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1.  Vitamin B12: A Tunable, Long Wavelength, Light-Responsive Platform for Launching Therapeutic Agents 
Accounts of chemical research  2015;48(11):2866-2874.
CONSPECTUS
Light-responsive agents offer the promise of targeted therapy, whose benefits include (i) prolonged action at the target site, (ii) overall reduced systemic dosage, (iii) reduced adverse effects, and (iv) localized delivery of multiple agents. Although photoactivated prodrugs have been reported, these species generally require short wavelengths (<450 nm) for activation. However, maximal tissue penetrance by light occurs within the “optical window of tissue” (600–900 nm), well beyond the wavelength range of most existing photocleavable functional groups. Furthermore, since multidrug therapy holds promise for the treatment of complex diseases, from cancer to neurological disorders, controlling the action of multiple drugs via wavelength modulation would take advantage of a property that is unique to light. However, discrimination between existing photoresponsive moieties has thus far proven to be limited.
We have developed a vitamin B12/light-facilitated strategy for controlling drug action using red, far-red, and NIR light. The technology is based on a light-triggered reaction displayed by a subset of B12 derivatives: alkyl-cob(III)alamins suffer photohomolysis of the C–Co(III) bond. The C–Co(III) bond is weak (<30 kcal/mol), and therefore all wavelengths absorbed by the corrin ring (330–580 nm) induce photocleavage. In addition, by appending fluorophores to the corrin ring, long wavelength light (>600 nm) is readily captured and used to separate the Co-appended ligand (e.g., a drug) from B12. Consequently, it is now feasible to preassign the wavelength of homolysis by simply installing a fluorescent antenna with the desired photophysical properties. The wavelength malleability inherent within this strategy has been used to construct photoresponsive compounds that launch different drugs by simply modulating the wavelength of illumination. In addition, these phototherapeutics have been installed on the surface and interior of cells, such as erythrocytes or neural stem cells, and released upon expoure to the appropriate wavelength. We have shown that cytotoxic agents, such as doxorubicin, anti-inflammatories, such as dexamethasone, and anti- and pro-vascular agents are readily released from cellular vehicles as biologically active agents. We have also demonstrated that the concept of “optical window of tissue” phototherapeutics is not just limited to prodrugs. For example, stem cells have received considerable attention in the area of regenerative medicine. Hydrogels serve as scaffolds for stem cell growth and differentiation. We have shown that the formation of hydrogels can be triggered, in the presence of cells, using appropriately designed alkyl-cob(III)alamins and long wavelength light. The potential applications of phototherapeutics are broad and include drug delivery for a variety of indications, tissue engineering, and surgery.
Graphical abstract
doi:10.1021/acs.accounts.5b00331
PMCID: PMC5240631  PMID: 26479305
2.  A Combinatorial Strategy for the Acquisition of Potent and Specific Protein Tyrosine Phosphatase Inhibitors 
Protein tyrosine phosphatases (PTPs), a large family of signaling enzymes, regulate many cellular processes, such as proliferation, differentiation, migration, apoptosis, and immune responses. Small molecule inhibitors against PTPs are valuable both as powerful tools to study the functions of target PTPs and as lead compounds for pharmacological development. Here, we describe a novel combinatorial library approach to target simultaneously both the active site pocket and a peripheral secondary binding site for the acquisition of potent and specific PTP inhibitors. Fluorescence tagging during combinatorial library synthesis enables fluorescence polarization-based high-throughput screening of the resulting library, leading to identification of a TC-PTP inhibitor.
doi:10.1007/978-1-62703-008-3_5
PMCID: PMC5231398  PMID: 22956133
Protein tyrosine phosphatases (PTPs); PTP inhibitor; Peripheral binding site; Fluorescence tagged; Fluorescence polarization; High-throughput screening
3.  Varenicline in smokers with diabetes: A pooled analysis of 15 randomized, placebo‐controlled studies of varenicline 
Abstract
Aims/Introduction
Stopping smoking deserves high priority in preventing complications of diabetes; however, only sparse data are available regarding the efficacy of pharmacotherapy in smokers with diabetes. We assessed the efficacy and safety of varenicline in smokers with diabetes who participated in 15 double‐blind, randomized, placebo‐controlled studies.
Materials and Methods
This retrospective pooled analysis included data from smokers of ≥10 cigarettes per day with diabetes. Participants received varenicline 1 mg b.i.d. or placebo for 12 weeks. We examined carbon monoxide‐confirmed continuous abstinence rates (CARs) for weeks 9–12, 9–24 and 9–52, and compared safety in participants with and without diabetes.
