA or 1E-6 DALYs pppy suggested by the WHO as benchmarks). The 1E-3 and 1E-2 pppy were selected as a series of loose annual infection risk benchmarks to calculate a practical acceptable exposure time. The results showed that for the acceptable exposure time in each specific exposure scenario, the exposure of females was consistently 0.3-0.4 times longer than that of males; the exposure of staffs was 3.6-3.9 times shorter than that of visiting researchers; the exposures of populations in the rotating-disc aeration mode were consistently 6.3-6.6 and 2.8-3.1 times longer than those in the microporous aeration mode for S. aureus and E. coli bioaerosols, respectively. The acceptable exposure time with the use of personal protective equipment (PPE) was 33.4-35.0 times as long as that without PPE. The US EPA benchmark is stricter than the WHO benchmark with regard to the estimation of the acceptable exposure time of S. aureus or E. coli bioaerosols. The 1E-3 pppy is more appropriate and practical than the US EPA benchmark, but the 1E-2 pppy is notably too loose for health risk management. This research can assist managers of WWTPs to formulate a justified exposure time and develop applicable administrative and personal intervention strategies. The results can enrich the knowledge bases of reverse QMRA to elect a series of loose health-based target risk benchmarks for health risk management.


Dissociation between time reproduction of actions and of intervals in patients with Parkinson's disease.
Alterations in temporal estimation have been observed in patients with Parkinson's disease (PD) and have been associated to dopaminergic dysfunction. Nevertheless, levodopa treatment and deep brain stimulation of the subthalamic nucleus (DBS-STN) have been shown to improve motor deficits and temporal estimation skills in such patients. So far, temporal estimation tasks in PD patients have evaluated the ability to reproduce intervals of time, but never the duration of an action. Here we investigated: (1) the ability of PD patients to reproduce the duration of their previous actions as compared to their ability to reproduce intervals of time and (2) the effect that DBS-STN has on both skills. Nineteen PD patients with DBS-STN and 19 controls were requested to reproduce the duration of an action and that of an interval of time. The patients were tested in the following treatment conditions: on stimulation/off medication, off stimulation/off medication and off stimulation/on medication. The results demonstrated that patients in the off stimulation/off medication condition under-reproduced the duration of their actions while accurately reproducing the duration of time intervals. The accuracy of the performance improved significantly in both treatment regimens. Our results indicate that in PD patients the ability to reproduce motor acts can be dissociated from that of reproducing time intervals and that it can be improved by the administration of medical or surgical treatment.


Calcium channel antagonists decrease the ethanol withdrawal syndrome.
Withdrawal from chronic ethanol intake results in a syndrome of tremor and hyperexcitability, which can progress to seizures and death. Drugs used therapeutically to alleviate the syndrome have sedative actions and dependence liability of their own. The basis of the syndrome is unclear, although ethanol affects many neuronal functions, including membrane calcium conductance. Calcium channel blocking drugs have been used in cardiovascular disorders; they bind to high affinity sites in the brain but have few overt actions on the central nervous system. We have tested the effects of four calcium channel antagonists on the ethanol withdrawal syndrome in rats. Nitrendipine and nimodipine abolished all spontaneous seizures and prevented or reduced seizures following an audiogenic stimulus, and mortality. Verapamil significantly decreased seizure incidence and both it and flunarizine lowered mortality. The dihydropyridines were considerably more effective than diazepam in the withdrawal syndrome but had little effect on pentylenetetrazol seizures, against which diazepam gave good protection. The calcium channel inhibitors showed no sedative activity in normal animals. The results provide evidence that alterations in calcium conductance may be involved in the ethanol withdrawal syndrome and offer possibilities for the development of non-sedative therapeutic treatment of this syndrome.


[Psychosocial therapy in psychiatry : Update of the DGPPN-S3 guidelines "Psychosocial therapies for severe mental illnesses"].
Severe mental illnesses are often associated with substantial impairments of psychosocial functioning and a high risk of social exclusion. Along with somatic and psychotherapeutic treatment approaches, psychosocial interventions are an integral component of treatment. Psychosocial therapies aim to improve participation and enable patients to live self-determined lives as far as possible. This paper provides an overview of the structure and recommendations of the German S3 guidelines "Psychosocial therapies for severe mental illnesses" of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN). In the DGPPN S3 guidelines psychosocial therapies are systematically described for the first time and recommendations are formulated on the basis of a systematic processing of scientific evidence and a formalized consensus process. The evidence-based and consensus-based guidelines formulate a total of 33 recommendations and 12 statements. For many psychosocial interventions there is a broad evidence base. In the field of individual interventions psychoeducation, social skills training and health-promoting interventions have been given the highest recommendation strength (A). In the field of system level interventions, team-based, multiprofessional community psychiatric approaches, supported employment and self-determined housing with mobile support (supported housing) are given A level recommendations. For other interventions, the current evidence base is less robust. The successful implementation of guidelines depends not only on the quality but also on the dissemination. Therefore, in addition to the treatment guidelines a short version, a patient version and a waiting room version were developed.


