Edentulation alters material properties of cortical bone in the human craniofacial skeleton: functional implications for craniofacial structure in primate evolution.
Skeletal adaptations to reduced function are an important source of skeletal variation and may be indicative of environmental pressures that lead to evolutionary changes. Humans serve as a model animal to investigate the effects of loss of craniofacial function through edentulation. In the human maxilla, it is known that edentulation leads to significant changes in skeletal structure such as residual ridge resorption and loss of cortical thickness. However, little is known about changes in bone tissue structure and material properties, which are also important for understanding skeletal mechanics but are often ignored. The aims of this study were to determine cortical material properties in edentulous crania and to evaluate differences with dentate crania and thus examine the effects of loss of function on craniofacial structure. Cortical bone samples from 15 edentulous human skulls were measured for thickness and density. Elastic properties and directions of maximum stiffness were determined by using ultrasonic techniques. These data were compared to those from dentate crania reported in a previous investigation. Cortical bone from all regions of the facial skeleton of edentulous individuals is thinner than in dentate skulls. Elastic and shear moduli, and density are similar or greater in the zygoma and cranial vault of edentulous individuals, whereas these properties are less in the maxilla. Most cortical bone, especially in edentulous maxillae, has reduced directional orientation. The loss of significant occlusal loads following edentulation may contribute to the change in material properties and the loss of orientation over time during the normal process of bone remodeling. These results suggest that area-specific cortical microstructural changes accompany bone resorption following edentulation. They also suggest that functional forces are important for maintaining bone mass throughout the craniofacial skeleton, even in areas such as the browridges, which have been thought to be little affected by function, because of low in vivo strains found there in several primate studies.


Inhibition of steroidogenesis in cultured Leydig tumor cells by 22-amino-23,24-bisnor-5-cholen-3 beta-O1 and (20R) 20-phenyl-5-pregnene-3 beta,20-diol.
Using the cholesterol side-chain cleavage enzyme purified from bovine adrenals, we have previously shown that 22-amino-23,24-bisnor-5-cholen-3-beta-ol (22-ABC) and (20R) 20-phenyl-5-pregnene-3 beta, 20 diol (20-PPD) are potent competitive inhibitors of this enzyme. The studies presented herein were designed to characterize the effects of these new inhibitors on steroid production by intact cells. Using cultured Leydig tumor cells, we compared the effects of 22-ABC, 20-PPD, and aminoglutethimide (a well-known inhibitor of the cholesterol side-chain cleavage enzyme) on hormone-stimulated steroidogenesis. Our results show that these compounds inhibit steroid production in a dose-dependent manner and that 20-PPD and 22-ABC are about 100 and 4 times more active, respectively, than aminoglutethimide. In these cells, the inhibitory effects of the new compounds seem to be localized exclusively at the conversion of cholesterol to pregnenolone.


Domain Formation and Conformational Changes in Gold Nanoparticle Conjugates Studied Using DPD Simulations.
A gold nanoparticle (AuNP) conjugate formed with 11-mercaptoundecanoic acid (MUA) and thiolated polyethylene glycol (SH-PEG) is simulated using dissipative particle dynamics (DPD) methods, obtaining an excellent agreement with previous experimental observations. The simulations cover the isolated components (AuNP, MUA, and SH-PEG), as well as pairs of components, and finally the all three components at the same time. In this latter case, changes in the order of addition of MUA and SH-PEG over the AuNP are also considered. The AuNP is formed by independent gold beads and keeps an almost spherical shape throughout the simulation. MUA forms micelles of four to six MUA units when dispersed in water, while SH-PEG stays individually and well solvated. When exposed to AuNP, both molecules show a tendency to form patches on the surface. SH-PEG displays two different conformations (radial and tangential) depending on its relative concentration and the presence of other molecules at the NP surface. When combined at subsaturation concentrations, MUA arrives faster to the AuNP surface than SH-PEG and forms patches while SH-PEG occupies the remaining free surface. In these conditions, the order of addition of the different components partially alters these results. When SH-PEG is added over an already formed MUA/AuNP partial layer, it adopts a radial conformation over the MUA formed patches; on the contrary, if MUA is added over an already formed SH-PEG/AuNP partial layer, much less SH-PEGs adopt a radial conformation and MUA patches are significantly smaller.


A qualitative assessment of perspectives on getting pregnant: the Social Position and Family Formation study.
Intentions-oriented approaches to measuring pregnancy do not necessarily align with how people view and approach pregnancy. Our objective was to obtain an in-depth understanding of the notions women and men hold regarding pregnancy. We conducted semi-structured in-depth interviews with 176 heterosexual women and men ages 18-35, in the United States. Data were analyzed using grounded theory methodology. Participants described notions of getting pregnant in one of three ways. One group of participants used language that solely described pregnancy as a deliberate process, either premeditated or actively avoided. Another described pregnancy as a predetermined phenomenon, due to fate or something that 'just happens.' The third group represented a blending of both notions. Our findings underscore the need to shift the current paradigm of deliberate intentions to one that recognizes that pregnancy can also be viewed as predetermined. These findings can be used to improve measurement, health services, and better direct public health resources.


Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases.
Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTPalpha promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants.


Characterization of Atrial Fibrillation Episode Patterns: A Comparative Study.
The episode patterns of paroxysmal atrial fibrillation (AF) may carry important information on disease progression and complication risk. However, existing studies offer very little insight into to what extent a quantitative characterization of AF patterns can be trusted given the errors in AF detection and various types of shutdown, i.e., poor signal quality and non-wear. This study explores the performance of AF pattern characterizing parameters in the presence of such errors. To evaluate the performance of the parameters AF aggregation and AF density, both previously proposed to characterize AF patterns, the two measures mean normalized difference and the intraclass correlation coefficient are used to describe agreement and reliability, respectively. The parameters are studied on two PhysioNet databases with annotated AF episodes, also accounting for shutdowns due to poor signal quality. The agreement is similar for both parameters when computed for detector-based and annotated patterns, which is 0.80 for AF aggregation and 0.85 for AF density. On the other hand, the reliability differs substantially, with 0.96 for AF aggregation but only 0.29 for AF density. This finding suggests that AF aggregation is considerably less sensitive to detection errors. The results from comparing three strategies to handle shutdowns vary considerably, with the strategy that disregards the shutdown from the annotated pattern showing the best agreement and reliability. Due to its better robustness to detection errors, AF aggregation should be preferred. To further improve performance, future research should put more emphasis on AF pattern characterization.


Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD.
Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.


Retroposon analysis and recent geological data suggest near-simultaneous divergence of the three superorders of mammals.
As a consequence of recent developments in molecular phylogenomics, all extant orders of placental mammals have been grouped into 3 lineages: Afrotheria, Xenarthra, and Boreotheria, which originated in Africa, South America, and Laurasia, respectively. Despite this advancement, the order of divergence of these 3 lineages remains unresolved. Here, we performed extensive retroposon analysis with mammalian genomic data. Surprisingly, we identified a similar number of informative retroposon loci that support each of 3 possible phylogenetic hypotheses: the basal position for Afrotheria (22 loci), Xenarthra (25 loci), and Boreotheria (21 loci). This result indicates that the divergence of the placental common ancestor into the 3 lineages occurred nearly simultaneously. Thus, we examined whether these molecular data could be integrated into the geological context by incorporating recent geological data. We obtained firm evidence that complete separation of Gondwana into Africa and South America occurred 120 +/- 10 Ma. Accordingly, the previous reported time frame (division of Pangea into Gondwana and Laurasia at 148-138 Ma and division of Gondwana at 105 Ma) cannot be used to validate mammalian divergence order. Instead, we use our retroposon results and the recent geological data to propose that near-simultaneous divisions of continents leading to isolated Africa, South America, and Laurasia caused nearly concomitant divergence of the ancient placental ancestor into 3 lineages, Afrotheria, Xenarthra, and Boreotheria, approximately 120 Ma.


Investigation of Adhesive Joining Strategies for the Application of a Multi-Material Light Rail Vehicle.
To meet the high demand for lightweight energy-efficient and safe structures for transport applications, a current state-of-the-art light rail vehicle structure is under development that adopts a multi-material design strategy. This strategy creates the need for advanced multi-material joining technologies. The compatibility of the adhesive with a wide range of material types and the possibility of joining multi-material structures is also a key advantage to its success. In this paper, the feasibility of using either epoxy or polyurethane adhesive joining techniques applied to the multi-material vehicle structure is investigated. Importantly, consideration is given to the effect of variation in bond thickness for both families of structural adhesives. Multi-material adhesively bonded single lap joints with different adhesives of controlled bond thicknesses were manufactured and tested in order to experimentally assess the shear strength and stiffness. The torsional stiffness and natural frequency of the vehicle were modelled using a global two-dimensional finite element model (FEM) with different adhesive properties, and the obtained vehicle performances were further explained by the coupon-level experimental tests. The results showed that the vehicle using polyurethane adhesive with a target bond thickness of 1.0 mm allowed for optimal modal frequency and weight reduction.


Kappa light chain gene rearrangement in T-cell acute lymphoblastic leukemia.
Immunoglobulin and T-cell receptor gene rearrangement assays are sensitive methods of detecting clonality in lymphoproliferative disorders. The lack of lineage specificity of immunoglobulin heavy chain and T-cell receptor beta and gamma gene probes in acute leukemia is well established. However, immunoglobulin light chain gene rearrangement traditionally has been considered a highly specific indicator of a clonal B-lineage process. The authors describe a case of T-cell acute lymphoblastic leukemia in which Southern blot hybridization studies showed rearrangement of the T-cell receptor beta chain gene. Unexpectedly, the immunoglobulin kappa light chain gene also was rearranged; no immunoglobulin heavy chain gene rearrangement was seen. Kappa rearrangement was confirmed with the use of three restriction endonucleases. No rearrangements were seen from normal skin tissue, making a restriction enzyme site polymorphism highly unlikely. Northern blot studies showed a normal-size, T-cell receptor beta chain gene transcript; no immunoglobulin RNA was identified. These results describe the first reported case of kappa light chain gene rearrangement in a T-cell acute lymphoblastic leukemia. The findings emphasize the necessity of interpreting molecular hybridization studies in conjunction with routine morphology and immunophenotyping studies.


