Global and local morphometric differences in recently abstinent methamphetamine-dependent individuals.
Methamphetamine (MA) is associated with behavioral and cognitive deficits that may be related to macrostructural abnormalities. Quantitative anatomical comparisons between controls and methamphetamine-dependent individuals have produced conflicting results. We examined local and global differences in brain structure in 61 abstinent methamphetamine-dependent individuals and 44 controls with voxel-based morphometry and tissue segmentation. We related regional differences in gray matter density and whole brain segmentation volumes to performance on a behavioral measure of impulsivity and group membership using multiple linear regression. Within the MA group, we related cortical and subcortical gray matter density to length of abstinence. Controls had greater density relative to MA in bilateral insula and left middle frontal gyrus. Impulsivity was higher in the MA group and, within all subjects, impulsivity was positively correlated with gray matter density in posterior cingulate cortex and ventral striatum and negatively correlated in left superior frontal gyrus. Length of abstinence from MA was associated with greater amygdalar density. Earlier age of first use of MA (in subjects who initiated use before age 21) was associated with smaller intracranial volume. The findings are consistent with multiple possible mechanisms including neuroadaptations due to addictive behavior, neuroinflammation as well as dopaminergic and serotonergic neurotoxicity.


[A bifid ureter with a blind branch].
To report on a case of bifid ureter with a blind-ending branch. A case of bifid right ureter with a blind-ending branch and complete duplication of the contralateral ureter in a 38-year-old female patient is described. The patient had consulted for pain referred to the right iliac fossa and recurrent urinary infection. An excretory urogram disclosed the ureteric anomaly, which was confirmed by retrograde pyelography. Uretero-ureteric reflux to the blind-ending branch was found during surgery and excision of the blind-ending branch was performed. This ureteric anomaly is basically diagnosed radiologically. Treatment is initially conservative, although complications or severe symptoms may warrant surgical excision of the blind-ending ureter.


Quantum Zeno Suppression of Intramolecular Forces.
We show that Born-Oppenheimer surfaces can intrinsically decohere, implying loss of coherence among constituent electronic basis states. We consider the example of interatomic forces due to resonant dipole-dipole interactions within a dimer of highly excited Rydberg atoms, embedded in an ultracold gas. These forces rely on a coherent superposition of two-atom electronic states, which is destroyed by continuous monitoring of the dimer state through a detection scheme utilizing the background gas atoms. We show that this intrinsic decoherence of the molecular energy surface can gradually deteriorate a repulsive dimer state, causing a mixing of attractive and repulsive character. For sufficiently strong decoherence, a Zeno-like effect causes a complete cessation of interatomic forces. We finally show how short decohering pulses can controllably redistribute population between the different molecular energy surfaces.


Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model.
To provide rapid immunosuppression without side effects, we analyzed whether rapamycin alone, and regulatory T cells (Tregs) expanded ex vivo by rapamycin, suppressed colitis in a mouse model. Severe combined immunodeficiency (SCID) mice reconstituted with naive CD4(+) T cells were treated with or without intraperitoneal rapamycin. Body weight was evaluated. CD4(+) T cells were cultured in the presence of rapamycin for three 7-day rounds of stimulation. The ratio of Tregs to CD4(+) T cells was analyzed by flow cytometry. Naive CD4(+) T cells were transferred into SCID mice with CD4(+) T cells expanded in the presence or absence of rapamycin. Clinical symptoms of colitis, histological changes, and cytokine expression were investigated. Systemic rapamycin partially prevented the development of colonic inflammation in a transfer model of colitis, but decreased body weight in control mice. With rapamycin, stimulated CD4(+) T cells expanded eightfold in 3 weeks in vitro, and the proportion of Tregs increased to about 40%. Without rapamycin, CD4(+) T cells expanded 20-fold in 3 weeks, but the proportion of Tregs remained at about 15%. CD4(+) T cells expanded with rapamycin prevented the development of colitis in a naïve CD4(+) T-cell transfer model, in association with the downregulation of Th1 and Th17 responses. We demonstrated, for the first time, that CD4(+) T cells expanded with rapamycin in vitro suppressed colitis. Therefore, rapamycin-expanded Treg transfer therapy is expected to be efficacious for inflammatory bowel disease.


Multi-arm carriers composed of an antioxidant lignin core and poly(glycidyl methacrylate-co-poly(ethylene glycol)methacrylate) derivative arms for highly efficient gene delivery.
A lignin-based copolymer with good biocompability was successfully prepared via atom transfer radical polymerization (ATRP) for efficient gene delivery. Kraft lignin was modified into lignin-based macroinitiators and then poly(glycidyl methacrylate)-co-poly(ethylene glycol)methacrylate (PGMA-PEGMA) side chains were prepared via ATRP grafting onto lignin. Ethanolamine was sequentially functionalized onto lignin-PGMA-PEGMA and a cationic lignin-PGEA-PEGMA copolymer consisting of a lignin core and different-length PGEA-PEGMA side chains was produced. Lignin-PGEA-PEGMA copolymers could efficiently compact pDNA into nanoparticles with sizes ranging from 150 to 250 nm at N/P ratios of 10 or higher. The gene transfection efficiency depends greatly on the mass percentage of PGEA units and the N/P ratio. The lignin-PGEA-PEGMA with 46.9% (mass%) of PGEA units (i.e. LG100) has highest transfection efficiency in comparison with the copolymers with a lower amount of PGEA units. In addition, LG100 has high transfection efficiency under serum conditions, which is comparable to or much higher than PEI control in HEK 293T and Hep G2 cell lines. More importantly, lignin-PGEA-PEGMA copolymers have excellent antioxidant activity. The novel cationic lignin-PGEA-PEGMA copolymers can be promising gene carriers for gene delivery.


Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8+ T cells.
Efficient T cell proliferation requires costimulation via CD28/B7 or other pathways. Graft-vs-host disease (GVHD) is caused by activated donor T cells. We have found that the infusion of anti-B7.1 (CD80) + anti-B7.2 (CD86) mAb is effective in eliminating GVHD lethality induced by either CD8+ or CD4+ T cells. Donor CD4+ and CD8+ T cell expansion was inhibited by almost 100-fold as measured by enumerating thoracic duct lymphocytes (TDL) obtained early post-transplant. TDL retained anti-host responsiveness indicating that not all T cells were anergic. Although anti-CD80 or anti-CD86 mAb individually were ineffective in preventing CD8+ T cell GVHD lethality, each mAb was partially effective in CD4+ T cell-mediated GVHD. Because CD80 expression was found to be up-regulated on donor CD4+ TDL post-transplant, the GVHD capacity of donor CD4+ T cells deficient in CD80 was tested and found to be reduced similarly to that seen with anti-CD80 mAb. These studies demonstrate that anti-CD80 + anti-CD86 mAb infusion is effective in preventing GVHD lethality by inhibiting donor CD4+ or CD8+ T cell expansion and provide the first evidence that CD80 expression on donor T cells is critical for optimal GVHD lethality.


Evolution of TNF-induced apoptosis reveals 550 My of functional conservation.
The Precambrian explosion led to the rapid appearance of most major animal phyla alive today. It has been argued that the complexity of life has steadily increased since that event. Here we challenge this hypothesis through the characterization of apoptosis in reef-building corals, representatives of some of the earliest animals. Bioinformatic analysis reveals that all of the major components of the death receptor pathway are present in coral with high-predicted structural conservation with Homo sapiens. The TNF receptor-ligand superfamilies (TNFRSF/TNFSF) are central mediators of the death receptor pathway, and the predicted proteome of Acropora digitifera contains more putative coral TNFRSF members than any organism described thus far, including humans. This high abundance of TNFRSF members, as well as the predicted structural conservation of other death receptor signaling proteins, led us to wonder what would happen if corals were exposed to a member of the human TNFSF (HuTNFα). HuTNFα was found to bind directly to coral cells, increase caspase activity, cause apoptotic blebbing and cell death, and finally induce coral bleaching. Next, immortalized human T cells (Jurkats) expressing a functional death receptor pathway (WT) and a corresponding Fas-associated death domain protein (FADD) KO cell line were exposed to a coral TNFSF member (AdTNF1) identified and purified here. AdTNF1 treatment resulted in significantly higher cell death (P < 0.0001) in WT Jurkats compared with the corresponding FADD KO, demonstrating that coral AdTNF1 activates the H. sapiens death receptor pathway. Taken together, these data show remarkable conservation of the TNF-induced apoptotic response representing 550 My of functional conservation.


Photon-counting cine-cardiac CT in the mouse.
The maturation of photon-counting detector (PCD) technology promises to enhance routine CT imaging applications with high-fidelity spectral information. In this paper, we demonstrate the power of this synergy and our complementary reconstruction techniques, performing 4D, cardiac PCD-CT data acquisition and reconstruction in a mouse model of atherosclerosis, including calcified plaque. Specifically, in vivo cardiac micro-CT scans were performed in four ApoE knockout mice, following their development of calcified plaques. The scans were performed with a prototype PCD (DECTRIS, Ltd.) with 4 energy thresholds. Projections were sampled every 10 ms with a 10 ms exposure, allowing the reconstruction of 10 cardiac phases at each of 4 energies (40 total 3D volumes per mouse scan). Reconstruction was performed iteratively using the split Bregman method with constraints on spectral rank and spatio-temporal gradient sparsity. The reconstructed images represent the first in vivo, 4D PCD-CT data in a mouse model of atherosclerosis. Robust regularization during iterative reconstruction yields high-fidelity results: an 8-fold reduction in noise standard deviation for the highest energy threshold (relative to unregularized algebraic reconstruction), while absolute spectral bias measurements remain below 13 Hounsfield units across all energy thresholds and scans. Qualitatively, image domain material decomposition results show clear separation of iodinated contrast and soft tissue from calcified plaque in the in vivo data. Quantitatively, spatial, spectral, and temporal fidelity are verified through a water phantom scan and a realistic MOBY phantom simulation experiment: spatial resolution is robustly preserved by iterative reconstruction (10% MTF: 2.8-3.0 lp/mm), left-ventricle, cardiac functional metrics can be measured from iodine map segmentations with ~1% error, and small calcifications (615 μm) can be detected during slow moving phases of the cardiac cycle. Given these preliminary results, we believe that PCD technology will enhance dynamic CT imaging applications with high-fidelity spectral and material information.