The development of a computer-assisted curriculum in reproductive endocrinology and infertility for residents.
OBJECTIVE This study was undertaken to determine the features of an effective computer-based residency curriculum in reproductive endocrinology and infertility. A review of the literature to determine those features that have been used by training programs in medicine. Reproductive endocrinology and infertility division directors, current obstetrics and gynecology residents, and obstetrics and gynecology practitioners in the community were surveyed to evaluate critical subjects for study. Programs most successful in using computers in training health care providers use a case-based approach that prioritizes important subjects. Areas of greatest importance to the 3 groups surveyed include infertility, dysfunctional uterine bleeding, and management of the climacteric, and several other areas were also deemed critical. Benefits of computer-based learning include consistency, the ability to develop problem solving skills for life-long learning, and a self-paced approach, but its validity as a teaching tool will require rigorous appraisal.


Remapping versus short-term memory in visual stability across saccades.
Saccadic eye movements cause displacements of the image of the visual world projected on the retina. Despite the ubiquitous nature of saccades, subjective experience of the world is continuous and stable. In five experiments, we addressed the mechanisms that may support visual stability: matching of pre- and postsaccadic locations of the target by an internal copy of the saccade, or retention of the visual attributes of the target in short-term memory across the saccade. Healthy human adults were instructed to make a saccade to a peripheral Gabor patch. While the saccade was in midflight, the patch could change location, orientation, or both. The change occurred either immediately or following a 250-ms blank during which no visual stimuli were available. In separate experiments, subjects had to report either whether the patch stepped to the left or right or whether the orientation rotated clockwise or counterclockwise. Consistent with previous findings, we found that transsaccadic displacement discrimination was enhanced by the addition of the blank. However, contrary to previous findings reported in the literature, the feature change did not improve performance. Transsaccadic orientation change discrimination did not depend on either an irrelevant temporal blank or a simultaneous irrelevant target displacement. Taken together, these findings suggest that orientation is not a relevant visual feature for transsaccadic correspondence.


Dissociative experiences on ice--peritraumatic and trait dissociation during the cold pressor test.
The present study investigated the relationship between trait dissociation and peritraumatic dissociation during acute painful stimulation. In a sample of 70 undergraduate students, peritraumatic dissociation was induced by means of a cold pressor test, which basically consists of participants holding an arm in ice water for as long as possible. Results indicate that heightened trait dissociation scores were related to shorter durations that participants could sustain the task. However, trait dissociation was not associated with increases in acute dissociative symptoms (i.e., peritraumatic dissociation). These findings are in sharp contrast to the defensive function ascribed to both types of dissociation and also the commonly held assumption that peritraumatic and trait dissociation are intimately linked.


Fat ring sign and tumoral pseudocapsule sign in idiopathic mesenteric panniculitis complicated by protein-losing enteropathy.
A 66-year-old man complained of lower limb edema was diagnosed with mesenteric panniculitis because of fat ring sign and tumoral pseudocapsule sign on contrast-enhanced CT. Patient had edema due to protein-losing enteropathy associated with mesenteric panniculitis.


Exploring substance misuse behaviors among black girls in detention: Intersections of trauma, sex, and age.
High risk substance misuse, trauma and gang involvement are prevalent in adolescents and often occur with youth involved with the youth punishment system. Evidence suggests that system involvement is related to trauma histories, substance misuse, as well as gang involvement. This study investigated the associations between individual and peer factors and their relationship to problem drug and alcohol use among Black girls involved with the youth punishment system. Data were collected from 188 Black girls in detention at baseline, as well as 3 and 6 month follow up periods. Measures assessed were abuse history, trauma history, sex while using drugs and alcohol, age, government assistance, and drug use. Significant findings from the multiple regression analyses indicated that younger girls were more likely to have a higher prevalence of having a drug problem than older girls at baseline. Having sex while on drugs and alcohol at the 3 month follow up period was correlated with drug use. These findings highlight how individual and peer factors can influence problem substance misuse, their behavior and peer relationships among Black girls in detention.


TOPICAL CARBONIC ANHYDRASE INHIBITORS IN THE LONG-TERM TREATMENT OF JUVENILE X-LINKED RETINOSCHISIS.
To describe the response to long-term topical dorzolamide treatment in patients with juvenile X-linked retinoschisis and cystic-like foveal lesions. This was a retrospective interventional case series that included 18 eyes of 10 patients with genetically confirmed juvenile X-linked retinoschisis examined at the Cleveland Clinic Cole Eye Institute, a tertiary referral center, between 2005 and 2021. Patients were treated with topical 2% dorzolamide two to three times daily in both eyes. Two eyes were excluded because of retinal detachment. Primary outcome measures were logarithm of minimum angle of resolution visual acuity and optical coherence tomography based central subfield thickness. The mean follow-up was 8.38 years (SD, 3.41 years). The mean baseline and final central subfield thickness was 429.88 µ m (SD, 143.36 µ m) and 372.28 µ m, respectively (SD, 147.13 µ m, P = 0.10). The mean baseline and final logarithm of minimum angle of resolution visual acuity was 0.45 (SD, 0.17) and 0.34, respectively (SD, 0.22, P < 0.01). None of the patients experienced any side effects from topical dorzolamide. The study data support previous reports of improved visual acuity in X-linked retinoschisis patients on topical dorzolamide treatment. This is the longest follow-up for a series of juvenile X-linked retinoschisis patients treated with a topical carbonic anhydrase inhibitor to date. A large, prospective, randomized clinical trial is needed to provide stronger evidence regarding the efficacy of topical carbonic anhydrase inhibitors in juvenile X-linked retinoschisis.