Glycine: a non-invasive imaging biomarker to aid magnetic resonance spectroscopy in the prediction of survival in paediatric brain tumours.
Paediatric brain tumours have a high mortality rate and are the most common solid tumour of childhood. Identification of high risk patients may allow for better treatment stratification. Magnetic Resonance Spectroscopy (MRS) provides a non-invasive measure of brain tumour metabolism and quantifies metabolite survival markers to aid in the clinical management of patients. Glycine can be identified using MRS and has been recently found to be important for cancer cell proliferation in tumours making it a valuable prognostic marker. The aims of this study were to investigate glycine and its added value to MRS as a prognostic marker for paediatric brain tumours in a clinical setting. 116 children with newly diagnosed brain tumours were examined with short echo-time MRS at the Birmingham Children's Hospital and followed up for five years. Survival analysis was performed using Cox regression on the entire metabolite basis set with focus on glycine and three other established survival markers for comparison: n-acetylaspartate, scyllo-inositol and lipids at 1.3 ppm. Multivariate Cox regression was used in conjunction with risk values to establish if glycine added prognostic power when combined to the established survival markers. Glycine was found to be a marker of poor prognosis in the cohort (p < 0.05) and correlated with tumour grade (p < 0.01). The addition of glycine improved the prognostic power of MRS compared to using the combination of established survival markers alone. Tumour glycine was found to improve the MRS prediction of reduced survival in paediatric brain tumours aiding the non-invasive assessment of these children.


Pyridines in cigarette smoke inhibit hamster oviductal functioning in picomolar doses.
Past studies showed that chemicals in cigarette smoke inhibit oviductal functioning in vivo and in vitro. The purposes of this study were to identify individual toxicants in cigarette smoke solutions that inhibit various aspects of oviductal functioning and to determine their effective doses using in vitro bioassays. Solid phase extraction and gas chromatography-mass spectrometry (GC-MS) were used to identify individual chemicals in mainstream (MS) and sidestream (SS) cigarette smoke solutions. Pyridines, which were the most abundant class of compounds identified, were purchased, assayed for purity, and tested in dose-response studies on hamster oviducts. The lowest observable adverse effect level was determined for each pyridine derivative using the oocyte pick-up rate, ciliary beat frequency, and infundibular muscle contraction assays. 2-Methylpyridine, 4-methylpyridine, 2-ethylpyridine, 3-ethylpyridine, and 4-vinylpyridine were inhibitory at picomolar concentrations in all assays. This work shows picomolar doses of pyridines with single methyl or ethyl substitutions significantly inhibit oviductal functioning raising questions regarding the safety of these compounds.


Cleft lip nasal deformity.
The nasal deformity in the cleft lip patient is produced by the lower lateral cartilage being subluxed inferiorly and laterally, which falsely lengthens the nose on the cleft side. The columella is not short. It simply extends laterally to a dipped area in the rim of the nostril. The cleft lip nasal deformity is correctable at the time of primary lip repair by advancing the lower lateral cartilage superiorly and medially. The correction will last with the cartilage fixed to the upper lateral cartilage-septal junction, its normal position. A deficient repair will not improve. A good repair will last, will not interfere with growth of the nose, and will free the patient from years of unnecessary embarrassment . Correction of the cleft lip nasal deformity in the adult requires repositioning of the lower lateral cartilage similar to what can be and should be done in the infant.


Nonconvulsive status epilepticus in the critically ill elderly.
To describe the electrographic and clinical features of nonconvulsive status epilepticus (NCSE) in the critically ill elderly and to identify potential predictors of outcome. We prospectively identified 25 episodes of altered mentation and NCSE in 24 critically ill elderly patients associated with generalized, focal, or bihemispheric epileptiform EEG patterns. Patients with anoxic encephalopathy were excluded. Of 25 hospitalizations, 13 (52%) resulted in death, and 12 (48%) patients survived to discharge. Death was associated with the number of acute, life-threatening medical problems on presentation (survivors, 1.8; fatalities, 2.8; p = 0.013) and with generalized EEG pattern (p = 0.017). Higher doses or greater number of antiepileptic drugs (AEDs) did not improve outcome. Treatment with intravenous benzodiazepines was associated with increased risk of death (p = 0.033). Ten patients with advance directives were managed outside the intensive care unit (ICU). Mean hospitalization was 39 days in the ICU group and 22 for those with advance directives (p = 0.017). Severity of illness correlates with mortality in critically ill elderly patients with NCSE. Treatment with intravenous benzodiazepines may increase their risk of death. Aggressive ICU management may prolong hospitalization at considerable cost, without improving outcome. It is unclear whether NCSE affects outcome in the critically ill elderly or is merely a marker for severity of disease in predisposed patients. The benefits of aggressive therapy are unclear. Carefully controlled, prospective trials will be necessary to determine the best therapies for NCSE in the critically ill elderly and the appropriate role of the ICU in their management.


Targeting therapy to minimize antimicrobial use in preweaned calves: effects on health, growth, and treatment costs.
Prophylactic and therapeutic antimicrobial use in food animals is questioned because of the potential for development of resistant bacteria and future inability to use some antimicrobials for human or animal disease. The objectives of this study were to determine the effect of raising preweaned dairy calves without antimicrobials in the milk and minimizing therapeutic antimicrobial treatment on morbidity, mortality, weight gain, and treatment costs. Newborn calves (n = 358) were allocated to 1 of 4 groups, housed outdoors in individual hutches, and monitored for 28 d. Calves in the conventional therapy (CT) group were treated as per dairy protocol with sulfamethoxazole/trimethoprim, spectinomycin, penicillin, and bismuth-pectin for diarrhea. The targeted therapy (TT) group included bismuth-pectin for diarrhea and antimicrobial treatment only in cases of fever or depressed attitude. Within CT and TT groups, calves were equally assigned to receive neomycin and tetracycline in their milk for the first 2 wk of life (AB-milk) or no antimicrobials (NoAB-milk). Daily health evaluations included fecal consistency, respiratory disease, attitude, and hydration status as well as milk and grain consumption. A negative binomial model evaluated the total number of days with diarrhea days in each group. General linear models were used to assess average daily weight gain and grain consumption. Conventionally treated calves had 70% more days with diarrhea than TT calves, and AB-milk calves had 31% more days with diarrhea compared with NoAB-milk calves. The TT calves tended to have a higher average daily gain by 28 d and consumed more grain compared with CT calves. If antimicrobials were used only for diarrhea cases with fever, inappetence, or depression and no in-milk antimicrobials were used, a $10 per calf savings could be realized. Targeting antimicrobial therapy of calf diarrhea cases is prudent not only to save the drugs for future use but also to prevent the potential for antibiotic-associated diarrhea and reduce calf-rearing costs.


Bicycling injuries.
Bicycling injuries can be classified into bicycle contact, traumatic, and overuse injuries. Despite the popularity of cycling, there are few scientific studies regarding injuries. Epidemiological studies are difficult to compare due to different methodologies and the diverse population of cyclists studied. There are only three studies conducted on top level professionals. Ninety-four percent of professionals in 1 year have experienced at least one overuse injury. Most overuse injuries are mild with limited time off the bike. The most common site of overuse injury is the knee, and the most common site of traumatic injury is the shoulder, with the clavicle having the most common fracture. Many overuse and bicycle contact ailments are relieved with simple bike adjustments.


Prognostic and predictive significance of thymidylate synthase protein expression in non-small cell lung cancer: a systematic review and meta-analysis.
It remains controversial whether thymidylate synthase (TS) protein expression is associated with survival for patients with non-small cell lung cancer (NSCLC). To evaluate prognostic and predictive significance of tumor TS protein level in NSCLC. Electronic searches were performed for relevant studies in PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature Database. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled for meta-analysis. Subgroup and sensitivity analyses were performed. Publication bias was evaluated by funnel plot and Begg's test. Twenty-four studies, including 2280 patients, were eligible. This analysis showed that patients with low TS expression had statistically significantly longer OS and PFS than those with high TS (HR=0.51 and HR=0.49, respectively). Based on TS-targeted drug use status, TS expression was significantly associated with OS in pemetrexed (HR=0.42) and 5-Fluorouracil subgroups (HR=0.34), but not in no TS-targeted drug subgroup. There were similar results for PFS analyses. Sensitivity analysis indicated that the results were robust. Begg's test did not reveal any publication bias. Low TS protein expression is a favorable predictive factor for better OS/PFS in NSCLC patients treated with TS-targeted drugs. Prognostic value of TS protein expression needs further validation.


Experimental human infection with Asian Taenia saginata metacestodes obtained from naturally infected Korean domestic pigs.
The infectivity of metacestodes of Asian Taenia saginata, now tentatively called Taenia saginata taiwanensis, in human host was confirmed. The metacestodes used in experimental infection were collected from the livers of naturally infected domestic pigs at an abattoir in Cheongju City, Korea. The first gravid proglottid was spontaneously discharged 76 days after infection. Two worms were recovered two years later by chemotherapy. The scolex was unarmed. The number of main uterine branches, varying from 16 to 21, was similar to that of classical Taenia saginata. The liver of pigs was confirmed to be an infection source of Asian T. saginata in Korea.


