[Organization of stomatological care in Russian army during first World War 1914-1917 y].
The article presents issues on organization of stomatological care in Russian army during First World War. The author showed reasons of low efficiency of the treatment of soldiers with maxillofacial region. Injuries beginning of a new stage in the treatment of maxillofacial region fire wounds and origin of a new specialty developed a military maxillofacial surgery.


Cognitive change in aging: identifying gene-environment correlation and nonshared environment mechanisms.
We describe gene-environment processes that may help account for individual differences in successful aging. Our emphasis is on successful aging in the cognitive domain, wherein individuals come to use a variety of strategies to cope with changes in cognitive capacities. We focus on the role of executive control in particular and define gene-environment correlation and nonshared environmental mechanisms. The quantitative genetic methods used to identify these mechanisms are described, with examples from research in childhood, where such studies are now common. Future work will be most effective if it is guided by life-span development frameworks that address these processes, such as the developmental genotype-->environment theory of Scarr and McCartney and the selection/optimization/compensation theory of Baltes and Baltes.


Defining breast cancer intrinsic subtypes by quantitative receptor expression.
To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression. We merged 1,557 cases from three randomized phase III trials into a single data set. These breast tumors were centrally reviewed in each trial for quantitative ER, PR, and HER2 expression by immunohistochemistry (IHC) stain and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), with intrinsic subtyping by research-based PAM50 RT-qPCR assay. Among 283 HER2-negative tumors with <1% HR expression by IHC, 207 (73%) were basal-like; other subtypes, particularly HER2-enriched (48, 17%), were present. Among the 1,298 HER2-negative tumors, borderline HR (1%-9% staining) was uncommon (n = 39), and these tumors were heterogeneous: 17 (44%) luminal A/B, 12 (31%) HER2-enriched, and only 7 (18%) basal-like. Including them in the definition of triple-negative breast cancer significantly diminished enrichment for basal-like cancer (p < .05). Among 106 HER2-positive tumors with <1% HR expression by IHC, the HER2-enriched subtype was the most frequent (87, 82%), whereas among 127 HER2-positive tumors with strong HR (>10%) expression, only 69 (54%) were HER2-enriched and 55 (43%) were luminal (39 luminal B, 16 luminal A). Quantitative HR expression by RT-qPCR gave similar results. Regardless of methodology, basal-like cases seldom expressed ER/ESR1 or PR/PGR and were associated with the lowest expression level of HER2/ERBB2 relative to other subtypes. Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HR IHC cut point was <1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderline HR staining are molecularly diverse and may require additional assays to clarify underlying biology.


An economic evaluation of a perindopril-based blood pressure lowering regimen for patients who have suffered a cerebrovascular event.
Cerebrovascular disease (or stroke) is one of the main causes of long-term disability and the second leading cause of death worldwide. The economic impact of stroke is clearly seen, as it is the largest single cause of bed occupancy in hospitals in England and accounts for 6% of hospital costs. This analysis is the first to quantify the economic consequences of a blood pressure lowering regimen based on the PROGRESS study (perindopril-based regimen), for reducing future cardiovascular events. A Markov decision analytical model was used to estimate the cost per quality adjusted life year (QALY) of blood pressure lowering in the treatment of patients presenting with a cerebrovascular event. The health states are based upon Barthel indices for which resource utilisation and health benefits have previously been estimated. The participants for the economic analysis were obtained from the PROGRESS study database. 6,105 clinical study participants were recruited through both primary and secondary care centres. The mean age was 64 years; 70% were male in the original study. In the PROGRESS study, blood pressure lowering by a perindopril-based regimen was compared to standard care. Cost per quality adjusted life year for the duration of the study (4 years) and for a time span of 20 years. Using only direct hospital medical costs, the cost per QALY for a perindopril based regimen is pound 6,927 for the base study period and pound 10,133 for a 20-year time period. These results are sensitive to the cost of perindopril, the cost of the stroke unit, length of stay, and to a lesser extent, the cost of indapamide. This analysis demonstrates a cost-effective treatment for patients suffering a cerebrovascular event with a blood pressure lowering regimen. The findings of this study are in line with current decisions and guidance by the national institute for health and clinical excellence (NICE) in England.