Validity of the STRATIFY risk score of falls in nursing homes.
We investigated the performance of the STRATIFY risk assessment for fall risk in nursing home patients. This prospective study was conducted at the nursing home Antonius Binnenweg in Rotterdam from June 1 to December 31, 2000. Subjects included newly admitted patients of whom a STRATIFY score was obtained. Patients were followed for falls during a person-week observation period of 13 weeks. Measurements were age, sex, admission category, STRATIFY score, length of stay and number of falls. Of 120 patients (75 women, 45 men, average age 74.5 years), a STRATIFY score was available. Three months after admission 24 of these patients (20%) had died, 56 patients (47%) had been discharged and 40 (33%) still resided in the nursing home. Of the 120 patients included, 36 patients (30%) had fallen during the observation period. The risk of falling in the patient group with a STRATIFY score of 2 or more was 2.35 (95% confidence interval: 1.22, 4.52) times that of patients with a lower score. The sensitivity of the STRATIFY score was 50% (95% CI: 32, 67), specificity was 76.2% (95% CI: 65, 87.5). The STRATIFY risk score of falls gave disappointing results in our setting.


Effect of thoracic radiotherapy dose on the prognosis of advanced lung adenocarcinoma harboring EGFR mutations.
The aim of this study was to investigate the effects of different thoracic radiotherapy doses on OS and incidence of radiation pneumonia which may provide some basis for optimizing the comprehensive treatment scheme of these patients with advanced EGFR mutant lung adenocarcinoma. Data from 111 patients with EGFR-mutant lung adenocarcinoma who received thoracic radiotherapy were included in this retrospective study. Overall survival (OS) was the primary endpoints of the study. Kaplan-Meier method was used for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate analyses to determine the prognostic factors related to the disease. The mOS rates of the patients, who received radiotherapy dose scheme of less than 50 Gy, 50-60 Gy (including 50 Gy), and 60 Gy or more were 29.1 months, 34.4 months, and 51.0 months, respectively (log-rank P = 0.011). Although trend suggested a higher levels of pneumonia cases with increasing radiation doses, these lack statistical significance (χ2 = 1.331; P = 0.514). The multivariate analysis showed that the thoracic radiotherapy dose schemes were independently associated with the improved OS of patients (adjusted hazard ratio [HR], 0.606; 95% CI, 0.382 to 0.961; P = 0.033). For the patients with advanced EGFR-mutant lung adenocarcinoma, the radical thoracic radiotherapy dose scheme (≥ 60 Gy) could significantly prolong the OS of patients during the whole course management.


Food acquisition habits, nutrient intakes, and anthropometric data of Havasupai adults.
To describe the dietary patterns, anthropometric data, and food sources of Havasupai adults (> or = 18 years old) and determine the effect of age and gender. Dietary intakes (one 24-hour recall), anthropometric measures (body mass index [BMI], waist-to-hip ratio [WHR]) and demographic data, including sites of food purchases, were obtained. Food sources of selected nutrients were calculated from diet recalls. 92 adults (60 women, 32 men) from the Havasupai Reservation, Supai, Ariz. Descriptive statistics were generated for demographic data. Nutrient intakes, BMI, and WHR were compared across gender and age groups ("Younger" [18 to 59 years old] vs "older" [> or = 60 years old]) by one-way analysis of variance. Two-tailed t tests identified significant differences in selected food practices by age group. Diets were moderately high in fat (35% of energy), saturated fat (12%), and sugar (14%); intakes of zinc, calcium, vitamin A, vitamin B-6, and folate were frequently inadequate (less than two thirds of the Recommended Dietary Allowance). Of the 92 subjects, 76 (83%) were obese (BMI > or = 27). Fifty-four of the 60 women (90%) and 24 of the 32 men (75%) exhibited abdominal obesity (no age effect). Thirty-nine of the subjects (42%) consumed at least one food item purchased off the reservation on the day of the recall; the remaining 53 subjects (58%) consumed only food purchased or acquired on the reservation. Older Havasupai were significantly more dependent on the tribal store and other village food sources than were younger adults. Food sources of key nutrients did not differ by age or gender. The dietary patterns of isolated populations may be shaped by the unique limitations of their food sources as well as by factors such as age and gender. Individual and community-wide efforts to improve nutrient intakes and food patterns must recognize these geographic limitations. For populations such as the Havasupai, cooperative marketing and health promotion efforts between tribal officials, health care providers, and managers of the cafe and tribal store could improve the availability and consumption of a wider range of health-promoting foods.


