A possible role for mitochondrial dysfunction in migraine.
Migraine is a common neurological disorder characterised by debilitating head pain and an assortment of additional symptoms which can include nausea, emesis, photophobia, phonophobia and occasionally visual sensory disturbances. Migraine is a complex disease caused by an interplay between predisposing genetic variants and environmental factors. It affects approximately 12 % of studied Caucasian populations with affected individuals being predominantly female. Genes involved in neurological, vascular or hormonal pathways have all been implicated in predisposition towards developing migraine. All of these are nuclear encoded genes, but given the role of mitochondria in a number of neurological disorders and in energy production it is possible that mitochondrial variants may play a role in the pathogenesis of this disease. Mitochondrial DNA has been a useful tool for studying population genetics and human genetic diseases due to the clear inheritance shown through successive generations. Given the clear gender bias found in migraine patients it may be important to investigate X-linked inheritance and mitochondrial-related variants in this disorder. This paper explores the possibility that mitochondrial DNA changes may play a role in migraine. Few variants in the mitochondrial genome have so far been investigated in migraine and new studies should be aimed towards investigating the role of mitochondrial DNA in this common disorder.


A glycoprotein pneumococcal conjugate vaccine primes for antibody responses to a pneumococcal polysaccharide vaccine in Gambian children.
Streptococcus pneumoniae is a major cause of acute respiratory infections and acute bacterial meningitis in children. Pneumococcal polysaccharide vaccines are poorly immunogenic in this highly vulnerable group, but protein polysaccharide conjugate vaccines are likely to be more effective. To determine whether immunization of infants with a pneumococcal conjugate vaccine induces immunologic memory. Eighty-four Gambian children, who had been vaccinated previously with two or three doses of a pentavalent pneumococcal conjugate vaccine (CRM197) or with a Haemophilus influenzae type b (Hib) conjugate vaccine were immunized when approximately 2 years old with a 23-valent pneumococcal polysaccharide vaccine, and a blood sample was obtained 10 days later. Pneumococcal antibody titers in prevaccination and postvaccination sera were measured by enzyme-linked immunosorbent assay and by an opsonophagocytic assay. On revaccination with a pneumococcal polysaccharide vaccine, children who had previously received pneumococcal conjugate vaccine had higher antibody concentrations to each of the five polysaccharide components of the conjugate vaccine than did control children. For type 6B polysaccharide, which is poorly immunogenic in young children, postvaccination antibody concentrations were 0.37, 27.6 and 50.9 microg/ml in children who had received no previous pneumococcal immunization or two or three doses of conjugate vaccine, respectively. Type 14 antibodies produced after revaccination were of high avidity and had opsonic activity. Vaccination of young infants with two or three doses of a pneumococcal conjugate vaccine primes the immune system to respond strongly and rapidly on subsequent exposure to pneumococcal polysaccharide.


Lymphadenectomy in elderly/high risk patients: should it be different?
The global aging of population will lead a greater number of elderly patients to undergo surgical procedure in a near future. Concerning gastric cancer, the impact of lymphadenectomy on survival has been demonstrated in RCTs, and extended lymphadenectomy is now considered as gold standard of treatment in non-early tumors. However, the role of age as a prognostic factor and the benefit of extended surgery in elderly/high-risk patients are not clearly defined yet. From our revision of literature, it seems that surgery for gastric cancer may have a further tailorization, considering not only the stage of disease, but also patients' age and comorbidities.


The B cell surface molecule B1 is functionally linked with B cell activation and differentiation.
The B1 molecule is a 32,000 m.w. phosphorylated cell surface protein expressed exclusively by B cells from the mid pre-B until the plasma cell stage of differentiation. Two monoclonal antibodies (gamma 2a and mu) reactive with this molecule were used to assess the role of B1 in B cell activation, proliferation, and differentiation. The anti-B1 antibodies at concentrations ranging from 0.1 to 100 micrograms/ml significantly inhibited B cell proliferation induced by anti-mu antibodies, Staphylococcus aureus Cowan strain 1, activated T cells, and Epstein Barr virus. Although capable of inhibiting proliferation, anti-B1 antibody in soluble form or coupled to beads did not activate B cells or induce proliferation. Antibodies of comparable isotypes or against other B cell-restricted antigens, including B2, B4, B5, and HB-5, did not inhibit activation. Pretreatment of B cells with anti-B1 antibody did not inhibit activation, indicating that B cells had to be cultured with anti-B1 antibody for anti-B1-mediated inhibition to occur. Maximum inhibition was obtained when anti-B1 antibody was added at the initiation of culture. In agreement with this, growth factor-dependent proliferation of preactivated B cells was not inhibited by anti-B1 antibodies. Comparable inhibition of B cell activation was noted with antibodies reactive with class II antigens of the major histocompatibility complex with the exception that anti-B1 antibody inhibited immunoglobulin secretion in pokeweed mitogen assays, whereas anti-DR antibody did not. These results suggest that the B1 molecule may serve a central role in the regulation of B cell activation and differentiation.


Folded or Not? Tracking Bet v 1 Conformation in Recombinant Allergen Preparations.
Recombinant Bet v 1a (rBet v 1a) has been used in allergy research for more than three decades, including clinical application of so-called hypoallergens. Quantitative IgE binding to rBet v 1a depends on its native protein conformation, which might be compromised upon heterologous expression, purification, or mutational engineering of rBet v 1a. To correlate experimental/theoretical comparisons of IgE binding of defined molar ratios of folded/misfolded recombinant Bet v 1a variants and to determine accuracy and precision of immuno- and physicochemical assays routinely used to assess the quality of recombinant allergen preparations. rBet v 1a and its misfolded variant rBet v 1aS112P/R145P were heterologously expressed and purified from Escherichia coli. Structural integrities and oligomerisation of the recombinant allergens were evaluated by 1H-nuclear magnetic resonance (1H-NMR), circular dichroism (CD) spectroscopy, and dynamic light scattering (DLS). IgE binding of defined combinations of rBet v 1a and rBet v 1aS112P/R145P was assessed using immunoblotting (IB), enzyme-linked immunosorbent assay (ELISA) and mediator release (MR) of humanized rat basophilic leukemia cells sensitized with serum IgE of subjects allergic to birch pollen. Experimental and theoretically expected results of the analyses were compared. 1H-NMR spectra of rBet v 1a and rBet v 1aS112P/R145P demonstrate a native and highly disordered protein conformations, respectively. The CD spectra suggested typical alpha-helical and beta-sheet secondary structure content of rBet v 1a and random coil for rBet v 1aS112P/R145P. The hydrodynamic radii (RH) of 2.49 ± 0.39 nm (rBet v 1a) and 3.1 ± 0.56 nm (rBet v 1aS112P/R145P) showed monomeric dispersion of both allergens in solution. Serum IgE of birch pollen allergic subjects bound to 0.1% rBet v 1a in the presence of 99.9% of non-IgE binding rBet v 1aS112P/R145P. Immunoblot analysis overestimated, whereas ELISA and mediator release assay underestimated the actual quantity of IgE-reactive rBet v 1a in mixtures of rBet v 1a/rBet v 1aS112P/R145P with a molar ratio of rBet v 1a ≤ 10%. Valid conclusions on quantitative IgE binding of recombinant Bet v 1a preparations depend on the accuracy and precision of physico- and immunochemical assays with which natively folded allergen is detected.


Stem cell therapy for degenerative disc disease.
Low back pain is widely recognized as one of the most prevalent pathologies in the developed world. In the United States, low back pain is the most common health problem for adults under the age of 50, resulting in significant societal and personal costs. While the causes of low back pain are myriad, it has been significantly associated with intervertebral disc (IVD) degeneration. Current first-line therapies for IVD degeneration such as physical therapy and spinal fusion address symptoms, but do not treat the underlying degeneration. The use of tissue engineering to treat IVD degeneration provides an opportunity to correct the pathological process. Novel techniques are currently being investigated and have shown mixed results. One major avenue of investigation has been stem cell injections. Mesenchymal stem cells (MSCs) have shown promise in small animal models, but results in larger vertebrates have been mixed.


Unilateral condylar hyperplasia: a 3-dimensional quantification of asymmetry.
Objective quantifications of facial asymmetry in patients with Unilateral Condylar Hyperplasia (UCH) have not yet been described in literature. The aim of this study was to objectively quantify soft-tissue asymmetry in patients with UCH and to compare the findings with a control group using a new method. Thirty 3D photographs of patients diagnosed with UCH were compared with 30 3D photographs of healthy controls. As UCH presents particularly in the mandible, a new method was used to isolate the lower part of the face to evaluate asymmetry of this part separately. The new method was validated by two observers using 3D photographs of five patients and five controls. A significant difference (0.79 mm) between patients and controls whole face asymmetry was found. Intra- and inter-observer differences of 0.011 mm (-0.034-0.011) and 0.017 mm (-0.007-0.042) respectively were found. These differences are irrelevant in clinical practice. After objective quantification, a significant difference was identified in soft-tissue asymmetry between patients with UCH and controls. The method used to isolate mandibular asymmetry was found to be valid and a suitable tool to evaluate facial asymmetry.


Simultaneous determination of ranitidine and metronidazole in pharmaceutical formulations at poly(chromotrope 2B) modified activated glassy carbon electrodes.
A simple and sensitive electrochemical method for the simultaneous and quantitative detection of ranitidine (RT) and metronidazole (MT) was developed, based on a poly(chromotrope 2B) modified activated glassy carbon electrode (PCHAGCE). The PCHAGCE showed excellent electrocatalytic activity toward the reduction of both RT and MT in 0.1 mol/L phosphate buffer solution (pH 6.0). The peak-to-peak separations for the simultaneous detection of RT and MT between the two reduction waves in cyclic voltammetry were increased significantly from ∼0.1 V at activated GCE, to ∼0.55 V at PCHAGCE. By differential pulse voltammetry techniques, the reduction peak currents of RT and MT were both linear over the range of 1.0 × 10-5-4.0×10-4 mol/L. The detection limits (S/N = 3) were 5.4 × 10-7 mol/L and 3.3 × 10-7 mol/L for RT and MT, respectively. The modified electrode was successfully applied to the determination of RT and MT in pharmaceutical preparations and human serum as real samples with stable and reliable recovery data.