Epidemiology and patterns of transport-related fatalities in Austria 1980-2012.
Transport-related accidents remain the largest single cause of death among people aged 15 to 29 in the European Union, and despite the decrease in number of fatalities from 1990 onwards they remain a significant public health problem. The aim of this article was to analyze the long-term trends and patterns of transport-related fatalities, identify the anatomic distribution of most significant injuries in different road users, and identify the primary populations at risk of transport-related death in Austria between 1980 and 2013. Data on transport-related fatalities based on death certificates were obtained from Statistics Austria for the analyzed period. Crude and age-standardized mortality rates per 100,000 were calculated and broken down by age, gender, and month of death, and the anatomic distribution of most significant injuries were identified. Potential years of life lost before age 75 (PYLL-75) were used as a measure of public health impact. A total of 39,709 transport-related fatalities were identified for the studied years; 74% were males and the mean age was 42.1 years (range 0-103). A decrease in the number of fatalities (from 2018 in 1980 to 554 in 2012), mortality rates (from 26 in 1980 to 7 in 2012), and PYLL-75 (from 68,960 in 1980 to 14,931 in 2012) was observed. Introduction of major prevention milestones (compulsory use of seat belts or child restraints) may have contributed to this decrease. Men 16-24 years old were at the highest risk of transport-related death. Pedestrian victims were more likely to be women and car drivers and motorcyclists were more often men. Most fatal transport accidents occurred between the months of May and October and prevailingly in towns of fewer than 20,000 inhabitants. Injuries to the head were the most significant injuries in all user groups (>50% of cases in all road user types). Reduced mortality rates could translate into higher prevalence of long-term disabilities in survivors of transport accidents. Despite the decreasing trend observed, transport-related fatalities remain a serious public health issue in Austria. An increase in the mortality of motor vehicle drivers warrants more preventive action in this group. Further research is needed on other outcomes of transport accidents such as long-term disabilities to elucidate the true public health burden of transport accidents.


Residents' Reflections on Cost-Conscious Care after International Health Electives: A Single-Center Qualitative Study.
Estimates suggest 30% of health care expenditures are wasteful. This has led to increased educational interventions in graduate medical education (GME) training aimed to prepare residents for high value, cost-conscious practice. International health electives (IHE) are widely available in GME training and may be provide trainees a unique perspective on principles related to high value, cost-conscious care (HVCCC). The purpose of this study was to explore how trainee reflections on IHE experiences offer insight into HVCCC. The authors conducted an applied thematic analysis of narrative reflective reports of GME trainees' IHE experiences to characterize their perceptions of HVCCC. The Mayo International Health Program (MIHP) supports residents and fellows from all specialties across all Mayo Clinic sites. We included 546 MIHP participants from 2001 to 2020. The authors collected post-elective narrative reports from all MIHP participants. Reflections were coded and themes were organized into model for transformative learning during IHEs, focusing on HVCCC. GME trainees across 24 different medical specialties participated in IHEs in 73 different countries. Three components of transformative learning were identified: disorienting dilemma, critical reflection, and commitment to behavior change. Within the component of critical reflection, three topics related to HVCCC were identified: cost transparency, resource stewardship, and reduced fear of litigation. Transformation was demonstrated through reflection on future behavioral change, including cost-aware practice, stepwise approach to health care, and greater reliance on clinical skills. IHEs provide rich experiences for transformative learning and reflection on HVCCC. These experiences may help shape trainees' ideology of and commitment to HVCCC practices.


Clinical workload decreases the level of aerobic fitness in housestaff physicians.
To examine the relationship between clinical workload and aerobic fitness. Twenty healthy intern and resident volunteers were studied in a cross over manner to compare their aerobic fitness after a 1 month "easy" clinical rotation (ECR) to that after a 1 month "hard" clinical rotation (HCR). The ECR and HCR were prospectively estimated as requiring <60 (ECR) and >70 (HCR) total hours per week of hospital work respectively. Aerobic fitness was determined by directly measuring peak oxygen uptake (peakVO2) during peak cycle exercise testing after each rotation. Clinical workload for the month preceding the exercise test was estimated by documenting the amount of hospital work and sleep lost because of on-call duties. The average weekly amount of effective aerobic training for each rotation was also documented. Trainees had a 206.4 (P = 0.0019, 95% CI 94-318.8) mL/min or 3 mL/kg/min (P = 0.0019, 95% CI 1.5-4.4) improvement of peakVO2 after the ECR compared with the HCR. Trainees averaged 1 (95% CI 0.16-1.81) less hour per week of exercise training, 34.1 more hours per week of hospital work (95% CI 23.0-45.3, P < 0.0001) and lost 19.1 hours more sleep per month (95% CI 11.8-26.4, p < 0.0001) during the HCR compared with the ECR. There was no correlation between changes in peakVO2 and changes in exercise training between the two rotations. Clinical workload seems to adversely affect aerobic fitness independent of changes in exercise training. This supports previous less-objective survey data.


The effect of experimental fascioliasis on the pharmacokinetics of antipyrine and sulphadimidine in desert sheep.
Healthy adult male desert sheep were experimentally infected with Fasciola gigantica, to investigate the influence of experimental fasciolasis on the pharmacokinetics of antipyrine and sulphadimidine. Each animal received 500 metacercariae orally. The experimental infection was confirmed histologically, by detection of Fasciola eggs in faeces and by measuring the activities of the enzymes sorbitol dehydrogenase (SD), glutamate dehydrogenase (GD) and aspartate aminotransferase (AST) in plasma during the course of the disease. Changes in the pharmacokinetics of antipyrine and sulphadimidine were reported in the experimentally infected animals. Significant prolongation of antipyrine half life was observed 16 weeks after infection. The half-life of sulphadimidine was also significantly prolonged 5, 9 and 16 weeks after infection. Clearance of the sulphonamide was decreased significantly 5 and 9 weeks after infection and it regained its pre-infection value 16 weeks after infection.