Results
Of 6,771 participants, 323 had diabetes (varenicline n = 162; placebo n = 161). Week 9–12 CAR was higher with varenicline than placebo (43.8% vs 24.8%; odds ratio 2.36, 95% CI 1.47–3.79), as was week 9–24 CAR (27.5% vs 14.4%; odds ratio 2.25, 95% CI 1.27–4.00). Week 9–52 CAR was 18.4% for varenicline and 10.1% for placebo (odds ratio 2.00, 95% CI 0.90–4.49). The most commonly‐reported adverse events in participants with diabetes for varenicline vs placebo were: nausea (27.2% vs 8.1%); headache (9.3% vs 9.9%); and insomnia (8.6% vs 5.6%), incidences that were similar in participants without diabetes (29.6% vs 9.7%; 13.4% vs 10.9%; and 11.4% vs 7.1%, respectively). Weight gain in quitters with diabetes (1.7 kg) was similar to that of those without diabetes (2.1 kg).
Conclusions
Varenicline was an effective and well‐tolerated aid for smoking cessation in individuals with diabetes. Safety was comparable with participants without diabetes.
doi:10.1111/jdi.12543
PMCID: PMC5217903  PMID: 27223809
Diabetes mellitus; Smoking; Varenicline
4.  A physical/psychological and biological stress combine to enhance endoplasmic reticulum stress 
Toxicology and applied pharmacology  2015;289(2):313-322.
The generation of an immune response against infectious and other foreign agents is substantially modified by allostatic load, which is increased with chemical, physical and/or psychological stressors. The physical/psychological stress from cold-restraint (CR) inhibits host defense against Listeria monocytogenes (LM), due to early effects of the catecholamine norepinephrine (NE) from sympathetic nerves on β1-adrenoceptors (β1AR) of immune cells. Although CR activates innate immunity within 2 h, host defenses against bacterial growth is suppressed 2–3 days after infection (Cao and Lawrence 2002). CR enhances inducible nitric oxide synthase (iNOS) expression and NO production. The early innate activation leads to cellular reduction-oxidation (redox) changes of immune cells. Lymphocytes from CR-treated mice express fewer surface thiols. Splenic and hepatic immune cells also have fewer proteins with free thiols after CR and/or LM, and macrophages have less glutathione after the in vivo CR exposure or exposure to NE in vitro. The early induction of CR-induced oxidative stress elevates endoplasmic reticulum (ER) stress, which could interfere with keeping phagocytized LM within the phagosome or re-encapsuling LM by autophagy once they escape from the phagosome. ER stress-related proteins, such as glucose-regulated protein 78 (GRP78), have elevated expression with CR and LM. The results indicate that CR enhances the unfolded protein response (UPR), which interferes with host defenses against LM. Thus, it is postulated that increased stress, as exists with living conditions at low socioeconomic conditions, can lower host defenses against pathogens because of oxidative and ER stress processes.
doi:10.1016/j.taap.2015.09.013
PMCID: PMC4651807  PMID: 26391182
Oxidative stress; Beta Adrenoceptor; Neuroimmunology; Stress response; Listeria; autophagy
5.  Hydrogen and major element concentrations on 433 Eros: Evidence for an L‐ or LL‐chondrite‐like surface composition 
Meteoritics & Planetary Science  2015;50(3):353-367.
Abstract
A reanalysis of NEAR X‐ray/gamma‐ray spectrometer (XGRS) data provides robust evidence that the elemental composition of the near‐Earth asteroid 433 Eros is consistent with the L and LL ordinary chondrites. These results facilitated the use of the gamma‐ray measurements to produce the first in situ measurement of hydrogen concentrations on an asteroid. The measured value, 1100−700+1600 ppm, is consistent with hydrogen concentrations measured in L and LL chondrite meteorite falls. Gamma‐ray derived abundances of hydrogen and potassium show no evidence for depletion of volatiles relative to ordinary chondrites, suggesting that the sulfur depletion observed in X‐ray data is a surficial effect, consistent with a space‐weathering origin. The newfound agreement between the X‐ray, gamma‐ray, and spectral data suggests that the NEAR landing site, a ponded regolith deposit, has an elemental composition that is indistinguishable from the mean surface. This observation argues against a pond formation process that segregates metals from silicates, and instead suggests that the differences observed in reflectance spectra between the ponds and bulk Eros are due to grain size differences resulting from granular sorting of ponded material.