WITHDRAWN: Interventions for ear discharge associated with grommets (ventilation tubes).
The insertion of grommets (also known as ventilation or tympanostomy tubes) is one of the most common surgical procedures performed on children. Postoperative otorrhoea (discharge) is the most common complication with a reported incidence ranging from 10% to 50%. In the UK, many ENT surgeons treat with topical antibiotics/steroid combinations, but general practitioners, mainly through fears of ototoxicity, are unlikely to prescribe these and choose systemic broad-spectrum antibiotics. 1. To identify the most effective non-surgical management of discharge from ears with grommets in place.2. To identify the risks of non-surgical management for this condition (e.g. ototoxicity), and to set benefits of treatment against these risks. We searched the Cochrane Ear, Nose and Throat Disorders Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2005), MEDLINE (1966 to 2005) and EMBASE (1974 to 2005). We also searched the CINAHL, AMED, LILACS, ISI WEB OF KNOWLEDGE, ISI PROCEEDINGS, mRCT, NNR, ZETOC, KOREAMED, CSA, MEDCARIB, INDMED and SAMED databases. The date of the last search was February 2005. Randomised controlled trials of adults or children, with any type of grommet and an ear with discharge were included. The trials compared treatment with placebo or one treatment with another. The primary outcome measure was the duration of the discharge. The trials were selected independently according to the above criteria by the four reviewers. Differences in opinion over the inclusion of studies were resolved by discussion. The studies were graded using the CASP critical appraisal tool. Analyses were based on the presence of discharge seven days from the onset of treatment. There was very little good quality evidence. Four studies were included, all of them investigating different interventions and therefore a meta-analysis was not possible.Only one study demonstrated a significant difference. Oral amoxicillin clavulanate was compared to placebo in 79 patients. The odds of having a discharge persisting eight days after starting treatment was 0.19 (95% CI 0.07 to 0.49) . The number needed to treat to achieve that benefit is 2.5. Participants in both arms of this study also received daily aural toilet. The results will therefore not be applicable to most settings including primary care. No significant benefit was shown in the two studies investigating steroids (oral prednisolone with oral amoxicillin clavulanate and topical dexamethasone with topical ciprofloxacin ear drops), or the one study comparing an antibiotic-steroid combination (Otosporin®) drops versus spray (Otomize®) (although more patients preferred the spray form). The authors of this review have been unable to identify the most effective intervention or to assess the associated risks. Research is urgently needed into the effectiveness of oral versus topical antibiotics in this group of patients. Clinicians considering antibiotic treatment need to balance any potential benefit against the risks of side effects and antibiotic resistance.


Production of interleukin (IL)-10 and IL-12 by murine colonic dendritic cells in response to microbial stimuli.
Intestinal dendritic cells (DC) are likely to regulate immunity to gut microflora, but little is known about their responses to bacterial antigens. Therefore, DC from normal murine colon were characterized and their cytokine responses to components of Gram-negative and/or Gram-positive bacteria assessed. Cells were obtained by digestion of colonic tissue and contained DC that were identified by flow cytometry as CD11c(+) major histocompatibility complex (MHC) class II(+) cells. Purified DC were obtained by immunomagnetic separation plus cell sorting. DC had the morphology of immature myeloid cells, were endocytically active, expressed low levels of co-stimulatory molecules and stimulated a weak allogeneic mixed leucocyte reaction. Analysis of flow cytometry data by a sensitive subtraction method allowed measurement of production of interleukin (IL)-12 and IL-10 by small numbers of gut DC by intracellular staining. Fewer than 5% of unstimulated DC produced either IL-10 or IL-12. IL-10 production was significantly up-regulated following stimulation with Bifidobacteria longum, but not after exposure to lipopolysaccharide (LPS) or Streptococcus faecium. In contrast, colonic DC produced IL-12 in response to both LPS and B.longum. Thus, colonic DC can produce both IL-12 and IL-10 following bacterial stimulation. Cell wall components from different bacteria stimulate distinct responses and may direct immune responses differentially in the gut.


Gate-variable optical transitions in graphene.
Two-dimensional graphene monolayers and bilayers exhibit fascinating electrical transport behaviors. Using infrared spectroscopy, we find that they also have strong interband transitions and that their optical transitions can be substantially modified through electrical gating, much like electrical transport in field-effect transistors. This gate dependence of interband transitions adds a valuable dimension for optically probing graphene band structure. For a graphene monolayer, it yields directly the linear band dispersion of Dirac fermions, whereas in a bilayer, it reveals a dominating van Hove singularity arising from interlayer coupling. The strong and layer-dependent optical transitions of graphene and the tunability by simple electrical gating hold promise for new applications in infrared optics and optoelectronics.


Comprehensive profiling of dopamine regulation in substantia nigra and ventral tegmental area.
Dopamine is a vigorously studied neurotransmitter in the CNS. Indeed, its involvement in locomotor activity and reward-related behaviour has fostered five decades of inquiry into the molecular deficiencies associated with dopamine regulation. The majority of these inquiries of dopamine regulation in the brain focus upon the molecular basis for its regulation in the terminal field regions of the nigrostriatal and mesoaccumbens pathways; striatum and nucleus accumbens. Furthermore, such studies have concentrated on analysis of dopamine tissue content with normalization to only wet tissue weight. Investigation of the proteins that regulate dopamine, such as tyrosine hydroxylase (TH) protein, TH phosphorylation, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) protein often do not include analysis of dopamine tissue content in the same sample. The ability to analyze both dopamine tissue content and its regulating proteins (including post-translational modifications) not only gives inherent power to interpreting the relationship of dopamine with the protein level and function of TH, DAT, or VMAT2, but also extends sample economy. This translates into less cost, and yet produces insights into the molecular regulation of dopamine in virtually any paradigm of the investigators' choice. We focus the analyses in the midbrain. Although the SN and VTA are typically neglected in most studies of dopamine regulation, these nuclei are easily dissected with practice. A comprehensive readout of dopamine tissue content and TH, DAT, or VMAT2 can be conducted. There is burgeoning literature on the impact of dopamine function in the SN and VTA on behavior, and the impingements of exogenous substances or disease processes therein (1-5). Furthermore, compounds such as growth factors have a profound effect on dopamine and dopamine-regulating proteins, to a comparatively greater extent in the SN or VTA (6-8). Therefore, this methodology is presented for reference to laboratories that want to extend their inquiries on how specific treatments modulate behaviour and dopamine regulation. Here, a multi-step method is presented for the analyses of dopamine tissue content, the protein levels of TH, DAT, or VMAT2, and TH phosphorylation from the substantia nigra and VTA from rodent midbrain. The analysis of TH phosphorylation can yield significant insights into not only how TH activity is regulated, but also the signaling cascades affected in the somatodendritic nuclei in a given paradigm. We will illustrate the dissection technique to segregate these two nuclei and the sample processing of dissected tissue that produces a profile revealing molecular mechanisms of dopamine regulation in vivo, specific for each nuclei (Figure 1).


The role of packaged water in meeting global targets on improved water access.
Packaged water (as either refill, bottled, or sachet water) has become an important element of water security in many low- and middle-income countries, owing to poor reliability and lack of piped water infrastructure. However, over time and across countries, the Demographic and Health Surveys monitoring program has inconsistently classified packaged water components as either improved or unimproved. Using data collected as part of the Performance Monitoring and Accountability 2020 (PMA2020) surveys on water options in nine study geographies across eight countries, we identified five geographies where packaged water constituted one of several options for 5% or more of users. In this study, four scenarios were designed in which packaged water components were variously classified as either improved or unimproved. Unimproved water use was highest in scenarios where sachet or refill water was classified as an unimproved source. Across the four scenarios, the difference in the use of unimproved water as the main option was highest (65%) in Nigeria (Lagos). That difference increased to 78% when considering all regular options. The development of these scenarios highlights the importance of classifying a source as improved or unimproved in the overall metric that indicates progress at national and international levels.


Interventional treatment of a symptomatic neonatal hepatic cavernous hemangioma using the Amplatzer vascular plug.
Percutaneous intervention is one treatment option for symptomatic hepatic hemangioma in infants. We report the case of a newborn (birth weight 4060 g) with a large hepatic cavernous hemangioma, which presented early with high cardiac output failure due to arteriovenous shunting and signs of incipient Kasabach-Merritt syndrome. We performed a successful superselective transcatheter coil embolization of three feeding arteries on the seventh day of life. Because of remaining diffuse very small arteries causing a relevant residual shunt, additional occlusion of the three main draining veins was necessary with three Amplatzer vascular plugs. Cardiac failure resolved immediately. Without any additional therapy the large venous cavities disappeared within the following months. The tumor continues to regress in size 8 months after the intervention.


The use of seal scarers as a protective mitigation measure can induce hearing impairment in harbour porpoises.
Acoustic deterrent devices (ADDs) are used to deter seals from aquacultures but exposure of harbour porpoises (Phocoena phocoena) occurs as a side-effect. At construction sites, by contrast, ADDs are used to deter harbour porpoises from the zone in which pile driving noise can induce temporary threshold shifts (TTSs). ADDs emit such high pressure levels that there is concern that ADDs themselves may induce a TTS. A harbour porpoise in human care was exposed to an artificial ADD signal with a peak frequency of 14 kHz. A significant TTS was found, measured by auditory evoked potentials, with an onset of 142 dB re 1 μPa2s at 20 kHz and 147 dB re 1 μPa2s at 28 kHz. The authors therefore strongly recommend to gradually increase and down regulate source levels of ADDs to the desired deterrence range. However, further research is needed to develop a reliable relationship between received levels and deterrence.


