Mesenchymal stem/stromal cell extracellular vesicles: From active principle to next generation drug delivery system.
It has been demonstrated that the biological effector of mesenchymal stem/stromal cells (MSCs) is their secretome, which is composed of a heterogeneous pool of bioactive molecules, partially enclosed in extracellular vesicles (EVs). Therefore, the MSC secretome (including EVs) has been recently proposed as possible alternative to MSC therapy. The secretome can be considered as a protein-based biotechnological product, it is probably safer compared with living/cycling cells, it presents virtually lower tumorigenic risk, and it can be handled, stored and sterilized as an Active Pharmaceutical/Principle Ingredient (API). EVs retain some structural and technological analogies with synthetic drug delivery systems (DDS), even if their potential clinical application is also limited by the absence of reproducible/scalable isolation methods and Good Manufacturing Practice (GMP)-compliant procedures. Notably, EVs secreted by MSCs preserve some of their parental cell features such as homing, immunomodulatory and regenerative potential. This review focuses on MSCs and their EVs as APIs, as well as DDS, considering their ability to reach inflamed and damaged tissues and to prolong the release of encapsulated drugs. Special attention is devoted to the illustration of innovative therapeutic approaches in which nanomedicine is successfully combined with stem cell therapy, thus creating a novel class of "next generation drug delivery systems."


[Comparison of effects of nebivolol and atenolol on P-wave dispersion in patients with hypertension].
P-wave dispersion has been shown to be a noninvasive electrocardiographic predictor for development of atrial fibrillation . Thus it may be possible to attenuate atrial fibrillation risk through normalization of P-wave variables and improvement in P-wave dispersion may be an important goal in treatment of hypertension. To compare the effects of nebivolol, a new b-blocker that have additional vasodilating activity via acting on endothelium and nitric oxide release, and atenolol on P-wave duration and dispersion in patients with mild-to-moderate hypertension. A total of 34 newly-diagnosed hypertensive patients were enrolled in the study. The patients were randomly assigned to receive treatment with either nebivolol (5 mg) or atenolol (50 mg). P-wave durations (Pmin and Pmax) and P-wave dispersion were measured before and one month after treatment. While Pmin increased (50,6 +/- 11,2 ms to 54,7 +/- 9,1 ms, p=0,05), Pmax decreased (111,9 +/- 9,1 ms to 104,0 +/- 12,4 ms, p=0,003) and P-wave dispersion decreased (62,5 +/- 10,6 ms to 51,3 +/- 8,9 ms, p < 0,001) with nebivolol, Pmin increased (44,4 +/- 9,8 ms to 58,0 +/- 15,5 ms, p=0,02), Pmax didn t change (106,1 +/- 13,8 ms to 107,0 +/- 11,6 ms, p=NS) and P-wave dispersion decreased (61,7 +/- 15,0 ms to 49,0 +/- 13,7 ms, p < 0.001) with atenolol. However, there was no statistical difference between pre- and post-treatment values of two groups. Both nebivolol and atenolol are effective in improvement of P-wave dispersion in patients with hypertension and there s no significant difference between them.


Supraoptic nucleus of the Brattleboro rat has an altered afferent noradrenergic input.
The distribution of fluorescent varicosities in the supraoptic nucleus of Brattleboro rats was compared to that in normal rats. The Brattleboro rat, which is characterized by a genetic absence of vasopressin, had fewer fluorescent varicosities in apposition to the vasopressin-deficient perikarya. The oxytocin-producing neurons in the same nucleus were hyperinnervated. These data suggest that the target neuron peptide (vasopressin) is necessary for the maintenance of normal noradrenergic innervation patterns.


Immunohistochemical localization of carcinogen-metabolizing enzymes within the rat and hamster exocrine pancreas.
The P-450 cytochromes, reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase, epoxide hydrolase, and glutathione S-transferases all play important roles in the bioactivation and detoxication of various classes of chemical mutagens and carcinogens. The present investigation was undertaken to determine if and where these enzymes are located within the exocrine pancreas, a tissue that is a target for chemically induced neoplasia. In this study, reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase, two isozymes of cytochrome P-450 (cytochromes P-450 PB-B and BNF-B), epoxide hydrolase, and glutathione S-transferases B, C/A, and E were each localized at the light microscopic level within exocrine pancreases of untreated rats and hamsters utilizing the unlabeled antibody peroxidase-antiperoxidase staining technique. Immunohistochemical staining for each of these enzymes was apparent within acinar cells in pancreases of Holtzman, Sprague-Dawley, Wistar, and Fischer 344 rats. Staining for the reductase, the epoxide hydrolase, and the glutathione S-transferases was also observed within the epithelia of both interlobular and intralobular ducts in the exocrine pancreases of these rat strains, whereas staining for cytochromes P-450 PB-B and BNF-B was not readily detectable within epithelial cells of the rat pancreatic duct system. In the exocrine pancreas of the Syrian golden hamster, immunohistochemical staining for reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase, epoxide hydrolase, and glutathione S-transferases B and C/A was similar to that observed within the rat exocrine pancreas. In contrast, acinar and duct cells in the hamster pancreas both appeared to be stained for cytochrome P-450 PB-B, whereas staining for cytochrome P-450 BNF-B could not be readily detected within either acinar or duct cells, and staining for glutathione S-transferases E did not appear to be present within duct cells in the hamster pancreas. The results of this investigation therefore suggest that highly reactive and toxic electrophilic metabolites of procarcinogens may be generated to the greatest extent within acinar cells in the rat pancreas, whereas these metabolites may be produced within both acinar and duct cells in the hamster pancreas. Regardless of where they are formed, reactive metabolites may be enzymatically detoxicated within both acinar and duct cells in the rat and hamster exocrine pancreas.


Identification of seroreactive regions of the human papillomavirus type 16 protein E4, E6, E7 and L1.
Small fragments of the DNA of human papillomavirus type 16 (HPV-16) were randomly cloned into the bacteriophage fd which expresses the resulting peptides as part of its capsid. Antisera raised against different HPV-16 fusion proteins were used for screening of the phage clones and the reacting peptides were determined by sequencing the inserted HPV-16 DNA fragments of the positive recombinants. Seroreactive regions of the proteins derived from the E4, E6, E7 (two regions) and L1 (three regions) open reading frames could be found by this approach. Of these seven regions, four were defined by at least two overlapping inserts, thus limiting the domains to between 10 and 15 amino acids. In the case of the E4 open reading frame, the same region identified by immunoscreening was also found when synthetic overlapping octapeptides were tested by ELISA with the anti-E4 antiserum. Using an approach to predict 'receptor-like' regions within the respective proteins, five of the seven regions were also identified. From the data on these regions, synthetic peptides were produced and used for the detection of antibodies against HPV-16 proteins in human sera by ELISA.


Factors influencing quantitative CT measurements of solitary pulmonary nodules.
Quantitative computed tomographic (CT) measurement of pulmonary nodules has not been widely applied despite favorable reports. Its usefulness has been questioned by some investigators. A series of experiments on six different scanners was undertaken to study the factors that affect the applicability of this technique. The type of reconstruction algorithm, the design of the CT system, the true slice thickness, and the beam kilovoltage were the most important factors identified. These factors can produce large variations in the CT numbers of pulmonary nodules, preventing direct comparison of results from scanner to scanner. Before undertaking studies of pulmonary nodules, the effect of these variables in each individual scanner should be evaluated. Despite the current lack of standardization, reliable CT number measurements using a specific kilovoltage and slice thickness should be possible on every modern scanner provided it is positionally uniform and gives a linear response to varying densities. We propose that the CT number above which a pulmonary nodule can be considered benign should be the representative CT number of a 1 cm diameter syringe filled with a hydrous calcium chloride solution of 40 mg/ml of water and scanned in air. A better understanding of the physics of lung nodule densitometry is necessary for the proper application of this technique in the management of patients with solitary pulmonary nodules.


Brain-Specific Angiogenesis Inhibitor 3 Is Expressed in the Cochlea and Is Necessary for Hearing Function in Mice.
Mammalian auditory hair cells transduce sound-evoked traveling waves in the cochlea into nerve stimuli, which are essential for hearing function. Pillar cells located between the inner and outer hair cells are involved in the formation of the tunnel of Corti, which incorporates outer-hair-cell-driven fluid oscillation and basilar membrane movement, leading to the fine-tuned frequency-specific perception of sounds by the inner hair cells. However, the detailed molecular mechanism underlying the development and maintenance of pillar cells remains to be elucidated. In this study, we examined the expression and function of brain-specific angiogenesis inhibitor 3 (Bai3), an adhesion G-protein-coupled receptor, in the cochlea. We found that Bai3 was expressed in hair cells in neonatal mice and pillar cells in adult mice, and, interestingly, Bai3 knockout mice revealed the abnormal formation of pillar cells, with the elevation of the hearing threshold in a frequency-dependent manner. Furthermore, old Bai3 knockout mice showed the degeneration of hair cells and spiral ganglion neurons in the basal turn. The results suggest that Bai3 plays a crucial role in the development and/or maintenance of pillar cells, which, in turn, are necessary for normal hearing function. Our results may contribute to understanding the mechanisms of hearing loss in human patients.


[Medical errors in hospitalized patients].
To review the current literature and to discuss medical errors in hospitalized patients emphasizing its incidence, predisposing factors and prevention mechanism. Special attention is given to medication errors and adverse drug events in newborn infants and pediatric patients. Bibliographic review of the current literature through electronic search in Medline data-base, with selection of the most relevant articles. Even though most medical errors are not reported, it is important to notice that its incidence is greater than previously assumed. In the USA, approximately one million of patients/year are victims of medical errors and adverse drug events. Today, deaths resulting from these episodes are the fourth cause of mortality in the USA. In neonatal and pediatric intensive care units, where the complexity and frequency of technical procedures are high, medical errors are frequent. Fifteen percent of all admissions to a neonatal intensive care unit is followed by medical errors. Most of these errors occur during night shifts and include incorrect administration of drugs (35%) and errors regarding the interpretation of medical prescription (26%). Environmental factors (noise, heat), psychological factors (anxiety, stress) and physiologic factors (fatigue, absence of sleep) contribute to the occurrence of errors. Recent study shows that after working 24 hours without sleeping, the performance of a health professional is similar to a legally drunk person (serum alcohol level > or =0.08%). Errors are part of human behavior. The prevention of errors should include a careful review of the organizational system. Medical errors should be seen as an opportunity to change or re-structure the system and to improve the quality of health care delivered and patient safety.