doi:10.1111/maps.12434
PMCID: PMC5114864  PMID: 27917034
6.  Intense energetic electron flux enhancements in Mercury's magnetosphere: An integrated view with high‐resolution observations from MESSENGER 
Abstract
The MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) mission to Mercury has provided a wealth of new data about energetic particle phenomena. With observations from MESSENGER's Energetic Particle Spectrometer, as well as data arising from energetic electrons recorded by the X‐Ray Spectrometer and Gamma‐Ray and Neutron Spectrometer (GRNS) instruments, recent work greatly extends our record of the acceleration, transport, and loss of energetic electrons at Mercury. The combined data sets include measurements from a few keV up to several hundred keV in electron kinetic energy and have permitted relatively good spatial and temporal resolution for many events. We focus here on the detailed nature of energetic electron bursts measured by the GRNS system, and we place these events in the context of solar wind and magnetospheric forcing at Mercury. Our examination of data at high temporal resolution (10 ms) during the period March 2013 through October 2014 supports strongly the view that energetic electrons are accelerated in the near‐tail region of Mercury's magnetosphere and are subsequently “injected” onto closed magnetic field lines on the planetary nightside. The electrons populate the plasma sheet and drift rapidly eastward toward the dawn and prenoon sectors, at times executing multiple complete drifts around the planet to form “quasi‐trapped” populations.
Key Points
Shows where energetic particles are accelerated at MercuryDemonstrates quasi‐trapping of energetic electronsAnswers decades‐old questions about Mercury substorms
doi:10.1002/2015JA021778
PMCID: PMC5076489  PMID: 27830111
Mercury magnetosphere; particle bursts; substorms; electron acceleration
7.  Geochemistry of the lunar highlands as revealed by measurements of thermal neutrons 
Abstract
Thermal neutron emissions from the lunar surface provide a direct measure of bulk elemental composition that can be used to constrain the chemical properties of near‐surface (depth <1 m) lunar materials. We present a new calibration of the Lunar Prospector thermal neutron map, providing a direct link between measured count rates and bulk elemental composition. The data are used to examine the chemical and mineralogical composition of the lunar surface, with an emphasis on constraining the plagioclase concentration across the highlands. We observe that the regions of lowest neutron absorption, which correspond to estimated plagioclase concentrations of >85%, are generally associated with large impact basins and are colocated with clusters of nearly pure plagioclase identified with spectral reflectance data.
Key Points
We report the first map of macroscopic neutron absorption for the lunar surfaceElemental composition and variability across the lunar highlands is discussedLarge (>45 km diameter) locations with >85 wt % plagioclase content are identified
doi:10.1002/2015JE004950
PMCID: PMC5076490  PMID: 27830110
Moon; neutrons; lunar highlands; plagioclase
8.  Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats 
eLife  null;5:e18146.
Brain and spinal injury reduce mobility and often impair sensorimotor processing in the spinal cord leading to spasticity. Here, we establish that complete transection of corticospinal pathways in the pyramids impairs locomotion and leads to increased spasms and excessive mono- and polysynaptic low threshold spinal reflexes in rats. Treatment of affected forelimb muscles with an adeno-associated viral vector (AAV) encoding human Neurotrophin-3 at a clinically-feasible time-point after injury reduced spasticity. Neurotrophin-3 normalized the short latency Hoffmann reflex to a treated hand muscle as well as low threshold polysynaptic spinal reflexes involving afferents from other treated muscles. Neurotrophin-3 also enhanced locomotor recovery. Furthermore, the balance of inhibitory and excitatory boutons in the spinal cord and the level of an ion co-transporter in motor neuron membranes required for normal reflexes were normalized. Our findings pave the way for Neurotrophin-3 as a therapy that treats the underlying causes of spasticity and not only its symptoms.
DOI: http://dx.doi.org/10.7554/eLife.18146.001
eLife digest
Injuries to the brain and spinal cord cause disability in millions of people worldwide. Physical rehabilitation can restore some muscle control and improve mobility in affected individuals. However, no current treatments provide long-term relief from the unwanted muscle contractions and spasms that affect as many as 78% of people with a spinal cord injury. These spasms can seriously hamper a person’s ability to carry out day-to-day tasks and get around independently. A few treatments can help in the short term but have side effects; indeed while Botox injections are used to paralyse the muscle, these also reduce the chances of useful improvements. As such, better therapies for muscle spasms are needed; especially ones that reduce spasms in the arms.
Rats with injuries to the spinal cord between their middle to lower back typically develop spasms in their legs or tail, and rat models have helped scientists begin to understand why these involuntary movements occur. Now, Kathe et al. report that cutting one specific pathway that connects the brain to the spinal cord in anesthetised rats leads to the development of spasms in the forelimbs as well. Several months after the surgery, the rats had spontaneous muscle contractions in their forelimbs and walked abnormally. Further experiments showed that some other neural pathways in the rats became incorrectly wired and hyperactive and that this resulted in the abnormal movements.