Transposition of the Intratemporal Facial to Hypoglossal Nerve for Reanimation of the Paralyzed Face: The VII to XII TranspositionTechnique.
The hypoglossal nerve has long been an axonal source for reinnervation of the paralyzed face. In this study, we report our experience with transposition of the intratemporal facial nerve to the hypoglossal nerve for facial reanimation. To determine the feasibility and outcomes of the transposition of the infratemeporal facial nerve for end-to-side coaptation to the hypoglossal nerve for facial reanimation. A case series of 20 patients with facial paralysis who underwent mobilization and transposition of the intratemporal segment of the facial nerve for an end-to-side coaptation to the hypoglossal nerve (the VII to XII technique). Participants were treated between January 2007 and December 2014 at a tertiary care center. Outcome measures include paralysis duration, facial tone, facial symmetry at rest, and with smile, oral commissure excursion, post-reanimation volitional smile, and synkinesis. Demographic data, the effects of this technique on facial tone, symmetry, oral commissure excursion and smile recovery were evaluated. Preoperative and postoperative photography and videography were reviewed. Facial symmetry was assessed with a facial asymmetry index. Smile outcomes were evaluated with a visual smile recovery scale, and lip excursion was assessed with the MEEI-SMILE system. All 20 patients had adequate length of facial nerve mobilized for direct end-to-side coaptation to the hypoglossal nerve. The median duration of facial paralysis prior to treatment was 11.4 months. Median follow-up time was 29 months. Three patients were excluded from functional analysis due to lack of follow-up. Facial symmetry at rest and during animation improved in 16 of 17 patients. The median (range) time for return of facial muscle tone was 7.3 (2.0-12.0) months. A significant reduction in facial asymmetry index occurred at rest and with movement. The MEEI FACE-gram software detected a significant increase in horizontal, vertical, overall lip excursion and smile angle. No patient developed significant tongue atrophy, impaired tongue mobility, or speech or swallow dysfunction. Mobilization of the intratemporal segment of the facial nerve provides adequate length for direct end-to-end coaptation to the hypoglossal nerve and is effective in restoring facial tone and symmetry after facial paralysis. The resulting smile is symmetric or nearly symmetric in the majority of patients with varying degree of dental show. The additional length provided by utilizing the intratemporal segment of the facial nerve reduces the deficits associated with complete hypoglossal division/splitting, and avoids the need for interposition grafts and multiple coaptation sites. 4.


Modeling multiple sea level rise stresses reveals up to twice the land at risk compared to strictly passive flooding methods.
Planning community resilience to sea level rise (SLR) requires information about where, when, and how SLR hazards will impact the coastal zone. We augment passive flood mapping (the so-called "bathtub" approach) by simulating physical processes posing recurrent threats to coastal infrastructure, communities, and ecosystems in Hawai'i (including tidally-forced direct marine and groundwater flooding, seasonal wave inundation, and chronic coastal erosion). We find that the "bathtub" approach, alone, ignores 35-54 percent of the total land area exposed to one or more of these hazards, depending on location and SLR scenario. We conclude that modeling dynamic processes, including waves and erosion, is essential to robust SLR vulnerability assessment. Results also indicate that as sea level rises, coastal lands are exposed to higher flood depths and water velocities. The prevalence of low-lying coastal plains leads to a rapid increase in land exposure to hazards when sea level exceeds a critical elevation of ~0.3 or 0.6 m, depending on location. At ~1 m of SLR, land that is roughly seven times the total modern beach area is exposed to one or more hazards. Projected increases in extent, magnitude, and rate of persistent SLR impacts suggest an urgency to engage in long-term planning immediately.


CAD/CAM fabrication accuracy of long- vs. short-span implant-supported FDPs.
To compare the precision of fit of long-span vs. short-span implant-supported screw-retained fixed dental prostheses (FDPs) made from computer-aided-design/computer-aided-manufactured (CAD/CAM) titanium and veneered with ceramic. The null hypothesis was that there is no difference in the vertical microgap between long-span and short-span FDPs. CAD/CAM titanium frameworks for an implant-supported maxillary FDP on implants with a flat platform were fabricated on one single master cast. Group A consisted of six 10-unit FDPs connected to six implants (FDI positions 15, 13, 11, 21, 23, 25) and group B of six 5-unit FDPs (three implants, FDI positions 21, 23, 25). The CAD/CAM system from Biodenta Swiss AG (Berneck, Switzerland) was used for digitizing (laser scanner) the master cast and anatomical CAD of each framework separately. The frameworks were milled (CAM) from a titanium grade V monobloc and veneered with porcelain. Median vertical distance between implant and FDP platforms from the non-tightened implants (one-screw test on implant 25) was calculated from mesial, buccal, and distal scanning electron microscope measurements. All measurements showed values <40 μm. Total median vertical microgaps were 23 μm (range 2-38 μm) for group A and 7 μm (4-24 μm) for group B. The difference between the groups was statistically significant at implant 21 (P = 0.002; 97.5% CI -27.3 to -4.9) and insignificant at implant 23 (P = 0.093; -3.9 to 1.0). CAD/CAM fabrication including laboratory scanning and porcelain firing was highly precise and reproducible for all long- and short-span FDPs. While all FDPs showed clinically acceptable values, the short-span FDPs were statistically more precise at the 5-unit span distance.


High prevalence of altered cardiac repolarization in patients with COPD.
Altered cardiac repolarization and increased dispersion of repolarization have been identified as risk factors for sudden cardiac death (SCD). The prevalence of and the mechanisms contributing to altered cardiac repolarization are currently unknown in COPD. In 91 COPD patients, 32 controls matched for age, cardiovascular risk and medication, and 41 healthy subjects, measures of cardiac repolarization and dispersion of repolarization (QTc interval, QT dispersion) were derived from 12-lead electrocardiography (ECG). Prevalence rates of heart rate corrected QT (QTc) >450ms and QT dispersion >60ms were determined to assess the number of subjects at risk for SCD. Univariate and multivariate analyses were used to identify possible factors contributing to altered cardiac repolarization. QTc was found to be prolonged in 31.9% and QT dispersion in 24.2% of the COPD patients compared to 12.5% in matched controls and 0% in healthy subjects. The QTc interval was longer in COPD patients compared to matched and healthy controls respectively (437.9 ± 29.5 vs. 420.1 ± 25.3 ms, p = 0.001 and vs. 413.4 ± 18.2 ms, p < 0.001). QT dispersion was significantly increased in COPD patients compared to healthy subjects (45.4 (34.8 , 59.5) vs. 39.7 (29.3 , 54.8) ms, p = 0.049). Only oxygen saturation was independently associated with QTc duration in multivariate analysis (β = -0.29, p = 0.015). One third of a typical COPD population has altered cardiac repolarization and increased dispersion of repolarization, which may be related to hypoxia. Altered cardiac repolarization may expose these patients to an increased risk for malignant ventricular arrhythmias and SCD.


Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors.
Allogeneic hematopoietic cell transplantation has an established role in the treatment of adults with acute lymphoblastic leukemia whose survival when recipients of grafts from adult unrelated donors approaches that of recipients of grafts from sibling donors. Our aim was to determine the role of mismatched unrelated cord blood grafts in transplantation for 802 adults with acute lymphoblastic leukemia in first or second complete remission. Using Cox regression we compared outcomes after 116 mismatched single or double cord blood transplants, 546 peripheral blood progenitor cell transplants and 140 bone marrow transplants. The characteristics of the recipients and their diseases were similar except cord blood recipients were younger, more likely to be non-Caucasians and more likely to have a low white blood cell count at diagnosis. There were differences in donor-recipient human leukocyte antigen-match depending on the source of the graft. Most adult donor transplants were matched at the allele-level considering human leukocyte antigens-A, -B, -C and -DRB1. In contrast, most cord blood transplants were mismatched and considered antigen-level matching; 57% were mismatched at two loci and 29% at one locus whereas only 29% of adult donor transplants were mismatched at one locus and none at two loci. There were no differences in the 3-year probabilities of survival between recipients of cord blood (44%), matched adult donor (44%) and mismatched adult donor (43%) transplants. Cord blood transplants engrafted slower and were associated with less grade 2-4 acute but similar chronic graft-versus-host disease, relapse, and transplant-related mortality. The survival of cord blood graft recipients was similar to that of recipients of matched or mismatched unrelated adult donor grafts and so cord blood should be considered a valid alternative source of stem cells for adults with acute lymphoblastic leukemia in the absence of a matched unrelated adult donor.


Pivotal role of M-DC8⁺ monocytes from viremic HIV-infected patients in TNFα overproduction in response to microbial products.
HIV infects activated CD4⁺ T cells and induces their depletion. Progressive HIV infection leading to AIDS is fueled by chronic immune hyperactivation, mediated by inflammatory cytokines like TNFα. This has been related to intestinal epithelial damage and microbial LPS translocation into the circulation. Using 11-color flow cytometry, cell sorting, and cell culture, we investigated the numbers and TNFα production of fully defined circulating dendritic cell and monocyte populations during HIV-1 infection. In 15 viremic, untreated patients, compared with 8 treated, virologically suppressed patients or to 13 healthy blood donors, circulating CD141 (BDCA-3)⁺ and CD1c (BDCA-1)⁺ dendritic cell counts were reduced. Conversely, CD14⁺ CD16⁺⁺ monocyte counts were increased, particularly those expressing M-DC8, while classical CD14⁺⁺ CD16⁻ M-DC8⁻ monocyte numbers were unchanged. Blood mononuclear cells from viremic patients produced more TNFα in response to LPS than those from virologically suppressed patients. M-DC8⁺ monocytes were mostly responsible for this overproduction. Moreover, M-DC8⁺ monocytes differentiated in vitro from classical monocytes using M-CSF and GM-CSF, which is increased in viremic patient's plasma. This M-DC8⁺ monocyte population, which is involved in the pathogenesis of chronic inflammatory diseases like Crohn disease, might thus be considered as a major actor in the immune hyperactivation fueling HIV infection progression.