Host-microbial co-metabolites modulated by human milk oligosaccharides relate to reduced risk of respiratory tract infections.
Human milk oligosaccharides (HMOs) are structurally diverse oligosaccharides present in breast milk, supporting the development of the gut microbiota and immune system. Previously, 2-HMO (2'fucosyllactose, lacto-N-neotetraose) compared to control formula feeding was associated with reduced risk of lower respiratory tract infections (LRTIs), in part linked to lower acetate and higher bifidobacteria proportions. Here, our objective was to gain further insight into additional molecular pathways linking the 2-HMO formula feeding and LRTI mitigation. From the same trial, we measured the microbiota composition and 743 known biochemical species in infant stool at 3 months of age using shotgun metagenomic sequencing and untargeted mass spectrometry metabolomics. We used multivariate analysis to identify biochemicals associated to 2-HMO formula feeding and LRTI and integrated those findings with the microbiota compositional data. Three molecular pathways stood out: increased gamma-glutamylation and N-acetylation of amino acids and decreased inflammatory signaling lipids. Integration of stool metagenomic data revealed some Bifidobacterium and Bacteroides species to be implicated. These findings deepen our understanding of the infant gut/microbiome co-metabolism in early life and provide evidence for how such metabolic changes may influence immune competence at distant mucosal sites such as the airways.


Global phylogenetics of Diuraphis noxia (Hemiptera: Aphididae), an invasive aphid species: evidence for multiple invasions into North America.
The Russian wheat aphid, Diruaphis noxia (Kudjumov) (Hemiptera: Aphididae), is globally one of the most devastating pests of bread wheat, Tritium aestivum L., durum wheat, Triticum turgidum L., and barley, Hordeum vulgare L. Several sources of D. noxia resistance have been incorporated in commercial wheat and barley genotypes, but up to eight virulent biotypes, defined based on their ability to damage different wheat and barley genotypes, now occur across the western United States since the first appearance of D. noxia in North America in 1986. Critical to the study of D. noxia and other invasive species is an understanding of the number and origin of invasions that have occurred, as well as the rate or potential of postinvasion adaptation and geographic range expansion. The goal of this study was to determine whether D. noxia biotypes are by-products of a single invasion or multiple invasions into North America. We used the genome-wide technique of amplified fragment length polymorphisms, in combination with 22 collections of D. noxia from around the world, to assess this question, as well as patterns of genetic divergence. We found multiple lines of evidence that there have been at least two D. noxia invasions of different origin into North America, each resulting in subsequent postinvasion diversification that has since yielded multiple biotypes.


Self-harm and suicidal behaviour among incarcerated adults in the Australian Capital Territory.
Suicide is the leading cause of death in prisons worldwide. Improved understanding of the factors associated with suicide is necessary to inform targeted suicide prevention and interventions. Here we aim to (a) document the prevalence of suicide attempts, suicidal ideation, self-harm, and mental disorder; and (b) identify demographic, mental health, and criminal justice correlates of suicidal ideation, in a sample of incarcerated adults in Australia. Data were obtained from the 2016 Detainee Health and Wellbeing Survey conducted in the Alexander Maconochie Centre, the Australian Capital Territory's only adult prison. Interviews with 98 incarcerated adults were conducted in October 2016. Descriptive statistics were calculated for all measures. Crude differences between participants who reported experiencing suicidal ideation in their lifetime and those who did not were compared using Fisher's exact test. Nearly half of the participants (48%, n = 47) reported lifetime suicidal ideation and 31% (n = 30) reported attempting suicide at some point in their lives. Eighteen participants (18%) reported a lifetime history of having engaged in self-harm. Factors significantly associated with suicidal ideation included lifetime history of mental disorder, self-harm, experiencing a drug overdose, and being hospitalized in the past 12 months. The burden of suicidal ideation and prior suicide attempts among people in prison is substantial. Incarceration is a pivotal opportunity to identify people with a history of mental health problems and target interventions aimed at reducing adverse outcomes including suicide mortality.


The effects of absenteeism on nurses remaining on duty at a tertiary hospital of Limpopo province.
Absenteeism is a global problem in the working force and this is no exception in the nursing profession. Much attention has been drawn to factors that contribute to absenteeism; however, little attention has been placed on the effects of absenteeism on nurses remaining on duty by their colleagues. Nurses absent themselves leaving behind their colleagues to execute their part of work. To investigate the effects of absenteeism on nurses who remained on duty at a tertiary hospital in Limpopo province. A quantitative descriptive research approach was chosen to enable the researchers to achieve the research aim. Data collected using structured questionnaires were analysed by descriptive statistics. The findings indicated that absenteeism has an effect on both the nurses' psychological and professional well-being, as well as the quality of patient care provided as a result of psychological stress, low morale of nurses and increased workload. The study further revealed the provision of substandard care to patients by those nurses who are remaining on duty, resulting in risk of medical errors that could jeopardise their professional credibility. Therefore, absenteeism creates an unhealthy working environment for nurses remaining on duty. Nurse managers should provide platforms to address psychological and professional problems experienced by nurses remaining on duty. The study further recommends the introduction of policies that would address absenteeism in the workplace and how nurses who remain on duty could be assisted with the workload of colleagues who continuously absent themselves.


Community Partners Join Forces: Battling Obesity and Diabetes Together.
Our objectives was to create an initiative to change the culture of a small community to improve quality of life as it relates to health for the residents through the use of health-related educational sessions, a coordinated fitness and nutrition program, and the construction of community fitness trails. We compared the use of a health-focused community driven program to the status quo in seeking opportunities to improve perception and understanding of one's health and overall quality of life for participants. Among the various techniques identified to improve a community's health outcomes, dissemination of information through the use of educational sessions empowered citizens to take control of their health status, and ultimately, their quality of life. This came with zero negative impacts for those providing the education, as well as those participating in the sessions. Although the application of these methods depends on local resources, leadership, and partnerships, programs similar to those presented here can help to improve quality of life for citizens in communities across the country facing the challenges secondary to a sedentary lifestyle.


DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome.
Embryonal rhabdomyosarcoma (ERMS) is the most common childhood sarcoma and is a component of the familial pleuropulmonary blastoma (PPB)-predisposition syndrome. Using the PPB model, we hypothesized that DICER1 mutations would be found in familial and sporadic forms of ERMS. Blood samples from four children with familial PPB and ERMS, and 52 sporadic ERMS tumors were tested for DICER1 mutations. Germline DICER1 mutations were found in all four patients with familial PPB and 2 of 52 (3.8%) sporadic ERMS had somatic mutations. Our findings confirm the pathogenetic relationship between ERMS and PPB suggesting that ERMS may result from abnormal miRNA regulation.


The importance of understanding and measuring health system structural, functional, and clinical integration.
We explore if there are ways to characterize health systems-not already revealed by secondary data-that could provide new insights into differences in health system performance. We sought to collect rich qualitative data to reveal whether and to what extent health systems vary in important ways across dimensions of structural, functional, and clinical integration. Interviews with 162 c-suite executives of 24 health systems in four states conducted through "virtual" site visits between 2017 and 2019. Exploratory study using thematic comparative analysis to describe factors that may lead to high performance. We used maximum variation sampling to achieve diversity in size and performance. We conducted, transcribed, coded, and analyzed in-depth, semi-structured interviews with system executives, covering such topics as market context, health system origin, organizational structure, governance features, and relationship of health system to affiliated hospitals and POs. Health systems vary widely in size and ownership type, complexity of organization and governance arrangements, and ability to take on risk. Structural, functional, and clinical integration vary across systems, with considerable activity around centralizing business functions, aligning financial incentives with physicians, establishing enterprise-wide EHR, and moving toward single signatory contracting. Executives describe clinical integration as more difficult to achieve, but essential. Studies that treat "health system" as a binary variable may be inappropriately aggregating for analysis health systems of very different types, at different degrees of maturity, and at different stages of structural, functional, and clinical integration. As a result, a "signal" indicating performance may be distorted by the "noise." Developing ways to account for the complex structures of today's health systems can enhance future efforts to study systems as complex organizations, to assess their performance, and to better understand the effects of payment innovation, care redesign, and other reforms.


The influence of social factors on the control of asthma.
The relationships of pulmonary function with age, duration of asthma and social factors were studied in 630 asthmatics. Pulmonary function was assessed by peak flow rate at routine attendance (actual function). Persistence of obstruction was demonstrated by a trial of corticosteroids where necessary. The best obtainable peak flow rate was recorded (maximum function). Unrelieved potentially reversible obstruction was assessed by actual/maximum function. Age and duration of asthma were directly associated with poor control of reversible wheeze as well as with persistent obstruction. In addition poor control of potentially reversible wheezè was related to lower social class, current cigarette smoking and lack of central heating. Persistent obstruction was related to life time amount smoked, passive smoking and lack of central heating.