Does high caregiver stress predict nursing home entry?
This study estimates how informal care, paid formal care, and caregiver stress or burden relate to nursing home placement. Data came from the 1999 National Long Term Care Survey and were merged with administrative data. Results show that stress is a strong predictor of entry over follow-up periods of up to two years, and physical strain and financial hardship are important predictors of high levels of caregiver stress. The estimates indicate that reducing these stress factors would significantly reduce caregiver stress and, as a result, nursing home entry. We conclude that initiatives to reduce caregiver stress hold promise as a strategy to avoid or defer nursing home entry.


A systematic approach to diabetes care.
Effective care for patients with diabetes in general practice requires a systematic approach. This can be achieved by establishing a patient register and recall system, by using a checklist or protocol, and by developing a team approach, involving practice staff and other professionals outside the practice. Education and mutual support are also essential components of diabetes care.


The art of atom descriptor design.
This review provides an overview of descriptions of atoms applied to the understanding of phenomena like chemical reactivity and selectivity, pKa values, Site of Metabolism prediction, or hydrogen bond strengths, but also the substitution of quantum mechanical calculations by machine learning models for energies, forces or even spectrosocopic properties and finally the fast calculation of atomic charges for force field parametrization. The descriptor space ranges from derivatives of the wavefunctions or electron density via quantum mechanics derived descriptors to classical descriptions of atoms and their embedding in a molecule. The common denominator for all approaches is the thorough understanding of the physics of the chemical problem that guided the design of the atom descriptor. Quantum mechanics (QM) and machine learning (ML) finally are converging to a new discipline, namely QM/ML.


Physician assistant dual employment.
National health workforce supply and demand models help predict requirements built on individual annual productivity assumptions. Dual employment rarely is addressed, yet in 2015, about 13.5% of certified physician assistants (PAs) reported two or more clinical positions. Of PAs working two positions, 44% reported the main reason was to supplement earnings, followed by role variety. The mean number of hours worked by all certified PAs was 40.7 per week and the average number of patients was 75. Dual-employed PAs averaged more than 51 hours and 97 patients per week. This new finding reveals an added dimension to provider productivity statistics requiring refinements to annual output calculations.


Cytocompatible click-based hydrogels with dynamically tunable properties through orthogonal photoconjugation and photocleavage reactions.
To provide insight into how cells receive information from their external surroundings, synthetic hydrogels have emerged as systems for assaying cell function in well-defined microenvironments where single cues can be introduced and subsequent effects individually elucidated. However, as answers to more complex biological questions continue to be sought, advanced material systems are needed that allow dynamic alteration of the three-dimensional cellular environment with orthogonal reactions that enable multiple levels of control of biochemical and biomechanical signals. Here, we seek to synthesize one such three-dimensional culture system using cytocompatible and wavelength-specific photochemical reactions to create hydrogels that allow orthogonal and dynamic control of material properties through independent spatiotemporally regulated photocleavage of crosslinks and photoconjugation of pendant functionalities. The results demonstrate the versatile nature of the chemistry to create programmable niches to study and direct cell function by modifying the local hydrogel environment.


[Auditory screening in public schools in Bilbao].
In this work we present a hearing screening practised to 2802 six years children, attending to Public Schools in Bilbao area, during 1988, 1989 and 1990. We used the screening audiometry as method, placing the normality level in 30 dB H1 ISO. We obtained a prevalence of 6.6% and a 7.6% of false positives. Transmission hearing losses represent almost 70% and levels of low and moderate hearing loss were the most frequent, reading 88.6%. We also confirmed as parameters that contribute to hearing loss detection, the level and bilaterality of hearing loss, being language delay one of the most frequent reasons of suspicion. We also discovered that the vast majority of hearing losses that cause invalidation, deep and severe, have a perinatal origin, so early screenings would enable and early diagnostic and many benefits. In spite of all the screenings mant hearing losses are not detected, but they are moderate and can never cause incapacitation, being of little hearing relevance.


Halogenation of SiC for band-gap engineering and excitonic functionalization.
The optical excitation spectra and excitonic resonances are investigated in systematically functionalized SiC with Fluorine and/or Chlorine utilizing density functional theory in combination with many-body perturbation theory. The latter is required for a realistic description of the energy band-gaps as well as for the theoretical realization of excitons. Structural, electronic and optical properties are scrutinized and show the high stability of the predicted two-dimensional materials. Their realization in laboratory is thus possible. Large band-gaps of the order of 4 eV are found in the so-called GW approximation, with the occurrence of bright excitons, optically active in the four investigated materials. Their binding energies vary from 0.9 eV to 1.75 eV depending on the decoration choice and in one case, a dark exciton is foreseen to exist in the fully chlorinated SiC. The wide variety of opto-electronic properties suggest halogenated SiC as interesting materials with potential not only for solar cell applications, anti-reflection coatings or high-reflective systems but also for a possible realization of excitonic Bose-Einstein condensation.


Nucleotide sequence of the gene for perfringolysin O (theta-toxin) from Clostridium perfringens: significant homology with the genes for streptolysin O and pneumolysin.
The nucleotide sequence was determined for the gene encoding the thiol-activated cytolysin, perfringolysin O (theta-toxin), from Clostridium perfringens. The nucleotide-sequence-derived primary structure of perfringolysin O is 499 residues long and exhibits a 27-amino-acid signal peptide. The calculated molecular weight of the secreted (mature) form of perfringolysin O is 52,469. The deduced amino-terminal sequence of perfringolysin O is identical to that determined for purified perfringolysin O. Hydropathy analysis indicated that, except for the signal peptide, no major stretches of hydrophobic residues are present. Extensive amino acid sequence homology (65%) was detected with the low-molecular-weight form of streptolysin O, and a lesser amount (42%) was detected with pneumolysin. The nucleotide sequence of the perfringolysin O gene (pfo) exhibits approximately 60% homology with the streptolysin O gene (slo) and 48% homology with the pneumolysin gene (ply). All three toxins contain an identical region of 12 amino acids, which includes the essential cysteine of all three toxins. The location of these 12 residues was conserved in all three toxins when the primary sequences were aligned for maximum homology.


Beneficial impact of cardiac heavy metal scavenger metallothionein in sepsis-provoked cardiac anomalies dependent upon regulation of endoplasmic reticulum stress and ferroptosis but not autophagy.
Sepsis represents a profound proinflammatory response with a major contribution from oxidative injury. Here we evaluated possible impact of heavy metal scavenger metallothionein (MT) on endotoxin lipopolysaccharide (LPS)-induced oxidative stress, endoplasmic reticulum (ER) stress, autophagy, and ferroptosis enroute to myocardial injury along with interplay among these stress domains. Echocardiographic, cardiomyocyte mechanical and intracellular Ca2+ responses were monitored in myocardia from WT and transgenic mice with cardiac-selective MT overexpression challenged with LPS. Oxidative stress, stress signaling (p38, ERK, JNK), ER stress, autophagy, and ferroptosis were scrutinized. RNAseq analysis revealed discrepant patterns in ferroptosis between LPS-exposed and normal murine hearts. LPS insult enlarged LV end systolic dimension, suppressed fractional shortening, ejection fraction, maximal velocity of shortening/relengthening and peak shortening, as well as elongated relengthening along with dampened intracellular Ca2+ release and reuptake. In addition, LPS triggered oxidative stress (lowered glutathione/glutathione disulfide ratio and O2- production), activation of stress cascades (p38, ERK, JNK), ER stress (GRP78, PERK, Gadd153, and IRE1α), inflammation (TNFα and iNOS), unchecked autophagy (LCB3, Beclin-1 and Atg7), ferroptosis (GPx4 and SLC7A11) and interstitial fibrosis. Although MT overexpression itself did not reveal response on cardiac function, it attenuated or mitigated LPS-evoked alterations in echocardiographic, cardiomyocyte contractile and intracellular Ca2+ characteristics, O2- production, TNFα level, ER stress and ferroptosis (without affecting autophagy, elevated AMP/ATP ratio, and iNOS). In vitro evidence revealed beneficial effects of suppression of oxidative stress, ER stress and ferroptosis against LPS-elicited myocardial anomalies. These data strongly support the therapeutic promises of MT and ferroptosis in septic cardiomyopathy.


MORPHOMETRY OF FIRST-STAGE LARVAE OF ORTHOSTRONGYLUS MACROTIS (NEMATODA: PROTOSTRONGYLIDAE), LUNGWORM OF WILD UNGULATES FROM WESTERN NORTH AMERICA.
Orthostrongylus macrotis (Dikmans, 1931) is a protostrongylid lungworm in wild ungulates from western North America, including mule and Columbia black-tailed deer, pronghorn, and rarely moose and elk. The lack of morphological data for certain developmental stages of O. macrotis and the unresolved taxonomic status of the genus indicate a more detailed morphological characterization of the species is necessary. We provide a detailed description of first-stage larvae (L1) of O. macrotis including morphological, morphometric, and molecular data. Species identity was confirmed based on molecular sequence data from the internal transcribed spacer subunit 2 (ITS-2) and large subunit (28S) rDNA. A fragment of the cytochrome oxidase c subunit 1 (COI) was also sequenced, followed by the determination of genetic distance and phylogenetic analyses. Integrated data describing L1 of O. macrotis contributes to a broader understanding of the parasite fauna of wild ungulates from North America and may be of relevance for a future revision of the genus. Further, we outline information for differentiation among species of North American protostrongylids, with typical spike-tailed L1s, circulating among free-ranging and semi-domestic ungulates.