Antivirals Targeting the Neuraminidase.
The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.


Interprofessional education for first year psychology students: career plans, perceived relevance and attitudes.
Undergraduate psychology students have been largely excluded from interprofessional education (IPE) initiatives. In contrast to many health professions, undergraduate psychology students do not engage in work placements as part of their degree, and many enter careers outside the health care context. However, the collaborative skills gained through an IPE experience may well be beneficial to students who work in this wider context. This research examines whether undergraduate psychology students' views of IPE vary according to their planned career directions, and if so, whether the perceived relevance of IPE mediates the relationships. A sample of 188 Australian university undergraduate psychology students completed an online questionnaire following completion of a first-year IPE health sciences program. Path analysis indicated that psychology students' attitudes towards IPE are associated with both professional identification and practitioner orientation, fully mediated through the perceived relevance of IPE to future career and study plans. Stronger professional identification and practitioner orientation were associated with greater perceived relevance and more positive and less negative attitudes towards IPE. Placing a stronger emphasis on the generalizability of IP skills taught may increase students' awareness of the relevance outside of the health context, reducing disengagement of students planning alternative careers.


Tear of peroneus longus in long distance runners due to enlarged peroneal tubercle.
Tear of the Peroneus longus in association with a prominent peroneal tubercle is rare. Recently we treated two long distance runners who developed lateral ankle pain. Maximum tenderness was located over the lateral surface of the heel in the area of the peroneal tendons. Imaging disclosed a tear of the peroneus longus at the area of the peroneal tubercle. Following resection of the peroneal tubercle and repair of the peroneus longus, both patients regained full activity with no pain. This report describes the clinical presentation and surgical management of this rare injury.


[Cytologic survey of CSF in the meningeal hemorrhages (author's transl)].
We have selected a group of young patients, without any pathological past, admitted in the hospital after traffic accidents. CSF was examined at various periods after the accident as well on the cytological as on the biological point. If the lumbar punction is undertaken in the very few hours after the trauma or at the time of the onset of a meningeal syndrom, the presence of oxyhemoglobin may confirm the abnormal bleeding and makes difference with the stitching of a vessel during the punction. The presence of macrophages red blood cell containing may characterize a 2--3 days bleeding. The presence of macrophages containing iron pigment may confirm that the bleeding appeared at least 6--7 days before the cytological patterns and the chromoprotein assays provide a valuable help to the physiologist and may be applied to all types of meningeal hemorrhages.


The recovery of walking in stroke patients: a review.
We reviewed the literature on walking recovery of stroke patients as it relates to the following subjects:epidemiology of walking dysfunction, recovery course of walking, and recovery mechanism of walking (neural control of normal walking, the evaluation methods for leg motor function, and motor recovery mechanism of leg).The recovery of walking is one of the primary goals in stroke patients, along with the recovery of hand function and cognition. Walking function has greater potential for recovery than hand function because motor function of the leg is less dependent on the lateral corticospinal tract than that of hand function. This suggests that detailed knowledge of walking can be used to increase the likelihood that stroke patients recover their ability to walk. Therefore, we suggest that further research should focus on these topics, especially, on the neural control mechanism of walking and motor recovery mechanisms of the leg in stroke patients.


Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing, Non-interventional VARGADO Study.
To evaluate the efficacy and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) who progressed after chemotherapy and immune checkpoint inhibitor (ICI) therapy. VARGADO (NCT02392455) is an ongoing, prospective, non-interventional, real-world study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC. Data were collected during routine visits. We report the results from cohort B (n = 80), who received third-line nintedanib plus docetaxel after first-line chemotherapy and second-line ICI therapy. The median duration of follow-up was 12.4 months. Median progression-free survival from initiation of third-line nintedanib plus docetaxel was 6.4 months (95% confidence interval 4.8, 7.3); median overall survival was 12.1 months (95% confidence interval 9.4, 13.5). The 1-year overall survival rate after initiation of third-line nintedanib plus docetaxel treatment (primary end point) was 52% (95% confidence interval 38.0%, 64.4%). Among 64 patients with a documented response, the objective response rate was 50% (n = 32; one complete response and 31 partial responses) and the disease control rate was 86% (n = 55). There were no new safety signals or unexpected toxicities. Among all treated patients, 74% (n = 59) experienced drug-related adverse events, most commonly (nintedanib-related/docetaxel-related) diarrhoea (34%/24%), a decreased white blood cell count (11%/19%) and nausea (13%/16%). Nintedanib plus docetaxel demonstrated a high response rate and disease stabilisation in the third-line setting after failure of prior chemotherapy and ICI treatment, with a manageable safety profile. These results suggest that nintedanib plus docetaxel represents an efficient treatment option after failure of prior ICIs. The ongoing VARGADO study provides valuable real-world data to inform clinical decision-making regarding treatment sequencing after chemotherapy and ICI failure in patients with adenocarcinoma NSCLC.


A genome-wide association study identifies genomic regions for virulence in the non-model organism Heterobasidion annosum s.s.
The dense single nucleotide polymorphisms (SNP) panels needed for genome wide association (GWA) studies have hitherto been expensive to establish and use on non-model organisms. To overcome this, we used a next generation sequencing approach to both establish SNPs and to determine genotypes. We conducted a GWA study on a fungal species, analysing the virulence of Heterobasidion annosum s.s., a necrotrophic pathogen, on its hosts Picea abies and Pinus sylvestris. From a set of 33,018 single nucleotide polymorphisms (SNP) in 23 haploid isolates, twelve SNP markers distributed on seven contigs were associated with virulence (P<0.0001). Four of the contigs harbour known virulence genes from other fungal pathogens and the remaining three harbour novel candidate genes. Two contigs link closely to virulence regions recognized previously by QTL mapping in the congeneric hybrid H. irregulare × H. occidentale. Our study demonstrates the efficiency of GWA studies for dissecting important complex traits of small populations of non-model haploid organisms with small genomes.


Relative fitness and replication capacity of a multinucleoside analogue-resistant clinical human immunodeficiency virus type 1 isolate with a deletion of codon 69 in the reverse transcriptase coding region.
Deletions, insertions, and amino acid substitutions in the beta3-beta4 hairpin loop-coding region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been associated with resistance to nucleoside RT inhibitors when appearing in combination with other mutations in the RT-coding region. In this work, we have measured the in vivo fitness of HIV-1 variants containing a deletion of 3 nucleotides affecting codon 69 (Delta69) of the viral RT as well as the replication capacity (RC) ex vivo of a series of recombinant HIV-1 variants carrying an RT bearing the Delta69 deletion or the T69A mutation in a multidrug-resistant (MDR) sequence background, including the Q151M complex and substitutions M184V, K103N, Y181C, and G190A. Patient-derived viral clones having RTs with Delta69 together with S163I showed increased RCs under drug pressure. These data were consistent with the viral population dynamics observed in a long-term-treated HIV-1-infected patient. In the absence of drugs, viral clones containing T69A replicated more efficiently than those having Delta69, but only when patient-derived sequences corresponding to RT residues 248 to 527 were present. These effects could be attributed to a functional interaction between the C-terminal domain of the p66 subunit (RNase H domain) and the DNA polymerase domain of the RT. Finally, recombinant HIV-1 clones bearing RTs with MDR-associated mutations, including deletions at codon 69, showed increased susceptibilities to protease inhibitors in phenotypic assays. These effects correlated with impaired Gag cleavage and could be attributed to delayed maturation and decreased production of active protease in those variants.


Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones.
Previous work has shown that guidance cues trigger rapid changes in protein dynamics in retinal growth cones: netrin-1 stimulates both protein synthesis and degradation, while Sema3A elicits synthesis, and LPA induces degradation. What signaling pathways are involved? Our studies confirm that p42/44 MAPK mediates netrin-1 responses and further show that inhibiting its activity blocks cue-induced protein synthesis. Unexpectedly, p38 MAPK is also activated by netrin-1 in retinal growth cones and is required for chemotropic responses and translation. Sema3A- and LPA-induced responses, by contrast, require a single MAPK, p42/p44 and p38, respectively. In addition, we report that caspase-3, an apoptotic protease, is rapidly activated by netrin-1 and LPA in a proteasome- and p38-dependent manner and is required for chemotropic responses. These findings suggest that the apoptotic pathway may be used locally to control protein levels in growth cones and that the differential activation of MAPK pathways may underlie cue-directed migration.


What roles do contemporaneous and cumulative incomes play in the income-child health gradient for young children? Evidence from an Australian panel.
The literature to date shows that children from poorer households tend to have worse health than their peers, and the gap between them grows with age. We investigate whether and how health shocks (as measured by the onset of chronic conditions) contribute to the income-child health gradient and whether the contemporaneous or cumulative effects of income play important mitigating roles. We exploit a rich panel dataset with three panel waves called the Longitudinal Study of Australian children. Given the availability of three waves of data, we are able to apply a range of econometric techniques (e.g. fixed and random effects) to control for unobserved heterogeneity. The paper makes several contributions to the extant literature. First, it shows that an apparent income gradient becomes relatively attenuated in our dataset when the cumulative and contemporaneous effects of household income are distinguished econometrically. Second, it demonstrates that the income-child health gradient becomes statistically insignificant when controlling for parental health and health-related behaviours or unobserved heterogeneity.