Tip-jump response of an amplitude-modulated Atomic Force Microscope.
The dynamic behaviors of an Atomic Force Microscope are of interest, and variously unpredictable phenomena are experimentally measured. In practical measurements, researchers have proposed many methods for avoiding these uncertainties. However, causes of these phenomena are still hard to demonstrate in simulation. To demonstrate these phenomena, this paper claims the tip-jump motion is a predictable process, and the jumping kinetic energy results in different nonlinear phenomena. It emphasizes the variation in the eigenvalues of an AFM with tip-sample distance. This requirement ensures the phase transformations from one associated with the oscillation mode to one associated with the tip-jump/sample-contact mode. Also, multi-modal analysis was utilized to ensure the modal transformation in varying tip-sample distances. In the presented model, oscillations with various tip-sample distances and with various excitation frequencies and amplitudes were compared. The results reveal that the tip-jump motion separates the oscillation orbit into two regions, and the jumping kinetic energy, comparing with the superficial potential energy, leads the oscillation to be bistable or intermittent. The sample-contact condition associates to bifurcation and chaos. Additionally, the jumping is a strong motion that occurs before the tip-sample contacts, and this motion signal can replace the sample-contact-signal to avoid destroying the sample.


Vigilant and hypervigilant decision making.
Recent studies have argued that deficient decision making under stress is due to adoption of a hypervigilant style of decision making, which has been characterized as disorganized and inefficient. However, under the conditions that characterize many real-world or naturalistic tasks, a hypervigilant pattern of decision making may be adaptive, because the decision maker does not have the luxury of implementing a more elaborate analytic procedure. This study examined the effectiveness of vigilant and hypervigilant decision-making strategies on a naturalistic task. Results indicated that participants who used a hypervigilant decision-making strategy performed better than those who used a vigilant strategy. Implications for decision making in naturalistic environments are discussed.


Critical elements for local Indigenous water security in Canada: a narrative review.
Indigenous communities in Canada are over-represented with respect to poor water quality and water advisories. To date, approaches to solve this water crisis have been founded in the Western Science (WS) context with little to no consultation or dialogue with those communities most impacted, and without regard for culture. A literature review was undertaken to: (i) document Indigenous Knowledge (IK), and perspectives regarding water and (ii) to identify current local water security tools utilized by Indigenous communities. The aim is to provide sound evidence regarding the value of ownership and leadership by Indigenous communities in the context of current and appropriate resources available to (re)claim these roles. Solutions must remain consistent with, and founded upon, traditional Indigenous worldviews and cultural values to ensure sustainable water security. Literature reviewed from the past ten years revealed one overarching creation theme with three water-specific themes in Indigenous communities; namely, water from natural sources, water as a life-giving entity, and water and gender. Ultimately, there needs to be a new framing of local water security with the development of tools which engage IK and WS in order to assess local water security and appropriately inform interventions, policies, regulations and legislation.


Nicotinic Acetylcholine Receptors Expressed by Striatal Interneurons Inhibit Striatal Activity and Control Striatal-Dependent Behaviors.
Acetylcholine is an important modulator of striatal activity, and it is vital to controlling striatal-dependent behaviors, including motor and cognitive functions. Despite this significance, the mechanisms determining how acetylcholine impacts striatal signaling are still not fully understood. In particular, little is known about the role of nAChRs expressed by striatal interneurons. In the present study, we used FISH to determine which neuronal types express the most prevalent beta2 nicotinic subunit in the mouse striatum. Our data support a common view that nAChR expression is mostly restricted to striatal interneurons. Surprisingly though, cholinergic interneurons were identified as a population with the highest expression of beta2 nicotinic subunit. To investigate the functional significance of beta2-containing nAChRs in striatal interneurons, we deleted them by injecting the AAV-Cre vector into the striatum of beta2-flox/flox male mice. The deletion led to alterations in several behavioral domains, namely, to an increased anxiety-like behavior, decrease in sociability ratio, deficit in discrimination learning, and increased amphetamine-induced hyperlocomotion and c-Fos expression in mice with beta2 deletion. Further colocalization analysis showed that the increased c-Fos expression was present in both medium spiny neurons and presumed striatal interneurons. The present study concludes that, despite being relatively rare, beta2-containing nAChRs are primarily expressed in striatal neurons by cholinergic interneurons and play a significant role in behavior.SIGNIFICANCE STATEMENT A large variety of nAChRs are expressed in the striatum, a brain region that is crucial in the control of behavior. The complexity of receptors with different functions is hindering our understanding of mechanisms through which striatal acetylcholine modulates behavior. We focused on the role of a small population of beta2-containing nAChRs. We identified neuronal types expressing these receptors and determined their impact in the control of explorative behavior, anxiety-like behavior, learning, and sensitivity to stimulants. Additional experiments showed that these alterations were associated with an overall increased activity of striatal neurons. Thus, the small population of nicotinic receptors represents an interesting target for a modulation of response to stimulant drugs and other striatal-based behavior.


On the concept of third occipital headache.
One of the putative causes of headache is osteoarthritis of the C2-3 zygapophysial joint. A technique for blocking the third occipital nerve which innervates this joint was devised and used as a screening procedure for headache mediated by this nerve. Seven out of ten consecutive patients presenting with suspected cervical headache were found to suffer pain mediated by the third occipital nerve and stemming from a C2-3 zygapophysial joint. Because third occipital headache may be indistinguishable clinically from tension or other forms of headache, third occipital nerve blocks are advocated as means of establishing this largely unrecognised diagnosis.


Pink Esthetic Score Outcomes Around Three Implant-Abutment Configurations: 3-Year Results.
To evaluate the influence that three different implant-abutment interface designs had on peri-implant mucosal outcomes as assessed by the pink esthetic score (PES) 3 years after delayed implant placement and immediate provisionalization. Adult subjects (n = 141) requiring replacement of a bounded single tooth in the anterior maxilla as well as first premolar sites were randomized to receive one of three unique implant-abutment interface designs (conical interface [CI]; flat-to-flat interface [FI]; or platform-switch interface [PS]). Treatment included immediate provisionalization with prefabricated titanium abutments, followed by custom computer-aided design/computer-aided manufacturing (CAD/CAM) zirconia abutments and cement-retained, all-ceramic crowns delivered after 12 weeks. Bilateral (anterior sites) or unilateral (premolar sites) digital clinical photographs were made at 1, 3, 6, 12, 24, and 36 months post-implant placement. Five calibrated faculty evaluators who previously scored the 1-year PES image dataset scored the 24- and 36-month photographs using a digital, cloud-based tablet interface. Six hundred ten clinical photographs were evaluated, resulting in a total of 3,050 sum PES values and 21,350 individual PES values. Faculty evaluator intrarater and interrater reliability were found to be "substantial," with intraclass correlation coefficient (ICC) values of 0.76 and 0.77, respectively. All three implant-abutment interface groups demonstrated acceptable esthetics at 3 years (mean sum PES = 10.1 ± 1.9, 4.0 to 13.2), with no single group demonstrating significantly greater mean sum PES values than another at the 3-year follow-up or at any recall interval in between. No significant differences were observed in mean sum PES scores for subjects randomized to one of three different implant-abutment interface geometries. Within the limitations of this study thus far, the first 6 months following definitive prosthesis delivery appear to still be the most significant with regard to improvement in PES outcomes for all three treatment groups.


Expression of ribonucleotide reductase after ionizing radiation in human cervical carcinoma cells.
Ribonucleotide reductase (RR), the rate-limiting enzyme in the de novo synthesis of deoxynucleotide triphosphates (dNTPs), is a potential target for cancer therapy. We characterized the response of RR in a human cervical carcinoma cell line, Caski, after damage by ionizing radiation (IR). We also investigated the cell cycle regulation of both the regulatory (R1) and catalytic (R2) RR subunits in an attempt to distinguish between a direct DNA damage induction of RR by IR and a cell cycle-dependent expression of RR after IR. Confluent, growth-arrested Caski cells showed a > or = 5-fold increase in R2 mRNA and an 18-fold increase in R2 protein as cells entered S phase after serum stimulation. The R2 protein levels peaked in late S phase and returned to lower basal levels in G2-M. No changes in R1 mRNA and protein levels occurred with progression through the cell cycle after serum stimulation. In growth-arrested Caski cells treated with IR (6 Gy) without serum stimulation, a similar rise (17-fold) in R2 protein was evident at 24 h after IR and was associated with a 4-fold increase in in situ RR enzyme activity, but no increases in R1 and R2 mRNA nor R1 protein were found. E2 promoter binding factor 1 mRNA and protein levels also showed no change after IR. Growth-arrested controls (no IR and no serum stimulation) showed <4-fold elevation in R2 protein. These data suggest that RR plays a role in IR-mediated damage responses in Caski cells, which appears different than RR regulation after a proliferation (serum) stimulus. Such a response to IR in human tumor cells has not been reported previously. The use of specific R2 protein or RR enzyme inhibitors after IR may enhance IR cytotoxicity by altering this potential RR-mediated repair pathway.


Spatiotemporal dynamics of single-letter reading: a combined ERP-FMRI study.
This work investigates the neural correlates of single-letter reading by combining event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI), thus exploiting their complementary spatiotemporal resolutions. Three externally-paced reading tasks were administered with an event-related design: passive observation of letters and symbols and active reading aloud of letters. ERP and fMRI data were separately recorded from 8 healthy adults during the same experimental conditions. Due to the presence of artifacts in the EEG signals, two subjects were discarded from further analysis. Independent Component Analysis was applied to ERPs, after dimensionality reduction by Principal Component Analysis: some independent components were clearly related to specific reading functions and the associated current density distributions in the brain were estimated with Low Resolution Electromagnetic Tomography Analysis method (LORETA). The impulse hemodynamic response function was modeled as a linear combination of linear B-spline functions and fMRI statistical analysis was performed by multiple linear regression. fMRI and LORETA maps were superimposed in order to identify the overlapping activations and the activated regions specifically revealed by each modality. The results showed the existence of neuronal networks functionally specific for letter processing and for explicit verbal-motor articulation, including the temporo-parietal and frontal regions. Overlap between fMRI and LORETA results was observed in the inferior temporal-middle occipital gyrus, suggesting that this area has a crucial and multifunctional role for linguistic and reading processes, likely because its spatial location and strong interconnection with the main visual and auditory sensory systems may have favored its specialization in grapheme-phoneme matching.