Venous access ports: indications, implantation technique, follow-up, and complications.
The subcutaneous venous access device (SVAD or "port") is a critical component in the care of patients with chronic disease. The modern SVAD provides reliable access for blood withdrawal and medication administration with minimal disruption to a patient's lifestyle. Because of improved materials and catheter technology, today's ports are lighter and stronger and capable of high-pressure injections of contrast for cross-sectional imaging. The majority of SVAD placement occurs in interventional radiology departments due to their ability to provide this service at lower costs, lower, complication rates, and greater volumes. Port-insertion techniques vary depending on the operator, but all consist of catheter placement in the central venous circulation followed by subcutaneous pocket creation and port attachment to the catheter with fixation and closure of the pocket. Venous access challenges occasionally occur in patients with central vein occlusions, necessitating catheterization of collateral veins or port placement in alternate locations. Complications of SVADs include those associated with the procedure as well as short- (<30 days) and long-term problems. Procedural and early complications are quite rare due to the near-universal use of real-time ultrasound guidance for vein puncture, but they can include hematoma, catheter malposition, arrhythmias, and pneumothorax. Late problems include both thrombotic complications (native venous or port-catheter thrombosis) and infections (tunnel or pocket infections or catheter-associated bloodstream infections). Most guidelines suggest that 0.3 infections/1000 catheter days is an appropriate upper threshold for the insertion of SVADs.


Effect of androgen deprivation therapy on the expression of prostate cancer biomarkers MSMB and MSMB-binding protein CRISP3.
We have investigated the effects of short-term neoadjuvant and long-term androgen deprivation therapies (ADTs) on β-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) expression in prostate cancer patients. We also studied if MSMB expression was related to genotype and epigenetic silencing. Using an Affymetrix cDNA microarray analysis, we investigated the expression of MSMB, CRISP3, androgen receptor (AR), KLK3 and Enhancer of Zeste Homologue-2 (EZH2) in tissue from prostate cancer patients receiving (n=17) or not receiving (n=23) ADT before radical prostatectomy. MSMB, CRISP3 and AR were studied in tissue from the same patients undergoing TURP before and during ADT (n=16). MSMB genotyping of these patients was performed by TaqMan PCR. MSMB and KLK3 expression levels decreased during ADT. Expression levels of AR and CRISP3 were not affected by short-term ADT but were high in castration-resistant prostate cancer (CRPC) and metastases. Levels of EZH2 were also high in metastases, where MSMB was low. Genotyping of the MSMB rs10993994 polymorphism showed that the TT genotype conveys poor MSMB expression. MSMB expression is influenced by androgens, but also by genotype and epigenetic silencing. AR and CRISP3 expression are not influenced by short-term ADT, and high levels were found in CRPC and metastases.


Multimodal impairment-based physical therapy for the treatment of patients with post-concussion syndrome: A retrospective analysis on safety and feasibility.
Demonstrate implementation, safety and feasibility of multimodal, impairment-based physical therapy (PT) combining vestibular/oculomotor and cervical rehabilitation with sub-symptom threshold exercise for the treatment of patients with post-concussion syndrome (PCS). University hospital outpatient sports medicine facility. Twenty-five patients (12-20 years old) meeting World Health Organization criteria for PCS following sport-related concussion referred for supervised PT consisting of sub-symptom cardiovascular exercise, vestibular/oculomotor and cervical spine rehabilitation. Retrospective cohort. Post-Concussion Symptom Scale (PCSS) total score, maximum symptom-free heart rate (SFHR) during graded exercise testing (GXT), GXT duration, balance error scoring system (BESS) score, and number of adverse events. Patients demonstrated a statistically significant decreasing trend (p < 0.01) for total PCSS scores (pre-PT M = 18.2 (SD = 14.2), post-PT M = 9.1 (SD = 10.8), n = 25). Maximum SFHR achieved on GXT increased 23% (p < 0.01, n = 14), and BESS errors decreased 52% (p < 0.01, n = 13). Two patients reported mild symptom exacerbation with aerobic exercise at home, attenuated by adjustment of the home exercise program. Multimodal, impairment-based PT is safe and associated with diminishing PCS symptoms. This establishes feasibility for future clinical trials to determine viable treatment approaches to reduce symptoms and improve function while avoiding negative repercussions of physical inactivity and premature return to full activity.


Enhancement of Antioxidative and Intestinal Anti-inflammatory Activities of Glycated Milk Casein after Fermentation with Lactobacillus rhamnosus 4B15.
In this study, we investigated the glycoproteomics of glycated milk casein (GMC) and GMC fermented by Lactobacillus rhamnosus 4B15 (FGMC) and determined their biological implications. There was a significant increase in the antioxidative and anti-inflammatory activities of GMC with galactose, which were higher than those of GMC with glucose (GMC-glc). Furthermore, the fermentation of GMC by L. rhamnosus 4B15 synergistically enhanced the above activities compared to those of unfermented GMC. Especially, fermented GMC-glc (FGMC-glc) possessed remarkably improved reducing power and radical scavenging activities. Moreover, FGMC-glc ameliorated the inflammatory response and tight junction-related intestinal epithelial dysfunction. Additionally, hexose-derived glycation and modification sites in protein sequences of GMC were identified. In particular, glycosylation and sulfation of serine and threonine residues were observed, and distinct modification sites were detected after fermentation. Therefore, these results indicated that glycation-induced modification of casein and fermentation correlated strongly with the enhanced functional properties.


Microplastic contamination in Lake Winnipeg, Canada.
Microplastics are an emerging contaminant of concern in aquatic ecosystems. To better understand microplastic contamination in North American surface waters, we report for the first time densities of microplastics in Lake Winnipeg, the 11th largest freshwater body in the world. Samples taken 2014 to 2016 revealed similar or significantly greater microplastic densities in Lake Winnipeg compared with those reported in the Laurentian Great Lakes. Plastics in the lake were largely of secondary origin, overwhelmingly identified as fibres. We detected significantly greater densities of microplastics in the north basin compared to the south basin of the lake in 2014, but not in 2015 or 2016. Mean lake-wide densities across all years were comparable and not statistically different. Scanning electron microscopy with energy dispersive X-ray spectroscopy indicated that 23% of isolated particles on average were not plastic. While the ecological impact of microplastics on aquatic ecosystems is still largely unknown, our study contributes to the growing evidence that microplastic contamination is widespread even around sparsely-populated freshwater ecosystems, and provides a baseline for future study and risk assessments.


On models of quantitative genetic variability: a stabilizing selection-balance model.
A model of stabilizing selection on a multilocus character is proposed that allows the maintenance of stable allelic polymorphism and linkage disequilibrium. The model is a generalization of Lerner's model of homeostasis in which heterozygotes are less susceptible to environmental variation and hence are superior to homozygotes under phenotypic stabilizing selection. The analysis is carried out for weak selection with a quadratic-deviation model for the stabilizing selection. The stationary state is characterized by unequal allele frequencies, unequal proportions of complementary gametes, and a reduction of the genetic (and phenotypic) variance by the linkage disequilibrium. The model is compared with Mather's polygenic balance theory, with models that include mutation-selection balance, and others that have been proposed to study the role of linkage disequilibrium in quantitative inheritance.


Ocular inflammatory effects of intravitreally-injected tumor necrosis factor.
Many of the pathophysiologic effects of bacterial endotoxin have recently been attributed to a monokine, tumor necrosis factor (TNF). The rabbit eye is extremely sensitive to locally injected endotoxin. The authors have investigated the possible contribution of TNF to ocular inflammation in a rabbit model. The intravitreal injection of 10(5) to 5 X 10(5) units of recombinant human TNF produced a sustained disruption of the blood-aqueous barrier as manifested by elevated aqueous humor protein levels. In addition, 83% of rabbits receiving this dose of TNF developed hyperemia of limbal vessels and early neovascularization of the cornea. Many developed posterior synechiae (fibrous adhesions between the iris and the lens). TNF induced only a slight cellular response in the anterior chamber. Histologic studies confirmed the presence of new vessels and demonstrated a marked mononuclear infiltrate within and beneath the epithelium of the iris and ciliary body. Lower doses of TNF produced inconsistent results. Heating TNF completely destroyed its inflammatory effects. The time course of the ocular response to TNF and the quantity of recombinant protein needed to produce consistent effects were vastly different from effects observed with interleukin-1. For example, 24 hours after an intravitreal injection, 2.2 X 10(4) ng of TNF (5 X 10(5) units) produced significantly less protein extravasation and polymorphonuclear leukocyte infiltration than 4 ng of recombinant interleukin-1. Similarly, 24 hours after intravitreal injection, 1 ng of Escherichia coli endotoxin tended to be a more potent inflammatory stimulus than this quantity of TNF. These observations indicate that the ocular pathophysiologic effects of TNF can be readily distinguished from changes induced by either endotoxin or another endotoxin induced monokine, interleukin-1.


Effect of standard tuberculosis treatment on plasma cytokine levels in patients with active pulmonary tuberculosis.
Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy. Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion. Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p = 0.0017). No significant changes were observed in other studied immune mediators. These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals.


Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.
The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.