Next, Kathe et al. asked whether using gene therapy to deliver a protein that is required for neural circuits to form between muscles and the spinal cord (called neurotrophin-3) would stop the involuntary movements in the forelimbs. Delivering the gene therapy directly into the forelimb muscles of the disabled rats a day after their injury increased the levels of neurotrophin-3 in these muscles. Rats that received this treatment had fewer spasms and walked better than those that did not. Further experiments confirmed that this was because the rats’ previously hyperactive and abnormally wired neural circuits became more normal after the treatment.
Together these results suggest that neurotrophin-3 might be a useful treatment for muscle spasms in people with spinal injury. There have already been preliminary studies in people showing that treatment with neurotrophin-3 is safe and well tolerated. Future studies are needed to confirm that it could be useful in humans.
DOI: http://dx.doi.org/10.7554/eLife.18146.002
doi:10.7554/eLife.18146
PMCID: PMC5070949  PMID: 27759565
spasticity; neurotrophins; movement disorder; central nervous system injury; Rat
9.  IgG4 related lung disease extending to the thoracic vertebrae 
IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect practically every organ. Although it was first identified in pancreas and salivary glands, major organs like liver, biliary tree, kidney, thyroid glands and lungs are commonly involved, sometimes resulting in organ failure. We describe a case of an 41-year-old man presented with back pain after a rotator cuff injury. A Computed Tomography (CT) revealed incidentally a right lower lobe paravertebral lesion extending across the T5 and T6 vertebral levels and invading into the adjacent pleural surface. The laboratory findings and the CT guided biopsy were inconclusive. Morphological and immunohistochemical findings after a lung biopsy by video-assisted thoracic surgery (VATS) were suggestive to IgG4-related lung disease (IgG4-RLD), which was confirmed with high serum levels of IgG4. This represents the first case of a IgG4-RLD lesion located in the mediastinum and extending to the adjacent pleural surface and vertebrae and should be included in the differential diagnosis of posterior mediastinal masses.
doi:10.1016/j.rmcr.2016.10.008
PMCID: PMC5066297  PMID: 27766198
IgG4 lung disease; Vertebral invasion; Lung surgery
10.  Optogenetic Apoptosis: Light-Triggered Cell Death 
An optogenetic Bax has been designed that facilitates light-induced apoptosis. We demonstrate that mitochondrial recruitment of a genetically encoded light-responsive Bax results in the release of mitochondrial proteins, downstream caspase 3 cleavage, changes in cellular morphology, and ultimately cell death. Mutagenesis of a key phosphorylatable residue or modification of the C-terminus mitigates background levels (dark) of apoptosis due to Bax overexpression. The mechanism of optogenetic Bax-mediated apoptosis was explored using a series of small molecules known to interfere with various steps in programmed cell death. Optogenetic Bax appears to form a mitochondrial apoptosis-induced channel analogous to that of endogenous Bax.
doi:10.1002/anie.201506346
PMCID: PMC4819321  PMID: 26418181
apoptosis; optogenetics; protein engineering; synthetic biology; photochemistry
11.  A retained foreign body granuloma mimicking a left ventricular psuedoanuerysm 
Highlights
•Retained foreign objects describes a mass composed of a central cotton core surrounded by foreign body reaction.•It represents an unfortunate event for the patient and the surgeon with severe implications.•This case highlights the important clinical history features for diagnosing this surgical error.•Need for implementing definite strategies to avoid retained foreign objects in surgical practice.
Introduction
Gossypiboma, also referred to as a textiloma, gauzoma or muslinoma describe a mass in the body composed of a central cotton core surrounded by a foreign body reaction. It has an estimated incidence of 1/1000–1/10000 surgeries, occurring in the abdomen (56%), pelvis (18%) and least commonly the thorax (11%) and represents an unfortunate event for both the patient and the operating surgeon with severe liability implications.
Presentation of case
We report a case of a 49-year-old male with Marfan Syndrome who was admitted to the cardiology department with a four day history of shortness of breath and associated dull, non-radiating chest pain. Past history included a previous Bentall procedure for a type-A aortic dissection and coronary artery bypass grafting involving a saphenous vein graft to the right coronary artery.
A computed tomography (CT) scan showed a round, heterogeneous mass measuring 14 × 9 cm with lobulated contours, situated adjacent to the left ventricle along the left posterior region of the aorta. The mass was resected and further dissection revealed a plastic band harboured from the core of the mass.