What Are the Challenges Faced by Village Doctors in Provision of Basic Public Health Services in Shandong, China? A Qualitative Study.
Background: Village doctors, as gatekeepers for the health of rural residents in China, are confronted with adversity in providing the basic public health services (BPHS), which has significantly impeded them from providing high quality BPHS. This study aimed to explore the obstacles and difficulties faced by village doctors in order to improve the quality and efficiency of BPHS provision and increase the health level of the population. Methods: In-depth interviews were employed to conduct this qualitative study. A total of 51 village doctors in four cities of Shandong Province were interviewed. The interviews were transcribed, anonymized, and imported into NVivo11.0 to facilitate management. Thematic framework analysis employing the constant comparison method was applied to the data analysis. Results: The main challenges faced by village doctors comprised the shortage, gender imbalance, and poor education of village doctors; older village doctors in some villages; low income; lack of social security; inappropriate performance assessment; inadequate professional BPHS training; heavy workload; and insufficient cooperation from rural residents, which have exacerbated the quality, efficiency, and accessibility of BPHS to some extent. Conclusions: Village doctors, as the important BPHS providers in rural Shandong, are facing a wide range of challenges. It is urgent for government officials and policy makers to consider these challenges and concentrate on improving the quality of BPHS provision by developing relevant and practical strategies.


Unburdening expectation and operating between: architecture in support of palliative care.
The role of design and materials in the enactment and experience of healthcare has gained increasing attention across the fields of evidence-based design, architecture, anthropology, sociology and cultural geography. Evidence-based design, specifically, seeks to understand the ways in which the built environment can support the healing process. In the context of palliative care, however, the very measure of healing differs vastly. Physicians Mount and Kearney suggest that 'it is possible to die healed', and that such healing can be facilitated through the provision of 'a secure environment grounded in a sense of connectedness' (2003: 657). Acknowledging this critical difference raises important questions around the various ways through which the built environment might support healing, but also about the potential of architecture to impart care. This paper reports on 15 interviews with architects, experienced in the design of palliative care settings, from the UK, USA and Australia, to provide a deeper understanding of the questions being asked within the briefing processes for these facilities, the intentions embedded in the ways that architects respond, and the kinds of compromises deemed allowable (by various stakeholders) within the procurement process. Our findings suggest that palliative care architects often respond to two briefs, one explicit and the other unspoken. Design responses in relation to the first include: formally expressing a differentiation in the philosophy of care (signalling difference), attention to quality, extending comfort and providing 'moments'. The second relates to the unburdening of palliative care facilities from their associative baggage and responding to the tension between the physical and imaginative inhabitation of space. In revealing the presence of this hidden brief, and the relationship between the two, this paper invites a broader discussion regarding the capacity of architecture to support palliative care patients, their families and staff.


Long wavelength behavior of the fundamental mode in microstructured optical fibers.
Using a novel computational method, the fundamental mode in index-guided microstructured optical fibers with genuinely infinite cladding is studied. It is shown that this mode has no cut-off, although its area grows rapidly when the wavelength crosses a transition region. The results are compared with those for w-fibers, for which qualitatively similar results are obtained.


Everolimus tablets for patients with subependymal giant cell astrocytoma.
Better understanding of aberrantly active molecular pathways in tumors offers potential to develop more specific and less toxic therapies. Abnormal mammalian target of rapamycin (mTOR) complex signaling and defects in TSC1 and TSC2 have been associated with the development of subependymal giant cell astrocytomas (SEGAs) in tuberous sclerosis complex (TSC) patients. Recently, mTOR inhibitors such as everolimus have shown encouraging benefit for patients with SEGAs. The authors discuss a molecular genetic pathway linked with TSC, specifically the role of two proteins whose functional absence is responsible for most SEGA tumors that arise in TSC patients. The authors also examine the rationale for targeted agents against this pathway therapeutically and describe the clinical evidence underlying the FDA approval of everolimus for patients with inoperable SEGAs. Everolimus (Afinitor) selectively targets a molecular defect of SEGAs in TSC patients. Although surgery is effective, most SEGAs recur. An agent that inhibits an underlying molecular abnormality represents a particularly attractive therapeutic option for patients with inoperable or recurrent tumors. Studies are also underway to assess everolimus in treating other sequelae of TSC, and other gliomas. Finally, additional research aimed at better understanding aberrant cell signaling pathways may lead to the development of more effective therapeutics.


Subtractive CRISPR screen identifies the ATG16L1/vacuolar ATPase axis as required for non-canonical LC3 lipidation.
Although commonly associated with autophagosomes, LC3 can also be recruited to membranes by covalent lipidation in a variety of non-canonical contexts. These include responses to ionophores such as the M2 proton channel of influenza A virus. We report a subtractive CRISPR screen that identifies factors required for non-canonical LC3 lipidation. As well as the enzyme complexes directly responsible for LC3 lipidation in all contexts, we show the RALGAP complex is important for M2-induced, but not ionophore drug-induced, LC3 lipidation. In contrast, ATG4D is responsible for LC3 recycling in M2-induced and basal LC3 lipidation. Identification of a vacuolar ATPase subunit in the screen suggests a common mechanism for non-canonical LC3 recruitment. Influenza-induced and ionophore drug-induced LC3 lipidation lead to association of the vacuolar ATPase and ATG16L1 and can be antagonized by Salmonella SopF. LC3 recruitment to erroneously neutral compartments may therefore represent a response to damage caused by diverse invasive pathogens.


Latina mothers' attributions, emotions, and reactions to the problem behaviors of their children with developmental disabilities.
We examined the applicability of attribution theory to mothers' perceptions and reactions to their child's problem behavior. Participants were 149 Latina mothers of children with developmental disabilities who were interviewed regarding specific incidents in which their child exhibited a behavior problem. The findings indicate that most mothers viewed their child as not being responsible for the behavior problem. Furthermore, as predicted by attribution theory, mothers who ascribed relatively high responsibility to the child were significantly more likely to report negative emotions (anger and frustration) and aggressive/harsh behavioral reactions than mothers who ascribed low responsibility. Also. mothers were more likely to ascribe high responsibility to the child when the problem was characterized as a behavioral excess than as a behavioral deficit. The results provide support for the applicability of an attributional framework and may have important implications for helping parents in addressing the problem behaviors of their children with developmental disabilities.


[Tryptophan-induced fasciitis-scleroderma-eosinophilia syndrome].
A fasciitis-sclerodermia-eosinophilia syndrome developed in four female patients, aged between 55 and 75 years, after the ingestion of tryptophan, 1.5-6.0 g daily, for 13 months to 7 years. It began characteristically with hard oedema of the limbs, sometimes also of the trunk. Later there occurred diffuse indurations of the body surface with fixation of the skin to fascial planes. This was associated with mainly sensory peripheral neuropathy. Three of the patients had an eosinophilia (12-30%). Histological examination revealed a cell-poor fasciitis, fibrosis of the cutis and subcutis, perimyositis and epidermal atrophy of varying degree. Erythrocyte sedimentation rate was at most slightly increased. Antinuclear antibodies were demonstrated in one patient (1:80). Serum aldolase concentration was raised (3.4-5.4 U/l), while creatine kinase was normal. The disease progressed even after tryptophan was discontinued, in only one patient there was improvement during glucocorticoid treatment. In two cases the skin induration regressed slowly after administration of methotrexate (15 mg weekly) and hydroxychloroquine (400 mg daily).


[Effects of NMDA and non-NMDA agonists on the respiratory rhythmical discharge of the hypoglossal nerve in the medullary slice from neonatal rats].
To study the possible role of the NMDA and non-NMDA receptor on the generation and modulation of basic respiratory rhythm. Experiments were performed on the medullary slices isolated from the neonatal rats. Respiratory rhythmical discharge activity (RRDA) of the hypoglossal nerve was recorded by suction electrode, then the effects of the excitatory amino acids and its antagonists on the RRDA were investigated by adding these drugs into the perfused modified Kreb's solution. After applying the non-NMDA receptor agonist KA, it was found that the respiratory circle and the expiratory time were lightly lengthened, but the NMDA receptor agonist NMDA had no effect on the RRDA. Both of the mutual antagonist DNQX and AP-5 remarkably decreased the discharge frequency and the integral amplitude, accompanied by the shortening of the inspiratory time, DNQX simultaneously shortened the respiratory circle and the expiratory time. During the generation and modulation of the mammalian respiratory rhythm, NMDA receptor may mainly play a role in the amplitude of the respiratory activity, the non-NMDA receptor can not only affect the amplitude of the respiratory discharge also modulate the frequency of the respiratory rhythm.


[Technical Note: Subclavian artery misplacement of a 12F Shaldon catheter: percutaneous repair with a local closure device under temporary balloon tamponade].
A case of subsequent percutaneous repair using a local closure device with a collagen block (VasoSeal(R)) and temporary balloon tamponade after inadvertent subclavian artery misplacement of a 12F Shaldon catheter is reported. Balloon occlusion safely prevented displacement of collagen into the vascular lumen by occluding the 12F entry site. Furthermore, collagen-induced coagulation was facilitated.


Hyponatremia and inflammation: the emerging role of interleukin-6 in osmoregulation.
Although hyponatremia is a recognized complication of several inflammatory diseases, its pathophysiology in this setting has remained elusive until recently. A growing body of evidence now points to an important role for interleukin-6 in the non-osmotic release of vasopressin. Here, we review this evidence by exploring the immuno-neuroendocrine pathways connecting interleukin-6 with vasopressin. The importance of these connections extends to several clinical scenarios of hyponatremia and inflammation, including hospital-acquired hyponatremia, postoperative hyponatremia, exercise-associated hyponatremia, and hyponatremia in the elderly. Besides insights in pathophysiology, the recognition of the propensity for antidiuresis during inflammation is also important with regard to monitoring patients and selecting the appropriate intravenous fluid regimen, for which recommendations are provided.