Role of warm water bath in inducing micturition in postoperative urinary retention after anorectal operations.
The relation of micturition to sitting in a warm water bath was studied in 30 healthy volunteers and 21 patients with urinary retention after hemorrhoidectomy. The rectal temperature, vesical and urethral pressures as well as the EMG activity of the external urethral sphincter were recorded before sitting in and immediately after getting out of the sitz bath at 40, 45 and 50 degrees C. In the 40 degrees C bath, 16 of the 30 normal subjects reported spontaneous micturition and 14 voluntarily induced micturition. The number of spontaneous micturitions increased with higher-temperature baths. Spontaneous micturition occurred in 19 patients with urinary retention when they sat in the sitz bath; 2 patients did not micturate and were catheterized. The urethral pressure in both the normal and retention subjects showed significant reduction which increased with higher-temperature baths. There were no significant changes in the vesical pressure or EMG activity of the external urethral sphincter with water baths. Micturition on sitting in a warm water bath seems to be initiated by reflex internal urethral sphincter relaxation. A thermo-sphincter reflex is likely to be involved.


Statistical approaches for analyzing mutational spectra: some recommendations for categorical data.
In studies examining the patterns or spectra of mutational damage, the primary variables of interest are expressed typically as discrete counts within defined categories of damage. Various statistical methods can be applied to test for heterogeneity among the observed spectra of different classes, treatment groups and/or doses of a mutagen. These are described and compared via computer simulations to determine which are most appropriate for practical use in the evaluation of spectral data. Our results suggest that selected, simple modifications of the usual Pearson X2 statistic for contingency tables provide stable false positive error rates near the usual alpha = 0.05 level and also acceptable sensitivity to detect differences among spectra. Extensions to the problem of identifying individual differences within and among mutant spectra are noted.


The effectiveness of transdermal opioid in the management multiple rib fractures: randomized clinical trial.
The most commonly observed pathology in chest traumas is rib fracture, and the most important clinical symptom is severe pain. To investigate the effectiveness of intramuscular opioid (IMO), intravenous patient-controlled analgesia (IVPCA) and the Fentanyl transdermal therapeutic system (TTS) in the management of rib fracture pain. Prospective randomized clinical trial. In our prospective and randomised study, we included 45 patients with a diagnosis of multiple rib fractures. There were three groups and intercostal nerve blockage (ICB) in the first day and oral paracetamol for five days was administered to each group as standard. In Group IMO (n=15), 4×40 mg pethidine HCl was administered to the patients, while in Group IVPCA (n=15) this was 5 μg/mL continuous intravenous fentanyl and was 50 μg fentanyl TTS in Group TTS (n=15). The demographics, injury data and vital signs of the patients were recorded. Pain was scored using Visual Analogue Scale (VAS). The pain during lying down (VASl) and mobilisation (VASm) was detected. There were no differences between the three groups regarding age, sex, the trauma pattern, the number and distribution of costal fracture localisations, the presence of additional pathology, complications, thoracal catheter and the duration of thoracal catheter. No significant difference between the groups regarding systolic and diastolic arterial tension, number of breaths and beats in a minute was observed (p>0.05). We observed an improvement in the mean VAS score after treatment in all three groups. The mean VASl score significantly decreased after treatment in each group (p<0.05). The mean VASl and VASm scores measured on the 1(st), 2(nd), 3(rd), 4(th) and 5(th) days were found to be higher in Group IMO than in Groups IVPCA and TTS; however, these differences were not statistically significant (p>0.05). In the analgesia of patients with multiple rib fractures, TTS administration with ICB showed similar effectiveness with IVPCA administration with ICB. In the management of pain due to multiple rib fractures, TTS administration is a safe, non-invasive and effective procedure.


Enantioselective synthesis of axially chiral biaryls by the Pd-catalyzed Suzuki-Miyaura reaction: substrate scope and quantum mechanical investigations.
We report efficient syntheses of axially chiral biaryl amides in yields ranging from 80-92%, and with enantioselectivity in the range 88-94% ee employing an asymmetric Suzuki-Miyaura process with Pd(OAc)(2) and KenPhos as ligand. These studies demonstrate that electron-rich and electron-deficient o-halobenzamides can be efficiently coupled with 2-methyl-1-naphthylboronic acid and 2-ethoxy-1-naphthylboronic acid. The yields and selectivities of the reactions are independent of the nature of halogen substituent on the benzamide coupling partner. Our investigations demonstrate that axially chiral heterocyclic and biphenyl compounds can also be synthesized with this methodology. We also report computational studies used to determine the origin of stereoselectivity during the selectivity-determining reductive elimination step of the related coupling of tolyl boronic acid with naphthylphosphonate bromide that was reported in a previous publication (J. Am. Chem. Soc. 2000, 122, 12051-12052). These studies indicate that the stereoselectivity arises from a combination of weak -(C)H..O interactions as well as steric interactions between the tolyl and naphthylphosphonate addends in the transition state for C-C coupling.


Watch, Imagine, Attempt: Motor Cortex Single-Unit Activity Reveals Context-Dependent Movement Encoding in Humans With Tetraplegia.
Planning and performing volitional movement engages widespread networks in the human brain, with motor cortex considered critical to the performance of skilled limb actions. Motor cortex is also engaged when actions are observed or imagined, but the manner in which ensembles of neurons represent these volitional states (VoSs) is unknown. Here we provide direct demonstration that observing, imagining or attempting action activates shared neural ensembles in human motor cortex. Two individuals with tetraplegia (due to brainstem stroke or amyotrophic lateral sclerosis, ALS) were verbally instructed to watch, imagine, or attempt reaching actions displayed on a computer screen. Neural activity in the precentral gyrus incorporated information about both cognitive state and movement kinematics; the three conditions presented overlapping but unique, statistically distinct activity patterns. These findings demonstrate that individual neurons in human motor cortex reflect information related to sensory inputs and VoS in addition to movement features, and are a key part of a broader network linking perception and cognition to action.


Dietary Capsicum and Curcuma longa oleoresins increase intestinal microbiome and necrotic enteritis in three commercial broiler breeds.
Three commercial broiler breeds were fed from hatch with a diet supplemented with Capsicum and Curcuma longa oleoresins, and co-infected with Eimeria maxima and Clostridium perfringens to induce necrotic enteritis (NE). Pyrotag deep sequencing of bacterial 16S rRNA showed that gut microbiota compositions were quite distinct depending on the broiler breed type. In the absence of oleoresin diet, the number of operational taxonomic units (OTUs), was decreased in infected Cobb, and increased in Ross and Hubbard, compared with the uninfected. In the absence of oleoresin diet, all chicken breeds had a decreased Candidatus Arthromitus, while the proportion of Lactobacillus was increased in Cobb, but decreased in Hubbard and Ross. Oleoresin supplementation of infected chickens increased OTUs in Cobb and Ross, but decreased OTUs in Hubbard, compared with unsupplemented/infected controls. Oleoresin supplementation of infected Cobb and Hubbard was associated with an increased percentage of gut Lactobacillus and decreased Selenihalanaerobacter, while Ross had a decreased fraction of Lactobacillus and increased Selenihalanaerobacter, Clostridium, Calothrix, and Geitlerinema. These results suggest that dietary Capsicum/Curcuma oleoresins reduced the negative consequences of NE on body weight and intestinal lesion, in part, through alteration of the gut microbiome in 3 commercial broiler breeds.


Thyroid hormone and vitamin D regulate VGF expression and promoter activity.
The Siberian hamster (Phodopus sungorus) survives winter by decreasing food intake and catabolizing abdominal fat reserves, resulting in a sustained, profound loss of body weight. Hypothalamic tanycytes are pivotal for this process. In these cells, short-winter photoperiods upregulate deiodinase 3, an enzyme that regulates thyroid hormone availability, and downregulate genes encoding components of retinoic acid (RA) uptake and signaling. The aim of the current studies was to identify mechanisms by which seasonal changes in thyroid hormone and RA signaling from tanycytes might ultimately regulate appetite and energy expenditure. proVGF is one of the most abundant peptides in the mammalian brain, and studies have suggested a role for VGF-derived peptides in the photoperiodic regulation of body weight in the Siberian hamster. In silico studies identified possible thyroid and vitamin D response elements in the VGF promoter. Using the human neuroblastoma SH-SY5Y cell line, we demonstrate that RA increases endogenous VGF expression (P<0.05) and VGF promoter activity (P<0.0001). Similarly, treatment with 1,25-dihydroxyvitamin D3 increased endogenous VGF mRNA expression (P<0.05) and VGF promoter activity (P<0.0001), whereas triiodothyronine (T3) decreased both (P<0.01 and P<0.0001). Finally, intra-hypothalamic administration of T3 blocked the short day-induced increase in VGF expression in the dorsomedial posterior arcuate nucleus of Siberian hamsters. Thus, we conclude that VGF expression is a likely target of photoperiod-induced changes in tanycyte-derived signals and is potentially a regulator of seasonal changes in appetite and energy expenditure.


Controlling factors in the rates of oxidation of anilines and phenols by triplet methylene blue in aqueous solution.
Anilines and phenols are structurally similar compound classes that both are susceptible to oxidation by excited state triplet sensitizers but undergo oxidation by different mechanisms. To gain an understanding of the factors that control the rate of oxidation of anilines and phenols by triplet excited states, a kinetic study was performed on the oxidation of substituted anilines and phenols by methylene blue. The rate constants of one-electron transfer from anilines to triplet state methylene blue and their dependence on the reaction free energy are well fit to a Sandros-Boltzmann model. The observed rate constants are also well modeled when aniline oxidation potentials derived computationally are used. For phenols, the proton-coupled electron transfer rate constants were found to correlate primarily with O-H bond dissociation free energy and secondarily with phenol pKa. Rate constants for phenols could be modeled using computed bond dissociation free energies. These results provide a basis for predicting aniline and phenol oxidation rates, which could be valuable, for example, in assessing the likely persistence and fate of aniline- and phenol-based aqueous environmental pollutants.