A Multimodal Evaluation of an Emergency Department Electronic Tracking Board Utility Designed to Optimize Stretcher Utilization.
Objectives The primary objective of this study was to evaluate the impact of an electronic tracking board feature encouraging staff to prompt optimal patient location on total stretcher time (TST) amongst patients moved to a chair in an internal emergency department (ED) waiting room. As a secondary objective, we also sought to identify facilitators and barriers to the tool's use amongst the ED staff. Methods Using an administrative database, a retrospective cohort design was used to compare TST between visits where the tool was used and not used amongst patients relocated from initial assessment space to a chair over an 11.5 month period. A mixed-methods design was used to investigate facilitators and barriers to the tool's use amongst the ED staff. Response proportions were used to report Likert scale questions; thematic analysis was used to code themes. Results A total of 56,852 patients met the inclusion criteria and were moved to a chair. The tool was used 4,301 times, with "OK for chairs" selected for 3,917/56,852 (6.9%) patients and "not OK for chairs" selected 384/56,852 (0.7%) times. Patient characteristics were similar between both groups. Median interquartile range (IQR) TST amongst patients moved to a chair via the prompt was shorter than when the prompt was not used (148.2 (112.6) mins vs 154.4 (115.4) mins, p = 0.005). A total of 125 questionnaires were completed; 95% of staff were aware of the tool and 70% agreed/strongly agreed the tool could improve ED flow. Commonly reported physician barriers to use were forgetting to use the tool; common nursing barriers were lack of chair space and increased workload. Conclusions Despite low function use, prompt use was associated with reduced TST amongst ED patients relocated to a chair.


Low-adhesion and low-swelling hydrogel based on alginate and carbonated water to prevent temporary dilation of wound sites.
Hydrogel-based wound dressings have been developed for rapid wound healing; however, their adhesive properties have not been adequately investigated. Excessive adhesion to the skin causes wound expansion and pain when hydrogels absorb exudates and swell at wound sites. Herein, we developed a low-adhesion and low-swelling hydrogel dressing using alginate, which is non-adhesive to cells and skin tissue, CaCO3, and carbonated water. The alginate/CaCO3 solution rapidly formed a hydrogel upon the addition of carbonated water, and the CO2 in the hydrogel diffused into the atmosphere, preventing acidification and obtaining a pH value suitable for wound healing. Remarkably, the skin adhesion and swelling of the hydrogel were 11.9- to 16.5-fold and 1.9-fold lower, respectively, than those of clinical low-adhesion hydrogel dressings. In vivo wound-healing tests in mice demonstrated its therapeutic efficacy, and the prepared hydrogel prevented temporary wound dilation during early healing. These results illustrate the importance of controlling skin adhesion and swelling in wound dressings and demonstrate the potential clinical applications of this wound-friendly hydrogel dressing.


Systematic analysis of research on religious variables in four major psychiatric journals, 1978-1982.
The authors conducted a systematic analysis of quantitative research on religious variables found in four psychiatric journals between 1978 and 1982. Of the 2,348 psychiatric articles reviewed, 59 included a quantified religious variable. In this research, the religious variable chosen was most often a single static measure of religion rather than multiple dynamic measures. In addition, other available religious research was seldom cited. Comparison with systematic analyses of religious research in psychology and sociology suggests that psychiatric research lacks conceptual and methodological sophistication. The data suggest that the academic knowledge and skills needed to evaluate religion have not been absorbed into the psychiatric domain.


Casein kinase 1 regulates sterol regulatory element-binding protein (SREBP) to control sterol homeostasis.
Sterol homeostasis is tightly controlled by the sterol regulatory element-binding protein (SREBP) transcription factor that is highly conserved from fungi to mammals. In fission yeast, SREBP functions in an oxygen-sensing pathway to promote adaptation to decreased oxygen supply that limits oxygen-dependent sterol synthesis. Low oxygen stimulates proteolytic cleavage of the SREBP homolog Sre1, generating the active transcription factor Sre1N that drives expression of sterol biosynthetic enzymes. In addition, low oxygen increases the stability and DNA binding activity of Sre1N. To identify additional signals controlling Sre1 activity, we conducted a genetic overexpression screen. Here, we describe our isolation and characterization of the casein kinase 1 family member Hhp2 as a novel regulator of Sre1N. Deletion of Hhp2 increases Sre1N protein stability and ergosterol levels in the presence of oxygen. Hhp2-dependent Sre1N degradation by the proteasome requires Hhp2 kinase activity, and Hhp2 binds and phosphorylates Sre1N at specific residues. Our results describe a role for casein kinase 1 as a direct regulator of sterol homeostasis. Given the role of mammalian Hhp2 homologs, casein kinase 1δ and 1ε, in regulation of the circadian clock, these findings may provide a mechanism for coordinating circadian rhythm and lipid metabolism.