Association of the US President's Emergency Plan for AIDS Relief's Funding With Prevention of Mother-to-Child Transmission of HIV in Kenya.
From 2004 to 2014, the US President's Emergency Plan for AIDS Relief (PEPFAR) invested more than $248 000 000 in the prevention of mother-to-child transmission (PMTCT) of HIV in Kenya. Concurrently, child mortality in Kenya decreased by half. To identify the extent to which the decrease in child mortality in Kenya is associated with PEPFAR funding for PMTCT of HIV. This population-based survey study conducted in Kenya estimated the association between annual per capita PEPFAR funding for PMTCT (annual PCF) and cumulative per capita PEPFAR funding for PMTCT (cumulative PCF), extracted using 2004-2014 country operational reports as well as individual-level health outcomes, extracted from the 2003, 2008-2009, and 2014 Kenya Demographic and Health Surveys and the 2007 and 2012 Kenya AIDS Indicator Surveys. The study included children of female respondents to the 2003, 2008-2009, and 2014 Kenya Demographic and Health Surveys who were born 1 to 60 months (for neonatal mortality) or 12 to 60 months (for infant mortality) before the survey, as well as female respondents who had recently given birth and reported on HIV testing during antenatal care (ANC) during the 2007-2014 surveys. Results were adjusted for year, province, and survey respondent characteristics. Statistical analysis was performed from July 8, 2016, to December 10, 2018. Neonatal mortality was defined as death within the first month of life and infant mortality was defined as death within the first year of life. HIV testing during ANC was defined as receiving counseling on PMTCT, undergoing an HIV test, and receiving test results during ANC. The analysis included 33 181 neonates (16 870 boys), 26 876 infants (13 679 boys), and 20 775 mothers (mean [SD] age, 28.0 [6.7] years). PEPFAR funding was not associated with neonatal mortality. A $0.33 increase in annual PCF, corresponding to the difference between the 75th and 25th (interquartile range) percentiles of funding, was significantly associated with a 16% (95% CI, 4%-27%) reduction in infant mortality after a 1-year lag. A 14% to 16% reduction persisted after 2- and 3-year lags, and comparable reductions were observed for unlagged and 1-year lagged cumulative PCF. An increase of 1 interquartile range in cumulative PCF was associated with a 7% (95% CI, 3%-11%) increase in HIV testing during ANC, which intensified with subsequent lags. Between 2004 and 2014, sustained funding levels of $0.33 annual PCF could have averted 118 039 to 273 924 infant deaths. Evidence from publicly available data suggests that PEPFAR's PMTCT funding was associated with a reduction in infant mortality and an increase in HIV testing during ANC in Kenya. The full outcome of funding may not be realized until several years after allocation.


Handling, ACTH, ACTH1-24, and naloxone effects on preening behavior in domestic chickens.
Excessive grooming behavior has been well documented in various animals as a result of stress or intraventricularly administered ACTH and ACTH1-24. In the present study, handling, ACTH, and ACTH1-24 were associated with significant increases in preening of domestic chickens when compared to saline-treated controls. Naloxone-treated birds showed preening levels similar to those of unhandled and saline-treated birds.


Genome sequence of Mycobacterium yongonense RT 955-2015 isolate from a patient misdiagnosed with multidrug-resistant tuberculosis: First clinical detection in Tanzania.
Mycobacterium yongonense is a recently described novel species belonging to Mycobacterium avium complex, which is the most prevalent aetiology of non-tuberculous mycobacteria associated with pulmonary infections, and poses tuberculosis diagnostic challenges in high-burden, resource-constrained settings. Whole genome shotgun sequencing and comparative microbial genomic analyses were used to characterize the isolate from a patient diagnosed with multidrug-resistant tuberculosis (MDR-TB) after relapse. The genome sequence of the first case of M. yongonense (M. yongonense RT 955-2015) in Tanzania is presented. Sequence analysis revealed that the RT 955-2015 strain had a high similarity to M. yongonense 05-1390(T) (98.74%) and Mycobacterium chimaera DSM 44623(T) (98%). Its 16S rRNA showed similarity to Mycobacterium paraintracellulare KCTC 290849(T) (100%), Mycobacterium intracellulare ATCC 13950(T) (100%), M. chimaera DSM 44623(T) (99.9%), and M. yongonense 05-1390(T) (98%). The strain exhibited a substantially different rpoB sequence to that of M. yongonense 05-1390 (95.16%), but closely related to that of M. chimaera DSM 44623(T) (99.86%), M. intracellulare ATCC 13950(T), (99.53%), and M. paraintracellulare KCTC 290849(T) (99.53%). In light of the OrthoANI algorithm and phylogenetic analysis, it was concluded that the isolate was M. yongonense Type II genotype, which is an indication that the patient was misdiagnosed with TB/MDR-TB and received inappropriate treatment.


Impact of pericardiectomy on exercise capacity and sleep of patients with chronic constrictive pericarditis.
Heart failure is associated with exercise intolerance and sleep- disordered breathing; however, studies in patients with chronic constrictive pericarditis are scarce. The purpose of our study was to assess exercise capacity and sleep in patients with chronic constrictive pericarditis (CCP) undergoing a pericardiectomy. We studied consecutive patients scheduled for pericardiectomy due to symptomatic CCP. Were performed quality of life (Minnesota Living with Heart Failure Questionnaire-MLHFQ) and sleep questionnaires (Epworth, Pittsburgh Sleep Quality Index-PSQI), serum B-type natriuretic peptide (BNP), serum C-reactive protein, transthoracic echocardiography, cardiopulmonary exercise test and overnight polysomnography immediately before and six months after pericardiectomy. Twenty-five patients (76% males, age: 45.5±13.8 years, body mass index: 24.9±3.7 kg/m2, left ventricular ejection fraction: 60±6%) with CCP (76% idiopathic, 12% tuberculosis) were studied. As compared to the preoperative period, pericardiectomy resulted in reduction in BNP (143 (83.5-209.5) vs 76 (40-117.5) pg/mL, p = 0.011), improvement in VO2 peak (18.7±5.6 vs. 25.2±6.3 mL/kg/min, p<0.001), quality of life (MLHFQ score 62 (43,5-77,5) vs. 18 (8,5-22), p<0,001) and sleep (PSQI score 7.8±4.1 vs. 4.7±3.7, p<0.001) and no significant change in sleep disordered breathing (apnea hypopnea index-AHI 15.6 (8.3-31.7) vs. 14.6 (5.75-29.9) events/h, p = 0.253). Patients with symptomatic CCP showed reduced exercise capacity and sleep-disordered breathing. After pericardiectomy, there was improvement in exercise capacity and neutral effect on sleep-disordered breathing.