Initiation of endochondral calcification is related to changes in the redox state of hypertrophic chondrocytes.
The level of pyridine nucleotides (NADH and NAD+) in the mineralizing growth plate of the chick was ascertained by high-resolution scanning microfluorimetry and biochemical analysis. Scanning electron microscopy and light microscopy were used to relate the concentrations of NADH and NAD+ to stages of chondrocyte maturation. A dramatic increase was found in the relative concentration of reduced pyridine nucleotides in the hypertrophic zone. On either side of this zone, in proliferating and calcifying cartilage, there was a decrease in NADH fluorescence, and the NADH/NAD+ ratio was depressed. The finding that NADH accumulated in the tissue zone associated with the earliest deposition of bone mineral supports the hypothesis that a change in the redox state initiates tissue mineralization.


SU-E-J-163: Video-Based Patient Motion Detection during the Treatment Delivery.
During the treatment, a patient is continuously monitored by video cameras. The therapists are supposedly to watch the monitors and interrupt the treatment if any significant patient motion is spotted. Unfortunately, patient motion can easily be overlooked with this manual approach, especially when there are many other monitors in the control console area. Motion detection algorithms can help to prevent this situation by alerting therapists if a significant motion is detected. We propose a method based on matrix decomposition into low rank and sparse matrices to separate background and moving objects from a video camera. The matrix is formed with image frames of the video and after decomposition, the low rank component represents the background and the sparse component is used to identify moving subjects in the video. The matrix decomposition is performed by solving a convex optimization problem via an efficient alternating direction method. Combining prior knowledge about the motion of treatment machines, our method can reliably extract the actual patient motion from the machine motion and background changes. We tested the algorithm using videos obtained from a volunteer lying on the treatment couch under the linac. We managed to isolate the patient and treatment machine motions from the background. Our algorithm can separate the patient motion from the background and therefore makes it possible to efficiently detect when this motion is above a certain threshold. This method requires that a large number of frames are acquired, but the concept can be extended to real time by adaptively update the low rank component.


Effect of cardiopulmonary bypass on neutrophil activity in pediatric open-heart surgery.
The nature of the participation of neutrophils in the post-cardiopulmonary bypass (CPB) inflammatory response is not very clear. The aim of our study was to investigate alterations in neutrophil phagocytic activity and adhesion molecule expression on these cells in children during and after CPB. Twenty-one children aged 6-33 months with congenital heart disease, scheduled for pri mary corrective surgery, were enrolled. The expressions of CD11b adhesion molecules and Fc? receptor on neutrophils and their phagocytic activity were evaluated. The studied markers were sequentially measured before, at the initiation of, and after CPB. During the course of the operation, CD11b molecule expression on neutrophils showed a slight elevation at the start of CPB (876.5+/-104.8 mean fluorescence intensity, MFI, vs. 768.1+/-178.2; p = 0.0047), followed by a significant decrease to 689.01+/-166.7 MFI after completion of the procedure. The expression of CD11b molecule on neutrophils measured at the end of CPB inversely correlated with the duration of CPB (r = -0.68, p = 0.00059). The expression of CD16 antigen dropped significantly at the start of CPB (1164.6+/-307.3 MFI vs. 1327.4+/-345.3 MFI; p = 0.0007) and remained decreased until the end of CPB (814.0+/-198.1 MFI). These findings suggest that the characteristics of the neutrophil response to cardiac surgery appear to depend on many factors. We demonstrated a link between the duration of CPB and adhesion molecule expression on neutrophils.


Meaning-Making Process Related to Temporality During Breast Cancer Traumatic Experience: The Clinical Use of Narrative to Promote a New Continuity of Life.
Previous research has agreed that meaning-making is a key element in the promotion of patients' well-being during and after a traumatic event such as cancer. In this paper, we focus on an underestimated key element related to the crisis/rupture of this meaning-making process with respect to the time perspective. We consider 40 narratives of breast cancer patients at different times of treatment, undergoing chemotherapy and biological therapy. We collected data through writing technique. We performed an interpretative thematic analysis of the data and highlighted specific ways to signify time during the different treatment phases. Our central aspect "the time of illness, the illness of time" demonstrates that the time consumed by illness has the risk of becoming an illness of time, which transcends the end of the illness and absorbs a patient's past, present, and future, thus saturating all space for thought and meaning. The study suggests that narrative can become a therapeutic and preventive tool for women with breast cancer in a crisis of temporality, and enable the promotion of new semiotic connections and a specific functional resynchronization with the continuity/discontinuity of life. This is useful during the illness and medical treatment and also after the treatment.


Exercise preconditioning protects against spinal cord injury in rats by upregulating neuronal and astroglial heat shock protein 72.
The heat shock protein 72 (HSP 72) is a universal marker of stress protein whose expression can be induced by physical exercise. Here we report that, in a localized model of spinal cord injury (SCI), exercised rats (given pre-SCI exercise) had significantly higher levels of neuronal and astroglial HSP 72, a lower functional deficit, fewer spinal cord contusions, and fewer apoptotic cells than did non-exercised rats. pSUPER plasmid expressing HSP 72 small interfering RNA (SiRNA-HSP 72) was injected into the injured spinal cords. In addition to reducing neuronal and astroglial HSP 72, the (SiRNA-HSP 72) significantly attenuated the beneficial effects of exercise preconditioning in reducing functional deficits as well as spinal cord contusion and apoptosis. Because exercise preconditioning induces increased neuronal and astroglial levels of HSP 72 in the gray matter of normal spinal cord tissue, exercise preconditioning promoted functional recovery in rats after SCI by upregulating neuronal and astroglial HSP 72 in the gray matter of the injured spinal cord. We reveal an important function of neuronal and astroglial HSP 72 in protecting neuronal and astroglial apoptosis in the injured spinal cord. We conclude that HSP 72-mediated exercise preconditioning is a promising strategy for facilitating functional recovery from SCI.


Evidence for suppression of hepatic glucose-6-phosphatase with carbohydrate feeding.
The mechanism by which exogenous glucose stimulates the incorporation of hepatic glucose-6-phosphate into glycogen in fasted rats has not been clearly delineated. We gave glucose intragastrically over a 3.5-h period during which liver glycogen was deposited at linear rates. Simultaneous primed continuous infusion of [2-3H] or [3-3H]glucose established that under these conditions absolute carbon flow through hepatic glucose-6-phosphatase was greatly suppressed. After 1 h, hepatic [UDP-glucose] and [glucose-6-phosphate] had fallen by 50-60% and the former remained low throughout the experiment. By contrast, [glucose-6-phosphate] rebounded to its initial value by 2 h and remained at this level during the subsequent hour. We interpret the data as follows. Exogenous glucose, in addition to acting as a precursor of liver glucose-6-phosphate, causes diversion of the latter away from free glucose formation and into glycogen synthesis. The fall in [UDP-glucose] is in accord with a glucose-induced activation of glycogen synthase, as proposed by Hers (Annu. Rev. Biochem. 1976; 45:167-89.). However, the fall-rise sequence of glucose-6-phosphate concentration constitutes the first direct evidence in vivo for simultaneous inhibition at the level of glucose-6-phosphatase.


Percutaneous iliosacral screw fixation in S1 and S2 for posterior pelvic ring injuries: technique and perioperative complications.
Percutaneous iliosacral screw placement allows for minimally invasive fixation of posterior pelvic ring instabilities. The objective of this study was to describe the technique for screws in S1 and S2 using conventional C-arm and to evaluate perioperative complications. Thirty-eight consecutive patients after percutaneous pelvic ring fixation with cannulated screws in S1 and S2 using conventional C-arm fluoroscopy were analysed. Accuracy of screw placement, nerval lesions, need for second surgery, operation time, and time to full weight bearing were assessed postoperatively and during regular follow-up examinations. Twenty-one patients underwent unilateral screw fixation and 17 patients underwent bilateral screw fixation. In total, 83 screws were placed. Mean age of the patients was 52 ± 19 years. Mean operation time was 16 ± 7 min/screw. Mean follow-up was 5 ± 3 months. Time to full weight bearing in 28 patients was 9 ± 4 weeks. Eight patients were still not able to support full weight bearing, partially due to concomitant injuries. Patients without concomitant injuries that affected walking were able to bear full weight after 8 ± 4 weeks (n = 17). Two patients had persistent postoperative hypaesthesia. No motor weakness was apparent and no postoperative bleeding was observed. Secondary surgery due to screw malpositioning or loosening had to be performed in four patients. The presence of a screw in S2 was not indicated for perioperative complications. Percutaneous iliosacral screw fixation is a rapid and definitive treatment for posterior pelvic ring injuries with a low risk of secondary bleeding during posterior pelvic stabilization. The technique using standard C-arm fluoroscopy was also found to be safe for screws placed in S2.


Dendritic cell-based vaccination: powerful resources of immature dendritic cells against pancreatic adenocarcinoma.
Pancreatic adenocarcinoma (PAC) has a poor prognosis. One treatment approach, investigated here, is to reinforce antitumor immunity. Dendritic cells (DCs) are essential for the development and regulation of adaptive host immune responses against tumors. A major role for DCs may be as innate tumoricidal effector cells. We explored the efficacy of vaccination with immature (i)DCs, after selecting optimal conditions for generating immunostimulatory iDCs. We used two models, C57BL/6Jrj mice with ectopic tumors induced by the PAC cell line, Panc02, and genetically engineered (KIC) mice developing PAC. Therapeutic iDC-vaccination resulted in a significant reduction in tumor growth in C57BL/6Jrj mice and prolonged survival in KIC mice. Prophylactic iDC-vaccination prevented subcutaneous tumor development. These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8+ T-cells, and natural killer (NK)1.1+ cells, that express granzyme B associated with Lamp-1 and IFN-γ. Efficacy of iDC-vaccination was CD8+ T-cell-dependent but NK1.1+ cell-independent. We demonstrated the ability of DCs to produce peroxynitrites and to kill tumor cells; this killing activity involved peroxynitrites. Altogether, these findings make killer DCs the pivotal actors in the beneficial clinical outcome that accompanies antitumor immune responses. We asked whether efficacy can be improved by combining DC-vaccination with the FOLFIRINOX regimen. Combined treatment significantly increased the lifespan of KIC mice with PAC. Prolonged treatment with FOLFIRINOX clearly augmented this beneficial effect. Combining iDC-vaccination with FOLFIRINOX may therefore represent a promising therapeutic option for patients with PAC.