Gene therapy in the CNS: intracerebral grafting of genetically modified cells.
Grafting cells to the CNS has been suggested and applied as a potential approach to CNS therapy through the selective replacement of cells lost as a result of disease or damage. Independently, studies aimed at direct genetic therapy in model systems have recently begun to suggest conceptually new approaches to the treatment of several kinds of human genetic disease, especially those caused by single gene enzyme deficiencies. We suggest that a combination of these two approaches, namely the graftment into the CNS of genetically modified cells, may provide a new approach toward the restoration of some functions in the damaged or diseased CNS. We present evidence for the feasibility of this approach, including a description of some current techniques for mammalian cell gene transfer and CNS grafting, and several possible approaches to clinical applications. Specifically, we report that fibroblasts, genetically modified to secrete NGF by infection with a retroviral vector and implanted into the brains of rats with a surgical lesion of the fimbria-fornix, prevented the degeneration of cholinergic neurons that would die without treatment.


[Psychological stress in the earthquake survivors: the psychological aftermath of the Wenchuan earthquake].
To investigate the psychological stress in the survivors of the May 12, 2008 Wenchuan earthquake transferred to Guangzhou for treatment, and explore the association between the psychological stress and the physical injuries related to the earthquake to promote both the physical and psychological recoveries of the survivors. Fifty-five earthquake survivors, including 27 with 28 without physical injuries, were transferred in our hospital 1 week after the earthquake. The Posttraumatic Stress Disorder (PTSD) Checklist-Civilian version (PCL-C) and the Self Reporting Questionnaire (SRQ) were used to investigate the psychological stress in these survivors. The earthquake caused serious psychological stress in these survivors, and 43.63% of the survivors had high PCL-C scores (50 or above) and 78.18% had high SRQ scores (over 7), with 41.82% having high scores for both PCL-C and SRQ. The survivors with physical injuries generally had high PCL-C and SRQ scores (49.780-/+14.503 and 12.110-/+4.619, respectively), which, however, were not statistically different from the scores of the survivors without injuries (44.460-/+13.206 and 10.460-/+5.000, respectively, P>0.05). The injured survivors showed high scores for the subscales of persistent avoidance symptoms and of anger and irritability, in which the item scores for "efforts to avoid activities or places that arouse recollections of the earthquake" and "feeling of detachment or estrangement from others" were significantly different between the survivor with physical injuries and those without (P=0.034 and 0.018, respectively). The Wenchuan earthquake causes serious psychological stress in the survivors, and the wounded are more inclined to have persistent avoidance symptoms and enhanced irritability. In addition to the care of the physical injuries, psychological counseling and social support may help ameliorate the psychological trauma in the survivors and reduce the incidence of PTSD.


Stable fiber delivery of radio-frequency signal based on passive phase correction.
A novel passive phase correction method for stable fiber transfer of radio-frequency (RF) signal is proposed and demonstrated. By employing only one local oscillator and two frequency mixers in the local station, an RF signal received by an optical remote antenna unit is transmitted to the local station with very small phase jitter. An experiment is performed. When a 6 GHz RF signal is delivered through a 20 km single-mode fiber, effective cancellation of the RF signal's phase jitter induced by environmental perturbations is achieved. The residual jitter is less than 1.33 ps (about 0.05 rad). The proposed scheme requires no active mechanism to compensate the fiber-length fluctuations, and is thus compact, cost-effective, and easy to implement.


Liver ischemia/reperfusion injury: processes in inflammatory networks--a review.
Liver ischemia/reperfusion (IR) injury is typified by an inflammatory response. Understanding the cellular and molecular events underpinning this inflammation is fundamental to developing therapeutic strategies. Great strides have been made in this respect recently. Liver IR involves a complex web of interactions between the various cellular and humoral contributors to the inflammatory response. Kupffer cells, CD4+ lymphocytes, neutrophils, and hepatocytes are central cellular players. Various cytokines, chemokines, and complement proteins form the communication system between the cellular components. The contribution of the danger-associated molecular patterns and pattern recognition receptors to the pathophysiology of liver IR injury are slowly being elucidated. Our knowledge on the role of mitochondria in generating reactive oxygen and nitrogen species, in contributing to ionic disturbances, and in initiating the mitochondrial permeability transition with subsequent cellular death in liver IR injury is continuously being expanded. Here, we discuss recent findings pertaining to the aforementioned factors of liver IR, and we highlight areas with gaps in our knowledge, necessitating further research.


The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the brachyury gene regulatory network.
The notochord is the distinctive characteristic of chordates; however, the knowledge of the complement of transcription factors governing the development of this structure is still incomplete. Here we present the expression patterns of seven transcription factor genes detected in the notochord of the ascidian Ciona intestinalis at various stages of embryonic development. Four of these transcription factors, Fos-a, NFAT5, AFF and Klf15, have not been directly associated with the notochord in previous studies, while the others, including Spalt-like-a, Lmx-like, and STAT5/6-b, display evolutionarily conserved expression in this structure as well as in other domains. We examined the hierarchical relationships between these genes and the transcription factor Brachyury, which is necessary for notochord development in all chordates. We found that Ciona Brachyury regulates the expression of most, although not all, of these genes. These results shed light on the genetic regulatory program underlying notochord formation in Ciona and possibly other chordates.