Unpacking the impact of adverse childhood experiences on adult mental health.
Exposure to childhood adversity has an impact on adult mental health, increasing the risk for depression and suicide. Associations between Adverse Childhood Experiences (ACEs) and several adult mental and behavioral health outcomes are well documented in the literature, establishing the need for prevention. The current study analyzes the relationship between an expanded ACE score that includes being spanked as a child and adult mental health outcomes by examining each ACE separately to determine the contribution of each ACE. Data were drawn from Wave II of the CDC-Kaiser ACE Study, consisting of 7465 adult members of Kaiser Permanente in southern California. Dichotomous variables corresponding to each of the 11 ACE categories were created, with ACE score ranging from 0 to 11 corresponding to the total number of ACEs experienced. Multiple logistic regression modeling was used to examine the relationship between ACEs and adult mental health outcomes adjusting for sociodemographic covariates. Results indicated a graded dose-response relationship between the expanded ACE score and the likelihood of moderate to heavy drinking, drug use, depressed affect, and suicide attempts in adulthood. In the adjusted models, being spanked as a child was significantly associated with all self-reported mental health outcomes. Over 80% of the sample reported exposure to at least one ACE, signifying the potential to capture experiences not previously considered by traditional ACE indices. The findings highlight the importance of examining both cumulative ACE scores and individual ACEs on adult health outcomes to better understand key risk and protective factors for future prevention efforts.


Understanding how lake populations of arctic char are structured and function with special consideration of the potential effects of climate change: a multi-faceted approach.
Size dimorphism in fish populations, both its causes and consequences, has been an area of considerable focus; however, uncertainty remains whether size dimorphism is dynamic or stabilizing and about the role of exogenous factors. Here, we explored patterns among empirical vital rates, population structure, abundance and trend, and predicted the effects of climate change on populations of arctic char (Salvelinus alpinus) in two lakes. Both populations cycle dramatically between dominance by small (≤300 mm) and large (>300 mm) char. Apparent survival (Φ) and specific growth rates (SGR) were relatively high (40-96%; SGR range 0.03-1.5%) and comparable to those of conspecifics at lower latitudes. Climate change scenarios mimicked observed patterns of warming and resulted in temperatures closer to optimal for char growth (15.15 °C) and a longer growing season. An increase in consumption rates (28-34%) under climate change scenarios led to much greater growth rates (23-34%). Higher growth rates predicted under climate change resulted in an even greater predicted amplitude of cycles in population structure as well as an increase in reproductive output (Ro) and decrease in generation time (Go). Collectively, these results indicate arctic char populations (not just individuals) are extremely sensitive to small changes in the number of ice-free days. We hypothesize years with a longer growing season, predicted to occur more often under climate change, produce elevated growth rates of small char and act in a manner similar to a "resource pulse," allowing a sub-set of small char to "break through," thus setting the cycle in population structure.


New applications for biocatalysts.
Biocatalysis has always been a key focus area in biotechnology and new approaches for the utilization of biocatalysts have continued to emerge over the past year. Significant progress has been made in the biocatalytic production of both synthetic and natural polymers, in the generation of novel biocatalysts using genetic and biochemical approaches or through identification of new biological sources, in the immobilization of biocatalysts and their modification with amphiphilic polymers, and in the modulation of the stereochemistry of enzymatic reactions.


Bradykinin causes a transient rise of intracellular Ca2+-activity in cultured neural cells.
The concentration of intracellular free calcium ions was measured by spectrofluorometry in suspensions of quin2 loaded neural cell lines: neuroblastoma X glioma hybrid cells (clones 108CC15 and 108CC25) and polyploid rat glioma cells (clone C6-4-2). In these cells, bradykinin elicits a transient increase of the cytosolic Ca2+-activity in a dose-dependent manner (half-maximal effect at about 10 nM). The effect requires the presence of extracellular Ca2+. The time to peak is at most 10 s, the decay to the original level lasts 1 min and is followed by a period of 1-4 min during which Ca2+ activity is slightly below control value. Lys-bradykinin and Met-Lys-bradykinin evoke similar effects as bradykinin, but at concentrations 10 times lower. The cells desensitize upon repeated addition of bradykinin. Under the same conditions des-Arg1-bradykinin, des-Arg9-bradykinin, angiotensin II, substance P, apamin and histamine exerted no influence on the concentrations of free Ca2+. Similar to their effect in neural cell lines, bradykinin and Lys-bradykinin induce in primary astroglia-rich cultures from rat brain an increase in the concentration of cytosolic Ca2+ with the peak reached within 30 s and the decay to the original level lasting approximately 4 min. The significance of this effect of bradykinin on the cytosolic Ca2+-activity is discussed in relation to previous findings that bradykinin in the same cell lines induces a hyperpolarization, a rise of the cyclic GMP level and a breakdown of phosphoinositides.


Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas.
The gene products of CDH13 and CDH1, H-cadherin and E-cadherin, respectively, play a key role in cell-cell adhesion. Inactivation of the cadherin-mediated cell adhesion system caused by aberrant methylation is a common finding in human cancers, indicating that the CDH13 and CDH1 function as tumor suppressor and invasion suppressor genes. In this study, we analyzed the expression of H-cadherin mRNA and E-cadherin protein in 5 normal pituitary tissues and 69 primary pituitary adenomas including all major types by quantitative real-time RT-PCR (qRT-PCR) and immunohistochemistry, respectively. Reduced expression of H-cadherin was detected in 54% (28/52) of pituitary tumors and was significantly associated with tumor aggressiveness (P<0.05). E-cadherin expression was lost in 30% (21 of 69) and significantly reduced in 32% (22 of 69) of tumors. E-cadherin expression was significantly lower in grade II, III, and IV than in grade I adenomas (P=0.015, P=0.029, and P=0.01, respectively). Using methylation-specific PCR (MSP), promoter hypermethylation of CDH13 and CDH1 was detected in 30 and 36% of 69 adenomas, respectively, but not in 5 normal pituitary tissues. Methylation of CDH13 was observed more frequently in invasive adenomas (42%) than in non-invasive adenomas (19%) (P<0.05) and methylation of CDH1 was more frequent in grade IV adenomas compared with grade I adenomas (P<0.05). Methylation of either CDH13 or CDH1 was identified in 35 cases (51%) and was more frequent in grade IV invasive adenomas than in grade I non-invasive adenomas (P<0.05 and P<0.05, respectively). Downregulation of expression was correlated with promoter hypermethylation in CDH13 and CDH1. In conclusion, the tumor-specific downregulation of expression and methylation of CDH13 and CDH1, alone or in combination, may be involved in the development and invasive growth of pituitary adenomas.


Chemotherapy: new uses for old drugs.
Using chemotherapy drugs as antiangiogenic agents is a new use for drugs that have been around for a long time. The favorable toxicity profile and reduced cost make low-dose continuous "metronomic" chemotherapy trials appealing, but there is still much to be learned. Challenges ahead include determination of the optimal tumor types, drugs, doses, schedules, and response monitoring (end points). The measurement of angiogenic growth factors and inhibitors and of circulating endothelial progenitor cells or their precursors represents promising strategies in these areas.


Systematic optimization for production of the anti-MRSA antibiotics WAP-8294A in an engineered strain of Lysobacter enzymogenes.
WAP-8294A is a group of cyclic lipodepsipeptides and considered as the first-in-class new chemical entity with potent activity against methicillin-resistant Staphylococcus aureus. One of the roadblocks in developing the WAP-8294A antibiotics is the very low yield in Lysobacter. Here, we carried out a systematic investigation of the nutritional and environmental conditions in an engineered L. enzymogenes strain for the optimal production of WAP-8294A. We developed an activity-based simple method for quick screening of various factors, which enabled us to optimize the culture conditions. With the method, we were able to improve the WAP-8294A yield by 10-fold in small-scale cultures and approximately 15-fold in scale-up fermentation. Additionally, we found the ratio of WAP-8294A2 to WAP-8294A1 in the strains could be manipulated through medium optimization. The development of a practical method for yield improvement in Lysobacter will facilitate the ongoing basic research and clinical studies to develop WAP-8294A into true therapeutics.


Localization of Receptors for Sex Steroids and Pituitary Hormones in the Female Genital Duct throughout the Reproductive Cycle of a Viviparous Gymnophiona Amphibian, Typhlonectes compressicauda.
Reproduction in vertebrates is controlled by the hypothalamo-pituitary-gonadal axis, and both the sex steroid and pituitary hormones play a pivotal role in the regulation of the physiology of the oviduct and events occurring within the oviduct. Their hormonal actions are mediated through interaction with specific receptors. Our aim was to locate α and β estrogen receptors, progesterone receptors, gonadotropin and prolactin receptors in the tissues of the oviduct of Typhlonectes compressicauda (Amphibia, Gymnophiona), in order to study the correlation between the morphological changes of the genital tract and the ovarian cycle. Immunohistochemical methods were used. We observed that sex steroids and pituitary hormones were involved in the morpho-functional regulation of oviduct, and that their cellular detection was dependent on the period of the reproductive cycle.


Impact of solid-fluid interfacial layer and nanoparticle diameter on Maxwell nanofluid flow subjected to variable thermal conductivity and uniform magnetic field.
The utilization of Maxwell fluid with nanoparticle suspension exhibits promising prospects in enhancing the efficacy of energy conversion and storage mechanisms. They have the potential to be utilized in sophisticated cooling systems for power generation facilities, thereby augmenting the overall energy efficacy. Keeping this in mind, the current research examines the Maxwell nanofluid flow over a rotating disk with the impact of a heat source/sink. The present study centers on the examination of flow characteristics in the existence of a uniform magnetic field. The conversion of governing equations into ordinary differential equations is achieved using appropriate similarity variables. To derive the Nusselt number (Nu) and skin friction (SF) model related to the flow and temperature parameters, the suggested back-propagation artificial neural networking (ANN) technique is used. The Runge-Kutta-Fehlberg fourth-fifth order (RKF-45) method is used to solve the reduced equations and produce the necessary data to create the Nu and SF model. Both the Nu and SF models require 1000 data for training the network, respectively. Graphs are utilized to communicate numerical outcomes. The results concluded that the upsurge in magnetic parameter drops the velocity profile but advances the heat transport. Rise in the thermal conductivity parameter, increases the heat transport.