Modulation of expression of rat mitochondrial 2-oxoglutarate carrier in NRK-52E cells alters mitochondrial transport and accumulation of glutathione and susceptibility to chemically induced apoptosis.
We previously showed that two anion carriers of the mitochondrial inner membrane, the dicarboxylate carrier (DIC; Slc25a10) and oxoglutarate carrier (OGC; Slc25a11), transport glutathione (GSH) from cytoplasm into mitochondrial matrix. In the previous study, NRK-52E cells, derived from normal rat kidney proximal tubules, were transfected with the wild-type cDNA for the DIC expressed in rat kidney; DIC transfectants exhibited increased mitochondrial uptake and accumulation of GSH and were markedly protected from chemically induced apoptosis. In the present study, cDNAs for both wild-type (WT) and a double-cysteine mutant of rat OGC (rOGC and rOGC-C221,224S, respectively) were expressed in Escherichia coli, purified, and reconstituted into proteoliposomes to assess their function. Although both WT rOGC and rOGC-C221,224S exhibited transport properties for GSH and 2-oxoglutarate that were similar to those found in mitochondria of rat kidney proximal tubules, rates of transport and mitochondrial accumulation of substrates were reduced by >75% in rOGC-C221,224S compared with the WT carrier. NRK-52E cells were stably transfected with the cDNA for WT-rOGC and exhibited 10- to 20-fold higher GSH transport activity than nontransfected cells and were markedly protected from apoptosis induced by tert-butyl hydroperoxide (tBH) or S-(1,2-dichlorovinyl)-L-cysteine (DCVC). In contrast, cells stably transfected with the cDNA for rOGC-C221,224S were not protected from tBH- or DCVC-induced apoptosis. These results provide further evidence that genetic manipulation of mitochondrial GSH transporter expression alters mitochondrial and cellular GSH status, resulting in markedly altered susceptibility to chemically induced apoptosis.


Factors influencing hip protector use among community-dwelling older adults.
To obtain a better understanding of the issues that influence hip protector use among community-dwelling older adults. The study used a longitudinal, crossover design. A convenience sample of 32 participants used four different brands of hip protectors, each for a 1-week period. Data were collected by weekly telephone interviews and a mailed questionnaire administered at baseline and follow-up. Participant perceptions regarding hip protectors were assessed using both open-ended questions and Likert-type items. The most common concerns about hip protectors mentioned in response to open-ended questions involved: discomfort, poor fit, inconvenience and unfavourable effects on appearance. Participants spontaneously mentioned at least one of these barriers in over 70% of the interviews. In contrast, participants spontaneously mentioned the protective benefits offered by hip protectors in only 16% of the interviews. The intention to continue using a particular hip protector after the study ended was associated with the number of hours the hip protector was worn during the study (p<0.01). After controlling for other variables, beliefs concerning the amount of protection that a hip protector provided was positively associated with the number of hours the hip protector was worn during the study (p<0.05) and the intention to continue using the hip protector after the study (p<0.01). Study findings suggest that the use of hip protectors by community-dwelling older adults is influenced by beliefs about both barriers to use and the amount of protection provided.


Current practice of inguinal hernia repair at University of Cape Town affiliated hospitals: implications for training.
Various inguinal hernia repair techniques exist, without one 'single best' option. Hernia society guidelines recommend laparoscopic repair as one of its mainstays, provided surgeons are adequately trained. The current practice for hernia repair in South Africa as well as the surgical registrar exposure to laparoscopic repair training is unknown. To quantify the current practice of inguinal hernia surgery in hospitals affiliated to the University of Cape Town (UCT) and to assess trainee exposure to laparoscopic repair. Adult patients who underwent inguinal hernia repair during the 12-month study period, at the four UCT affiliated hospitals were included. Collected data parameters included age, gender, primary or recurrent, uni- or bilateral hernia, primary surgeon consultant or non-consultant, operative time, and open or laparoscopic technique used. Three hundred and seventy-seven patients were included. Eighty-eight (23.2%) repairs were performed laparoscopically, of which five (5.7%) were converted to open. Non-consultants were present at 70/88 (79.5%) cases performed laparoscopically and were the primary surgeon at only 15 (17%). Laparoscopic repair was performed for 63.6% of bilateral versus 19.5% of unilateral hernias, 39.4% of recurrent hernias and 45% of hernias in females. Two of the four hospitals in this study performed 81.8% of all laparoscopic repairs. Inguinal hernias in our setting are predominantly repaired by open surgery. The likelihood of laparoscopic repair varies significantly depending on which hospital the patient is referred to. Non-consultants have limited exposure to performing laparoscopic hernia repairs as the primary surgeon.


Nonlinear relationship between alpha 1-adrenergic receptor occupancy and norepinephrine-stimulated calcium flux in cultured vascular smooth muscle cells.
To determine the relationship between vascular alpha 1-adrenergic receptor occupancy and receptor-coupled calcium flux, we have studied [3H]prazosin binding and l-norepinephrine-induced 45Ca efflux in cultured vascular smooth muscle cells isolated from the rabbit aorta. In a crude cellular homogenate, [3H]prazosin bound to a single high affinity site (Kd = 0.096 nM; Bmax = 105 +/- 15 fmol/mg of protein), whereas l-norepinephrine (NE) binding was best described by a two-site model with 43 +/- 8% of sites of high affinity (KH = 92 +/- 3 nM) and 57 +/- 7% of sites of low affinity (KL = 7460 +/- 4330 nM). NE-stimulated 45Ca efflux was concentration-dependent (EC50 = 108 nM) and potently inhibited by prazosin (IC50 = 0.15 nM), but not yohimbine (no inhibition at 10 microM). For the total receptor pool identified by [3H]prazosin binding, the relationship between receptor occupancy by NE and NE-stimulated 45Ca efflux was markedly nonlinear, such that 50% of maximum NE-stimulated efflux occurred with occupancy of only approximately 7% of receptors. Likewise, following irreversible inactivation of 69 +/- 5% of receptors by phenoxybenzamine, maximal NE-stimulated 45Ca efflux was decreased by only 8 +/- 2%. These two experimental approaches provide direct evidence for the presence in cultured rabbit aortic smooth muscle cells of a sizable pool of alpha 1-adrenergic receptors in excess of those needed for maximum NE-stimulated 45Ca efflux. This evidence of "spare" receptors, together with the finding of two affinity states of agonist binding, raises the possibility of functional heterogeneity of alpha 1-adrenergic receptors in this system.


Dominance relationships in a family pack of captive arctic wolves (Canis lupus arctos): the influence of competition for food, age and sex.
Dominance is one of the most pervasive concepts in the study of wolf social behaviour but recently its validity has been questioned. For some authors, the bonds between members of wolf families are better described as parent-offspring relationships and the concept of dominance should be used just to evaluate the social dynamics of non-familial captive pack members (e.g., Mech & Cluff, 2010). However, there is a dearth of studies investigating dominance relationships and its correlates in wolf family packs. Here, we applied a combination of the most commonly used quantitative methods to evaluate the dominance relationships in a captive family pack of 19 Arctic wolves. We found a significant linear and completely transitive hierarchy based on the direction of submissive behaviours and found that dominance relationships were not influenced by the competitive contexts (feeding vs. non-feeding context). A significant linear hierarchy also emerges amongst siblings once the breeding pair (the two top-ranking individuals) is removed from analyses. Furthermore, results suggest that wolves may use greeting behaviour as a formal signal of subordination. Whereas older wolves were mostly dominant over younger ones, no clear effect of sex was found. However, frequency of agonistic (submissive, dominant and aggressive) behaviours was higher between female-female and male-male dyads than female-male dyads and sex-separated linear hierarchies showed a stronger linearity than the mixed one. Furthermore, dominance status was conveyed through different behavioural categories during intra-sexual and inter-sexual interactions. Current results highlight the importance of applying a systematic methodology considering the individuals' age and sex when evaluating the hierarchical structure of a social group. Moreover, they confirm the validity of the concept of dominance relationships in describing the social bonds within a family pack of captive wolves.


Overcoming roadblocks in clinical innovation via high fidelity simulation: use of a phantom simulator to achieve FDA and IRB approval of a clinical trial of fetal embolization of vein of Galen malformations.
Vein of Galen malformation (VOGM) is a rare, life-threatening vascular malformation in neonates and is treated with embolization. However, even at the most experienced centers, patients face high mortality and morbidity. In utero treatment options have been limited by lack of animal models or simulations. To create a novel ultrasound phantom simulator for a preclinical feasibility study of in utero fetal intervention for VOGM. Novel phantoms were designed and built in two configurations of spherical and windsock shape from cryogel material to mimic the salient vasculature of the fetal VOGM, based on real-patient fetal MR imaging dimensions. Critical anatomy was realistically mimicked within this model and transtorcular ultrasound-guided coil deployment was simulated. Each phantom model was assessed before and after treatment to evaluate coil mass deposition within the target. The two phantoms underwent pretreatment T2-weighted MR imaging assessment, ultrasound-guided embolization, post-treatment MR and fluoroscopic imaging, and visual inspection of the sliced phantoms for target embolization verification. Postoperative MR scans confirmed realistic compact deposition of the coil masses within the central cavity. Phantom embolization results were submitted as part of the institutional review board and US Food and Drug Administration investigative device exemption approval for a first-in-humans clinical trial of fetal intervention for VOGM. A phantom simulator for fetal intervention of VOGM produces lifelike results during trial interventions, removing obstacles to feasibility and safety evaluations, typically precluded by non-availability of appropriate animal models. The study provides a proof of concept for potentially wider applications of medical simulation to enable novel procedural advancements in neurointerventions.