Enterohaemorrhagic Escherichia coli activates nitrate respiration to benefit from the inflammatory response for initiation of microcolony-formation.
For successful colonization, enterohaemorrhagic Escherichia coli (EHEC) injects virulence factors, called effectors, into target cells through the type three secretion system (T3SS), which is composed of a needle and basal body. Under anaerobic conditions, the T3SS machinery remains immature and does not have a needle structure. However, activation of nitrate respiration enhances the completion of the T3SS machinery. Because nitric oxide released by the host inflammatory response increases nitrate concentration, we sought to determine the effect of the inflammatory response on initiation of EHEC microcolony-formation. The colony-forming capacity was increased in accordance with the increase of nitrate in the medium. The addition of the nitric oxide-producing agent NOR-4 also enhanced the adherence capacity, which was dependent on nitrate reductase encoded by the narGHJI genes. Culture supernatant of epithelial cells, which was stimulated by a cytokine mixture, enhanced the colony-forming capacity of wild-type EHEC but not of the narGHJI mutant. Finally, colony formation by wild-type EHEC on epithelial cells, which were preincubated with heat-killed bacteria, was higher than the narGHJI mutant, and this effect was abolished by aminoguanidine hydrochloride, which is an iNOS (inducible nitric oxide synthase) inhibitor. These results indicate that the inflammatory response enhances EHEC adherence by increasing nitrate concentration.


Review of in vitro systems with potential for use in teratogenicity screening.
In this review an in vitro system is considered to be any developing tissue, organ, or organism other than mammalian embryo in situ. Before the various test systems that have been used or proposed are discussed, attention is given to the questions of whether all chemicals in the environment are in need of biological testing and what criteria should be used in making this judgment. Consideration is also given to selection of the appropriate level of rigorousness to be used in tests of different categories of chemicals. To aid in this, the characteristics of an optimal test are assembled and used as a standard for estimating the potential usefulness of the various in vitro systems. The systems discussed include bacteria and other unicellular organisms, somatic cells in culture, tissue culture, organ culture, intact invertebrate embryos (e.g., drosophila, sea urchins, sand dollars), intact lower vertebrate embryos (e.g., frogs, other amphibians, fish), cultured mammalian embryos, and incubating chick embryos. None of these are regarded as sufficiently validated in terms of comparisons with known teratogenic responses in pregnant mammals to warrant adoption as a reliable test at this time. Intact embryos of drosophila, sea urchins, amphibians, and fish are regarded as promising, but much research is needed to ascertain their predictive validity for mammals. The incubating chick embryo, however, possesses more of the essential features of the optimal system than any of the others. A tentative proposal using the chick is outlined, but it will require considerable further comparison with currently used procedures in pregnant mammals before its reliability can be fully evaluated.


Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis.
Severe alcoholic hepatitis (AH) has high mortality. We assessed the comparative effectiveness of pharmacological interventions for severe AH, through a network meta-analysis combining direct and indirect treatment comparisons. We conducted a systematic literature review, through February 2015, for randomized controlled trials of adults with severe AH (discriminant function ≥32 and/or hepatic encephalopathy) that compared the efficacy of active pharmacologic interventions (corticosteroids, pentoxifylline, and N-acetylcysteine [NAC], alone or in combination) with each other or placebo, in reducing short-term mortality (primary outcome) and medium-term mortality, acute kidney injury, and/or infections (secondary outcomes). We performed direct and Bayesian network meta-analysis for all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. We included 22 randomized controlled trials (2621 patients) comparing 5 different interventions. In a direct meta-analysis, only corticosteroids decreased risk of short-term mortality. In a network meta-analysis, moderate quality evidence supported the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-0.73) or in combination with pentoxifylline (RR, 0.53; 95% CrI, 0.36-0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality; low quality evidence showed that pentoxifylline also decreased short-term mortality (RR, 0.70; 95% CrI, 0.50-0.97). The addition of NAC, but not pentoxifylline, to corticosteroids may be superior to corticosteroids alone for reducing short-term mortality. No treatment was effective in reducing medium-term mortality. Imprecise estimates and the small number of direct trials lowered the confidence in several comparisons. In patients with severe AH, pentoxifylline and corticosteroids (alone and in combination with pentoxifylline or NAC) can reduce short-term mortality. No treatment decreases risk of medium-term mortality.