Major basement membrane components in Kaposi's sarcoma, angiosarcoma and benign vascular neogenesis.
Recent cell biologic studies have emphasized the importance of the basement membrane (BM) and its molecular components in angiogenesis. We immunostained 60 angioproliferative lesions (angiosarcoma, sclerosing hemangioma of skin, pyogenic granuloma, capillary hemangioma, lymphangioma, glomangioma and granulation tissue) and 23 cases of Kaposi's sarcoma (KS) for the major macromolecular components laminin, collagen type IV, fibronectin and heparan sulfate proteoglycan (HSPG). Normal structures served as aggregate controls in each group, and semiquantitative scoring reflected the degree of consistency of staining about blood and lymphatic endothelium and vascular sheath (pericyte/smooth muscle) within and peripheral to each lesion. Benign and reactive vasoproliferations consistently maintained immunoreactivity for each BM component around endothelium and sheath components of blood vessels. Angiosarcoma showed from 20 to more than 60% less consistent immunoreactivity by comparison, although the score variances were greater than for non-malignant lesions. Staining about blood vessel endothelium was both strong and consistent among histologic stages in KS with the exception of HSPG, which was weakly immunoreactive in all stages. Marked selective HSPG loss was characteristic only of KS and normal lymphendothelium, and in the light of evidence for a role for HSPG in the assembly and maintenance of BM, suggests that reduced HSPG may be responsible for the loss of ultrastructural integrity of perivascular BM in both.


Marrow-derived mesenchymal stem cells: role in epithelial tumor cell determination.
Marrow stroma represents an advantageous environment for development of micrometastatic cells. Within the cellular structure of marrow stroma, mesenchymal stem cells (MSC) have been postulated as an interacting target for disseminated cancer cells. The studies reported here were performed to gain more information on the interaction of the human breast cancer cell line MCF-7 with human bone marrow-derived MSC cells and to investigate whether this interaction affects tumor cell properties. The results showed that after co-culture with MSC, changes were detected in the morphology, proliferative capacity and aggregation pattern of MCF-7 cells, but these parameters were not affected after the co-culture of MSC cells with a non-tumorigenic breast epithelial cell line, MCF-10. Since the indirect culture of MCF-7 with MSC or its products also resulted in functional changes in the tumor cells, we evaluated whether these effects could be attributed to growth factors produced by MSC cells. It was found that VEGF and IL-6 mimic the effects produced by MSC or its products on the proliferation and aggregation properties of MCF-7, cells, respectively. Thus, it seems that after entry of disseminated tumor cells into the marrow space, their proliferative and morphogenetic organization patterns are modified after interaction with distinct stromal cells and/or with specific signals from the marrow microenvironment.


20α- and 20β-dihydrocortisone may interfere in LC-MS/MS determination of cortisol in saliva and urine.
Background LC-MS/MS methods offer high selectivity in cortisol determinations. However, endogenous steroid metabolites may still interfere and compromise the results, for example in the diagnosis of Cushing's syndrome. Erroneously elevated cortisol may, in particular, be misleading at the low concentrations found in salivary samples obtained at late night and after dexamethasone suppression. Methods Interferences in our LC-MS/MS method used for determination of cortisol in saliva and urine were identified by comparing their retention times and mass spectra with those of pure candidate substances. The chromatographic conditions used in our LC-MS/MS method, including column and mobile phase gradient, were varied in order to separate the target compound from the interferences. Results Two interferences, which were co-eluting or eluting close to cortisol in our original method, were successfully separated from cortisol by adjustment of the chromatographic conditions. These interferences were found in both urine and saliva and were identified as the two endogenous cortisol isomers 20α- and 20β-dihydrocortisone. The isomers share molecular mass and mass spectrometric fragmentation pattern with cortisol using electrospray ionization in the positive-ion mode. Both give rise to the transitions m/z 363.1>121.1, 363.1>115.1 and 363.1>97.1. In our original LC-MS/MS setup, the 20β-dihydrocortisone co-eluted with cortisol in the chromatography step resulting in false high determinations. Conclusions Cortisol determination by LC-MS/MS may suffer from erroneously elevated results unless 20α- and 20β-dihydrocortisone are chromatographically separated from cortisol.


Coincidence of blockade of synaptosomal 5-hydroxytryptamine uptake and decrease in tryptophan hydroxylase activity: effects of fenfluramine.
A single injection of fenfluramine hydrochloride resulted in a short-term increase in striate synaptosomal conversion of tryptophan to serotonin (5-HT) in rat brain. In contrast, D- and L-amphetamine sulfate resulted in a short-term decrease of this index of 5-HT biosynthesis. None of the amphetamines studied altered the kinetics of synaptosomal uptake of L-[3-14C]-tryptophan measured in the same striate preparation. Within 4 hours after fenfluramine administration, 3H-5-HT uptake into synaptosomes was markedly decreased; it returned to control levels in 10 to 14 days. Intrasynaptosomal tryptophan hydroxylase activity dropped markedly within 4 hours of drug administration and remained depressed for 10 to 14 days, its return to control levels coinciding with that of 3H-5-HT uptake. Only 5-HT cell body enzyme prepared from the lateral midbrain (B9) demonstrated a reduction in activity comparable to that seen in the synaptosomes; very small decreases occurred in cell body enzyme prepared from whole midbrain (B7, B8, B9) or medial midbrain (B7, B8). Lateral midbrain tryptophan hydroxylase activity returned to control levels by 8 days. In vitro, fenfluramine (100 muM) affected none of these indices of central 5-HT synthesis except 3H-5-HT uptake, which it reduced, and synaptosomal 3H-5-HT release, which it facilitated. The effects of fenfluramine on 5-HT biosynthesis persisted longer than those of D-amphetamine, which lasted less than 24 hours. However, the fenfluramine effects were much shorter than those reported for p-chloroamphetamine, which persist for up to 3 months. These three amphetamines apparently affect the lateral midbrain raphe nuclei selectively.


Human Papillomavirus Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) Cohort Study: Protocol Describing Design, Methods, and Research Goals.
Human papillomavirus (HPV) epidemiological research has generally been individual based, typically focusing on women, with couple-based research mostly consisting of cross-sectional assessment of prevalent HPV infection in both partners. The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study was set up to investigate the transmissibility of HPV among young, recently formed couples in Montreal, Canada. This paper provides an overview of the HITCH cohort study design and procedures as well as a narrative summary of the most important findings. HITCH is a longitudinal investigation of HPV transmission in recently formed heterosexual partnerships initiated within 6-month pre-enrollment, a time at which considerable transmission is believed to occur. A total of 549 newly formed dyads were recruited (2005-2011) from postsecondary institutions, including 502 young women and their male partners. An additional 46 males were enrolled at follow-up, as some women enrolled a subsequent partner at follow-up. Women aged 18-24 years were followed for 24 months for acquisition of HPV types not present at enrollment, whereas men returned for a single follow-up visit at month 4, for a sum total of 3361 clinic visits. The last follow-up visit occurred in January 2014. Extensive sociodemographic, sexual behavioral, and medical history data were collected every 2-4 months using computer-assisted, self-administered questionnaires. Furthermore, participants provided genital, blood, oral, and hand specimens for HPV assessment. Although in its early analysis stage, HITCH has produced important publications. Findings from HITCH have increased the available knowledge about the natural history of HPV transmission and its determinants, provided further evidence regarding oral-oral and oral-genital routes of HPV transmission, and supplied empirically valid epidemiological parameters of HPV transmission to assist mathematical modelers in health economic assessments. In addition, HITCH data were made available to several multistudy collaborations evaluating new HPV detection assays and evidence for-or-against HPV type replacement following the introduction of HPV vaccination. HITCH will continue to offer a unique resource for research on HPV transmission. RR1-10.2196/11284.


Virus polypeptide synthesis induced by herpes simplex virus in non-permissive rat XC cells.
The synthesis of virus polypeptides in rat XC cells infected with herpes simplex virus type 1 (HSV-1; 13VB4tsC75) was studied. At the permissive temperature the virus induced the synthesis, in a cascade fashion, of significant amounts of several early polypeptides (ICP 6, 8 and 39) and those late polypeptides that are relatively resistant to inhibition by phosphonoacetic acid in HEp2 cells (ICP 5, 11, 25, 29, 43 and 44). The infectious cycle appeared to become arrested in XC cells at about 7 to 9 h postinfection, because the relative concentrations of early and latest polypeptides labelled thereafter remained constant and the levels of several of the late virus polypeptides were severely reduced (ICP 2, 10, 24 and 26) or not synthesized at all (ICP 32, 34 and 37). When XC cells were infected at a very high m.o.i., only a small amount of virus DNA synthesis could be detected; the synthesis of cellular DNA was not impaired and the infected XC cells continued to replicate for several weeks at least. When XC cells were infected at the non-permissive temperature, only the immediate-early (IE) ICP 4 could be detected while IE ICP 0 and 22 were not observed. Infection of XC cells with HSV-1 (MP) also resulted in the production of early and late viral polypeptides. On the other hand, in XC cells infected with HSV-1 (F) and HSV-1 (HFEM), the synthesis of virus polypeptides could not be detected.


Systemic or regional chemotherapy: does it matter and should surgeons be involved?
TNF (tumour necrosis factor) is a new immunological anti-cancer agent which is too toxic for systemic use and relatively ineffective when used alone, but remarkably effective when used in closed circuit perfusion techniques together with other anti-cancer agents. Several studies have shown that when TNF is used with melphalan in closed circuit perfusion treatment for multiple melanoma metastases confined to a limb, a response rate of 80% can be achieved compared to a best response rate of 40% with melphalan alone. These findings confirm the difference in tumour responses which can be achieved with the appropriate use of regional chemotherapy in treatment of locally advanced tumours and the importance of surgical oncologists and vascular radiologists in maintaining and developing skills in integrated regional cancer treatment.


Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis.
Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.


Evaluating the Reasons for Partial and Non-immunization of Children in Wushishi Local Government Area, Niger State, Nigeria: Methodological Comparison.
Immunization of children against childhood preventable diseases has remained one of the most important cost effective and public health strategies to reduce childhood preventable morbidity and mortalities arising from infectious diseases. A recent report released by World Health Organization (WHO) stated that 1 in 10 infants did not receive vaccination in 2016. Also, a survey conducted in Bida Emirate Area of Niger State Nigeria in 2015 found that full routine immunization coverage in this area was less than 30%. The aim of this study was to establish the full routine immunization status and the reasons for its partial and non-immunization of children in Wushishi Local Government Area using WHO recommended cluster survey method and contrast with Factor Analysis (FA) method to see if the same results were achieved. The findings showed that the full immunization status for this area was very low (36%) and the results of analysis of reasons for failure from both methods seem contradictory. However, it reflected that lack of proper information was strongest for both methods. The disparity obtained in the two methods might be a result of methodological issues. The health implication is that much is expected to be done in the area of enlightenment campaign of the need for immunization and the need to complete the required basic dose especially in the rural areas.


Catalyst-controlled regioselectivity in phosphine catalysis: the synthesis of spirocyclic benzofuranones via regiodivergent [3 + 2] annulations of aurones and an allenoate.
Catalyst-controlled regiodivergent [3 + 2] annulations of aurones and allenoates have been developed. When a dipeptide phosphine catalyst with an l-d- configuration was employed, α-selective [3 + 2] annulation products could be obtained with good regioselectivities and enantioselectivities. With the employment of l-l- dipeptide phosphines, γ-selective annulation products could be selectively obtained with excellent enantioselectivities. By simply tuning the catalyst configurations, a wide range of α-selective or γ-selective spirocyclic benzofuranones with either aryl or alkyl substitutions could be readily prepared. DFT calculations suggest that the conformation of the dipeptide phosphines influences the hydrogen bonding interactions or the distortion energy, resulting in delicate energy differentiation in the transition states, and accounting for the observed regioselectivity.


[The use of immunological characteristics of the peripheral blood for the purpose of forensic medical expertise of the subjects exposed to ionizing radiation].
The objective of the present study was the comprehensive evaluation of quantitative and functional metabolic characteristics of human leukocytes following in vitro irradiation of peripheral blood samples at a dose of 0.25, 0.50, 1.0, and 4.0 Gy for the development of a rationale for their application as biological markers of radiation exposure in forensic medical expertise of the subjects affected by supernormal ionizing radiation. The total number of leukocytes, lymphocytes, and their subpopulations as well as the functional and metabolic status of neutrophils were determined. The results of the study indicate the possibility of using a set of functional metabolic characteristics of human leukocytes as the additional forensic medical criteria for diagnostics of radiation impact on living subjects.


Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs.
To determine whether a diet used for dogs with renal failure (renal food [RF]) was superior to an adult maintenance food (MF) in minimizing uremic crises and mortality rate in dogs with spontaneous chronic renal failure. Double-masked, randomized, controlled clinical trial. 38 dogs with spontaneous chronic renal failure. Dogs were randomly assigned to a group fed adult MF or a group fed RF and evaluated for up to 24 months. The 2 groups were of similar clinical, biochemical, and hematologic status. The effects of diets on uremic crises and mortality rate were compared. Changes in renal function were evaluated by use of serial evaluation of serum creatinine concentrations and reciprocal of serum creatinine concentrations. Compared with the MF, the RF had a beneficial effect regarding uremic crises and mortality rate in dogs with mild and moderate renal failure. Dogs fed the RF had a slower decline in renal function, compared with dogs fed the MF. Dietary modifications are beneficial in minimizing extrarenal manifestations of uremia and mortality rate in dogs with mild and moderate spontaneous chronic renal failure. Results are consistent with the hypothesis that delay in development of uremic crises and associated mortality rate in dogs fed RF was associated, at least in part, with reduction in rate of progression of renal failure.


Point spreading in turbid media with anisotropic single scattering.
Point spreading is investigated using general radiative transfer theory. We find that the single scattering anisotropy plays a significant role for point spreading together with the medium mean free path, single scattering albedo and thickness. When forward scattering dominates, the light will on average undergo more scattering events to give a specific optical response in reflectance measurements. This will significantly increase point spreading if the medium is low absorbing with large mean free path. Any fundamental and generic model of point spreading must capture the dependence on all of these medium characteristics.


Expression of PADI4 in patients with ankylosing spondylitis and its role in mediating the effects of TNF-α on the proliferation and osteogenic differentiation of human mesenchymal stem cells.
Peptidyl arginine deiminase, type IV (PADI4) plays an important role in inflammation and in the immune response, and it has been shown to be associated with rheumatoid arthritis, osteoarthritis and ankylosing spondylitis (AS). However, little is known about the precise role of PADI4 in the pathogenic process in vitro. In this study, we aimed to investigate the expression of PADI4 in the synovial tissue of patients with AS and to determine the potential effects of PADI4 on human mesenchymal stem cell (hMSC) proliferation and osteogenic differentiation under normal and pathological conditions. Synovial tissues were collected from 18 patients with AS and 11 control subjects. The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis revealed that the expression of PADI4 was upregulated in the patients with AS. In the hMSCs, the protein expression of PADI4 was increased following treatment with tumor necrosis factor-α (TNF-α) in a dose- and time-dependent manner. MTT assay revealed that TNF-α promoted hMSC proliferation. In addition, we found that TNF-α promoted the osteogenic differentiation of hMSCs, as demonstrated by an increase in alkaline phosphatase (ALP) activity, as well as an increase in the expression of bone morphogenetic protein 2 (BMP-2), runt-related transcription factor 2 (Runx2) and Osterix. The hMSCs were transfected with PADI4 siRNA to silence PADI4 expression. We found that, under normal conditions, the silencing of PADI4 did not have any effect on hMSC proliferation or osteogenic differentiation. However, in the presence of TNF-α, hMSC proliferation and osteogenic differentiation were induced. These effects were attenuated by the silencing of PADI4. In conclusion, the findings of this study demonstrate that the expression of PADI4 differs between patients with AS and normal subjects. In addition, our data suggest that PADI4 plays a role in hMSC proliferation and differentiation, which are induced by TNF-α.


[The neurotoxicity of benzodiazepines].
Molecular and clinical effects of benzodiazepines (BDZs) subsequent to their prenatal and postnatal application to animals and man are reviewed. BDZs interactions with neurotransmitter systems and with metabolic processes are presented and analysed. The experimental data obtained after prenatal application indicate that BDZs can cause malformations, functional deficits and long-lasting behavioural anomalies. The prenatal toxicity of BDZs is probably due to their interaction with neurotransmitter systems. Moreover, a BDZs interaction with mechanisms regulating the excitability of cell membranes and protein synthesis could also play a role. The consequences of prenatal exposition to BDZs in man, particularly their behavioural aspects, have not been sufficiently investigated as yet. Postnatal BDZs application can bring about behavioural disturbances and neurological deficits in animals and man. A part of this pathology can be compensated by means of the functional and structural redundance as well as the tolerance. Limitations in functional and morphological reserves of the nervous system can entail severe disturbances, e.g. cardio-respiratory insufficiency. The pharmacological and toxic BDZs effects could partly be due to their interactions with the same molecular mechanisms. These effects can possibly be mediated through BDZs receptors of the central and peripheral type. Regulatory mechanisms for excitability of cell membranes, cellular energetic processes and protein synthesis seem to be particularly sensitive to the BDZs impacts. A close dosis-effect relation for pharmacological and toxic BDZs effects does not seem to exist.


Hydraulic control of tuna fins: A role for the lymphatic system in vertebrate locomotion.
The lymphatic system in teleost fish has genetic and developmental origins similar to those of the mammalian lymphatic system, which is involved in immune response and fluid homeostasis. Here, we show that the lymphatic system of tunas functions in swimming hydrodynamics. Specifically, a musculo-vascular complex, consisting of fin muscles, bones, and lymphatic vessels, is involved in the hydraulic control of median fins. This specialization of the lymphatic system is associated with fish in the family Scombridae and may have evolved in response to the demand for swimming and maneuvering control in these high-performance species.


Understanding the spatiotemporal variability and trends of surface ozone over India.
With rising anthropogenic activities, surface ozone levels have increased across different parts of the world including India. Previous studies have shown that surface ozone shows distinct characteristics across India but these results are based on isolated locations and any comprehensive and spatiotemporally consistent study about surface ozone variability lacks thus far. Keeping these facts in mind, we utilize ground-based observations and reanalysis datasets to investigate spatiotemporal variations of surface ozone and its linkages with meteorology and precursors over Indian region. A validation exercise shows that the Copernicus Atmosphere Monitoring Service Reanalysis (CAMSRA) reasonably compares against the ground-based observations showing better correlations (> 0.7) over southern regions and relatively lesser (> 0.5) correlations over northern and eastern regions. We have further quantified this agreement in terms of range, mean absolute error (MAE), and root mean square error (RMSE). A time series analysis shows that the CAMSRA captures seasonal variations irrespective of location. Spatial distribution of surface ozone shows higher (lower) concentrations of about 40-60 ppb (15-20 ppb) during pre-monsoon (monsoon) months over northern and western parts and peninsular India. A prominent increase during May is noted over the northern region, especially over the Indo-Gangetic Plains (IGP). These seasonal variations are linked to solar radiation (SR), temperature, low-level circulation, and boundary layer height (BLH). CAMSRA-based surface ozone shows increasing trends across all four regions (north, east, west, and south India) and also India as a whole (0.069 ppb year-1, p = 0.001) with highest trends over the eastern region. Furthermore, principal component analysis (PCA) reveals that the first (second) mode shows a high percentage variance explained, ranging between 30 and 50% (10-20%). The corresponding PC-1 time series exhibits a notable increase in the surface ozone over south and central India, which corroborates the trend obtained through the area averaged time series. The second mode (PC-2) indicates prominent interannual variability over the IGP (southern India) in the pre-monsoon (post-monsoon). During the monsoon season, an interesting dipole pattern is noticeable, which closely resembles the active and break spell patterns of the Indian summer monsoon. Further, we quantify the weightage of precursors and meteorological parameters on surface ozone concentrations. The analysis suggests that PC1 of surface ozone is strongly influenced by CO and NOx (the precursors) while meteorology seems to dominate the PC2 during the pre-monsoon season. Overall, the results indicate that changes in the precursors or meteorological conditions have significant influences on the surface ozone concentrations across India.