Top-Down Characterization of Denatured Proteins and Native Protein Complexes Using Electron Capture Dissociation Implemented within a Modified Ion Mobility-Mass Spectrometer.
Electron-based fragmentation methods have revolutionized biomolecular mass spectrometry, in particular native and top-down protein analysis. Here, we report the use of a new electromagnetostatic cell to perform electron capture dissociation (ECD) within a quadrupole/ion mobility/time-of-flight mass spectrometer. This cell was installed between the ion mobility and time-of-flight regions of the instrument, and fragmentation was fast enough to be compatible with mobility separation. The instrument was already fitted with electron transfer dissociation (ETD) between the quadrupole and mobility regions prior to modification. We show excellent fragmentation efficiency for denatured peptides and proteins without the need to trap ions in the gas phase. Additionally, we demonstrate native top-down backbone fragmentation of noncovalent protein complexes, leading to comparable sequence coverage to what was achieved using the instrument's existing ETD capabilities. Limited collisional ion activation of the hemoglobin tetramer before ECD was reflected in the observed fragmentation pattern, and complementary ion mobility measurements prior to ECD provided orthogonal evidence of monomer unfolding within this complex. The approach demonstrated here provides a powerful platform for both top-down proteomics and mass spectrometry-based structural biology studies.


Anti-desmoglein 1 antibodies in Tunisian healthy subjects: arguments for the role of environmental factors in the occurrence of Tunisian pemphigus foliaceus.
Pemphigus foliaceus is an autoimmune blistering skin disease mediated by autoantibodies directed against desmoglein 1 and occurs as a sporadic form throughout the world, or as an endemic form called fogo selvagem in Brazil. Healthy subjects living in Brazilian endemic areas produce antidesmoglein 1 antibodies, suggesting the role of environmental factors in the initiation of the autoimmune response. Tunisia was described recently as an endemic area where the disease is characterized by its high rate among young people, especially women. An enzyme-linked immunosorbent assay using recombinant desmoglein 1 as antigen was used to detect antibodies against desmoglein 1 and calibrated with sera from 67 French healthy blood donors, 20 French pemphigus foliaceus patients and patients with other bullous skin diseases. When sera from 179 healthy Tunisian blood donors were tested, 31 (17%) were found positive. The desmoglein 1 binding activity of these 31 sera was confirmed in 10 cases by indirect immunofluorescence analysis and/or immunoblotting using human epidermal extract. Subclass analysis of antidesmoglein 1 antibodies showed that they were almost exclusively of the IgG2 subclass in positive normal sera and of IgG4 subclass in patients with PF. Thus, antibodies against desmoglein 1 are prevalent in normal subjects living in Tunisia which, along with their IgG2 isotype, suggests the role of the environment in the pathogenesis of this endemic type of pemphigus foliaceus and the need for additional factors to switch from a subclinical to a clinical form of the disease.


A Consanguinity Related Autosomal Translocation which Leads to Premature Ovarian Failure.
The premature ovarian failures with underlying chromosomal abnormalities are normally X-linked, although their associations with the autosomal and the Robertsonian translocations are also possible. Here, we are reporting a case of premature ovarian failure which was associated with a translocation between the long arm of chromosome 7 at q11.23 and the short arm of chromosome 5 at p15.3. The proband was a 26-year-old Malay woman who presented with premature ovarian failure, who was referred for cytogenetic testing due to the suspicion of a chromosomal anomaly. Her physical examination revealed that she had no abdominal or pelvic masses and that she had normal secondary sexual characteristics. Her medical history as well, revealed no points for concern. However, a consanguineous relationship existed, as the patient's paternal grandmother and maternal grandfather were biological cousins. Our present case indicated that region p15.3 of chromosome 5 and region q11.23 of chromosome 7 possibly carried essential genes for the ovarian function and that they postulated a link between the consanguinity and the chromosomal abnormalities.


Evaluation of Axonal Strain as a Predictor for Mild Traumatic Brain Injuries Using Finite Element Modeling.
Finite element (FE) models are often used to study the biomechanical effects of traumatic brain injury (TBI). Measures based on mechanical responses, such as principal strain or invariants of the strain tensor, are used as a metric to predict the risk of injury. However, the reliability of inferences drawn from these models depends on the correspondence between the mechanical measures and injury data, as well as the establishment of accurate thresholds of tissue injury. In the current study, a validated anisotropic FE model of the human head is used to evaluate the hypothesis that strain in the direction of fibers (axonal strain) is a better predictor of TBI than maximum principal strain (MPS), anisotropic equivalent strain (AESM) and cumulative strain damage measure (CSDM). An analysis of head kinematics-based metrics, such as head injury criterion (HIC) and brain injury criterion (BrIC), is also provided. Logistic regression analysis is employed to compare binary injury data (concussion/no concussion) with continuous strain/kinematics data. The threshold corresponding to 50% of injury probability is determined for each parameter. The predictive power (area under the ROC curve, AUC) is calculated from receiver operating characteristic (ROC) curve analysis. The measure with the highest AUC is considered to be the best predictor of mTBI. Logistic regression shows a statistical correlation between all the mechanical predictors and injury data for different regions of the brain. Peaks of axonal strain have the highest AUC and determine a strain threshold of 0.07 for corpus callosum and 0.15 for the brainstem, in agreement with previously experimentally derived injury thresholds for reversible axonal injury. For a data set of mild TBI from the national football league, the strain in the axonal direction is found to be a better injury predictor than MPS, AESM, CSDM, BrIC and HIC.


Restraint and Social Isolation Stressors Differentially Regulate Adaptive Immunity and Tumor Angiogenesis in a Breast Cancer Mouse Model.
The ability of stress to induce immune suppression is widely recognized, but the mechanisms underlying the effects of stress on the adaptive immune system during tumor progression are not completely understood. To study the effect of stress on the immune system in vivo, we used a preclinical immunocompetent mouse model bearing 4T1 mammary adenocarcinoma cells. Mice were randomized into 4 groups, including social isolation (SI), acute restraint stress (aRRS), chronic restraint stress (cRRS), or no stress (NS). We found that SI significantly decreased the number of tumor-bearing mice still alive at the end of protocol (28 days), compared to NS mice. Although we did not detect significant changes in primary tumor volume, we observed a significant increase in the endothelial marker CD31 in primary tumors of SI mice and in lung metastases in SI and RRS mice. Survival decline in SI mice was associated with significant decreases in splenic CD8 cells and in activated T cells. From a mechanistic standpoint, RRS increased expression of FOXP3, CXCL-10, and granzyme B in mouse tumors, and the effects were reversed by propranolol. Our data demonstrate that various forms of stress differentially impact adaptive immunity and tumor angiogenesis, and negatively impact survival.


The burden of spousal caregiving: a preliminary psychometric evaluation of the German version of the Zarit burden interview.
Despite a rapid increase in studies dealing with dementia caregivers in Europe, a valid German version of the most widely used measurement of caregiver burden (Zarit Burden Interview) has not yet been published. The purpose of this study is to evaluate the psychometric properties of the German Zarit Burden Interview (G-ZBI). Twenty-eight community-dwelling older couples with the husband suffering from dementia and the wife being the primary caregiver participated in this study. The G-ZBI and related constructs were assessed in order to test for reliability and construct validity. The G-ZBI revealed psychometric properties comparable with those of the original instrument and empirically validated translations. Results demonstrated high internal consistency (Cronbach's alpha 0.92) and good validity due to strong correlations with caregiver life satisfaction and depression, as well as patients' dependency, neuropsychiatric symptoms, and dementia severity. The psychometric qualities of the G-ZBI indicate that it is both a reliable and valid instrument to assess caregiver burden and to detect highly stressed individuals.


Birth history as a predictor of adverse birth outcomes: Evidence from state vital statistics data.
One of the most important predictors of preterm births (PTBs) or low-birth-weight births (LBWBs) is whether a mother has had a history of these birth outcomes. This study examined how different characterizations of birth history (e.g., any previous incidence of PTBs or LBWBs, immediate previous birth that was preterm or of low birth weight, and number of previous PTBs or LBWBs) were associated with PTBs or LBWBs. Based on birth records (n = 98,776) reported to the vital statistics electronic registration system in Nebraska from 2005 to 2014, mothers with a history of PTBs or LBWBs were more likely to have recurrences of these outcomes than those who did not have any history of PTBs or LBWBs. The adjusted odds ratios for recurrent PTBs ranged from 2.82 (95% CI: 2.62, 3.04) to 5.54 (95% CI: 4.67, 6.57) depending on how previous incidence of PTBs or LBWBs were characterized. The corresponding adjusted odds ratio for LBWBs ranged from 1.58 (95% CI: 1.43, 1.74) to 6.75 (95% CI: 4.96, 9.17). Relative to other measures used to characterize birth history, the use of number of previous PTBs or LBWBs allows for identifying mothers most vulnerable to recurrences of these birth outcomes. To help identify mothers at risk for future PTBs or LBWBs, it is beneficial to develop state-wide surveillance of reoccurrences for adverse birth outcomes which is feasible by integrating all separated birth records for the same mother using vital statistics data.