Ultrafast optical control using the Kerr nonlinearity in hydrogenated amorphous silicon microcylindrical resonators.
Microresonators are ideal systems for probing nonlinear phenomena at low thresholds due to their small mode volumes and high quality (Q) factors. As such, they have found use both for fundamental studies of light-matter interactions as well as for applications in areas ranging from telecommunications to medicine. In particular, semiconductor-based resonators with large Kerr nonlinearities have great potential for high speed, low power all-optical processing. Here we present experiments to characterize the size of the Kerr induced resonance wavelength shifting in a hydrogenated amorphous silicon resonator and demonstrate its potential for ultrafast all-optical modulation and switching. Large wavelength shifts are observed for low pump powers due to the high nonlinearity of the amorphous silicon material and the strong mode confinement in the microcylindrical resonator. The threshold energy for switching is less than a picojoule, representing a significant step towards advantageous low power silicon-based photonic technologies.


New experimental and theoretical tools for metabolic engineering of micro-organisms.
Presently an increasing gap is developing between our experimental capabilities in metabolic engineering of microbial metabolism and our quantitative theoretical understanding of the kinetic interaction between primary metabolism and product pathways. Such theoretical understanding is absolutely needed for a rational design of said metabolic engineering experiments and targets. To obtain such understanding in-vivo kinetic experiments and in-vivo kinetic models are needed. To this end the following new methods for in-vivo kinetic studies of Saccharomyces cerevisiae have recently been developed. The Bioscope device allows the reliable and repeated perturbation (e.g. glucose pulse, or inhibitor etc.) of steady state biomass outside the fermentor and subsequent sampling and quenching to measure glycolytical intermediates and nucleotides in a time frame of 0-70 seconds. Dynamic modelling of fermentor off-gas O2/CO2-measurements allows to calculate O2 uptake and CO2 production rates in such a perturbation experiment (0-70 seconds time windows). A new LC-MSMS based method has been developed to measure large sets of intracellular metabolites in said in-vivo kinetic experiments. It has been shown for the first time that in long chemostat cultivation (up to 800 hrs.) intracellular metabolites levels drop, showing absence of a real steady state. A new kinetic format, lin log kinetics, has been developed for describing the intracellular kinetic behavior of metabolic networks. This format allows general analytical solutions of networks flux, metabolic levels. From simulation studies it appears that this approach is remarkable accurate in describing intracellular metabolite dynamics and in metabolic design questions of where to change enzyme levels and how much to achieve a desired change in fluxes and metabolite levels. At this moment these tools are being applied in metabolic engineering studies of Saccharomyces cerevisiae and Penicillin chrysogenum.


Mystery of Sciatica Resolved - A Rare Case Report.
Schwannomas are common, benign, slow growing tumours of peripheral nerve sheath arising from the schwann cells of the neuroectoderm. They do not transverse the nerve but remain within the sheath on top of the nerve. They rarely present in the sciatic nerve. Sciatic schwannomas may mimic symptoms of herniated disc, usually with radiation of pain to buttocks and thigh region with inability to walk for long distances and sometimes may present with claudication. In the absence of low back pain and with a normal Lumbo-Sacral MRI study, causes intrinsic to sciatic nerve needs to be thought off, which often delays the diagnosis. Rarity in our case-patient presented with tingling sensation and inability to squat on hard surface for more than 10 minutes with a normal x-ray and MRI study of lumbosacral spine.


Surfactant protein B deficiency caused by a novel mutation involving multiple exons of the SP-B gene.
Inability to produce surfactant protein (SP)-B causes fatal neonatal respiratory disease. Homozygosity for a frameshift mutation (121ins2) in the gene encoding SP-B (SFTPB) is the predominant but not the exclusive cause of disease. To report a novel mutation in the SFTB gene. We analyzed tracheal aspirates, lung tissue obtained by in vivo lung biopsy and DNA from a newborn infant with lethal respiratory failure. DNA analysis revealed a large homozygous genomic deletion encompassing exon 7 and 8 of SFTPB gene, a mutation we described as c.673-1248del2959. The parents were both heterozygous carriers. Analysis of the SP profile in tracheal aspirates and lung tissue by immunohistochemistry, routine and electron microscopy supported the diagnosis of SP-B deficiency and suggested that this large mutation might lead to abnormal routing and processing of proSP-B and proSP-C. This report shows that SP-B deficiency can also be caused by a multi exon deletion in the SFTPB gene and this finding emphasizes the importance of using modern DNA analysis techniques capable of detecting multi exon deletions.


Impact of tip-apex distance and femoral head lag screw position on treatment outcomes of unstable intertrochanteric fractures using cephalomedullary nails.
Background Cephalomedullary nails are frequently used in unstable intertrochanteric fractures. The implant position is an important factor for surgical success. Thus, in the present study, finite element analysis methods were used to investigate the biomechanical behavior of five different cephalomedullary nail positions in unstable intertrochanteric fractures. Methods Five different cephalomedullary nail implant positions were investigated. The observed indicators were the maximum displacement of the lag screw, the stress on the intertrochanteric fracture with involvement of the posteromedial cortex, and the tip-apex distance. Results The smallest lag screw displacement was achieved when the implant was closer to the inferior femoral head. Lower stress was placed on the posteromedial cortex when the implant was positioned closer to the inferior femoral head. However, the tip-apex distance increased when the lag screw was positioned more inferiorly. Conclusions The results of this study suggest that positioning the lag screw closer to the inferior aspect of the femoral head can reduce stress on the posteromedial cortex and deformation of the implant in unstable intertrochanteric fractures. These findings provide a biomechanical basis for selection of the cephalomedullary nail implantation site. Level of evidence III.


Zeptomole electrochemical detection of metallothioneins.
Thiol-rich peptides and proteins possess a large number of biological activities and may serve as markers for numerous health problems including cancer. Metallothionein (MT), a small molecular mass protein rich in cysteine, may be considered as one of the promising tumour markers. The aim of this paper was to employ chronopotentiometric stripping analysis (CPSA) for highly sensitive detection of MT. In this study, we used adsorptive transfer stripping technique coupled with CPSA for detection of cysteine, glutathione oxidized and reduced, phytochelatin, bovine serum albumin, and metallothionein. Under the optimal conditions, we were able to estimate detection limits down to tens of fg per ml. Further, this method was applied to detect metallothioneins in blood serum obtained from patients with breast cancer and in neuroblastoma cells resistant and sensitive to cisplatin in order to show the possible role of metallothioneins in carcinogenesis. It was found that MT level in blood serum was almost twice higher as compared to the level determined in healthy individuals. This paper brings unique results on the application of ultra-sensitive electroanalytical method for metallothionein detection. The detection limit and other analytical parameters are the best among the parameters of other techniques. In spite of the fact that the paper is mainly focused on metallothionein, it is worth mentioning that successful detection of other biologically important molecules is possible by this method. Coupling of this method with simple isolation methods such as antibody-modified paramagnetic particles may be implemented to lab-on-chip instrument.


Real-Time Detection of Freezing Motions in Parkinson's Patients for Adaptive Gait Phase Synchronous Cueing.
Parkinson's disease is the second most common neurodegenerative disease worldwide reducing cognitive and motoric abilities of affected persons. Freezing of Gait (FoG) is one of the severe symptoms that is observed in the late stages of the disease and considerably impairs the mobility of the person and raises the risk of falls. Due to the pathology and heterogeneity of the Parkinsonian gait cycle, especially in the case of freezing episodes, the detection of the gait phases with wearables is challenging in Parkinson's disease. This is addressed by introducing a state-automaton-based algorithm for the detection of the foot's motion phases using a shoe-placed inertial sensor. Machine-learning-based methods are investigated to classify the actual motion phase as normal or FoG-affected and to predict the outcome for the next motion phase. For this purpose, spatio-temporal gait and signal parameters are determined from the segmented movement phases. In this context, inertial sensor fusion is applied to the foot's 3D acceleration and rate of turn. Support Vector Machine (SVM) and AdaBoost classifiers have been trained on the data of 16 Parkinson's patients who had shown FoG episodes during a clinical freezing-provoking assessment course. Two clinical experts rated the video-recorded trials and marked episodes with festination, shank trembling, shuffling, or akinesia. Motion phases inside such episodes were labeled as FoG-affected. The classifiers were evaluated using leave-one-patient-out cross-validation. No statistically significant differences could be observed between the different classifiers for FoG detection (p>0.05). An SVM model with 10 features of the actual and two preceding motion phases achieved the highest average performance with 88.5 ± 5.8% sensitivity, 83.3 ± 17.1% specificity, and 92.8 ± 5.9% Area Under the Curve (AUC). The performance of predicting the behavior of the next motion phase was significantly lower compared to the detection classifiers. No statistically significant differences were found between all prediction models. An SVM-predictor with features from the two preceding motion phases had with 81.6 ± 7.7% sensitivity, 70.3 ± 18.4% specificity, and 82.8 ± 7.1% AUC the best average performance. The developed methods enable motion-phase-based FoG detection and prediction and can be utilized for closed-loop systems that provide on-demand gait-phase-synchronous cueing to mitigate FoG symptoms and to prevent complete motoric blockades.


Neutralization determinants of laboratory strains and field isolates of equine arteritis virus: identification of four neutralization sites in the amino-terminal ectodomain of the G(L) envelope glycoprotein.
The N-terminal hydrophilic ectodomain of the G(L) envelope glycoprotein of equine arteritis virus (EAV) contains neutralization determinants of the virus. We developed a panel of 17 neutralizing murine monoclonal antibodies (MAbs) to further characterize the neutralization determinants of EAV. Included were 6 MAbs previously raised against a laboratory strain (EAVUCD) of the original Bucyrus strain of EAV, as well as 11 additional MAbs that were raised against a neutralization-resistant variant [escape mutant (EM)] virus (EM6D10) that was derived from EAVUCD. All MAbs raised against EAVUCD and 4 of the MAbs raised against EM6D10 (2B3, 5F8, 8D4, and 10B4) reacted with the corresponding G(L) envelope glycoprotein in a Western immunoblotting assay, whereas the remaining 7 MAbs raised against EM6D10 did not react with any viral protein in the immunoblotting assay but competitively inhibited the binding of MAbs 2B3, 5F8, 8D4, and 10B4, indicating that they also recognize epitopes on the G(L) protein. A panel of 18 EM viruses raised to the MAb panel, 19 field isolates of EAV from North America and Europe, the modified-live virus vaccine (ARVAC), and 3 other laboratory strains of EAV were characterized by microneutralization assay with the panel of neutralizing MAbs and polyclonal rabbit and horse antisera. Comparative analysis of the nucleotide sequences of ORF5 and the deduced amino acid sequences of the G(L) protein of individual EM viruses and field isolates of EAV identified four distinct neutralization sites. These sites include amino acids 49 (site A), 61 (site B), 67 through 90 (site C), and 99 through 106 (site D). With the notable exception of site A, the sites were all located in the V1 variable region (amino acids 61-121) within the second half of the N-terminal hydrophilic ectodomain of the G(L) protein. Site D includes several overlapping linear epitopes which appear to interact with amino acids in the other three sites to form conformationally dependent epitopes. Amino acid substitutions within any of these four sites can alter the neutralization phenotype of individual strains of EAV.