Learning based on patient case reviews: an interview study.
Recent theories on adult learning recommend that learning is situated in real-life contexts. Learning is considered a continuous process in which every new experience builds on, and integrates with, previously accumulated experiences. Reviewing and reflecting on patient cases is in line with this learning approach. There has, however, been remarkably little research into how patient cases might be applied in professional education. The purpose of this article is to present family physicians' perceptions of the learning process initiated by reviewing patient cases. Thirteen family physicians, who had all participated in a large project on cancer diagnosis in family practice (the CAP-project), currently carried out at the Research Unit for General Practice, University of Aarhus were interviewed on their experiences of reviewing patient cases. In the CAP-project family physicians (n = 467, 81%) in the County of Aarhus (640 000 inhabitants) completed 2,212 (83%) detailed questionnaires on all newly diagnosed patients with cancer encountered in their practices during a one year period (2004-2005). In order to complete the questionnaire the family physicians were required to perform a systematic case review of each patient: they had to consult their records to provide dates of symptom-presentation, investigations and treatments initiated, and reflect on previous encounters with the patients to give detailed information on his/hers knowledge of the patients' care seeking behaviour, mental health and risk factors.The purpose of this article is to present indebt interview-data on family physicians' perceptions of the learning process initiated by reviewing patient cases, and their evaluations of using patient case reviews as a learning method in family practice. The process of reflection initiated by reviewing patient cases enabled family physicians to reconsider their clinical work procedures which potentially supported the transition from individual competence to personal capability. According to the physicians, they were not only able to identify needed changes, some reported that they were able to transform these ideas into action and do things more effectively. According to our data this transition takes place, because the learning processes initiated were based on real life experiences which equally initiated reflections on what to improve, as well as how to improve their work. Patient case reviews initiate reflective processes providing feedback about performance in real life situations. Family physicians are in favour of patient case reviews as a learning method, because it embraces the complexities they encounter in their daily practice and is based on personal experiences.


Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis.
Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 μM, an inhibitor of protein kinase A, PKA), KN93 (1 μM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis.


Imaging Successive Intermediate States of the On-Surface Ullmann Reaction on Cu(111): Role of the Metal Coordination.
The in-depth knowledge about on-surface reaction mechanisms is crucial for the tailor-made design of covalently bonded organic frameworks, for applications such as nanoelectronic or -optical devices. Latest developments in atomic force microscopy, which rely on functionalizing the tip with single CO molecules at low temperatures, allow to image molecular systems with submolecular resolution. Here, we are using this technique to study the complete reaction pathway of the on-surface Ullmann-type coupling between bromotriphenylene molecules on a Cu(111) surface. All steps of the Ullmann reaction, i.e., bromotriphenylenes, triphenylene radicals, organometallic intermediates, and bistriphenylenes, were imaged with submolecular resolution. Together with density functional theory calculations with dispersion correction, our study allows to address the long-standing question of how the organometallic intermediates are coordinated via Cu surface or adatoms.


The impact of diabetes mellitus on outcomes of endoscopic sinus surgery: a nested case-control study.
Given the immune impairment associated with diabetes mellitus (DM), its impact on chronic rhinosinusitis (CRS) is a potentially relevant concern; however, it has not been well-studied. A single retrospective study reported worse postoperative quality of life outcomes in DM patients with CRS. Our study evaluated the effect of comorbid DM on outcomes of endoscopic sinus surgery (ESS) using a prospective study design. Using a multicentered, prospective cohort of patients (n = 437) undergoing ESS for recalcitrant CRS, a nested case-control comparison was performed between 20 adult DM patients (cases) and 20 non-DM patients (controls), matched 1:1 for age and Lund-Mackay computed tomography (CT) scores. Outcome measures included 22-item Sinonasal Outcome Test (SNOT-22), Rhinosinusitis Disability Index (RSDI), Patient Health Questionnaire (PHQ-2), and Brief Smell Identification Test (BSIT). Mean follow-up was similar between cases (mean ± standard deviation: 12.6 ± 6.0 months) and controls (12.9 ± 5.9 months; p = 0.862). All preoperative scores were statistically equivalent between DM and non-DM cohorts. Both cohorts showed significant post-ESS improvement in SNOT-22 (p = 0.001) and RSDI scores (p < 0.001), and no significant change in PHQ-2 or BSIT scores. The magnitude of score changes was statistically equivalent between the 2 cohorts for all outcome measures with no differences in postoperative score changes between insulin-dependent DM patients and those managed by oral hypoglycemics or dietary restriction (p ≥ 0.444). DM patients with CRS experience similar degrees of symptomatic benefit from ESS compared to controls. Insulin dependence does not appear to adversely affect surgical outcome but a larger cohort would better assess the effect of DM type and control on surgical outcomes in CRS.


Physiologic basis of vasodilator therapy for heart failure.
In congestive heart failure, an increase in impedance to left ventricular ejection appears to be an important factor in impairing left ventricular performance. Arteriolar narrowing and decreased arterial compliance will decrease the left ventricular ejection fraction, whereas reduction in venous capacitance will shift blood centrally and increase cardiac filling. These vascular events may result from activation of the sympathetic nervous system and the renin-angiotensin system. Vasodilator drugs, by relaxing the increased vascular tone, will reduce ventricular volume and increase stroke volume, and thus improve the patient's hemodynamic and myocardial metabolic state. Translation of this acute hemodynamic response into a therapeutic benefit from long-term therapy is an attractive but not yet entirely proved thesis. Long-term controlled trials must eventually establish the place of vasodilator drug therapy in the management of different types of congestive heart failure. Furthermore, additional insight is needed into the potential for selective therapy that is tailored to counteract specific mechanisms of vasoconstriction in individual patients.


Investigations of chemical warfare agents and toxic industrial compounds with proton-transfer-reaction mass spectrometry for a real-time threat monitoring scenario.
Security and protection against terrorist attacks are major issues in modern society. One especially challenging task is the monitoring and protection of air conditioning and heating systems of buildings against terrorist attacks with toxic chemicals. As existing technologies have low selectivity, long response times or insufficient sensitivity, there is a need for a novel approach such as we present here. We have analyzed various chemical warfare agents (CWAs) and/or toxic industrial compounds (TICs) and related compounds, namely phosgene, diphosgene, chloroacetone, chloroacetophenone, diisopropylaminoethanol, and triethyl phosphate, utilizing a high-resolution proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOFMS) instrument with the objective of finding key product ions and their intensities, which will allow a low-resolution quadrupole mass spectrometry based PTR-MS system to be used with high confidence in the assignment of threat agents in the atmosphere. We obtained high accuracy PTR-TOFMS mass spectra of the six compounds under study at two different values for the reduced electric field in the drift tube (E/N). From these data we have compiled a table containing product ions, and isotopic and E/N ratios for highly selective threat compound detection with a compact and cost-effective quadrupole-based PTR-MS instrument. Furthermore, using chloroacetophenone (tear gas), we demonstrated that this instrument's response is highly linear in the concentration range of typical Acute Exposure Guideline Levels (AEGLs). On the basis of the presented results it is possible to develop a compact and cost-effective PTR-QMS instrument that monitors air supply systems and triggers an alarm as soon as the presence of a threat agent is detected. We hope that this real-time surveillance device will help to seriously improve safety and security in environments vulnerable to terrorist attacks with toxic chemicals.


Detection of subtle left ventricular systolic dysfunction in patients with significant aortic regurgitation and preserved left ventricular ejection fraction: speckle tracking echocardiographic analysis.
The aim of this study was to characterize left ventricular (LV) mechanics in symptomatic and asymptomatic patients with moderate-to-severe or severe aortic regurgitation (AR) and preserved ejection fraction (left ventricular ejection fraction) using two-dimensional speckle tracking echocardiography (2D-STE). The association between baseline LV strain and development of indications for surgery in asymptomatic patients was also evaluated. A total of 129 patients with moderate-to-severe or severe AR and LVEF >50% (age 55 ± 17 years, 64% male, 53% asymptomatic at baseline) were included. Standard echocardiography and 2D-STE were performed at baseline. Compared with asymptomatic patients, symptomatic patients had significantly impaired LV longitudinal (-14.9 ± 3.0 vs. -16.8 ± 2.5%, P < 0.001), circumferential (-17.5 ± 2.9 vs. -19.3 ± 2.8%, P = 0.001), and radial (35.7 ± 12.2 vs. 43.1 ± 14.7%, P = 0.004) strains. Among 49 asymptomatic patients who were followed up, 26 developed indications for surgery (symptoms onset or LVEF ≤50%). These patients had comparable LV volumes, LVEF, and colour Doppler assessments of AR jet at baseline, but more impaired LV longitudinal (P = 0.009) and circumferential (P = 0.017) strains compared with patients who remained asymptomatic. Impaired baseline LV longitudinal (per 1% decrease, HR = 1.21, P = 0.04) or circumferential (per 1% decrease, HR = 1.22, P = 0.04) strain was independently associated with the need for surgery. Multidirectional LV strain was more impaired in symptomatic than in asymptomatic patients with moderate-to-severe or severe AR, despite preserved LVEF. In asymptomatic AR patients, longitudinal and circumferential strains identified patients who would require surgery during follow-up.