Conserved and Unique Putative Effectors Expressed in the Salivary Glands of Three Related Gall Midge Species.
Species in the stem gall midge genus Mayetiola (Diptera: Cecidomyiidae) cause serious damage to small grain crops. Among Mayetiola species are Hessian fly (Mayetiola destructor Say), barley midge (Mayetiola hordei Keiffer), and oat midge (Mayetiola avenae Marchal). Larvae of these species inject saliva into host tissues to manipulate plants. To identify putative effectors, transcriptomic analyses were conducted on transcripts encoding secreted salivary gland proteins (SSGPs) from first instar larvae of the barley and oat midges, since SSGPs are the most likely source for effector proteins delivered into host tissues. From barley midge, 178 SSGP-encoding unigenes were identified, which were sorted into 51 groups. From oat midge, 194 were obtained and sorted into 50 groups. Predicted proteins within a group had a highly conserved secretion signal peptide and shared at least 30% amino acid identity. Among the identified unigenes from both barley and oat midges, ~68% are conserved either among the three species or between two of them. Conserved SSGPs included members belonging to SSGP-1, SSGP-4, SSGP-11, and SSGP-71 families. Unconventional conservation patterns exist among family members within a species and among different gall midges, indicating that these genes are under high selection pressure, a characteristic of effector genes. SSGPs that are unique to each species were also identified. Those conserved SSGPs may be responsible for host manipulation since the three gall midges produce identical phenotypic symptoms to host plants, whereas the SSGPs unique to each species may be responsible for different host specificity.


Evaluating Dorsal Root Ganglion Stimulation in a Prospective Dutch Cohort.
Dorsal root ganglion (DRG) stimulation is a recent neuromodulation option that has delivered safe, effective pain relief for a number of etiologies. This prospective observational study was intended to establish the effectiveness of this treatment in a typical real-world clinical context. Participants with chronic, intractable pain of the trunk or lower limbs were recruited from multiple pain clinics in the Netherlands. Subjects were trialed and implanted with DRG stimulation systems. Pain, function, mood, and quality of life, ratings were collected through 12 months postimplant. Of the 66 subjects enrolled, failed back surgery syndrome, peripheral nerve injury, and complex regional pain syndrome formed the largest etiologies. Permanent implants were placed in 86.2% subjects (56/65). After 12 months of treatment, average pain ratings in subjects' primary area of pain decreased from 8.0 cm at baseline to 4.1 cm, and 49% of subjects had ≥50% reduction in pain (visual analog scale). In addition, functional capacity was increased, and mood and quality of life improved. No confirmed lead migrations were observed, and there was a low rate of infection. DRG stimulation significantly reduced the severity of subjects' pain and enabled participatory changes that improved quality of life through 12-months postimplant.


High Performance Predictable Quantum Efficient Detector Based on Induced-Junction Photodiodes Passivated with SiO2/SiNx.
We performed a systematic study involving simulation and experimental techniques to develop induced-junction silicon photodetectors passivated with thermally grown SiO2 and plasma-enhanced chemical vapor deposited (PECVD) SiNx thin films that show a record high quantum efficiency. We investigated PECVD SiNx passivation and optimized the film deposition conditions to minimize the recombination losses at the silicon-dielectric interface as well as optical losses. Depositions with varied process parameters were carried out on test samples, followed by measurements of minority carrier lifetime, fixed charge density, and optical absorbance and reflectance. Subsequently, the surface recombination velocity, which is the limiting factor for internal quantum deficiency (IQD), was obtained for different film depositions via 2D simulations where the measured effective lifetime, fixed charge density, and substrate parameters were used as input. The quantum deficiency of induced-junction photodiodes that would be fabricated with a surface passivation of given characteristics was then estimated using improved 3D simulation models. A batch of induced-junction photodiodes was fabricated based on the passivation optimizations performed on test samples and predictions of simulations. Photodiodes passivated with PECVD SiNx film as well as with a stack of thermally grown SiO2 and PECVD SiNx films were fabricated. The photodiodes were assembled as light-trap detector with 7-reflections and their efficiency was tested with respect to a reference Predictable Quantum Efficient Detector (PQED) of known external quantum deficiency. The preliminary measurement results show that PQEDs based on our improved photodiodes passivated with stack of SiO2/SiNx have negligible quantum deficiencies with IQDs down to 1 ppm within 30 ppm measurement uncertainty.


Candida albicans, a distinctive fungal model for cellular aging study.
The unicellular eukaryotic organisms represent the popular model systems to understand aging in eukaryotes. Candida albicans, a polymorphic fungus, appears to be another distinctive unicellular aging model in addition to the budding yeast Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe. The two types of Candida cells, yeast (blastospore) form and hyphal (filamentous) form, have similar replicative lifespan. Taking the advantage of morphologic changes, we are able to obtain cells of different ages. Old Candida cells tend to accumulate glycogen and oxidatively damaged proteins. Deletion of the SIR2 gene causes a decrease of lifespan, while insertion of an extra copy of SIR2 extends lifespan, indicating that like in S. cerevisiae, Sir2 regulates cellular aging in C. albicans. Interestingly, Sir2 deletion does not result in the accumulation of extra-chromosomal rDNA molecules, but influences the retention of oxidized proteins in mother cells, suggesting that the extra-chromosomal rDNA molecules may not be associated with cellular aging in C. albicans. This novel aging model, which allows efficient large-scale isolation of old cells, may facilitate biochemical characterizations and genomics/proteomics studies of cellular aging, and help to verify the aging pathways observed in other organisms including S. cerevisiae.


Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients.
Recent results have shown a correlation between survival and frequency of tumour infiltrating T lymphocytes in colorectal cancer patients. However, it remains unclear whether the frequency of regulatory T cells is higher in colorectal cancer as compared to normal colon. To address this question we analysed the frequency and function of regulatory T cells in the peripheral blood and tumour infiltrating lymphocytes of colorectal cancer patients. The proportion of regulatory T cells in the peripheral blood of colorectal cancer patients (mean 8%) was significantly higher than that in normal controls (mean 2.2%). There were significantly more regulatory T cells in tumour infiltrating lymphocytes (mean 19.2%) compared to lymphocytes from an autologous non-malignant portion of the colon (mean 9%). Regulatory T cells from colorectal cancer patients were FOXP3 positive and suppressed the proliferation of autologous CD4+ CD25- cells. A higher density of tumour infiltrating regulatory T cells was found in patients with advanced as compared to early disease. These results support the hypothesis that increased numbers of regulatory T cells in the blood and tumours of colorectal cancer patients may influence the immune response against cancer and suggest that strategies to overcome regulatory T cell activity may be beneficial in the treatment of human colorectal cancer.


Reward processing and future life stress: Stress generation pathway to depression.
Blunted reward sensitivity and life stress are each depressogenic. Additionally, individuals with clinical and psychosocial vulnerabilities are prone to experience or evoke dependent life stressors (e.g., interpersonal conflict) that, in turn, increase depression risk. However, no previous study has investigated the role of neural vulnerability factors in generating life stress. Therefore, the current study investigated whether a neural measure of reward sensitivity prospectively predicts the generation of life stress, which in turn mediates effects of these neural processes on subsequent depression. Participants were 467 never-depressed adolescent girls. Using event-related potentials, neural sensitivity to the difference between monetary reward and loss (the Reward Positivity [RewP]) was assessed at baseline. Negative life events were assessed twice via interview over the ensuing 18 months, yielding an index of total life stress over the follow-up period. A self-report dimensional measure of depression symptoms was administered at baseline and follow-up. After accounting for baseline age, depression, and race, a blunted RewP predicted greater dependent, but not independent, life stress over the follow-up. Mediation analyses revealed a significant indirect effect of the RewP on follow-up depression through dependent, but not independent, life stress. Our results suggest that neural processing reward and loss plays a crucial role in depressogenic stress generation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model.
Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+) and CD24(-/lo) population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery. hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein. The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the "window of opportunity" for intervention.


[Treatment of post-traumatic stress disorder in people with intellectual disability].
Patients with borderline intellectual functioning (BIF) or intellectual disability (ID) are more likely to develop post-traumatic stress disorder (PTSD). However, co-occurrence of BIF/ID and PTSD symptoms often leads to exclusion for treatment in regular mental health care centers.
 AIM: To determine whether standard treatment programs for PTSD can be used in the treatment of patients with BIF/ID.
 METHOD: Qualitative review of good practices, scientific literature and recent reports about BIF, ID and PTSD.
 RESULTS: Literature on evidence-based treatment programs for PTSD suggests that there is no need to be reluctant in starting treatment in patients with BIF/ID. Adjustment of communication and tempo is recommended.
 CONCLUSION: There is reason to believe that standard treatment can be used in treating patients with a low IQ. More research to confirm this assumption is necessary, taken into account the size of this patient group.


Marital Quality and Stress in Pregnancy Predict the Risk of Infectious Disease in the Offspring: The Norwegian Mother and Child Cohort Study.
The aim of this study was to explore the degree to which couples' relationship dissatisfaction and stressful life events during pregnancy predict the risk of infectious disease in the offspring during their first year of life. Data were obtained from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health. Pregnant women completed questionnaires in week 30 of pregnancy concerning the couples' relationship satisfaction and stressful life events. In follow-up questionnaires, the women reported whether their children (n = 74,801) had been subject to various categories of infectious disease: the common cold, throat infection, bronchitis, RS virus, pneumonia, pseudocroup, gastric flu, ear infection, conjunctivitis and urinary tract infection. Reports from two age groups of infants were used. Associations between the predictor and outcome variables were assessed via logistic regression and linear regression analyses. Separate logistic regression analyses for each disease and age group showed that prenatal relationship dissatisfaction and stressful life events were significantly associated with all reported categories of infectious disease. After controlling for socioeconomic factors, social support, smoking, breastfeeding, maternal depression, the sex of the offspring, and use of child care, 29 out of 32 tested associations were statistically significant. Finally, multivariate linear regression analyses showed that prenatal relationship dissatisfaction and stressful life events were significantly associated with the frequency, as well as the variety, of infectious disease in the offspring.