Effects of anti-oxytocin serum in Brattleboro rats.
Brattleboro rats were housed singly in metabolic cages and continuously infused with saline. Timed urine collections were analyzed for Na+ and K+; oxytocin (OT)-like material was estimated by RIA. OT infusions reduced urine flow and increased Na+ output. Urinary Na+/K+ ratios rose during OT infusion, falling below control values after infusion. Passive immunization with an OT antiserum reduced but did not prevent these renal effects of OT. In a second experiment, immunization had no effect on daily urine volume or Na+ output, even though high titers were achieved and excretion of endogenous OT-like material was reduced. We conclude that endogenous OT has little effect on Na+ excretion in these rats, although pharmacological doses of OT produced their known natriuretic effect.


Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman.
Vaginal atrophy (VA) is the thinning of the vaginal epithelial lining, typically the result of lowered estrogen levels during menopause. Some of the consequences of VA include increased susceptibility to bacterial infection, pain during sexual intercourse, and vaginal burning or itching. Although estrogen treatment is highly effective, alternative therapies are also desired for women who are not candidates for post-menopausal hormone therapy (HT). The ovariectomized (OVX) rat is widely accepted as an appropriate animal model for many estrogen-dependent responses in humans; however, since reproductive biology can vary significantly between mammalian systems, this study examined how well the OVX rat recapitulates human biology. We analyzed 19 vaginal biopsies from human subjects pre and post 3-month 17beta-estradiol treated by expression profiling. Data were compared to transcriptional profiling generated from vaginal samples obtained from ovariectomized rats treated with 17beta-estradiol for 6 hrs, 3 days or 5 days. The level of differential expression between pre- vs. post- estrogen treatment was calculated for each of the human and OVX rat datasets. Probe sets corresponding to orthologous rat and human genes were mapped to each other using NCBI Homologene. A positive correlation was observed between the rat and human responses to estrogen. Genes belonging to several biological pathways and GO categories were similarly differentially expressed in rat and human. A large number of the coordinately regulated biological processes are already known to be involved in human VA, such as inflammation, epithelial development, and EGF pathway activation. At the transcriptional level, there is evidence of significant overlap of the effects of estrogen treatment between the OVX rat and human VA samples.


The Estrogen Receptor α Signaling Pathway Controls Alternative Splicing in the Absence of Ligands in Breast Cancer Cells.
The transcriptional activity of estrogen receptor α (ERα) in breast cancer (BC) is extensively characterized. Our group has previously shown that ERα controls the expression of a number of genes in its unliganded form (apoERα), among which a large group of RNA-binding proteins (RBPs) encode genes, suggesting its role in the control of co- and post-transcriptional events. apoERα-mediated RNA processing events were characterized by the analysis of transcript usage and alternative splicing changes in an RNA-sequencing dataset from MCF-7 cells after siRNA-induced ERα downregulation. ApoERα depletion induced an expression change of 681 RBPs, including 84 splicing factors involved in translation, ribonucleoprotein complex assembly, and 3'end processing. ApoERα depletion results in 758 isoform switching events with effects on 3'end length and the splicing of alternative cassette exons. The functional enrichment of these events shows that post-transcriptional regulation is part of the mechanisms by which apoERα controls epithelial-to-mesenchymal transition and BC cell proliferation. In primary BCs, the inclusion levels of the experimentally identified alternatively spliced exons are associated with overall and disease-free survival. Our data supports the role of apoERα in maintaining the luminal phenotype of BC cells by extensively regulating gene expression at the alternative splicing level.


Information and Thermodynamics: Fast and Precise Approach to Landauer's Bound in an Underdamped Micromechanical Oscillator.
The Landauer principle states that at least k_{B}Tln2 of energy is required to erase a 1-bit memory, with k_{B}T the thermal energy of the system. We study the effects of inertia on this bound using as one-bit memory an underdamped micromechanical oscillator confined in a double-well potential created by a feedback loop. The potential barrier is precisely tunable in the few k_{B}T range. We measure, within the stochastic thermodynamic framework, the work and the heat of the erasure protocol. We demonstrate experimentally and theoretically that, in this underdamped system, the Landauer bound is reached with a 1% uncertainty, with protocols as short as 100 ms.


Cytoprotective propensity of Bacopa monniera against hydrogen peroxide induced oxidative damage in neuronal and lung epithelial cells.
Hydrogen peroxide (H2O2), a major reactive oxygen species (ROS) produced during oxidative stress, is toxic to the cells. Hence, H2O2 has been extensively used to study the effects of antioxidant and cytoprotective role of phytochemicals. In the present investigation H2O2 was used to induce oxidative stress via ROS production within PC12 and L132 cells. Cytoprotective propensity of Bacopa monniera extract (BME) was confirmed by cell viability assays, ROS estimation, lipid peroxidation, mitochondria membrane potential assay, comet assay followed by gene expression studies of antioxidant enzymes in PC12 and L132 cells treated with H2O2 for 24 h with or without BME pre-treatment. Our results elucidate that BME possesses radical scavenging activity by scavenging 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid), superoxide radical, and nitric oxide radicals. The IC50 value of BME against these radicals was found to be 226.19, 15.17, 30.07, and 34.55 µg/ml, respectively). The IC50 of BME against ROS, lipid peroxidation and protein carbonylation was found to be 1296.53, 753.22, and 589.04 µg/ml in brain and 1137.08, 1079.65, and 11101.25 µg/ml in lung tissues, respectively. Further cytoprotective potency of the BME ameliorated the mitochondrial and plasma membrane damage induced by H2O2 as evidenced by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase leakage assays in both PC12 and L132 cells. H2O2 induced cellular, nuclear and mitochondrial membrane damage was restored by BME pre-treatment. H2O2 induced depleted antioxidant status was also replenished by BME pre-treatment. This was confirmed by spectrophotometric analysis, semi-quantitative RT-PCR and western blot studies. These results justify the traditional usage of BME based on its promising antioxidant and cytoprotective property.


Antibiotic resistance patterns in human, animal, food and environmental isolates in Ghana: a review.
Many articles have been published on resistant microorganisms isolated from humans, animals, foods and the environment in Ghana. However, there are no reviews that summarize the information on the isolates and antibiotics tested so far in the country. This literature review was completed through "PubMed" and "Google Scholar" searches. We included publications from the period 1975-2015 with a laboratory-based methodology to determine antibiotic resistance of strains isolated in Ghana. In total, 60 articles were included in the analysis with 10% of the articles carrying out nationwide research on antibiotic resistance. The regions of Ghana with the highest published articles were Greater Accra (40%), Ashanti (21.7%) and Northern Region (10%). Most of the studies (86.7%) were related to isolates collected from human samples followed by environmental (5%), animal (3%) and food samples (2%). Ten different bacteria genera were observed in the studies. The most common was Escherichia coli, followed by Staphylococcus spp., Mycobacterium spp. and Streptococcus spp. The highest mean resistance rate was encountered in Escherichia coli (62.2%) followed by Klebsiella spp. (60.4%) and Pseudomonas spp. (52.1%). High resistance rates have been found in Ghana, however, the data are skewed and some regions of the country have been neglected. There is a need for higher quality research to establish and monitor resistance patterns in Upper West, Brong-Ahafo, Volta and Eastern Regions of Ghana.


Pain behaviours in Extremely Low Gestational Age infants.
To date, there are over 40 infant pain measures. Despite this plethora of measures, only 8 have included preterm infants and only 2 have included Extremely Low Gestational Age (ELGA; infants <28 weeks GA) in their development. Without reliable, valid and clinically useful indicators for procedural pain in ELGA infants, clinicians have no means to interpret the responses from an immature infant who may respond differently from infants of older GA. To examine the physiological, behavioural and biochemical responses to painful and non-painful procedures in ELGA infants and the influence of GA and sex. A prospective crossover design with 50 ELGA infants from one Canadian tertiary level NICU was conducted. Infants were assessed in random order during standardized painful (heel lance) and non-painful (diaper change) procedures. Physiological (heart rate, oxygen saturation) and behavioural (facial and body movement) indicators were continuously collected during 4 phases of the procedures. Biochemical (salivary cortisol) indicators were collected immediately before and 20 min following the procedures. Four facial actions (brow bulge, eye squeeze, nasolabial furrow, vertical mouth stretch) increased immediately following the heel lance. There were no specific changes in physiological, body movement or cortisol indicators following the heel lance. ELGA infants demonstrated greater body movements during the diaper change, which may reflect immature motor coordination. No differences in pain responses were found for infants born between 23-25 6/7 weeks GA and those between 26-28 weeks GA. Similarly, no gender differences were found. Changes in 4 facial actions were the most sensitive indicators of pain in ELGA infants. This finding is consistent with existing measures where facial actions are the most prominent pain indicators. Specific body movements such as those included in NIDCAP, may provide more information about pain in ELGA infants. Movements such as hand-on-face, finger splaying, fisting, arching or yawning need to be examined in future research.