Older adults' knowledge and perception of fall risk and prevention: a scoping review.
Falls are a leading cause of injury and mortality among older adults. While multiple strategies are effective at reducing fall risk, uptake is low. Understanding how older adults think about fall risk and prevention activities can inform outreach initiatives and engagement. We systematically searched PubMed, SCOPUS and Google Scholar for articles published between January 2015 and April 2023. Studies were eligible if they reported on knowledge or perception of fall risk and/or prevention among community-dwelling older adults. We included 53 studies from 20 different countries. Over half of the studies used qualitative methods, 19 used quantitative, and three used mixed methods. Most of the older adults could identify some fall risk factors and the consequences of falls. However, many older adults did not view themselves as at-risk for falls. Some older adults consider falls an inevitable part of ageing, while others believe that falls can be prevented. Cultural context may play a role in shaping these beliefs. Several studies reported on older adults' experiences and the perceived barriers and facilitators of participating in fall prevention activities. Improving the accuracy of older adults' perceptions of their own fall risk and highlighting the fact that many falls are preventable are two key messages that may help motivate older adults to take action to prevent falls. Older adults cite their healthcare provider as a trusted source of prevention information, and clinicians can leverage this opportunity to inform and motivate older adult patients about fall prevention.


Neurological outcomes of patients with history of obstructive sleep apnea after a cardiac arrest.
Cardiac arrest survivors may have disabilities due to hypoxic brain injury. Patients with obstructive sleep apnea are exposed to intermittent hypoxemia that may lead to ischemic preconditioning. We have hypothesized that patients with obstructive sleep apnea have better neurological outcomes following a cardiac arrest due to preconditioning of the brain. We retrospectively analyzed all the survivors of in-hospital cardiac arrest from January 2006 to September 2016. Patients with confirmed or suspected obstructive sleep apnea were selected for further analysis and those without were used as comparison. Primary outcome was neurological functionality on hospital discharge by the Cerebral Performance Category. A total of 739 patients had cardiac arrest within the study period. The immediate mortality rate was 59% (N=43) in patients with obstructive sleep apnea and 94% (N=623) in those without (p<0.001). Approximately 10% (N=73) were discharged alive and these were selected for further analysis. Patients without obstructive sleep apnea had more frequently "Poor" outcomes compared to those with obstructive sleep apnea (OR 2.91; 95% CI, 1.11-7.66; p=0.03). After adjusting in a multivariate analysis, obstructive sleep apnea was "protective" of "Poor" neurological outcomes: adjusted OR 0.21; 95% CI, 0.06-0.64; p=0.01. Patients with obstructive sleep apnea had better unadjusted survival rates, and favorable adjusted neurological outcomes at discharge compared to those without obstructive sleep apnea. These results suggest that obstructive sleep apnea patients may tolerate better acute brain ischemia due to preconditioning.


Evolution of antero-posterior patterning of the limb: Insights from the chick.
The developing limbs of chicken embryos have served as pioneering models for understanding pattern formation for over a century. The ease with which chick wing and leg buds can be experimentally manipulated, while the embryo is still in the egg, has resulted in the discovery of important developmental organisers, and subsequently, the signals that they produce. Sonic hedgehog (Shh) is produced by mesenchyme cells of the polarizing region at the posterior margin of the limb bud and specifies positional values across the antero-posterior axis (the axis running from the thumb to the little finger). Detailed experimental embryology has revealed the fundamental parameters required to specify antero-posterior positional values in response to Shh signaling in chick wing and leg buds. In this review, the evolution of the avian wing and leg will be discussed in the broad context of tetrapod paleontology, and more specifically, ancestral theropod dinosaur paleontology. How the parameters that dictate antero-posterior patterning could have been modulated to produce the avian wing and leg digit patterns will be considered. Finally, broader speculations will be made regarding what the antero-posterior patterning of chick limbs can tell us about the evolution of other digit patterns, including those that were found in the limbs of the earliest tetrapods.


Opening the toolkit for genetic analysis and control of Anopheles mosquito vectors.
Anopheles is the only genus of mosquitoes that transmit human malaria and consequently the focus of large scale genome and transcriptome-wide association studies. Genetic tools to define the function of the candidate genes arising from these analyses are vital. Moreover, genome editing offers the potential to modify Anopheles population structure at local and global scale to provide complementary tools towards the ultimate goal of malaria elimination. Major breakthroughs in Anopheles genetic analysis came with the development of germline transformation and RNA interference technology. Yet, the field has been revolutionised again by precise genome editing now possible through site-specific nucleases. Here we review the components of the current genetic toolkit available to study Anopheles, focusing particularly on how these technical advances are used to gain insight into malaria transmission and the design of genetic methods to control Anopheles vectors.


Spectrum of the Intensity Variations in 3C 273B.
The intensity variations in radio source 3C 273B have been measured at wavelengths of 31.3, 21.2, and 10.6 centimeters. At 31.3 centimeters the variation is quite small, indicating that the variable component of the source is optically thick at this wavelength. Study of several dijfferent model sources shows that the observed dependence of the intensity variations on frequency can best be explained by an increase of the electron density in a source region about 2 parsecs in diameter. This interpretation is consistent with the distance to 3C 273 determined from Hubble's law and the observed red shift.