Water footprint: applying the water footprint assessment method to Australian agriculture.
Water footprint assessment is essential for the evaluation of water scarcity that considers both direct and indirect water consumption along the supply chain. This paper presents the estimation of water footprint for locally grown fruits and vegetables in Australia. Water footprint was calculated based on the framework developed in the Water Footprint Assessment Manual for the crops which are the most practicable to grow in Australia. Nine different crops (apples, grapes, tomatoes, oranges, peaches/nectarines, cherries, potatoes, carrots/turnips and almonds) in the agricultural industry were selected and identified as the most water-consumptive crop and least water-consumptive crop. For each type of crop, the three main water footprint components (blue, green, and grey water) were calculated. It was found that almond had the highest water footprint (6671.96 m3 ton-1 ) and tomato had the lowest water footprint (212.24 m3 ton-1 ) in Australia. From the global comparison, it is revealed that total water footprint for Australian crops is much higher than the corresponding international average values, except for tomatoes, potatoes and almonds. Also, almonds had the highest water footprint among the nine crops investigated. The study provides an insight into future sustainable cropping patterns in Australia, which suggest that tomatoes, carrots/turnips, potatoes and apples should continue to be grown in Australia, whereas stone fruit (e.g., almonds) should no longer be grown because of its high water footprint. © 2020 Society of Chemical Industry.


Vagal control of diaphragm timing in cat while breathing at elevated lung volumes.
This paper proposes and tests an hypothesis to account for the roles of the volume and rate components of vagal feedback in determining the steady-state pattern of breathing during continuous positive pressure breathing (PPB) and expiratory threshold loading (ETL) in Dial anesthetized cats. During PPB the duration of diaphragm activity (Tdi) is shortened; the duration of its expiratory pause (Tep) is lengthened with little or no change in cycle duration (Tt); with onset of inspiration, flow (dV/dt) is increased; as inspiration proceeds, flow decelerates (d2V/dt2). During ETL Tdi, Tep and Tt are all prolonged; dV/dt is decreased at onset of inspiration, with either no change or an acceleration in flow as inspiration proceeds. PPB and ETL cause similar increases in resting lung volume and Tep, and high negative correlations between Tdi and flow. These relationship suggest that the 'volume component' of vagal feedback is one important factor controlling Tep whereas the 'rate component' contributes to the restraint of Tdi.


Effect of Organic or Inorganic Mineral Premix in the Diet on Laying Performance of Aged Laying Hens and Eggshell Quality.
In this study, we examined the effect of diets supplemented with organic and inorganic mineral premixes on the laying performance and eggshell quality of aged laying hens. A total of 600 68-week-old Hy-Line Brown laying hens were randomly assigned to 1 of 3 dietary treatments, repeated 5 times: Mash type basal diet, basal diet supplemented with an inorganic mineral premix (1.0 g/kg), and basal diet supplemented with an organic mineral premix (1.8 g/kg). The results showed that eggshell strength was higher (p < 0.01) in the inorganic mineral diet group than in the organic mineral and basal diet groups. Further, the levels of Fe and Mn in the liver were higher (p < 0.05) in the inorganic and organic mineral diet groups than in the basal diet group. The concentrations of Fe and Mg in the spleen were different (p < 0.05) among the treatment groups, with the highest levels reported in the organic mineral premix group. The concentrations of Cu, Zn, and Mn in the eggshell were different (p < 0.05) among the groups, with the highest levels reported in the inorganic and organic mineral premix diet groups. In conclusion, a diet containing organic mineral premix improved eggshell strength and had no detrimental effect on the laying performance of aged laying hens.


Correlates of drug treatment outcomes for African American and white male federal prisoners: results from the TRIAD study.
The purpose of this study was to compare the effects of family background and preincarceration socioenvironmental variables on three-year post-release drug use for African American and white prison-based drug treatment participants in order to explain the previously found disparities in rates of three-year post-release drug use between the two groups. There were two hypotheses: 1) for both groups, family background and preincarceration socioenvironmental variables would predict postrelease drug use more strongly than sociodemographic characteristics and preincarceration behaviors, and 2) the predictors would be different for each group. The sample included 279 African American and 512 white male treatment participants who were supervised by a U.S. probation officer following incarceration. Event history analyses were used to model time to first drug use during postrelease supervision. The results indicated that none of the family background factors or socioenvironmental variables predicted postrelease drug use. The variables predictive of drug use for one or both racial groups were limited to sociodemographic characteristics and preincarceration behaviors such as age at release, prior commitments, and preincarceration employment. Yet, there were no significant between-group differences for these predictors. The authors concluded that future assessment of the effects of socioenvironmental variables on postrelease drug use likely requires evaluation of the postrelease social environment at the time of release.


Identification and validation of aging-related genes in atrial fibrillation.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the clinic. Aging plays an essential role in the occurrence and development of AF. Herein, we aimed to identify the aging-related genes associated with AF using bioinformatics analysis. Transcriptome profiles of AF were obtained from the GEO database. Differential expression analysis was performed to identify AF-specific aging-related genes. GO and KEGG enrichment analyses were performed. Subsequently, the LASSO, SVM-RFE, and MCC algorithms were applied to screen aging-related genes. The mRNA expression of the screened genes was validated in the left atrial samples of aged rapid atrial pacing-induced AF canine models and their counterparts. The ROC curves of them were drawn to evaluate their diagnostic potential. Moreover, CIBERSORT was used to estimate immune infiltration. A correlation analysis between screened aging-related genes and infiltrating immune cells was performed. A total of 24 aging-related genes were identified, which were found to be mainly involved in the FoxO signaling pathway, PI3K-Akt signaling pathway, longevity regulating pathway, and peroxisome according to functional enrichment analysis. LASSO, SVM-RFE, and MCC algorithms identified three genes (HSPA9, SOD2, TXN). Furthermore, the expression levels of HSPA9 and SOD2 were validated in aged rapid atrial pacing-induced AF canine models. HSPA9 and SOD2 could be potential diagnostic biomarkers for AF, as evidenced by the ROC curves. Immune infiltration and correlation analysis revealed that HSPA9 and SOD2 were related to immune cell infiltrates. Collectively, these findings provide novel insights into the potential aging-related genes associated with AF. HSPA9 and SOD2 may play a significant role in the occurrence and development of AF.