Onset and limiting amplitude of yaw instability of a submerged three-tethered buoy.
In this paper the dynamics of a submerged axi-symmetric wave energy converter are studied, through mathematical models and wave basin experiments. The device is disk-shaped and taut-moored via three inclined tethers which also act as a power take-off. We focus on parasitic yaw motion, which is excited parametrically due to coupling with heave. Assuming linear hydrodynamics throughout, but considering both linear and nonlinear tether geometry, governing equations are derived in 6 degrees of freedom (DOF). From the linearized equations, all motions, apart from yaw, are shown to be contributing to the overall power absorption. At higher orders, the yaw governing equation can be recast into a classical Mathieu equation (linear in yaw), or a nonlinear Mathieu equation with cubic damping and stiffness terms. The well-known stability diagram for the classical Mathieu equation allows prediction of onset/occurrence of yaw instability. From the nonlinear Mathieu equation, we develop an approximate analytical solution for the amplitude of the unstable motions. Comparison with regular wave experiments confirms the utility of both models for making relevant predictions. Additionally, irregular wave tests are analysed whereby yaw instability is successfully correlated to the amount of parametric excitation and linear damping. This study demonstrates the importance of considering all modes of motion in design, not just the power-producing ones. Our simplified 1 DOF yaw model provides fundamental understanding of the presence and severity of the instability. The methodology could be applied to other wave-activated devices.


Nonalcoholic fatty liver disease and metabolic syndrome in postmenopausal women.
Nonalcoholic fatty liver disease (NAFLD) is considered the most common cause of chronic liver disease in the Western countries. NAFLD includes a spectrum ranging from a simple steatosis to a nonalcoholic steatohepatitis (NASH) which is defined by the presence of inflammatory infiltrate, cellular necrosis, hepatocyte ballooning, and fibrosis and cirrhosis that can eventually develop into hepatocellular carcinoma. Studies emphasize the role of insulin resistance, oxidative stress, pro-inflammatory cytokines, adipokines in the development and progression of NAFLD. It seems to be independently associated with type II diabetes mellitus, increased triglycerides, decreased HDL-cholesterol, abdominal obesity and insulin resistance. These findings are in accordance with the criteria used in the diagnosis of metabolic syndrome (MetS). Here, we will discuss the current knowledge on the epidemiology, pathophysiology and diagnosis of NAFLD and the association of metabolic syndrome in postmenopausal women.


Comparison of broiler performance when fed diets containing roundup ready (event RT73), nontransgenic control, or commercial canola meal.
A 42-d experiment compared the nutritional value of genetically modified glyphosate-tolerant (Roundup Ready event RT73) canola meal to that of conventional canola meal when fed to rapidly growing Ross x Ross 508 broilers using a randomized complete block design. Five pens of males and 5 pens of females were used in each of 8 canola meal treatments (glyphosate-tolerant, nontransgenic control, and 6 commercial varieties). Broilers (10 birds/pen) were fed approximately 25% wt/wt canola meal during the first 20 d and 20% wt/wt canola meal thereafter. In general, performance response variables for glyphosate-tolerant canola meal were not different (P > 0.05) than those for the nontransgenic and commercial canola meals. Carcass fat pad, breast meat, thighs, legs, and wings (on a percentage basis) were similar across treatments (P > 0.05). Expressed as percentage of live weight, chill weight of the broilers fed diets containing glyphosate-tolerant canola meal was not different from those fed all other diets, but some differences were observed between the nontransgenic control and commercial diets. No major differences were observed in percentage of moisture, protein, and fat in breast or thigh meat (P > 0.05) across treatments. Comparisons of the glyphosate-tolerant canola diet to the population of all other diets (combining sexes) showed no major differences (P > 0.05) in performance, carcass yields, or moisture, protein, and fat in breast and thigh meat. Broilers fed diets containing glyphosate-tolerant canola meal had similar growth performance to birds fed nontransgenic control and commercial canola diets.


Development of cytotrophoblast columns from explanted first-trimester human placental villi: role of fibronectin and integrin alpha5beta1.
Human first-trimester floating mesenchymal villi explanted onto gels of collagen I or Matrigel were observed to undergo de novo development of anchoring sites. These consisted of cytotrophoblast columns that formed by proliferation of stem villous cytotrophoblast cells, as revealed by whole-mount and thin-section microscopy and incorporation of bromodeoxyuridine into DNA. Column formation occurred exclusively at the distal tips of the villi. No column formation was observed in tissue explanted onto agarose. On Matrigel, the developing columns penetrated downwards into the matrix, whereas on collagen I, cytotrophoblast sheets spread across the surface of the gel and merged to form a shell. The developing columnar cytotrophoblast up-regulated integrins alpha1beta1 and alpha5beta1 and produced an extracellular matrix containing oncofetal fibronectin, as in vivo. Function-blocking antibodies were used to investigate the role of the integrin-fibronectin interaction in anchoring villus development on collagen I. Antibodies to fibronectin and the integrin subunits alpha5 and beta1, added at 24 h, all changed the pattern of cytotrophoblast outgrowth. Anti-fibronectin caused cell rounding within the cytotrophoblast sheet and increased the population of single cells at its periphery. Anti-integrin alpha5 caused rounding and redistribution of cells within the outgrowth. In the presence of anti-integrin beta1, cell-collagen interactions within the sheet were destabilized, often leading to the appearance of an annulus of aggregated cells at the periphery. These results show that 1) mesenchymal villi retain the potential to form anchoring sites until at least the end of the first trimester, 2) adhesion to a permissive extracellular matrix stimulates cytotrophoblast proliferation and differentiation along the extravillous lineage, 3) integrin alpha5beta1-fibronectin interactions contribute significantly to anchorage of the placenta to uterine extracellular matrix. We suggest that as the developing placenta ramifies, new sites of anchorage form whenever peripheral villi contact decidua. This process is predicted to contribute to the stability of the placental-decidual interface.


Disaster Preparedness in Home-based Primary Care: Policy and Training.
Veterans served by Veterans Health Administration (VHA) home-based primary care (HBPC) are an especially vulnerable population due to high rates of physical, functional, and psychological limitations. Home-bound patients tend to be an older population dealing with normal changes that accompany old age, but may not adequately be prepared for the increased risk that often occurs during disasters. Home health programs are in an advantageous position to address patient preparedness as they may be one of the few outside resources that reach community-dwelling adults. Problem This study further explores issues previously identified from an exploratory study of a single VHA HBPC program regarding disaster preparedness for HBPC patients, including ways in which policy and procedures support the routine assessment of disaster preparedness for patients, including patient education activities. This project involved semi-structured interviews with 31 practitioners and leadership at five VHA HBPC programs; three urban and two rural. Transcripts of the interviews were analyzed using content analysis techniques. Practitioners reported a need for further training regarding how to assess properly patient disaster preparedness and patient willingness to prepare. Four themes emerged, validating themes identified in a prior exploratory project and identifying additional issues regarding patient disaster preparedness: (1) individual HBPC programs generally are tasked with developing their disaster preparedness policies; (2) practitioners receive limited training about HBPC program preparedness; (3) practitioners receive limited training about how to prepare their patients for a disaster; and (4) the role of HBPC programs is focused on fostering patient self-sufficiency rather than presenting practitioners as first responders. There was significant variability across the five sites in terms of which staff have responsibility for preparedness policies and training. Variability across and within sites regarding how patient needs are addressed by preparedness policies, and in terms of preparedness training for HBPC providers, could place patients at heightened risk of morbidity or mortality following a disaster. Despite the diversity and uniqueness of HBPC programs and the communities they serve, there are basic aspects of preparedness that should be addressed by these programs. The incorporation of resources in assessment and preparedness activities, accompanied by increased communication among directors of HBPC programs across the country, may improve HBPC programs' abilities to assist their patients and their caregivers in preparing for a disaster.


The effect of guar gum on carbohydrate-, fat- and protein-stimulated gut hormone secretion: modification of postprandial gastric inhibitory polypeptide and gastrin responses.
The effect of incorporating guar gum into predominantly single-component meals of carbohydrate, fat or protein on liquid gastric emptying and on the secretion of gastric inhibitory polypeptide (GIP), gastrin and motilin, was studied in healthy human volunteers. Volunteers were given either 80 ml Hycal (carbohydrate meal), 150 g cooked lean minced beef (protein meal) or 200 ml double cream (fat meal) either with or without 5 or 6 g guar gum. Liquid gastric emptying was monitored in the fat and protein meals by taking 1.5 g paracetamol, consumed in water, with the meals and monitoring its appearance in circulation. Postprandial insulin and GIP levels were both significantly reduced by addition of guar gum to the carbohydrate meal. Postprandial GIP secretion was also reduced by addition of guar gum to the protein meal, but protein-stimulated gastrin secretion was enhanced by guar gum. There was a significant negative correlation between peak circulating gastrin levels and the corresponding GIP levels. Postprandial GIP secretion and plasma motilin levels were unaffected by addition of guar gum to the fat meal. 5 and 10 g guar gum/l solutions in water possessed buffering capacities between pH 2.75 and 5.5. Guar gum at 5 g/l caused no detectable change in liquid gastric-emptying time. The observed augmentation of gastrin secretion by guar gum following a protein meal could be due either to the buffering capacity of guar gum or to the attenuation of GIP secretion. It is possible that the chronic use of guar gum could be associated with changes in gastric acid secretion.