Discussion
The majority of cases of intrathoracic gossypiboma present as intractable cough or an incidental finding on radiological evaluation. Dyspnoea alone is relatively underreported as a presenting symptom of this condition
Conclusion
This case highlights the important clinical history features for diagnosing this surgical error, including persistent respiratory symptoms and a history of cardio-thoracic surgery. It also emphasizes on the need for implementing definite strategies to prevent the occurrence of gossypiboma in surgical practice.
doi:10.1016/j.ijscr.2016.09.021
PMCID: PMC5043397  PMID: 27689518
Retained foreign body; Granuloma; Cardiac surgery; Case report
12.  Newborn adipokines and birth outcomes 
Background
Adipokines can serve as a measure of adipose tissue activity. Although birthweight correlates with neonatal adiposity, findings for cord blood levels of adipokines and birth outcomes have been conflicted. Therefore, we determined the cross-sectional associations between adipokines measured in newborn dried blood spots (DBS) and birth outcomes.
Methods
The Upstate KIDS study enrolled mothers and infants from 2008 to 2010. Among infants whose parents consented to use of residual DBS from Newborn Screening, 2397 singletons and 1240 twins had adipokine measurements from the Human Obesity Panel (R&D Systems) by Luminex. Odds ratios were estimated by multivariable logistic regression for risk of birth outcomes of preterm delivery (<37 weeks for singletons, <32 for twins) and small for gestational age (SGA <10th for singletons and <3rd for twins age and sex specific percentiles) by adipokine quintiles. Generalized estimating equations were applied to account for correlations between twins.
Results
Singletons in the lowest compared to the highest quintile of adiponectin were more likely preterm (adjusted odds ratio 3.26; 95% confidence interval: 1.99-5.34), and SGA (1.81; 1.18-2.77). Similar associations were observed among twins. Resistin was associated with preterm birth (Q1 vs Q5: 2.08; 1.20-3.62) only among singletons. Adipsin had inconsistent associations after adjustment.
Conclusions
This large population based study demonstrates that newborn DBS measured adipokines are associated with birth outcomes, particularly preterm birth and SGA among those with lower adiponectin levels regardless of plurality.
doi:10.1111/ppe.12203
PMCID: PMC4484786  PMID: 26111443
13.  Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures 
RMD Open  2016;2(1):e000287.
Objective
To describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters.
Design
Prospective, open-label, long-term mechanism of action study.
Setting
University clinic.
Methods
MTX was initiated at a single weekly oral dose of 7.5 mg and dose adjusted for efficacy and toxicity for the duration of the study. Standard measures of disease activity were performed at baseline and every 6–36 months. Serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell (PBMC) cytokine production were assessed at each clinical evaluation.
Results
Cytokine concentrations exhibited multiple significant correlations with disease activity measures over time. The strongest correlations observed were for interleukin (IL)-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and IL-8 (r=0.25, p=0.01 for swollen joints). Significant decreases from baseline were observed in serum IL-1B, IL-6 and IL-8 concentrations. The most significant changes were observed for IL-6 (p<0.001). Significant increases from baseline were observed in IL-2 release from PBMCs ex vivo (p<0.01). In parallel, multiple statistically significant correlations were observed between MTX PKC measures and immune parameters. The change in swollen joint count correlated inversely with the change in area under the curve (AUC) for MTX (r=−0.63, p=0.007).
Conclusions
MTX therapy of patients with RA is accompanied by a variety of changes in serum cytokine expression, which in turn correlate strongly with clinical disease activity and MTX pharmacokinetics (PKCs). These data strongly support the notion that MTX mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion.
doi:10.1136/rmdopen-2016-000287
PMCID: PMC4913203  PMID: 27335660
Cytokines; Disease Activity; Methotrexate; Pharmacokinetics; Rheumatoid Arthritis
14.  Internet use and electronic gaming by children and adolescents with emotional and behavioural problems in Australia – results from the second Child and Adolescent Survey of Mental Health and Wellbeing 
BMC Public Health  2016;16:399.
Background
Concerns have been raised of a potential connection between excessive online activity outside the academic realm and increased levels of psychological distress in young people. Young Minds Matter: the second Australian Child and Adolescent Survey of Mental Health and Wellbeing provides estimates of the prevalence of online activity and allows an exploration of associations between this activity, a range of mental disorders, socio-demographic characteristics and risk taking behaviour.
Methods
Based on a randomized nationally representative sample, a household survey of mental health and wellbeing (Young Minds Matter) was conducted in 2013-14. Interviews were conducted with 6,310 parents and carers of 4–17 year-olds (55 % response rate), together with self-report questionnaires completed by 2,967 11–17 year-olds in these households (89 % response rate). The survey identified a range of mental disorders and emotional problems using a variety of diagnostic tools, with the self-report including questions about use of the Internet and electronic games. Five behaviours were measured related to this activity, with ‘problem behaviour’ being defined as exhibiting at least four out of five behaviours.