Fast Characterization of Inducible Regions of Atrial Fibrillation Models With Multi-Fidelity Gaussian Process Classification.
Computational models of atrial fibrillation have successfully been used to predict optimal ablation sites. A critical step to assess the effect of an ablation pattern is to pace the model from different, potentially random, locations to determine whether arrhythmias can be induced in the atria. In this work, we propose to use multi-fidelity Gaussian process classification on Riemannian manifolds to efficiently determine the regions in the atria where arrhythmias are inducible. We build a probabilistic classifier that operates directly on the atrial surface. We take advantage of lower resolution models to explore the atrial surface and combine seamlessly with high-resolution models to identify regions of inducibility. We test our methodology in 9 different cases, with different levels of fibrosis and ablation treatments, totalling 1,800 high resolution and 900 low resolution simulations of atrial fibrillation. When trained with 40 samples, our multi-fidelity classifier that combines low and high resolution models, shows a balanced accuracy that is, on average, 5.7% higher than a nearest neighbor classifier. We hope that this new technique will allow faster and more precise clinical applications of computational models for atrial fibrillation. All data and code accompanying this manuscript will be made publicly available at: https://github.com/fsahli/AtrialMFclass.


Lack of association between hemolysin production and acute inflammation in human urinary tract infection.
Hemolysins are cytolytic proteins which have been extensively characterized at the molecular level, however, their in vivo functions remain unclear. This study analyzed the association of hemolysin production with the inflammatory response in patients with urinary tract infection (UTI). Infants and children with their first episode of UTI (n = 644) were followed prospectively. The body temperature, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinary leucocyte count and renal concentrating capacity were used as measures of the inflammatory response. The hemolytic genotype (hly) of the Escherichia coli strain from each UTI episode was defined by DNA-DNA hybridization, and the phenotype by hemolysis in blood agar. There was no significant increase in the level of fever, CRP, ESR, or decrease in renal concentrating capacity during UTI episodes caused by hly positive compared to hly negative E. coli. Multiple regression analysis did not demonstrate significant associations of hly with elevated fever, CRP, ESR or reduced renal concentrating capacity. In contrast, patients infected with P fimbriated E. coli strains had higher fever, CRP, ESR and lower renal concentrating capacity than those infected with other strains. This association was not influenced by the hly genotype of the P fimbriated strains. The frequency of hly+ strains was not significantly higher in the subset of patients assigned a diagnosis of acute pyelonephritis compared to asymptomatic bacteriuria. This was in contrast to P fimbriae, which were accumulated in acute pyelonephritis. The results suggested that the acute inflammatory response to E. coli UTI is independent of hemolysin production. The inflammatogenic potential of uropathogenic E. coli clones was better described by the presence or absence of P-fimbriae than by hemolysin.


Free TRAM. Results and abdominal wall function.
This article reports on 151 breast reconstructions that have been performed in 139 patients using the free TRAM flap. The critical steps of that procedure are evaluated and the muscle-sparing technique used in harvesting the flap as well as the necessity of an accurate donor site closure are emphasized. The results confirm that the free TRAM flap breast reconstruction provides the patient with a reliable, long-lasting good result with respect to the shape and volume of the new breast mound with a justifiable complication rate.


Telencephalic progenitors maintain anteroposterior identities cell autonomously.
Grafting experiments have demonstrated that determination of anteroposterior (AP) identity is an early step in neural patterning that precedes dorsoventral (DV) specification [1,2]. These studies used pieces of tissue, however, rather than individual cells to address this question. It thus remains unclear whether the maintenance of AP identity is a cell-autonomous property or a result of signaling between cells within the grafted tissue. Previously, we and others [3-5] have used transplants of dissociated brain cells to show that individual telencephalic precursor cells can adopt host-specific DV identities when they integrate within novel regions of the telencephalon. We have now undertaken a set of transplantations during the same mid-neurogenic period used in the previous studies to assess the ability of telencephalic progenitors to integrate and differentiate into more posterior regions of the neuraxis. We observed that telencephalic progenitors were capable of integrating and migrating within different AP levels of the central nervous system (CNS). Despite this, we found that telencephalic progenitors that integrated within the diencephalon and the mesencephalon continued to express a telencephalic marker until adulthood. We speculate that during neurogenesis individual progenitors are determined in terms of their AP but not their DV identity. Hence, AP identity is maintained cell autonomously within individual progenitors.


Decreased binding capacity (Bmax) of muscarinic acetylcholine receptors in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD).
Monoaminergic dysregulation is implicated in attention-deficit/hyperactivity disorder (ADHD), and methylphenidate and amphetamines are the most frequently prescribed pharmacological agents for treating ADHD. However, it has recently been proposed that the core symptoms of the disorder might be due to an imbalance between monoaminergic and cholinergic systems. In this study, we used fibroblast cell homogenates from boys with and without ADHD as an extraneural cell model to examine the cholinergic receptor density, that is, muscarinic acetylcholine receptors (mAChRs). We found that the binding capacity (Bmax) of [³H] Quinuclidinyl benzilate (³H-QNB) to mAChRs was decreased by almost 50 % in the children with ADHD (mean = 30.6 fmol/mg protein, SD = 25.6) in comparison with controls [mean = 63.1 fmol/mg protein, SD = 20.5, p ≤ 0.01 (Student's unpaired t test)]. The decreased Bmax indicates a reduced cholinergic receptor density, which might constitute a biomarker for ADHD. However, these preliminary findings need to be replicated in larger ADHD and comparison cohorts.


The Po river water from the Alps to the Adriatic Sea (Italy): new insights from geochemical and isotopic (δ(18)O-δD) data.
Although the Po river is the most important fluvial system of Northern Italy, the systematic geochemical and isotopic investigations of its water are rare and were never reported for the whole basin. The present contribution aims to fill this knowledge gap, reporting a comprehensive data set including oxygen and hydrogen stable isotopes as well as major and trace element concentration of dissolved species for 54 Po river water samples, mainly collected in different hydrological conditions (peak discharge in April, drought in August) at increasing distance from the source, i.e., from the upper part of the catchment to the terminal (deltaic) part of the river at the confluence with the Adriatic Sea. The isotopic compositions demonstrate that the predominant part of the runoff derives from the Alpine sector of the catchment through important tributaries such as the Dora Baltea, Ticino, Adda, and Tanaro rivers, whereas the contribution from the Apennines tributaries is less important. The geochemical and isotopic compositions show that the Po river water attains a homogeneous composition at ca. 100 km from the source. The average composition is characterized by δ(18)O -9.8‰, δD -66.2‰, total dissolved solid (TDS) 268 mg/L, and chloride 17 mg/L and by a general Ca-HCO3 hydrochemical facies, which is maintained for most of the river stream, only varying in the terminal part where the river is diverted in a complex deltaic system affected by more significant evaporation and mixing with saline water evidenced by higher TDS and chloride content (up to 8198 and 4197 mg/L, respectively). Geochemical and isotopic maps have been drawn to visualize spatial gradients, which reflect the evolution of the river water composition at progressive distance from the source; more detailed maps were focused on the deltaic part in order to visualize the processes occurring in the transitional zone toward the Adriatic Sea. The data also highlight anthropogenic contributions, mainly represented by significant concentrations of nitrate (average 8 mg/L) and possibly arsenic (average 12 μg/L). These data allow the calculation of geochemical fluxes transferred from the river to the sea, and generally, they contribute to the definition of a "hydro-archive" which is useful to highlight ongoing variations in the related ecosystems.


Platelet-rich plasma (PRP) and Platelet-Rich Fibrin (PRF): surgical adjuvants, preparations for in situ regenerative medicine and tools for tissue engineering.
The recent developement of platelet concentrate for surgical use is an evolution of the fibrin glue technologies used since many years. The initial concept of these autologous preparations was to concentrate platelets and their growth factors in a plasma solution, and to activate it into a fibrin gel on a surgical site, in order to improve local healing. These platelet suspensions were often called Platelet-Rich Plasma (PRP) like the platelet concentrate used in transfusion medicine, but many different technologies have in fact been developed; some of them are even no more platelet suspensions, but solid fibrin-based biomaterials called Platelet-Rich Fibrin (PRF). These various technologies were tested in many different clinical fields, particularly oral and maxillofacial surgery, Ear-Nose-Throat surgery, plastic surgery, orthopaedic surgery, sports medicine, gynecologic and cardiovascular surgery and ophthalmology. This field of research unfortunately suffers from the lack of a proper accurate terminology and the associated misunderstandings, and the literature on the topic is quite contradictory. Indeed, the effects of these preparations cannot be limited to their growth factor content: these products associate many actors of healing in synergy, such as leukocytes, fibrin matrix, and circulating progenitor cells, and are in fact as complex as blood itself. If platelet concentrates were first used as surgical adjuvants for the stimulation of healing (as fibrin glues enriched with growth factors), many applications for in situ regenerative medicine and tissue engineering were developed and offer a great potential. However, the future of this field is first dependent on his coherence and scientific clarity. The objectives of this article is to introduce the main definitions, problematics and perspectives that are described in this special issue of Current Pharmaceutical Biotechnology about platelet concentrates.


Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure.
Systemic, femoral, and renal hemodynamics were evaluated in 7 control subjects and 20 cirrhotic patients with ascites, 14 of them without (group A) and 6 with (group B) functional renal failure. Hyperdynamic systemic circulation, increased plasma volume, and hyperreninism were present in groups A and B. These changes were more severe in group B, which showed, as compared with group A, lower total vascular resistances and mean arterial pressure together with increased cardiac index and plasma renin activity. Significant differences in regional hemodynamics were also observed between groups. In group A, femoral and renal fractions of cardiac output were respectively increased and reduced as compared with controls. By contrast, in group B, both fractions of cardiac output were reduced when compared either with controls or with group A. In the entire patient group there was a close direct correlation between femoral and renal fractions of cardiac output (r = 0.88; p less than 0.001) and both of them correlated independently with total vascular resistances (r = 0.79; p less than 0.001 in both cases). These results indicate that, in nonazotemic cirrhotics with ascites, vasodilatation in extrasplanchnic areas contributes to the genesis of the hyperdynamic circulation. The presence in group B of a reduced flow to extrasplanchnic territories, in association with an increase of the hyperdynamic circulatory status, suggests that exacerbation of splanchnic vasodilatation is involved in the development of the hepatorenal syndrome. Finally, in cirrhosis, the changes that occur in systemic hemodynamics appear to influence renal function and renal blood flow.