Substance use and the risk for sexual intercourse with and without a history of teenage pregnancy among adolescent females.
The present study examined the associations between initiation and intensity of substance use and with sexual experience with and without a history of teenage pregnancy. Participants were high school females (weighted n = 3,451) who participated in the 1999-2003 Youth Risk Behavior Surveillance System, a cross-sectional, nationally representative survey. Multinomial multivariable logistic regression was used to assess the likelihood of being sexually experienced (but never pregnant) and teenage pregnancy (reference group: never had sexual intercourse) as a function of age at substance use initiation (i.e., age 12 or younger, 13-14 years of age, and age 15 or older) and intensity of substance use (i.e., nonuser, experimental/ new or nondaily, nonexperimental/daily user) for alcohol, cigarettes, and marijuana, while controlling for race/ethnicity, metropolitan location, symptoms of depression, and illegal drug availability at school. A major finding of our study is that substance use behaviors across each substance (alcohol, cigarettes, and marijuana) independently contributed to an increased risk in sexual intercourse experience with and without a history of teenage pregnancy (vs. nonsexually experienced females). A dose-response relationship was also observed between an increased likelihood of a teenage pregnancy and marijuana behaviors. Furthermore, the risk for teenage pregnancy was compounded for daily cigarette smokers who initiated use at age 12 or younger. Screening substance use behaviors can help to identify girls who may benefit from pregnancy prevention strategies. Targeting cigarette and marijuana behaviors as early as age 12 or younger may provide an added benefit. Prevention strategies should also consider the role of race above and beyond substance use behaviors.


A twenty-four year retrospective study of dependent catheter paracentesis.
Dependent catheter paracentesis has been used on 590 patients over the last 24 years. The complication rate is zero. It is faster, as accurate, cheaper and less hypersensitive than diagnostic peritoneal lavage. Open, semi-open and closed diagnostic peritoneal lavage when used with trocars is unjustified because of a significant complication rate.


Identifying optimum performance trade-offs using a cognitively bounded rational analysis model of discretionary task interleaving.
We report the results of a dual-task study in which participants performed a tracking and typing task under various experimental conditions. An objective payoff function was used to provide explicit feedback on how participants should trade off performance between the tasks. Results show that participants' dual-task interleaving strategy was sensitive to changes in the difficulty of the tracking task and resulted in differences in overall task performance. To test the hypothesis that people select strategies that maximize payoff, a Cognitively Bounded Rational Analysis model was developed. This analysis evaluated a variety of dual-task interleaving strategies to identify the optimal strategy for maximizing payoff in each condition. The model predicts that the region of optimum performance is different between experimental conditions. The correspondence between human data and the prediction of the optimal strategy is found to be remarkably high across a number of performance measures. This suggests that participants were honing their behavior to maximize payoff. Limitations are discussed.


Correlates of risky alcohol and methamphetamine use among currently homeless male parolees.
Homeless men on parole are a hard-to-reach population with significant community reintegration challenges. This cross-sectional study describes sociodemographic, cognitive, psychosocial, and drug-related correlates of alcohol and methamphetamine use in 157 homeless male parolees (age range 18-60) enrolled in a substance abuse treatment center in Los Angeles, California. Logistic regression results revealed that being African American and older were negatively related to methamphetamine use, whereas being older and more hostile were related to riskier alcohol abuse. Findings from this study provide a greater understanding of correlates of methamphetamine and alcohol--two of the most detrimental forms of substances abused among currently homeless parolees.


Mandarin juice improves the antioxidant status of hypercholesterolemic children.
Oxidative stress has been linked to such degenerative diseases as atherosclerosis, and it has been suggested that increased dietary intake of antioxidants may reduce its progression. To determine the effect of mandarin juice consumption on biomarkers related to oxidative stress in hypercholesterolemic children. The diet of 48 children with plasma cholesterol >200 mg/dL and low-density lipoprotein cholesterol >130 mg/dL was supplemented for 28 days with 500 mL/day of pure (100%) mandarin juice (Citrus clementina Hort. ex Tan.). The composition of the mandarin juice was analyzed, and its antioxidant antiradical activity was evaluated in vitro. Malondialdehyde, carbonyl groups, vitamins E and C, erythrocyte-reduced glutathione, and plasma lipids were measured at the onset and at the end of the supplementation period. The paired Student t test was used to compare values before and after supplementation. Mandarin juice exerted a strong antioxidant effect mainly due to its high hydroxyl activity and, to a lesser extent, to its superoxide scavenger activity. At the end of the study, levels of the plasma biomarkers of oxidative stress were significantly decreased (malondialdehyde -7.4%, carbonyl groups -29.1%, P < 0.01), whereas the plasma antioxidants vitamin E and C (13.5%, P < 0.001 and 68.2%, P < 0.00001, respectively) and intraerythrocyte glutathione level (36.7%, P < 0.00001) were significantly increased. Plasma lipids and antibodies to oxidized low-density lipoproteins remained unchanged. Regular ingestion of mandarin juice significantly reduces plasma biomarkers of lipid and protein oxidation and enhances the antioxidant status of consumers.


Changes in Ideational Profiles of Women of Reproductive Age in Urban Nigeria: The Role of Health Communication.
Reproductive health indicators in Nigeria remain among the poorest in the world. Modern contraceptive prevalence rate has remained practically at the same level since 2003. Whereas contraceptive use is higher in urban compared with rural areas, the majority of urban women are not using a modern contraceptive method. Low contraceptive use in the country results from unfavorable ideational variables, including knowledge, values, beliefs, and norms. Ideational segmentation allows program planners to identify groups that are homogenous with respect to ideational variables and which have similar informational and skills strengthening needs. In this study, we conducted latent class analyses with longitudinal data collected from a sample of women in 2010/2011 and 2014 to identify distinct ideational segments among women of reproductive age in six Nigerian cities at the two points in time. The analysis revealed three ideational segments at baseline: (a) Inefficacious, misinformed and unsupported, labeled "Disempowered," 58.8%; (b) Efficacious, misinformed, and unsupported, labeled "Unsupported," 31.8%; and (c) efficacious, supported but misinformed, labeled "Skeptics, 9.4%. These groups differ in terms of sociodemographic characteristics and contraceptive use and intention to use. At endline, four ideational segments were identified: (a) Inefficacious, misinformed and unsupported, labeled "Disempowered," 28.9%; (b) Efficacious, supported but misinformed, labeled "Skeptics," 28.5%; (c) Efficacious, informed but unsupported, labeled "Unsupported," 27.0%; and (d) efficacious, informed and supported, labeled "Empowered," 15.6%. Exposure to Nigerian Urban Reproductive Health Initiative communication interventions was one of the most significant predictors of improvements in ideational characteristics over time. Messages tailored to the informational needs of the various ideational segments and that address their worldview are needed to increase contraceptive use.


Revolutionizing cardiovascular medicine: targeted therapies for the cardiac conduction system.
Arrhythmogenic cardiovascular disorders are associated with considerable morbidity and mortality. Whether cardiac conduction disease is caused by genetic defects, procedural perturbations, valvular disease, ischemia, aging, or heart failure, new therapies are warranted. In this issue of the JCI, Goodyer et al. used state-of-the-art technologies to image the cardiac conduction system (CCS) in real time and to deliver targeted therapies to the CCS and its subcomponents. These findings advance the ability to image and treat specific lineages within the adult heart with the potential for broader applications in the treatment of cardiovascular diseases.


Mortality among U.S. underground coal miners: a 23-year follow-up.
The mortality experience over 22-24 years of 8,899 working coal miners initially medically examined in 1969-1971 at 31 U.S. coal mines was evaluated. A cohort life-table analysis was undertaken on underlying causes of death, and proportional hazards models were fitted to both underlying, and underlying and contributing causes of death. Elevated mortality from nonviolent causes, nonmalignant respiratory disease (NMRD), and accidents was observed, but lung cancer and stomach cancer mortality were not elevated. Smoking, pneumoconiosis, coal rank region, and cumulative coal mine dust exposure were all predictors of mortality from nonviolent causes and NMRD. Mortality from nonviolent causes and NMRD was related to dust exposure within the complete cohort and also for the never smoker subgroup. Dust exposure relative risks for mortality were similar for pneumoconiosis, NMRD, and chronic airways obstruction. The findings confirm and enlarge upon previous results showing that exposure to coal mine dust leads to increased mortality, even in the absence of smoking.


Oxidative stress-mediated down-regulation of rat hydroxyacid oxidase 1, a liver-specific peroxisomal enzyme.
Hydroxyacid oxidase 1 (Hao1) is a liver-specific peroxisomal enzyme that oxidizes glycolate to glyoxylate with concomitant production of H2O2. In Hao1 messenger RNA (mRNA), an iron-responsive element (IRE) homologous to the sequence recognized by iron regulatory proteins (IRP), key regulators of iron homeostasis, is present, but the involvement of iron in Hao1 regulation remains unclear. In this study, we found a reduction of Hao1 mRNA content in livers of rats with chronic dietary iron overload, which showed decreased IRP activity and higher ferritin expression as expected, but also induction of heme oxygenase (HO-1), a marker of oxidative damage, and lipid peroxidation. Hao1 mRNA levels were not altered significantly in livers of rats administered doses of iron sufficient to induce ferritin expression and to repress IRP activity, but not to activate HO-1 and to promote lipid peroxidation, as well as in the liver of iron-deficient rats. These observations were not consistent with a post-transcriptional down-regulation of Hao1 by iron through the IRE/IRP pathway and suggested an effect of reactive oxygen species (ROS). Indeed, a marked decrease of Hao1 mRNA was observed in the liver of rats subjected to oxidative stress induced by either glutathione depletion or postischemic reperfusion. Nuclear run-on analysis showed an effect of ROS at the transcriptional level. In conclusion, down-regulation of Hao1 expression during oxidative stress may provide a mechanism to prevent excessive H2O2 formation in liver peroxisomes and may represent the prototype of a poorly recognized but potentially relevant response to oxidative injury involving down-regulation of ROS-producing enzymes.