Results
Levels of Internet use (98.9 %, CI 98.5–99.3 %) and electronic gaming (85.3 %, CI 83.9–86.6 %) were high, and 3.9 % (CI 3.2–4.6 %) of young people reported problem behaviour. The proportion of girls with very high levels of psychological distress and problem behaviour (41.8 %,CI 28.8–54.9 %) was twice that for boys (19.4 %, CI 7.7–31.1 %). Those engaging with a range of risk factors reported higher prevalence of problem behaviour than others. Youth who suffered from emotional problems or high levels of psychological distress spent the most time online or playing games. Multivariate analysis showed associations with problem behaviour and having attempted suicide, experiencing high to very high levels of psychological distress, using alcohol, and living in a poorly functioning family. It was not possible to determine the direction of the associations.
Conclusion
There are links between problem behaviours associated with Internet use and electronic gaming, and mental disorders and risk-taking behaviour in young people. Further studies are required to determine whether these are precursors or sequelae.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-3058-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12889-016-3058-1
PMCID: PMC4866411  PMID: 27178325
Mental disorders; Internet use; Electronic gaming; Internet problem behaviours; Children and adolescents
15.  Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint 
Cell Stress & Chaperones  2015;20(6):1013-1022.
Acute stress alters anti-bacterial defenses, but the neuroimmunological mechanisms underlying this association are not yet well understood. Metallothionein (MT), a cysteine-rich protein, is a stress response protein that is induced by a variety of chemical, biological, and psychological stressors, and MT has been shown to influence immune activities. We investigated MT’s role in the management of anti-bacterial responses that occur during stress, using a C57BL/6 (B6) strain that has targeted disruptions of the Mt1 and Mt2 genes (B6-MTKO), and a B6 strain that has additional copies of Mt (B6-MTTGN). The well-characterized listeriosis model was used to examine immune mechanisms that are altered by a 1-h stress treatment (cold-restraint, CR) administered just prior to bacterial infection. Intriguingly, MT gene doses both greater and lower than that of wild-type (WT) B6 mice were associated with improved host defenses against Listeria monocytogenes (LM). This augmented protection was diminished by CR stress in the MTKO mice, but transgenic mice with additional MT copies had no CR stress-induced increase in their listerial burden. During the transition from innate to adaptive immunity, on day 3 after infection, oxidative burst and apoptosis were assessed by flow cytometric methods, and cytokine transcription was measured by real-time quantitative PCR. MT gene expression and CR-stress affected the expression of IL-6 and TNFα. Additionally, these genetic and environmental modulations altered the generation of ROS responses as well as the number of apoptotic cells in livers and spleens. Although the level of MT altered the listerial response, MT expression was equally elevated by listerial infection with or without CR stress. These results indicate the ability of MT to regulate immune response mechanisms and demonstrate that increased amounts of MT can eliminate the immunosuppression induced by CR.
doi:10.1007/s12192-015-0630-z
PMCID: PMC4595426  PMID: 26267326
Metallothionein; Infection; Listeria; Apoptosis; Oxidative stress
16.  Using Avoidable Admissions to Measure Quality of Care for Cardiometabolic and Other Physical Comorbidities of Psychiatric Disorders: A Population-Based, Record-Linkage Analysis 
Objective:
Quality of care for comorbid physical disorders in psychiatric patients can be assessed by the number of avoidable admissions for ambulatory care sensitive (ACS) conditions. These are admissions for physical conditions that, with appropriate primary care, should not require inpatient treatment. Avoidable admissions for ACS conditions feature prominently in Australia’s National Health Performance Framework and have been used to assess health care provision for marginalized groups, such as Indigenous patients or those of lower socioeconomic status. They have not been applied to people with mental illness.
Methods:
A population-based, record-linkage analysis was used to measure ACS admissions for physical disorder in psychiatric patients of state-based facilities in Queensland, Australia, during 5 years.
Results:
There were 77 435 males (48.0%) and 83 783 females (52%) (total n = 161 218). Among these, 13 219 psychiatric patients (8.2%) had at least 1 ACS admission, the most common being for diabetes (n = 6086) and angina (n = 2620). Age-standardized rates were double those of the general population. Within the psychiatric group, and after adjusting for confounders, those who had ever been psychiatric inpatients experienced the highest rates of ACS admissions, especially for diabetes.
Conclusions:
In common with other marginalized groups, psychiatric patients have increased ACS admissions. Therefore, this measure could be used as an indicator of difficulties in access to appropriate primary care in Canada, given the availability of similar administrative data.