Localization of Arabidopsis FORKED1 to a RABA-positive compartment suggests a role in secretion.
When FORKED1 (FKD1) is mutated, asymmetric localization of PINFORMED1 (PIN1), particularly to the apical side of cells, fails to occur properly in developing veins, resulting in an open vein pattern. FKD1 encodes a protein with a Pleckstrin homology-like (PL) domain, suggesting interaction with phosphoinositides. FKD1 has been previously found to interact with an ADP ribosylation factor GTPase-activating protein (ARF-GAP) important for vein patterning, SCARFACE/VAN3 (SFC). We find that FKD1-green fluorescent protein (GFP) localizes to the plasma membrane and to punctae labeled by SFC-yellow fluorescent protein (YFP). Supporting the idea that the FKD1 PL domain recognizes phosphatidylinositol 4-phosphate [PtdIns(4)P], FKD1-GFP co-localizes with PtdIns(4)P markers, and is more cytosolic when in a background mutant for the PtdIns(4,5)P2 hydrolases CVP2 and CVL1. Both FKD1 and SFC partially co-localize with markers for the trans-Golgi network (TGN), at which endocytic and secretory pathways merge. FKD1-labeled punctae rarely co-localize with the endocytic marker FM4-64, suggesting that FKD1 is not involved primarily in the endocytic pathway. FKD1 and SFC co-localize with members of the RABA group of RAB-GTPases, which are proposed to act in the post-Golgi secretory pathway. The compartments labeled by FKD1 and SFC do not localize to membrane compartments induced by the fungal toxin brefeldin A (BFA). Collectively, our data suggest that FKD1 and SFC act in a BFA-insensitive secretory pathway.


Influenza and aging: age-related changes and the effects of thymosin on the antibody response to influenza vaccine.
Despite massive immunization programs, influenza remains a major cause of morbidity and mortality for elderly people. This may occur because immune senescent recipients may respond to vaccination with inadequate antibody production. We measured antibody response to the trivalent 1983-1984 influenza vaccine in young and elderly volunteers and found a significantly reduced response in the latter. The age-associated decreased antibody production was also observed in lymphocyte cultures in which specific antiinfluenza antibody synthesis was measured. In these cultures, however, the addition of a thymic hormone preparation (either thymosin fraction 5 or thymosin alpha 1) was shown to enhance specific antibody synthesis to a greater extent in the cultures established from the elderly volunteers. If this in vitro observation of thymosin induced increased antibody production reflects what might occur in a clinical trial in which elderly subjects receive thymosin coincident with vaccine, greater protection against influenza infection may result.


[Historical aspects of the determination of the time of death].
The origins of the determination of the time of death are presented with special reference to the signs of death, rigor mortis and body cooling, as well as to the supravital electrical response of skeletal muscle. The systematic method for future research resulting from these old experiments is presented, with the aim of making a more precise estimation of the time of death by standardization of the influencing factors.


Differential localization and turnover of infectious bronchitis virus 3b protein in mammalian versus avian cells.
Infectious bronchitis virus (IBV) 3b protein is highly conserved among group 3 coronaviruses, suggesting that it is important for infection. A previous report (Virology 2003, 311:16-27) indicated that transfected IBV 3b localized to the nucleus in mammalian cells using a vaccinia-virus expression system. Although we confirmed these findings, we observed cytoplasmic localization of IBV 3b with apparent exclusion from the nucleus in avian cells (IBV normally infects chickens). IBV 3b was virtually undetectable by microscopy in mammalian cells transfected without vaccinia virus and in IBV-infected mammalian cells because of a greatly reduced half-life in these cells. A proteasome inhibitor stabilized IBV 3b in mammalian cells, but had little effect on IBV 3b in avian cells, suggesting that rapid turnover of IBV 3b in mammalian cells is proteasome-dependent while turnover in avian cells may be proteasome-independent. Our results highlight the importance of using cells derived from the natural host when studying coronavirus non-structural proteins.


Central nervous system agents in the treatment of erectile dysfunction.
In the last two decades, a better understanding of the mechanisms governing erectile function and the pathophysiologies underlying erectile dysfunction (ED) have led re-searchers to investigate novel treatment concepts. Selective type-5 phosphodiesterase inhibitors are recommended as first-line therapy because of their high efficacy, but 30% to 40% of patients who have ED do not respond adequately to these agents and require alternative methods. The central nervous system plays a fundamental role in sexual behavior. Animal models have advanced our understanding of the neuroanatomic and neuropharmacologic basis of centrally induced penile erections. Clinical research with apomorphine has demonstrated efficacy in men who have a range of ED. Recent interest has focused on other centrally acting agents for ED treatment, including the melanocortin receptor agonists.