Brain injury from marked hypoxia in cats: role of hypotension and hyperglycemia.
The present study identifies several factors that govern brain pathologic response to marked hypoxia. None of 13 cats exposed to 25 minutes of marked hypoxia (FiO2 = 3.4%; PaO2 = 17 +/- 3 mm Hg, S.D.) that maintained mean arterial blood pressure (MABP) greater than 65 mm Hg were brain injured after reoxygenation and long term survival. In contrast, 12 of 13 exposed to the same hypoxia but that experienced reductions in MABP less than 45 mm Hg for 4 +/- 1 minutes developed a pattern of brain injury closely resembling that of humans surviving in a persistent vegetative state after cardiorespiratory arrest. Higher serum glucose and lactate concentrations and lower blood pH values significantly correlated with development of hypotension during hypoxia. Four of 8 cats exposed to 21 minutes of marked hypoxia followed by 4 minutes of 100% N2 breathing that also led to hypotension similarly developed brain injury. Among the hypoxic/hypotensive cats the magnitude of the hyperglycemic response to hypoxia as modulated by 0, 1, or 2 days of preexposure fasting, strongly correlated with occurrence and extent of brain damage. Peak cisterna magna CSF lactate concentrations 10 to 30 minutes into recovery distinguished those animals that remained brain-intact (less than 13 mM) from those that developed brain damage (greater than 15 mM) with 100% accuracy. Seven cats developed delayed cardiogenic shock 3 to 12 hours into the recovery period. This outcome was predicted by blood pH values less than 6.70 shortly after resuscitation while all 27 surviving cats exhibited values greater than 6.80.


Targeted deletion of the sciellin gene resulted in normal development and maturation.
Sciellin, together with other precursor proteins, was cross-linked by transglutaminase 1 to form the cornified envelope, an essential component of the physical barrier of the epidermis and stratified squamous epithelia. To more fully understand the function of sciellin in cornified envelope formation, we generated sciellin null mice. The mice appeared normal in their development and maturation and there were no structural features that distinguished them from littermate controls. Isolated cornified envelopes appeared normal in structure and were not more fragile to mechanical stress. There was no evidence of decreased barrier function or altered expression of other cornified envelope components. Transgenic mice expressing the repeat domain appeared to have a normal phenotype, like the null, and did not alter endogenous sciellin expression. We conclude that sciellin null mice had no structural anomalies and the transgenic mice did not act as a dominant-negative mutation.


A new myeloarchitectonic map of the human neocortex based on data from the Vogt-Vogt school.
The human cerebral cortex contains numerous myelinated fibres, the arrangement and density of which is by no means homogeneous throughout the cortex. Local differences in the spatial organization of these fibres render it possible to recognize areas with a different myeloarchitecture. The neuroanatomical subdiscipline aimed at the identification and delineation of such areas is known as myeloarchitectonics. During the period extending from 1910 to 1970, Oscar and Cécile Vogt and their numerous collaborators (The Vogt-Vogt school) published a large number of myeloarchitectonic studies on the cortex of the various lobes of the human cerebrum. Recently, one of us (Nieuwenhuys in Brain Struct Funct 218: 303-352, 2013) extensively reviewed these studies. It was concluded that the data available are adequate and sufficient for the composition of a myeloarchitectonic map of the entire human neocortex. The present paper is devoted to the creation of this map. Because the data provided by the Vogt-Vogt school are derived from many different brains, a standard brain had to be introduced to which all data available could be transferred. As such, the colin27 structural scan, aligned to the MNI305 template was selected. The procedure employed in this transfer involved computer-aided transformations of the lobar maps available in the literature, to the corresponding regions of the standard brain, as well as local adjustments in the border zones of the various lobes. The resultant map includes 180 myeloarchitectonic areas, 64 frontal, 30 parietal, 6 insular, 17 occipital and 63 temporal. The designation of the various areas with simple Arabic numbers, introduced by Oscar Vogt for the frontal and parietal cortices, has been extended over the entire neocortex. It may be expected that combination of the myeloarchitectonic data of the Vogt-Vogt school, as expressed in our map, with the results of the detailed cytoarchitectonic and receptor architectonic studies of Karl Zilles and Katrin Amunts and their numerous associates, will yield a comprehensive 'supermap' of the structural organization of the human neocortex. For the time being, i. e., as long as this 'supermap' is not yet available, our map may provide a tentative frame of reference for (a) the morphological interpretation of the results of functional neuroimaging studies; (b) the selection of starting points (seed voxels, regions-of-interest) in diffusion tractography studies and


Chiari innominate osteotomy in adults. Technique, indications and contra-indications.
The results are reported of 44 consecutive Chiari innominate osteotomies performed on 39 adult patients aged between 18 and 55 years for symptoms arising from disproportion between the acetabulum and the femoral head. Predisposing causes included congenital dysplasia of the acetabulum, congenital subluxation of the hip, and Perthes' disease. Follow-up averaged 5 years 2 months. Four pre-operative categories of dysplasia and degeneration were recognised. The analysis of the results from each category made possible the recognition of clinical and radiological features likely to provide a satisfactory result. Of 32 cases now considered to have been selected appropriately, 29 (90%) achieved a significant and apparently lasting improvement. In the other 12 cases there were 9 failures--an unacceptable proportion. The features predisposing to these poor results are discussed. The operation is not difficult. It is safe, and is less demanding than the complex alternative "double", "triple" and "dial" osteotomies. In successful cases there is reduction in symptoms and in limp, and improvement of radiological appearances beginning six months after surgery and progressing to a maximum recovery two to three years later.