The Role of Hypoxia, Hypoxia-Inducible Factor (HIF), and VEGF in Retinal Angiomatous Proliferation.
In industrialized countries, age-related macular degeneration (AMD) is the leading cause of blindness in elderly people. Hallmarks of the non-neovascular (dry) form of AMD are the formation of drusen and geographic atrophy, whereas the exudative (wet) form of the disease is characterized by invading blood vessels. In retinal angiomatous proliferation (RAP), a special form of wet AMD, intraretinal vessels grow from the deep plexus into the subretinal space. Little is known about the mechanisms leading to intraretinal neovascularization, but age-related changes such as reduction of choroidal blood flow, accumulation of drusen, and thickening of the Bruch's membrane may lead to reduced oxygen availability in photoreceptors. Such a chronic hypoxic situation may induce several cellular response pathways including the stabilization of hypoxia-inducible factors (HIFs) and the production of angiogenic factors, such as vascular endothelial growth factor (VEGF). Here, we discuss the potential contribution of hypoxia and HIFs in RAP disease pathology and in some mouse models for subretinal neovascularization.


High-resolution mapping of linear antibody epitopes using ultrahigh-density peptide microarrays.
Antibodies empower numerous important scientific, clinical, diagnostic, and industrial applications. Ideally, the epitope(s) targeted by an antibody should be identified and characterized, thereby establishing antibody reactivity, highlighting possible cross-reactivities, and perhaps even warning against unwanted (e.g. autoimmune) reactivities. Antibodies target proteins as either conformational or linear epitopes. The latter are typically probed with peptides, but the cost of peptide screening programs tends to prohibit comprehensive specificity analysis. To perform high-throughput, high-resolution mapping of linear antibody epitopes, we have used ultrahigh-density peptide microarrays generating several hundred thousand different peptides per array. Using exhaustive length and substitution analysis, we have successfully examined the specificity of a panel of polyclonal antibodies raised against linear epitopes of the human proteome and obtained very detailed descriptions of the involved specificities. The epitopes identified ranged from 4 to 12 amino acids in size. In general, the antibodies were of exquisite specificity, frequently disallowing even single conservative substitutions. In several cases, multiple distinct epitopes could be identified for the same target protein, suggesting an efficient approach to the generation of paired antibodies. Two alternative epitope mapping approaches identified similar, although not necessarily identical, epitopes. These results show that ultrahigh-density peptide microarrays can be used for linear epitope mapping. With an upper theoretical limit of 2,000,000 individual peptides per array, these peptide microarrays may even be used for a systematic validation of antibodies at the proteomic level.


Negative pressure therapy is effective to manage a variety of wounds in infants and children.
Negative pressure therapy (NPT) has been accepted as a valuable adjunct for wound closure in adults; however, reports on its effectiveness in young children and infants, including neonates, are limited. A retrospective chart review was conducted on children treated with NPT at a single institution between January 2003 and December 2005. Wound volumetric measurements were calculated at the start and end of therapy. Sixty-eight patients with 82 wounds were identified. The mean age was 8.5 years (range 7 days-18 years). Twenty patients (29%) were 2 years of age or younger, including eight neonates. Wound types included: pressure ulcers (n=13), extremity wounds (n=18), dehisced surgical wounds (n=19), open sternal wounds (n=10), wounds with fistulas (n=3), and complex abdominal wall defects (n=6). Low suction pressures (<100 mmHg) were generally used in children younger than 4 years of age. Following NPT, 93% of wounds decreased in volume. The average wound volume decrease was 80% (p<0.01, n=56). NPT can be effectively used to manage a variety of wounds in children and neonates. No major complications were identified in our retrospective review. Prospective studies are required to better refine the use of this technology in children.


The evolution of intelligence in mammalian carnivores.
Although intelligence should theoretically evolve to help animals solve specific types of problems posed by the environment, it is unclear which environmental challenges favour enhanced cognition, or how general intelligence evolves along with domain-specific cognitive abilities. The social intelligence hypothesis posits that big brains and great intelligence have evolved to cope with the labile behaviour of group mates. We have exploited the remarkable convergence in social complexity between cercopithecine primates and spotted hyaenas to test predictions of the social intelligence hypothesis in regard to both cognition and brain size. Behavioural data indicate that there has been considerable convergence between primates and hyaenas with respect to their social cognitive abilities. Moreover, compared with other hyaena species, spotted hyaenas have larger brains and expanded frontal cortex, as predicted by the social intelligence hypothesis. However, broader comparative study suggests that domain-general intelligence in carnivores probably did not evolve in response to selection pressures imposed specifically in the social domain. The cognitive buffer hypothesis, which suggests that general intelligence evolves to help animals cope with novel or changing environments, appears to offer a more robust explanation for general intelligence in carnivores than any hypothesis invoking selection pressures imposed strictly by sociality or foraging demands.


Replication of Clone 13, a naturally attenuated avirulent isolate of Rift Valley fever virus, in Aedes and Culex mosquitoes.
Rift Valley fever virus continues to cause large outbreaks of acute and febrile illness among humans and domestic animals in Africa. The high pathogenicity of the virus is mainly due to the non-structural protein derived from the S segment NSs, which was shown to inhibit the type I interferon expression at the transcriptional level and to suppress host cell RNA synthesis. Clone 13, a naturally attenuated clone containing a deletion of 70% in NSs, is a promising vaccine candidate as it has no pathogenicity for mice and is highly immunogenic leading to long-lasting immunity. If Clone 13 succeeds in inducing a transient viremia in inoculated animals, is a mosquito vector able to replicate Clone 13 and is the vector affected by viral infection? In this work, we orally infected two mosquito species, Aedes vexans and Culex pipiens quinquefasciatus, with the avirulent Clone 13. We showed that the mosquito Ae. vexans better replicated the avirulent Clone 13 than Cx. p. quinquefasciatus. Moreover, infection with Clone 13 did not cause any important changes in mosquito's life-history traits compared to noninfected females. Nevertheless, it is likely that Clone 13 would not be efficiently transmitted by mosquito vectors.


White matter changes in patients with friedreich ataxia after treatment with erythropoietin.
Erythropoietin (EPO) has received growing attention because of its neuroregenerative properties. Preclinical and clinical evidence supports its therapeutic potential in brain conditions like stroke, multiple sclerosis, and schizophrenia. Also, in Friedreich ataxia, clinical improvement after EPO therapy was shown. The aim of this study was to assess possible therapy-associated brain white matter changes in these patients. Nine patients with Friedreich ataxia underwent Diffusion Tensor Imaging (DTI) before and after EPO treatment. Tract-based spatial statistics was used for longitudinal comparison. We detected widespread longitudinal increase in fractional anisotropy and axial diffusivity (D||) in cerebral hemispheres bilaterally (P < .05, corrected), while no changes were observed within the cerebellum, medulla oblongata, and pons. To the best of our knowledge, this is the first DTI study to investigate the effects of EPO in a neurodegenerative disease. Anatomically, the diffusivity changes appear disease unspecific, and their biological underpinnings deserve further study.


Fermi interaction between the nu1 and the nu2+4 nu(s) bands of Ar...DN2(+).
Two rotationally fully resolved vibrational bands have been assigned unambiguously to the linear deuteron bound Ar...DN(2) (+) complex by using ground state combination differences. The ionic complex is formed in a supersonic planar plasma expansion optimized and controlled by a mass spectrometer and is detected in direct absorption using tunable diode lasers and applying production modulation spectroscopy. The band origins are located at 2436.272 cm(-1) and at 2435.932 cm(-1) and correspond to the nu(1) band (NN stretch) and to the nu(2)+4 nu(s) combination band (DN and intermolecular stretch), respectively. The two bands overlap strongly and the large intensity of the combination band is explained in terms of a Fermi interaction. This interaction perturbs the observed transitions, particularly for low J values. Least-squares fitting yields values for the Fermi interaction parameters of F(0)=0.332 cm(-1) and F(J)=-0.001 46 cm(-1) and results in accurate rotational constants. These are discussed both from an experimental and a theoretical point of view.


Shared decision-making in nursing education.
Shared decision-making is an effective management strategy that may have positive implications for nurse educators facing curricular and course delivery issues. Use of shared or participative decision-making recognizes that decisions made for the overall good of the organization should include those integrally involved, i.e., faculty, students and administration. Ultimately, effective student learning should be the outcome of decisions related to curricular and content delivery. In this anecdotal paper, the authors present shared decision-making (SDM) as a management strategy that may be effectively utilized in a range of situations in educational settings. An exemplar is presented regarding changes in course delivery methods at two sister schools of nursing. Strategies to promote successful implementation, as well as challenges in initiating SDM, are discussed. The information presented in this paper can benefit nurse educators by offering a collaborative approach to the issues of evolving nursing curricula and content delivery.