Use of Platelet Function Testing Before Pipeline Embolization Device Placement: A Multicenter Cohort Study.
Thromboembolic complications constitute a significant source of morbidity after neurointerventional procedures. Flow diversion using the pipeline embolization device for the treatment of intracranial aneurysms necessitates the use of dual antiplatelet therapy to reduce this risk. The use of platelet function testing before pipeline embolization device placement remains controversial. A retrospective review of prospectively maintained databases at 3 academic institutions was performed from the years 2009 to 2016 to identify patients with intracranial aneurysms treated with pipeline embolization device placement. Clinical and radiographic data were analyzed with emphasis on thromboembolic complications and clopidogrel responsiveness. A total of 402 patients underwent 414 pipeline embolization device procedures for the treatment of 465 intracranial aneurysms. Thromboembolic complications were encountered in 9.2% of procedures and were symptomatic in 5.6%. Clopidogrel nonresponders experienced a significantly higher rate of thromboembolic complications compared with clopidogrel responders (17.4% versus 5.6%). This risk was significantly lower in nonresponders who were switched to ticagrelor when compared with patients who remained on clopidogrel (2.7% versus 24.4%). In patients who remained on clopidogrel, the rate of thromboembolic complications was significantly lower in those who received a clopidogrel boost within 24 hours pre-procedure when compared with those who did not (9.8% versus 51.9%). There was no significant difference in the rate of hemorrhagic complications between groups. Clopidogrel nonresponders experienced a significantly higher rate of thromboembolic complications when compared with clopidogrel responders. However, this risk seems to be mitigated in nonresponders who were switched to ticagrelor or received a clopidogrel boost within 24 hours pre-procedure.


[Optimal hospital-home transition for a type 2 diabetic patient : some tools].
The prevalence of patients with type 2 diabetes who are hospitalized is constantly increasing. A minority of facilities have standardized hospital protocols for the diabetic patient regarding medication and continuity of care. This article offers practical tools to optimize the transition of diabetic patients because they are more at risk of readmission and adverse events. Establishing a structured and personalized discharge plan can help anticipate the hospital discharge and approach, in a more standardized way the different stages of an optimized transition. Thus, a patient-centered approach including treatment adaptation, early anticipation of needs at discharge, transmission of essential points of therapeutic education and organization of outpatient monitoring, could improve glycemic control and reduce the number of readmissions or emergency consultations.


MicroRNA alteration and putative target genes in high-grade prostatic intraepithelial neoplasia and prostate cancer: STAT3 and ZEB1 are upregulated during prostate carcinogenesis.
We aimed to identify alteration of cancer-related miRNAs in HGPIN and PCa, and to investigate the clinical implications of HGPIN as a precancerous lesion of PCa. Clinicopathologic analysis based on the status of HGPIN was performed in 388 patients who received radical prostatectomy between January 2005 and December 2008 in Severance Hospital. Among them, 10 paired HGPIN and PCa were prepared to perform miRNA microarray and quantitative real-time PCR. Fifty-two prostatectomy specimens were used to further validation of protein expression that was assessed by immunohistochemical staining (IHC) in matched non-neoplastic prostatic tissue (NPT), HGPIN, and PCa. Functional analysis was performed using a prostate normal cell line (RWPE-1) and two prostate cancer cell lines (LNCaP, PC-3) for comparison of expression of miR-155 and STAT3 mRNA before and after treatment of miR-155 mimetics/antagomir into each cell line. Patients with HGPIN had significantly less lymphovascular invasion, less lymph node metastasis, lower tumor volume, lower Gleason score, lower incidence of death, and longer overall survival compared to patients without HGPIN. MiR-155, miR-210, miR-153, and miR-200c were downregulated in HGPIN and PCa in common, compared to NPT. As putative target mRNAs, mRNA expression level of STAT3, ZEB1, and BACH1 was increased in PCa and HGPIN compared to NPT. mRNA expression level of ephrin-A3 was increased in PCa compared to NPT, and FGFRL1 was decreased in PCa compared to HGPIN and NPT. Protein expression assessed by IHC showed correlated results in STAT3, ZEB1, and ephrin-A3. Moreover, STAT3 and ZEB1 increased in a stepwise manner, from NPT to PCa. Treatment of miR-155 antagomir increased STAT3 mRNA expression in RWPE-1 cells, whereas treatment of miR-155 mimetics into PC-3 cells significantly decreased STAT3 expression. STAT3 and ZEB1 could be the key molecules altered at the early stages of carcinogenesis, especially in HGPIN. Prostate 76:937-947, 2016. © 2016 Wiley Periodicals, Inc.


Superoxide dismutase reduces islet microvascular injury induced by streptozotocin in the rat.
Intravenous administration of streptozotocin (STZ) leads to permanent diabetes mellitus in rats. We investigated the possible role of islet microcirculatory changes and free radical formation in this animal model. In vivo fluorescence microscopy was performed for 4 h after administration of STZ. Vascular permeability, capillary blood flow, and endothelial leukocyte adhesion were measured in endocrine and exocrine pancreatic tissue. The earliest microcirculatory event was an increase in vascular permeability in pancreatic islets, with a peak 1 h after STZ administration. The difference between islet and exocrine tissue light intensity was +15.8 +/- 5.6% at t = 60 min. Islet blood flow velocity significantly decreased after 3 h, whereas blood flow in the exocrine pancreas was not affected. Complete stasis of islet blood flow was observed only in rats receiving STZ. Neither increased leukocyte adhesion to islet vascular endothelium nor ischemia-reperfusion phenomena were observed. Prophylactic administration of the radical scavenger superoxide dismutase prevented STZ-induced damage to the islet microcirculation in the initial phase of this model. We conclude that STZ leads to severe microcirculatory disturbances within pancreatic islets in rats. Apparently, these changes are mediated at least in part by free oxygen radicals.


Outcomes after carotid endarterectomy: is there a high-risk population? A National Surgical Quality Improvement Program report.
Carotid endarterectomy (CEA) is the standard treatment of carotid stenosis for symptomatic and asymptomatic patients. Carotid angioplasty and stenting (CAS), however, has been proposed as alternative therapy for patients deemed at high-risk for CEA. This study examined 30-day adjudicated outcomes in a contemporary series of CEAs and assessed the validity of criteria used to define a potential high-risk patient population for CEA. Patients undergoing isolated CEA in private sector hospitals between Jan 1, 2005, and Dec 31, 2006, were identified using the prospectively gathered National Surgical Quality Improvement Program database. The primary study end points were 30-day stroke and death rates. Demographic, preoperative, and intraoperative variables were examined using multivariate models to identify variables associated with the study end points. Variables used to define systemic "high-risk" patients in the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) study (active cardiac disease, severe chronic obstructive pulmonary disease, and octogenarian status) were examined individually and in composite fashion for association with study endpoints. Of the 3949 CEAs performed, 59% were in men, 30% were "high-risk" (19% age >80), and 43% had a previous neurologic event. The 30-day stroke rate was 1.6%, the death rate was 0.7%, and combined stroke/death rate was 2.2%. Multivariate analysis showed that intraoperative transfusion (odds ratio [OR], 5.95; 95% confidence interval [CI], 1.71-20.66; P = .005), prior major stroke (OR, 5.34; 95% CI, 2.96-9.64; P < .0001), shorter height (surrogate for small artery size; OR, 1.09; 95% CI, 1.02-1.16; P = .010), and increased anesthesia time (OR, 1.02; 95% CI, 1.00-1.03; P = .008) were predictive of stroke. Critical limb ischemia (OR, 12.72; 95% CI, 3.49-46.40; P < .0001) and poor functional status (OR, 7.05; 95% CI, 2.95-16.82; P < .0001) were independent correlates of death. Systemic high-risk variables, either combined or individually, did not increase risk of stroke or death on multivariate analysis. CEA is associated with favorable 30-day outcomes across a spectrum of patient comorbidity features including octogenarian status. Anatomic and technical features are the important predictors of perioperative stroke, whereas critical limb ischemia and poor functional status are important predictors of death for patients undergoing CEA. These data refute the concept that CAS is preferred for patients deemed high-risk by virtue of systemic comorbidities.


Density-functional expansion methods: generalization of the auxiliary basis.
The formulation of density-functional expansion methods is extended to treat the second and higher-order terms involving the response density and spin densities with an arbitrary single-center auxiliary basis. The two-center atomic orbital products are represented by the auxiliary functions centered about those two atoms, and the mapping coefficients are determined from a local constrained variational procedure. This two-center variational procedure allows the mapping coefficients to be pretabulated and splined as a function of internuclear separation for efficient look up. The splines of mapping coefficients have a range no longer than that of the overlap integrals, and the auxiliary density appears as a single point-multipole expansion to all nonoverlapping atoms, thus allowing for the trivial implementation of a linear-scaling algorithm. The method is tested using Gaussian multipole expansions, and the effect of angular and radial completeness is explored. Several auxiliary basis sets are parametrized and compared to an auxiliary basis analogous to that used in the self-consistent-charge density-functional tight-binding model, and the method is demonstrated to greatly improve the representation of the density response with respect to a reference expansion model that does not use an auxiliary basis.


Total knee arthroplasty for corticosteroid associated avascular necrosis of the knee.
Despite their age, patients younger than 50 years who have collapse of their femoral condyles caused by steroid associated avascular necrosis have few options except total knee arthroplasty. There have been no specific reports of the results of total knee replacements for this disease. Between 1980 and 1993, 31 porous coated anatomic total knee replacements were performed in 21 patients younger than 50 years of age with avascular necrosis of the femoral condyles and tibial plateaus. There were 17 women and 4 men, with an average age of 36 years (range, 22-48 years). Seventeen of 21 patients had systemic lupus erythematosus, and all patients had a history of corticosteroid use. Patients underwent a complete clinical and radiographic evaluation at final followup that averaged 8.2 years (range, 2-16 years). Overall, there were 17 good and excellent results (55%). Eleven knees were revised for aseptic loosening (37%), and 3 additional knees (10%) ultimately were revised for deep sepsis. All 6 knees in patients with no diagnosis of systemic lupus erythematosus had excellent clinical results. There were only 11 of 25 successful outcomes (44%) in the patients with systemic lupus erythematosus. There were no differences in results when patients were stratified by degree of steroid use, cemented versus cementless fixation, or activity level.


Hyperventilation syndrome: an elegant but scientifically untenable concept.
The concept of hyperventilation and the principle of a vicious circle provide an elegant explanation for the development of a wide range of somatic and psychological symptoms, the so-called hyperventilation syndrome (HVS). The model has a high degree of credibility and has led to the development of therapeutic interventions that appeared beneficial. However, recent investigations dismiss hyperventilation as an important symptom-producing mechanism. First, the hyperventilation provocation test appears to be invalid as a diagnostic test. Second, studies using ambulant monitoring of pCO2 demonstrate that the vast majority of real-life attacks are not attended by decreases in pCO2. Third, the evaluation of therapy outcome studies indicate that the beneficial effect of breathing retraining is probably not mediated by reducing the tendency to hyperventilate. We conclude that a diagnosis of HVS should be avoided.