PMCID: PMC4679130  PMID: 26720507
avoidable admissions; equity; physical and psychiatric comorbidity; ambulatory care sensitive conditions
17.  B12-Mediated, Long Wavelength Photopolymerization of Hydrogels 
Medical hydrogel applications have expanded rapidly over the past decade. Implantation in patients by noninvasive injection is preferred, but this requires hydrogel solidification from a low viscosity solution to occur in vivo via an applied stimuli. Transdermal photo-cross-linking of acrylated biopolymers with photoinitiators and lights offers a mild, spatiotemporally controlled solidification trigger. However, the current short wavelength initiators limit curing depth and efficacy because they do not absorb within the optical window of tissue (600–900 nm). As a solution to the current wavelength limitations, we report the development of a red light responsive initiator capable of polymerizing a range of acrylated monomers. Photoactivation occurs within a range of skin type models containing high biochromophore concentrations.
doi:10.1021/jacs.5b00182
PMCID: PMC4610811  PMID: 25697508
18.  Influence of Extrinsic Risk Factors on National Football League Injury Rates 
Orthopaedic Journal of Sports Medicine  2016;4(3):2325967116639222.
Background:
The risk of injury associated with American football is significant, with recent reports indicating that football has one of the highest rates of all-cause injury, including concussion, of all major sports. There are limited studies examining risk factors for injuries in the National Football League (NFL).
Purpose:
To identify risk factors for NFL concussions and musculoskeletal injuries.
Study Design:
Case-control study; Level of evidence, 3.
Methods:
Injury report data were collected prospectively for each week over the 2012-2013 and 2013-2014 regular seasons for all 32 teams. Poisson regression models were used to identify the relationship between predetermined variables and the risk of the 5 most frequent injuries (knee, ankle, hamstring, shoulder, and concussion).
Results:
A total of 480 games or 960 team games (TGs) from the 2012-2013 and 2013-2014 regular seasons were included in this study. A trend to an increasing risk of concussion and TG ankle injury with decreasing mean game-day temperature was observed. The risk of TG concussion (incidence rate ratio [IRR], 2.16; 95% CI, 1.35-3.45; P = .001) and TG ankle injury (IRR, 1.48; 95% CI, 1.10-1.98; P = .01) was significantly greater for TGs played at a mean game-day temperature of ≤9.7°C (≤49.5°F) compared with a mean game-day temperature of ≥21.0°C (≥69.8°F). The risk of TG shoulder injury was significantly increased for TGs played on grass surfaces (IRR, 1.36; 95% CI, 1.02-1.81; P = .038) compared with synthetic surfaces. The risk of TG injury was not associated with time in season, altitude, time zone change prior to game, or distance traveled to a game.
Conclusion:
This study evaluated extrinsic risk factors for injury in the NFL. A hazardous association was identified for risk of concussion and ankle injury with colder game-day temperature. Further research should be conducted to substantiate this relationship and its potential implication for injury prevention initiatives.
doi:10.1177/2325967116639222
PMCID: PMC4820027  PMID: 27088102
National Football League; NFL; concussion; injury prevention; temperature; epidemiology
19.  The 4 June 2011 neutron event at Mercury: A defense of the solar origin hypothesis 
Abstract
We address the claim that an increase in the flux of neutrons detected by the Neutron Spectrometer (NS) on the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft in orbit about Mercury at 15:45 UTC on 4 June 2011 was generated by the impact of energetic ions onto spacecraft. We find this claim to be unwarranted. The claim is grounded on the erroneous assumption that the NS singles count rate is triggered only by energetic ions. Rather, because any mix of energetic ions, electrons, photons, and neutrons can trigger NS singles, these data do not provide a reliable constraint on the presence of energetic ions. The absence of an enhancement in the count rate of 1635‐keV gamma rays, as monitored by the MESSENGER Gamma‐Ray Spectrometer, provides independent evidence that a fluence of energetic protons sufficiently high to generate the neutron enhancement was not present during the neutron event. The interpretation that currently best matches the available data is that the neutron enhancement on 4 June 2011 was the result of solar neutrons.
Key Points
We address claim that neutrons from a 4 June 2011 event at Mercury are nonsolarThe claim is based on an erroneous assumption about instrument singles countsThe best interpretation of the neutron event is that the neutrons have a solar origin
doi:10.1002/2015JA021069
PMCID: PMC4758620  PMID: 26937331
neutron; Sun
20.  Key Features in the Management of Pulmonary Carcinosarcoma 
Case Reports in Pulmonology  2016;2016:2020146.