Cystoid macular edema: the apparent role of mechanical factors.
CME is the final common pathway of many intraocular and systemic diseases. It involves the retinal vasculature and often has a choroidal and vitreal component. Obviously, at some level of this complex pathophysiological process, mediators must be involved. The question is whether the characteristic distribution of vascular leakage and retinal edema is best explained by the diffusion of mediators released by from a remote site, as proposed by Miyake (see Miyake et al., 1989), or whether it reflects the distribution of pre-existing anatomical structures causing the local release of mediators by exerting mechanical stress. The fact that vitreous adhesions are present at the lens and vitreous base anteriorly and at the major vessels, optic disc, and macula posteriorly support the mechanical concept. The anatomic sites of vitreo-retinal attachments have in common the thinness of their basal lamina and firmness of their fibrous vitreal attachments to the Muller cells. Although adhesion at two opposite sites is the precondition for the development of traction, it will only be generated through intrinsic or extrinsic pathologic changes in the vitreous. In a normal anatomical situation, many vitreous fibers distribute tractional forces evenly to numerous Muller cell attachments. In partial PVDs, fewer fibers and Muller cells endure most of the traction. This may lead to chronic Muller cell irritation and local release of a variety of mediators which, in turn, may facilitate vascular leakage. Vitreous shrinkage and possibly chronic Muller cell irritation may, therefore, facilitate abnormal leakage at all sites of attachment. A typical example is pars planitis, with leakage at the peripheral retina and around major blood vessels, the disc and macula. This pattern of leakage suggests that vitreous traction may be a co-factor in many cases. Most traction develops slowly, passing through stages of partial PVD. The occurrence of a traumatic macular hole and vitreous base avulsion as a result of trauma is the exception. While the pattern of PVD in vivo has not been investigated in detail, PVD with normal adhesions is frequently found in age-related liquefaction and collapse of the vitreous. PVD with abnormal adhesions and shrinkage is found in association with diabetes, proliferative vitreoretinopathy, and inflammation. As to the macula itself, two types of attachment are suggested, a firm central foveolar attachment and a larger, weaker perifoveal attachment, corresponding to the nuclear and cortical vitreous and to two types of pathologic traction; anteroposterior and tangential.(ABSTRACT TRUNCATED AT 400 WORDS)


Immunologic inhibition of ultraviolet radiation-induced tumor suppressor cell activity.
Long-term exposure of C3H mice to ultraviolet radiation resulted in the formation of suppressor T cells that recognize ultraviolet radiation-induced regressor skin cancers as a class before the appearance of overt tumors. Administration of monoclonal antibodies to the product of the I-Jk subregion of the major histocompatibility complex or low doses of cyclophosphamide in vivo inhibited the development or activity of these cells. This activity of the monoclonal antibody was eliminated by adsorption on B10.BR (I-Jk) but not B10.D2 (I-Jd) splenocytes. These findings provide evidence that elements expressing the I-J determinant are important in regulating the host response prior to the overt development of ultraviolet radiation-induced skin cancers and suggest novel therapeutic approaches to malignancies or other diseases involving suppressor T cells in their pathogenesis.


[Chronic recurrent multifocal osteomyelitis in children].
We have studied retrospectively a series of 10 children presenting with chronic multifocal osteomyelitis (8 girls, 2 boys, 7 to 16 years). All patients had plain films, bone scintigraphies and histological studies. Three had CT scan and/or MRI. compared with literature data, we observed only one case of palmoplantar pustulosis and only 2 cases of lysis of the medial extremity of the clavicle; in addition, we report one case of lateral extremity of the clavicle and 2 vertebral locations. The radiological pattern was typical: at the beginning of the disease, plain films showed lytic areas which became progressively osteosclerotic with enlargement of the bone. In all the cases, bone scintigraphy revealed high uptake areas which were often infraclinical. The diagnosis was delayed from 3 months to 3 years. This emphasizes the difficulty of the diagnosis which relies on the association of clinical, biological and radiological elements. Biopsies are required to rule out an infectious bacterial osteomyelitis or a tumoral process. The pathogenesis of OCMR remains unknown, but the relation with the SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is general accepted because of the similar features of the osteitis. The long term follow up appears to be uncertain 6 of our patients are still symptomatic after five years despite anti inflammatory treatment.


Approach to a large rare diaphragmatic hernia in a patient undergoing cardiac surgery.
Hernia of Morgagni is an unusual congenital defect of the sternal portion of the diaphragm. Its concurrence with cardiac surgical pathology is rarely described in the literature. Notwithstanding, huge hernia of Morgagni have been noted to cause serious peri-operative impediment and complications. We report the case of a 50-year-old gentleman with a massive Morgagni hernia that threatened strangulation during cardiopulmonary bypass. We describe the combined surgical approach undertaken to repair this hernia, with an accompanying review of the literature relating to misadventure and management of similar large hernia coinciding with cardiac surgery.


Generation of Novel Traj18-Deficient Mice Lacking Vα14 Natural Killer T Cells with an Undisturbed T Cell Receptor α-Chain Repertoire.
Invariant Vα14 natural killer T (NKT) cells, characterized by the expression of a single invariant T cell receptor (TCR) α chain encoded by rearranged Trav11 (Vα14)-Traj18 (Jα18) gene segments in mice, and TRAV10 (Vα24)-TRAJ18 (Jα18) in humans, mediate adjuvant effects to activate various effector cell types in both innate and adaptive immune systems that facilitates the potent antitumor effects. It was recently reported that the Jα18-deficient mouse described by our group in 1997 harbors perturbed TCRα repertoire, which raised concerns regarding the validity of some of the experimental conclusions that have been made using this mouse line. To resolve this concern, we generated a novel Traj18-deficient mouse line by specifically targeting the Traj18 gene segment using Cre-Lox approach. Here we showed the newly generated Traj18-deficient mouse has, apart from the absence of Traj18, an undisturbed TCRα chain repertoire by using next generation sequencing and by detecting normal generation of Vα19Jα33 expressing mucosal associated invariant T cells, whose development was abrogated in the originally described Jα18-KO mice. We also demonstrated here the definitive requirement for NKT cells in the protection against tumors and their potent adjuvant effects on antigen-specific CD8 T cells.


Emerging nondestructive approaches for meat quality and safety evaluation-A review.
Meat is one of the most consumed agro-products because it contains proteins, minerals, and essential vitamins, all of which play critical roles in the human diet and health. Meat is a perishable food product because of its high moisture content, and as such there are concerns about its quality, stability, and safety. There are two widely used methods for monitoring meat quality attributes: subjective sensory evaluation and chemical/instrumentation tests. However, these methods are labor-intensive, time-consuming, and destructive. To overcome the shortfalls of these conventional approaches, several researchers have developed fast and nondestructive techniques. Recently, electronic nose (e-nose), computer vision (CV), spectroscopy, hyperspectral imaging (HSI), and multispectral imaging (MSI) technologies have been explored as nondestructive methods in meat quality and safety evaluation. However, most of the studies on the application of these novel technologies are still in the preliminary stages and are carried out in isolation, often without comprehensive information on the most suitable approach. This lack of cohesive information on the strength and shortcomings of each technique could impact their application and commercialization for the detection of important meat attributes such as pH, marbling, or microbial spoilage. Here, we provide a comprehensive review of recent nondestructive technologies (e-nose, CV, spectroscopy, HSI, and MSI), as well as their applications and limitations in the detection and evaluation of meat quality and safety issues, such as contamination, adulteration, and quality classification. A discussion is also included on the challenges and future outlooks of the respective technologies and their various applications.


Effects of thiamine deficiency on brain metabolism: implications for the pathogenesis of the Wernicke-Korsakoff syndrome.
Chronic alcoholism results in thiamine deficiency as a consequence of inadequate dietary intake and of impaired absorption of the vitamin. In addition, there is evidence to suggest that alcohol reduces thiamine phosphorylation to thiamine pyrophosphate (TPP) in brain. TPP is a cofactor for the pyruvate dehydrogenase complex (PDHC), alpha-ketoglutarate dehydrogenase (alpha KGDH) and transketolase (TK), three enzymes involved in cerebral glucose and energy metabolism. Pyrithiamine-induced thiamine deficiency in the rat results in early, selective, reversible reductions of alpha KGDH in brain; PDHC activities are unaffected. Reductions of alpha KGDH are accompanied by decreased aspartate, glutamate and GABA and by concomitantly increased alanine in the brain of thiamine-deficient animals. It is suggested that decreased alpha KGDH, rather than decreased PDHC constitutes 'the biochemical lesion' in thiamine deficiency encephalopathy first enunciated by Peters in the 1930s. If sufficiently prolonged and severe, thiamine deficiency results in brain cell death. Possible mechanisms involved include compromised cerebral energy metabolism and focal accumulation of lactate, both of which could result from decreased activities of alpha KGDH. In addition, it is proposed that brain cell death in severe thiamine deficiency may result from excessive release of excitotoxic amino acids. Comparable mechanisms could be involved in the cell death and in the pathogenesis of the thiamine-unresponsive symptoms of the Wernicke-Korsakoff Syndrome in humans.


Salinization as a driver of eutrophication symptoms in an urban lake (Lake Wilcox, Ontario, Canada).
Lake Wilcox (LW), a shallow kettle lake located in southern Ontario, has experienced multiple phases of land use change associated with human settlement and residential development in its watershed since the early 1900s. Urban growth has coincided with water quality deterioration, including the occurrence of algal blooms and depletion of dissolved oxygen (DO) in the water column. We analyzed 22 years of water chemistry, land use, and climate data (1996-2018) using principal component analysis (PCA) and multiple linear regression (MLR) to identify the contributions of climate, urbanization, and nutrient loading to the changes in water chemistry. Variations in water column stratification, phosphorus (P) speciation, and chl-a (as a proxy for algal abundance) explain 76 % of the observed temporal trends of the four main PCA components derived from water chemistry data. MLR results further imply that the intensity of stratification, quantified by the Brunt-Väisälä frequency, is a major predictor of the changes in water quality. Other important factors explaining the variations in nitrogen (N) and P speciation, and the DO concentrations, are watershed imperviousness and lake chloride concentrations that, in turn, are closely correlated. We conclude that the observed in-lake water quality trends over the past two decades are linked to urbanization via increased salinization associated with expanding impervious land cover, rather than increasing external P loading. The rising salinity promotes water column stratification, which reduces the oxygenation of the hypolimnion and enhances internal P loading to the water column. Thus, stricter controls on the application and runoff of de-icing salt should be considered as part of managing eutrophication symptoms in lakes of cold climate regions.