Developing and Evaluating an AI-Based Computer-Aided Diagnosis System for Retinal Disease: Diagnostic Study for Central Serous Chorioretinopathy.
Although previous research has made substantial progress in developing high-performance artificial intelligence (AI)-based computer-aided diagnosis (AI-CAD) systems in various medical domains, little attention has been paid to developing and evaluating AI-CAD system in ophthalmology, particularly for diagnosing retinal diseases using optical coherence tomography (OCT) images. This diagnostic study aimed to determine the usefulness of a proposed AI-CAD system in assisting ophthalmologists with the diagnosis of central serous chorioretinopathy (CSC), which is known to be difficult to diagnose, using OCT images. For the training and evaluation of the proposed deep learning model, 1693 OCT images were collected and annotated. The data set included 929 and 764 cases of acute and chronic CSC, respectively. In total, 66 ophthalmologists (2 groups: 36 retina and 30 nonretina specialists) participated in the observer performance test. To evaluate the deep learning algorithm used in the proposed AI-CAD system, the training, validation, and test sets were split in an 8:1:1 ratio. Further, 100 randomly sampled OCT images from the test set were used for the observer performance test, and the participants were instructed to select a CSC subtype for each of these images. Each image was provided under different conditions: (1) without AI assistance, (2) with AI assistance with a probability score, and (3) with AI assistance with a probability score and visual evidence heatmap. The sensitivity, specificity, and area under the receiver operating characteristic curve were used to measure the diagnostic performance of the model and ophthalmologists. The proposed system achieved a high detection performance (99% of the area under the curve) for CSC, outperforming the 66 ophthalmologists who participated in the observer performance test. In both groups, ophthalmologists with the support of AI assistance with a probability score and visual evidence heatmap achieved the highest mean diagnostic performance compared with that of those subjected to other conditions (without AI assistance or with AI assistance with a probability score). Nonretina specialists achieved expert-level diagnostic performance with the support of the proposed AI-CAD system. Our proposed AI-CAD system improved the diagnosis of CSC by ophthalmologists, which may support decision-making regarding retinal disease detection and alleviate the workload of ophthalmologists.


Recombinant human erythropoietin therapy in patients with rheumatoid arthritis with the anemia of chronic disease.
We treated 5 patients with rheumatoid arthritis (RA) with anemia of chronic disease with recombinant human erythropoietin (rHuEPO) for 11 weeks. An increase in hematocrit (Hct) greater than 5 was seen in 4 patients after 4 weeks of therapy. The 5th patient had a significant rise in Hct when the dosage of rHuEPO was increased to 150 units/kg from the 4th to 7th week. The subcutaneous administration of rHuEPO dose, reduced by one third with respect to initial dose, maintained an effective Hct value in all the 5 patients during the last 4 weeks of therapy. There was no change in disease activity. In one patient Hct normalization completely resolved symptoms of angina pectoris and permitted hip replacement surgery in another. No side effects occurred during rHuEPO therapy. We conclude that HuEPO is an effective, safe and well tolerated therapy for RA patients with severe anemia of chronic disease.


Exact solution of stochastic gene expression models with bursting, cell cycle and replication dynamics.
The bulk of stochastic gene expression models in the literature do not have an explicit description of the age of a cell within a generation and hence they cannot capture events such as cell division and DNA replication. Instead, many models incorporate the cell cycle implicitly by assuming that dilution due to cell division can be described by an effective decay reaction with first-order kinetics. If it is further assumed that protein production occurs in bursts, then the stationary protein distribution is a negative binomial. Here we seek to understand how accurate these implicit models are when compared with more detailed models of stochastic gene expression. We derive the exact stationary solution of the chemical master equation describing bursty protein dynamics, binomial partitioning at mitosis, age-dependent transcription dynamics including replication, and random interdivision times sampled from Erlang or more general distributions; the solution is different for single lineage and population snapshot settings. We show that protein distributions are well approximated by the solution of implicit models (a negative binomial) when the mean number of mRNAs produced per cycle is low and the cell cycle length variability is large. When these conditions are not met, the distributions are either almost bimodal or else display very flat regions near the mode and cannot be described by implicit models. We also show that for genes with low transcription rates, the size of protein noise has a strong dependence on the replication time, it is almost independent of cell cycle variability for lineage measurements, and increases with cell cycle variability for population snapshot measurements. In contrast for large transcription rates, the size of protein noise is independent of replication time and increases with cell cycle variability for both lineage and population measurements.


Greater participation by veterinarians in the reproductive management of dairy cattle.
A program involving greater veterinary participation in detection of estrus and artificial insemination of cattle was evaluated in a 700-cow dairy herd from January 1987 through August 1988. Previous reproductive performance was below normal. First-service pregnancy rate from artificial insemination was 42%, and mean number of nonpregnant days for the cows was 120. Between postpartum days 55 and 62, all cows with functional corpus luteum assessed by rectal palpation were administered prostaglandin each Monday morning. Return visits were made to the herd each Thursday and Friday to observe cows and to inseminate those in estrus. On the other 5 days of the week, the owner or his employees inseminated all cows in estrus. The first-service pregnancy rate for 842 cows observed in estrus and inseminated by the veterinarian was 59%. The pregnancy rate for cows inseminated by the owner and his employees increased from 42% to 50%. The mean number of nonpregnant days for all 700 cows decreased from 120 to 98 days, resulting in approximately $46,000 of increased income for the dairyman or approximately a 4 to 1 return on investment in veterinary service. Results indicate that veterinarians could improve herd reproductive performance and solve chronic herd breeding problems by more actively participating with their clients in estrus detection and artificial insemination programs in cattle. The program allows practicing veterinarians an opportunity to observe cows for estrous behavior, establish their own pregnancy rate data, demonstrate to owners the importance of observing primary signs of estrus, and teach expert artificial insemination techniques.


[Inequity in health: its historical development].
Health inequity, main issue of contemporary debates on public health, is based on philosophical and historical concepts that date back to the idea of justice from classic Greece. The Aristotelian approach on distributive justice and its higher form, epiekeia or equity, has been reviewed, as well as how this evolves from the Middle Ages and modernity to the heart of the debate of a variety of thinkers such as liberal Rawls and Nobel laureate Amartya Sen. On this conceptual debate lies the World Health Organization version that links equity to health determinants and intends to make it operational through the equitable provision of health services.


Teething myths among community health officers.
Many symptoms are attributed to teething in infants as a result of myths and opinions of people in the community. These myths have given false security with the belief that these symptoms are part of the teething process. The purpose of the study was to investigate the beliefs and practices of Community health Officers about teething. 60% of the respondents whose responses were analyzed believed that children have systemic problems during teething periods. Fever and diarrhea were the most frequent symptoms associated with teething. As health care providers at the community level, there is a need for this cadre of health care providers to separate cultural beliefs from scientific and proven medical practices. This can be achieved by their attendance at regular refresher courses organized for them after their graduation.


Estimating the dispersal of Lepeophtheirus salmonis sea lice within and among Atlantic salmon sites of the Bay of Fundy, New Brunswick.
The objective of this study was to estimate the impact of infestation pressures on the abundance of the parasitic sea louse, Lepeophtheirus salmonis, in the Bay of Fundy, New Brunswick (NB), Canada, using the Fish-iTrends database for the years 2009-2018. Infestation pressures were calculated as time-lagged weighted averages of the abundance of adult female (AF) sea lice within a site (internal infestation pressure: IIP) and among sites (external infestation pressure: EIP). The EIP weights were calculated from seaway distances among sites and a Gaussian kernel density for bandwidths of 5 to 60 km. The EIP with a bandwidth of 10 km had the best fit, as determined with Akaike's information criterion, and historical AF sea lice abundance. This estimated dispersal distance of 10 km was similar to previous studies in Norway, Scotland and in New Brunswick. The infestation pressures estimated from empirical AF sea lice abundance within and among sites significantly increased the abundance of AF sea lice (p < .001). This study concludes that sea lice burdens within Atlantic salmon farms in the Bay of Fundy, NB, are affected by within site management and could be improved by synchronizing treatments between sites.


Prophylactic oophorectomy in Ontario.
To determine the indications, patterns of practice, and complication rates for prophylactic oophorectomy in Ontario. From hospital discharge abstracts, 82 hospitals were identified where at least one patient had a prophylactic oophorectomy since 1992. Ethics approval for the chart review was obtained from 41 hospitals (50%), was denied at 10 (12%) and is pending at 31 facilities. Using the International Classification of Disease diagnostic code for family history of ovarian cancer (V16.4) and prophylactic oophorectomy (V50.42), the medical records departments were asked to retrieve the charts. One abstractor reviewed the charts using a standard form to collect demographic information, indications for surgery, details of surgery and complications. From 1992-1998, 263 women underwent PO in 41 hospitals. A BRCA1 or BRCA2 mutation was recorded in 16 cases. Thirty-six patients had a past history of breast cancer. In 127 women, a family history was the sole reason for surgery; the remaining 136 women had a coexisting gynecologic complaint. Laparotomy was used exclusively in 155 cases, laparoscopy in 79 and vaginal access in 12 cases. Seventeen women required conversion to laparotomy during the operation. The mean length of hospital stay was 3.7 days (0-14 days). Thirty-six women (14%) had complications. We have described the indications for surgery, trends in surgical practice and surgical complications for women receiving prophylactic oophorectomy in Ontario. Prior to prophylactic oophorectomy, the indications and benefits should be clear to both patient and physician. Optimally, all women should receive genetic counseling to help define risk for ovarian and breast cancer, medical and surgical options, impact of oophorectomy on cancer risk, risk of surgical complications, and the consequences and management of surgical menopause.