Pulmonary carcinosarcoma represents a category of extremely rare tumours accounting for 0.1% of all lung malignancies. It is defined as a poorly differentiated non-small-cell carcinoma that contains a component of sarcoma or sarcoma-like elements. These biphasic tumours typically have a poor prognosis due to late diagnosis and early metastases. Preoperative tissue diagnosis is usually difficult due to the heterogeneity of the tumour, with biopsies often just reflecting one element of the tumour. By means of a case illustration and review of the literature, we discuss the optimal management of patients with pulmonary carcinosarcoma.
doi:10.1155/2016/2020146
PMCID: PMC4775788  PMID: 26989547
21.  Eliciting parental support for the use of newborn blood spots for pediatric research 
Background
Biomarkers of exposures such as infection or environmental chemicals can be measured in small volumes of blood extracted from newborn dried blood spots (DBS) underscoring their potential utility for population-based research. However, few studies have evaluated the feasibility and utility of this resource; particularly the factors associated with parental consent, and the ability to retrieve banked samples with sufficient remaining volume for epidemiologic research.
Methods
At 8 months postpartum, 5,034 mothers of infants born (2008–2010) in New York (57 counties excluding New York City) were asked to consent for the use of residual DBS for the quantification of cytokines and environmental chemicals. Mothers were part of the Upstate KIDS study, a longitudinal birth cohort designed to evaluate child development through 3 years of age. Information on parental and infant characteristics was obtained from birth certificates and maternal report at 4 months postpartum. Multivariate logistic regression was used to identify factors associated with parental consent and with successful retrieval of DBS.
Results
Sixty-two percent (n = 3125) of parents consented. Factors significantly associated with consent included non-Hispanic ethnicity (odds ratio 2.04; 95 % CI: 1.43–2.94), parity (1.29; 1.05–1.57), maternal obesity (1.42; 1.11–1.80) and reported alcohol use during pregnancy (1.51; 1.12–2.06). However, these associations corresponded to small absolute differences in proportions (4 to 8 %), suggesting that the two groups remained comparable. Infant characteristics such as preterm delivery did not significantly differ by consent status among singletons and only ventilator use (OR 2.39; 95 % CI: 1.06–5.41) remained borderline significant among twins in adjusted analyses. Among consented infants, 99 % had at least one 3.2 mm punch successfully retrieved for biomarker analyses and 84 % had a full DBS circle available.
Conclusion
Parental characteristics varied slightly by consent, and the availability of samples for research purposes was high, demonstrating the feasibility of this resource for population based research.
doi:10.1186/s12874-016-0120-8
PMCID: PMC4741027  PMID: 26846420
Blood spot; Consent; Newborn Screening
23.  Sclerosing hemangioma of the lung showing strong FDG avidity on PET scan: Case report and review of the current literature 
Sclerosing Hemangioma is a rare lung tumor with polymorphic histologic features that usually occurs in middle aged women. Based on many immunohistochemical and ultrastructural studies, it is most probably derived from undifferentiated respiratory epithelial cells. Symptoms are usually due to enlargement of the tumor and compression of the surrounding tissues. Occurrence of multiple lesions or metastasis is extremely rare although some authors consider sclerosing hemangioma as a potentially low grade malignancy tumor. It usually presents with low to moderate uptake on FDG PET imaging. We present a case of sclerosing hemangioma with strong FDG avidity on PET scan in a 41 year old lady with history of haemoptysis. A full review of the literature on this topic was performed.
doi:10.1016/j.rmcr.2015.12.005
PMCID: PMC4821325  PMID: 27222778
Sclerosing hemangioma; PET avidity; Lung
24.  The Potential Malignancy of a Solitary Fibrous Tumour of the Lung 
Case Reports in Pathology  2015;2015:209490.
Solitary fibrous tumours (SFTs) are rare neoplasms that in the majority of cases are benign. We present the case of a 52-year-old male, with a 23-year history of a slow growing pleural mass, presenting to our department with worsening dyspnoea and localised chest discomfort. The purpose of this case report is to highlight the potential malignancy of a solitary fibrous tumour of the lung along with the key features in diagnosis and management.
doi:10.1155/2015/209490
PMCID: PMC4697093  PMID: 26793400
25.  A novel sutureless technique for the repair of coronary sinus injuries 
Journal of Thoracic Disease  2015;7(12):2359-2361.
Coronary Sinus injury related to cardioplegia catheter insertion is a rare complication associated with significant morbidity and mortality risk. We describe a simple, safe and effective sutureless technique for the management of coronary sinus injury. This technique was developed in a porcine haemostatic workshop in Hamburg, Germany.
doi:10.3978/j.issn.2072-1439.2015.12.43
PMCID: PMC4703680  PMID: 26793359
Coronary sinus injury; myocardial protection; haemostatic agents

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