[Investigation of the influence of metal markers on dose distributions and dose evaluation indices in intensity modulated radiation therapy plans for prostate cancer].
The aim of this study was to evaluate the influence of metal markers on dose distributions and dose evaluation indices in intensity modulated radiation therapy (IMRT) plans for prostate cancer. The dose distribution calculation in the prostate IMRT was performed in a virtual phantom with and without insertion of the metal markers. The deviations of Dmax, Dmin, homogeneity index (HI), Dmean, D2, D98, and D95 of clinical target volume (CTV) and planning target volume (PTV) were obtained for estimation of the influence on the dose evaluation indices. Analytical anisotropic algorithm (AAA) and Acuros external beam (AXB) algorithms were employed for calculating the dose distributions. There were no deviations in any dose evaluation indices in dose distributions calculated by using AAA, whereas the maximum deviations for CTV and PTV by using AXB were +7.93% and +6.43% for Dmax, -16.61% and -1.77% for Dmin, +29.46% and +8.34% for HI, +0.15% and +0.02% for Dmean, +1.50% and +0.24% for D2, respectively. Additional data were -0.20% in D98 (CTV) and -0.27% in D95 (PTV). This study suggests that local dose changes, which were produced around metal markers, affected dose distributions and the dose evaluation indices.


Matrix density mediates polarization and lumen formation of endothelial sprouts in VEGF gradients.
Endothelial cell (EC) sprouting morphogenesis is a critical step during angiogenesis, the formation of new blood vessels from existing conduits. Here, three-dimensional sprouting morphogenesis was examined using in vitro microfluidic devices that enabled the separate and simultaneous tuning of biomechanical and soluble biochemical stimuli. Quantitative analysis of endothelial sprout formation demonstrated that the ability of vascular endothelial growth factor (VEGF) to regulate stable sprout formation was mediated by the density of the surrounding collagen/fibronectin matrix. The coordinated migration and proliferation of multiple ECs to form stable sprouts were enhanced at intermediate matrix densities (1.2-1.9 mg ml(-1)), while lower densities resulted in uncoordinated migration (0.3-0.7 mg ml(-1)) and higher densities resulted in broad cell clusters that did not elongate (2.7 mg ml(-1)). Within the permissive range of matrix biomechanics, higher density matrices resulted in shorter, thicker, and slower-growing sprouts. The sprouts in higher density matrices also were more likely to polarize towards higher VEGF concentrations, included more cells per cross-sectional area, and demonstrated more stable lumen formation compared to sprouts in lower density matrices. These results quantitatively demonstrate that matrix density mediates VEGF-induced sprout polarization and lumen formation, potentially by regulating the balance between EC migration rate and proliferation rate.


Trends in screening breast magnetic resonance imaging use among US women, 2006 to 2016.
Supplemental breast cancer screening with breast magnetic resonance imaging (MRI) is recommended for women at high risk of breast cancer. To the authors' knowledge, recent national trends in breast MRI use are unknown. The authors used claims data from a large national insurer to calculate screening breast MRI rates from 2006 to 2016 in a US cohort of 10 million women aged 20 to 64 years. Use was stratified by subgroups of women with a BRCA mutation, family history of breast cancer, and prior breast cancer history and stratified by age. Joinpoint regression evaluated annual changes in trends. The total sample included 37,447 screening breast MRI examinations in 25,617 women. Overall screening breast MRI rates were low and increased from 2.9 to 12.1 examinations per 10,000 women from 2006 to 2016. MRI use in women with a BRCA mutation increased by 21% on average annually from 210.8 per 10,000 women to 1562.0 per 10,000 women from 2006 to 2016. By 2016, women aged 50 to 64 years who had a BRCA mutation had the highest use of breast MRI (1669.6 MRI examinations per 10,000 women) compared with younger women (1198.4 MRI examinations per 10,000 women, 1519.1 MRI examinations per 10,000 women, and 1567.2 MRI examinations per 10,000 women, respectively, among women aged 20-29 years, 30-39 years, and 40-49 years). Women with a BRCA mutation comprised <1% of the current study population but received approximately 9% of screening breast MRI examinations. Breast MRI rates among women with a family history of breast cancer or prior breast cancer history initially increased from 2006 to 2008, but then stabilized or decreased. The increases in breast MRI use observed in the current study have indicated improvements in concordance with breast imaging guidelines. However, women with BRCA mutations remain underscreened, particularly younger women, thereby identifying a clear gap with which to enhance access.


Treatment of Parkinson's disease : what's on the horizon?
Few neurological diseases have received as much attention and investment in research as Parkinson's disease. Although great strides have been made in the development of agents to treat this neurodegenerative disease, none yet address the underlying problem associated with it, the progressive loss of dopaminergic neurons. Current therapeutic strategies for Parkinson's disease focus primarily on reducing the severity of its symptoms using dopaminergic medications. Although providing substantial benefit, these agents are burdened by adverse effects and long-term complications. This review highlights new and emerging therapies for Parkinson's disease, categorised as symptomatic, neuroprotective and neurorestorative, although at times, this distinction is not easily made. Novel symptomatic treatments target nondopaminergic areas in the hope of avoiding the motor complications seen with dopaminergic therapies. Two emerging treatment approaches under investigation are adenosine A(2A) receptor antagonists (such as istradefylline [KW-6002]) and glutamate AMPA receptor antagonists (such as talampanel [LY-300164]). In 2003, the results from two studies using istradefylline in patients with Parkinson's disease were published, with both showing a positive benefit of the study drug when used as adjunctive therapy to levodopa. In non-human primate models of Parkinson's disease, talampanel has been found to have antiparkinsonian effects when administered as high-dose monotherapy and antidyskinetic effects on levodopa-induced dyskinesias. NS-2330, another drug currently undergoing clinical trials, is a triple monoamine reuptake inhibitor that has therapeutic potential in both Parkinson's and Alzheimer's disease. A phase II proof-of-concept study is currently underway in early Parkinson's disease. However, a recently published study in advanced Parkinson's disease showed no therapeutic benefit of NS-2330 in this patient population. Even more exciting are agents that have a neuroprotective or neurorestorative role. These therapies aim to prevent disease progression by targeting the mechanisms involved in the pathogenesis of Parkinson's disease. Several lines of investigation for neuroprotective therapies have been taken, including the antioxidant coenzyme Q10 (ubidecarenone) and anti-apoptotic agents such as CEP-1347. Studies in patients with Parkinson's disease with coenzyme Q10 have suggested that it slows down functional decline. The PRECEPT study is currently in progress to assess the neuroprotective role of CEP-1347 in the early phase of the disease. Gene therapy is another exciting arena and includes both potentially neuroprotective and neurorestorative agents. Novel methods include subthalamic glutamic acid decarboxylase gene therapy and the use of glial cell line-derived neurotrophic factor (GDNF). Eleven of 12 patients have been enrolled in the first FDA-approved phase I subthalamic glutamic acid decarboxylase gene therapy trial for Parkinson's disease, with currently no evidence of adverse events. GDNF delivered intracerebroventricularly was studied in a small population of patients with Parkinson's disease, but unfortunately did not reveal positive results. Other methods of administering GDNF include direct delivery via infusions into the basal ganglia and the use of viral vectors; thus far, these approaches have shown promising results. This is an exciting and rewarding time for research into Parkinson's disease. With so many therapies currently under investigation, the time is ripe for the beginning of a new phase of treatment strategies.


Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis.
Prone positioning for ARDS has been performed for decades without definitive evidence of clinical benefit. A recent multicenter trial demonstrated for the first time significantly reduced mortality with prone positioning. This meta-analysis was performed to integrate these findings with existing literature and test whether differences in tidal volume explain conflicting results among randomized trials. Studies were identified using MEDLINE, EMBASE, Cochrane Register of Controlled Trials, LILACS, and citation review. Included were randomized trials evaluating the effect on mortality of prone versus supine positioning during conventional ventilation for ARDS. The primary outcome was risk ratio of death at 60 days meta-analyzed using random effects models. Analysis stratified by high (>8 ml/kg predicted body weight) or low (≤ 8 ml/kg PBW) mean baseline tidal volume was planned a priori. Seven trials were identified including 2,119 patients, of whom 1,088 received prone positioning. Overall, prone positioning was not significantly associated with the risk ratio of death (RR 0.83; 95% CI 0.68-1.02; p = 0.073; I (2) = 64%). When stratified by high or low tidal volume, prone positioning was associated with a significant decrease in RR of death only among studies with low baseline tidal volume (RR 0.66; 95% CI 0.50-0.86; p = 0.002; I (2) = 25%). Stratification by tidal volume explained over half the between-study heterogeneity observed in the unstratified analysis. Prone positioning is associated with significantly reduced mortality from ARDS in the low tidal volume era. Substantial heterogeneity across studies can be explained by differences in tidal volume.


Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence.
Because overexpression of the glucose-6-phosphatase catalytic subunit (G-6-Pase) in both type 1 and type 2 diabetes may contribute to the characteristic increased rate of hepatic glucose production, we have investigated whether the insulin response unit (IRU) identified in the mouse G-6-Pase promoter is conserved in the human promoter. A series of human G-6-Pase-chloramphenicol acetyltransferase (CAT) fusion genes was transiently transfected into human HepG2 hepatoma cells, and the effect of insulin on basal CAT expression was analyzed. The results suggest that the IRU identified in the mouse promoter is conserved in the human promoter, but that an upstream multimerized insulin response sequence (IRS) motif that is only found in the human promoter appears to be functionally inactive. The G-6-Pase IRU comprises two distinct promoter regions, designated A and B. Region B contains an IRS, whereas region A acts as an accessory element to enhance the effect of insulin, mediated through region B, on basal G-6-Pase gene transcription. We have previously shown that the accessory factor binding region A is hepatocyte nuclear factor-1, and we show here that the forkhead protein FKHR is a candidate for the insulin-responsive transcription factor binding region B.


Control of Listeria monocytogenes on cold-smoked salmon using chitosan-based antimicrobial coatings and films.
The relatively high incidence of Listeria monocytogenes in ready-to-eat (RTE) products such as cold-smoked salmon is of serious concern. The objective of this study was to evaluate the efficacy of chitosan-based edible coatings and films incorporating 3 generally recognized as safe (GRAS) antimicrobials, sodium lactate (SL), sodium diacetate (SD), and potassium sorbate (PS), against L. monocytogenes on cold-smoked salmon. Salmon samples were surface-inoculated with a 5-strain cocktail of Listeria monocytogenes to a final concentration of 4.4 log CFU/cm(2) and then either coated with chitosan solutions or wrapped with chitosan films with or without the 3 antimicrobials. The samples were then vacuum packaged and stored at 4 °C for 30 d. The chitosan coatings with or without the antimicrobials consistently showed higher efficacy against L. monocytogenes than chitosan films having the same compositions. The most effective film treatments, chitosan films containing 1.2% SL/0.25% SD or 2.4% SL, achieved ≥ 1.3 log reductions of L. monocytogenes during the 30 d of refrigerated storage, while the most effective coating treatments, chitosan coatings containing 1.2% SL/0.25% SD or 0.15% PS/0.125% SD, achieved ≥ 2.8 log reductions. Practical Application: This study shows that chitosan-based edible coatings and films hold promise and can potentially assist fishery industries in their efforts to control L. monocytogenes.


Natural Killer Anti-Tumor Activity Can Be Achieved by In Vitro Incubation With Heat-Killed BCG.
Natural Killer cell receptors allow this heterogeneous immune population to efficiently fight both tumors and infection, so their use as immunotherapy agents is an active field of research. Cytokine activation, particularly by myeloid cell-derived IL15, can induce potent NK anti-tumor responses. While studying the mechanism of action of intravesical instillations of Bacille Calmette-Guérin (BCG) as therapy for patients with high risk non-muscle invasive bladder cancer, we showed that BCG can activate a cytotoxic CD56bright NK cell population which efficiently recognized bladder cancer cells. This pioneer immunotherapy provides an invaluable model to understand the role of different immune populations in tumor elimination. However, during the propagation of BCG worldwide a large number of genetically diverse BCG substrains developed. Here, we investigated the capacity of different BCG substrains to promote NK cell activation and confirmed that they were able to activate lymphocytes. Tice, Connaught and Moreau were the substrains with a stronger NK activation effect as measured by CD56 upregulation. Surprisingly, dead mycobacteria also stimulated PBMC cultures and we further demonstrate here that subcellular fractions of BCG-Tice, in the absence of live mycobacteria, could also induce an NK cell response. Lipids from BCG-Tice, but not from Mycobacterium bovis, stimulated NK cell activation and degranulation, whereas the aqueous fraction of either bacteria did not activate lymphocytes. However, delipidated BCG-Tice bacteria were able to activate effector cells (CD3+CD56+ and NK, CD3-CD56+). These data demonstrate that different components of mycobacteria can stimulate different immune subpopulations resulting in phenotypes suitable for cancer elimination.


Role of gene polymorphisms in vitamin D metabolism and in multiple sclerosis.
Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) resulting in neurological impairment and disability. There is evidence that adequate vitamin D levels may lower the risk of MS development. The aetiology of MS is complex and involves both genetic and environmental factors. In fact, not one but several genes are believed to lead to the disease. As for environmental factors, one of the most important risk factors is vitamin D deficiency, which, in turn, is closely related to gene polymorphisms that play a role in vitamin D metabolism and regulation. However, information about these gene polymorphisms is quite contradictory. The aim of this review is to discuss the association between some of the vitamin D-related gene variants and MS.


Patellar tendon ultrasonography and jumper's knee in female basketball players: a longitudinal study.
To compare patellar tendon sonographic findings at baseline and at follow-up in active female basketball players with and without symptoms of jumper's knee. We hypothesized that baseline sonographic morphology would not reliably predict prognosis and, in particular, that it would not predict the need for surgery. Prospective longitudinal study with 12-month minimum follow-up. Institutional elite athlete study group in Australia (Victorian Institute of Sport Tendon Study Group). A total of 15 female elite basketball players with 23 sonographically abnormal tendons and 15 matched control basketball players with 23 sonographically normal tendons. Sonographic patellar tendon appearance and clinical assessment of symptoms of jumper's knee at baseline and follow-up. Dimensions of abnormal regions were measured. At baseline, the 23 subject tendons contained sonographic hypoechoic regions (six currently symptomatic, eight previously symptomatic only, and nine never symptomatic). At follow-up, the hypoechoic areas in seven tendons had resolved (and caused no symptoms), the hypoechoic areas in 11 tendons had remained essentially the same size (five were symptomatic), and the hypoechoic areas in five tendons had expanded (three symptomatic). At baseline, there were no differences between the mean +/- SD cross-sectional areas of the abnormalities in the tendons that subsequently resolved (15.9 +/- 10.1 mm2) and those that remained unchanged (39.3 +/- 25.8) or expanded (25.3 +/- 12.5). The presence of a baseline sonographic abnormality predicted symptoms of jumper's knee at follow-up (p < 0.05), but the presence of symptoms of jumper's knee at baseline also predicted symptoms at follow-up (p < 0.05). No subject or control missed any games or underwent surgical treatment. Patellar tendon sonographic hypoechoic areas can resolve, remain unchanged, or expand in active sports-women without predicting symptoms of jumper's knee. Thus, symptoms were not directly related to sonographic tendon morphology. Sonographic hypoechoic regions ought not to constitute per se an indication for surgery.


Development of a conceptual model of cancer caregiver health literacy.
Caregivers play a vital role in caring for people diagnosed with cancer. However, little is understood about caregivers' capacity to find, understand, appraise and use information to improve health outcomes. The study aimed to develop a conceptual model that describes the elements of cancer caregiver health literacy. Six concept mapping workshops were conducted with 13 caregivers, 13 people with cancer and 11 healthcare providers/policymakers. An iterative, mixed methods approach was used to analyse and synthesise workshop data and to generate the conceptual model. Six major themes and 17 subthemes were identified from 279 statements generated by participants during concept mapping workshops. Major themes included: access to information, understanding of information, relationship with healthcare providers, relationship with the care recipient, managing challenges of caregiving and support systems. The study extends conceptualisations of health literacy by identifying factors specific to caregiving within the cancer context. The findings demonstrate that caregiver health literacy is multidimensional, includes a broad range of individual and interpersonal elements, and is influenced by broader healthcare system and community factors. These results provide guidance for the development of: caregiver health literacy measurement tools; strategies for improving health service delivery, and; interventions to improve caregiver health literacy.


Mdm2 and Mdm4 loss regulates distinct p53 activities.
Mutational inactivation of p53 is a hallmark of most human tumors. Loss of p53 function also occurs by overexpression of negative regulators such as MDM2 and MDM4. Deletion of Mdm2 or Mdm4 in mice results in p53-dependent embryo lethality due to constitutive p53 activity. However, Mdm2(-/-) and Mdm4(-/-) embryos display divergent phenotypes, suggesting that Mdm2 and Mdm4 exert distinct control over p53. To explore the interaction between Mdm2 and Mdm4 in p53 regulation, we first generated mice and cells that are triple null for p53, Mdm2, and Mdm4. These mice had identical survival curves and tumor spectrum as p53(-/-) mice, substantiating the principal role of Mdm2 and Mdm4 as negative p53 regulators. We next generated mouse embryo fibroblasts null for p53 with deletions of Mdm2, Mdm4, or both; introduced a retrovirus expressing a temperature-sensitive p53 mutant, p53A135V; and examined p53 stability and activity. In this system, p53 activated distinct target genes, leading to apoptosis in cells lacking Mdm2 and a cell cycle arrest in cells lacking Mdm4. Cells lacking both Mdm2 and Mdm4 had a stable p53 that initiated apoptosis similar to Mdm2-null cells. Additionally, stabilization of p53 in cells lacking Mdm4 with the Mdm2 antagonist nutlin-3 was sufficient to induce a cell death response. These data further differentiate the roles of Mdm2 and Mdm4 in the regulation of p53 activities.


Did the post war repatriation of Lebanese physicians drive recent Lebanese medical graduates to emigrate? An observational study.
A significant number of Lebanese medical graduates have emigrated from Lebanon. The objective of this study was to evaluate the hypothesis that the repatriation of Lebanese physicians educated abroad has contributed to the international emigration of recent Lebanese medical graduates. We analyzed the demographic and educational characteristics and the year of registration of physicians registered with the two physician associations in Lebanon as of 2007. We then analyzed the number of new and total registrants and the physician density for the years 1977-2006. Finally we calculated the percentage of Lebanese graduates of the years 1977-2006 registered as of 2007. As of 2007, 10,918 physicians were registered in Lebanon. Most were male (80.4%) and graduated from either Lebanese (36.4%) or Eastern European (30.6%) medical schools. The top three regions of specialty training were Western Europe (31.8%), Eastern Europe (28.4%) and Lebanon (25.7%). About half the physicians registered with the Lebanese Order of Physicians as of 2007 joined during the 1990 s decade; only 26.2% of these graduated from Lebanese medical schools during that decade. The number of new registrants increased dramatically in the early 1990 s and started decreasing in the early 2000s. About 60% of Lebanese medical graduates of the years 1977-2006 were registered in Lebanon as of 2007. Categorizing Lebanese medical graduates by their year of graduation, the percentage registered in Lebanon as of 2007 showed a "dip" for those who graduated in the early 1990 s. The high number of physicians educated abroad returning to Lebanon after the end of the civil war may have driven recent Lebanese medical graduates to emigrate.