Comparison of Ticagrelor and Clopidogrel in Patients With Acute Coronary Syndrome at High Bleeding or Ischemic Risk.
Current guidelines recommend individualizing the choice and duration of P2Y12 inhibitor therapy based on the trade-off between bleeding and ischemic risk. However, whether a potent P2Y12 inhibitor (ticagrelor) or a less potent one (clopidogrel) is more appropriate in patients with acute coronary syndrome (ACS) in the setting of high bleeding or ischemic risk is not clear. The study aimed to compare the clinical outcomes of clopidogrel and ticagrelor in patients with ACS at high bleeding or ischemic risk. A total of 5,713 patients with ACS were included in this retrospective study. The Cox proportional hazard regression model was adjusted by applying the inverse probability weighted approach to reduce treatment selection bias. The primary clinical outcome was all-cause death. Secondary outcomes included in-hospital death, ACS, target vessel revascularization, stent thrombosis, stroke, or clinically significant or major bleeding. The median follow-up duration was 53.6 months. After multivariable Cox model using an inverse probability weighted approach, all-cause death in the overall population and subgroups of patients at high bleeding risk, and/or at high ischemic risk were not significantly different between clopidogrel and ticagrelor. Rates for secondary outcomes were also similar between the groups. In conclusion, ticagrelor and clopidogrel are associated with comparable clinical outcomes in patients with ACS irrespective of bleeding and ischemic risk.


Novel control by the CA3 region of the hippocampus on neurogenesis in the dentate gyrus of the adult rat.
The dentate gyrus is a site of continued neurogenesis in the adult brain. The CA3 region of the hippocampus is the major projection area from the dentate gyrus. CA3 sends reciprocal projections back to the dentate gyrus. Does this imply that CA3 exerts some control over neurogenesis? We studied the effects of lesions of CA3 on neurogenesis in the dentate gyrus, and on the ability of fluoxetine to stimulate mitotic activity in the progenitor cells. Unilateral ibotenic-acid generated lesions were made in CA3. Four days later there was no change on the number of either BrdU or Ki67-positive progenitor cells in the dentate gyrus. However, after 15 or 28 days, there was a marked reduction in surviving BrdU-labelled cells on the lesioned side (but no change in Ki-67+ cells). pCREB or Wnt3a did not co-localise with Ki-67 but with NeuN, a marker of mature neurons. Lesions had no effect on the basal expression of either pCREB or Wnt3a. Subcutaneous fluoxetine (10 mg/kg/day) for 14 days increased the number of Ki67+ cells as expected on the control (non-lesioned) side but not on that with a CA3 lesion. Nevertheless, the expected increase in BDNF, pCREB and Wnt3a still occurred on the lesioned side following fluoxetine treatment. Fluoxetine has been reported to decrease the number of "mature" calbindin-positive cells in the dentate gyrus; we found this still occurred on the side of a CA3 lesion. We then showed that the expression GAP-43 was reduced in the dentate gyrus on the lesioned side, confirming the existence of a synaptic connection between CA3 and the dentate gyrus. These results show that CA3 has a hitherto unsuspected role in regulating neurogenesis in the dentate gyrus of the adult rat.


Prey sensing and response in a nematode-trapping fungus is governed by the MAPK pheromone response pathway.
Detection of surrounding organisms in the environment plays a major role in the evolution of interspecies interactions, such as predator-prey relationships. Nematode-trapping fungi (NTF) are predators that develop specialized trap structures to capture, kill, and consume nematodes when food sources are limited. Despite the identification of various factors that induce trap morphogenesis, the mechanisms underlying the differentiation process have remained largely unclear. Here, we demonstrate that the highly conserved pheromone-response MAPK pathway is essential for sensing ascarosides, a conserved molecular signature of nemaotdes, and is required for the predatory lifestyle switch in the NTF Arthrobotrys oligospora. Gene deletion of STE7 (MAPKK) and FUS3 (MAPK) abolished nematode-induced trap morphogenesis and conidiation and impaired the growth of hyphae. The conserved transcription factor Ste12 acting downstream of the pheromone-response pathway also plays a vital role in the predation of A. oligospora. Transcriptional profiling of a ste12 mutant identified a small subset of genes with diverse functions that are Ste12 dependent and could trigger trap differentiation. Our work has revealed that A. oligospora perceives and interprets the ascarosides produced by nematodes via the conserved pheromone signaling pathway in fungi, providing molecular insights into the mechanisms of communication between a fungal predator and its nematode prey.


A Long-Term Study of Young Children's Rapport, Social Emulation, and Language Learning With a Peer-Like Robot Playmate in Preschool.
Prior research has demonstrated the importance of children's peers for their learning and development. In particular, peer interaction, especially with more advanced peers, can enhance preschool children's language growth. In this paper, we explore one factor that may modulate children's language learning with a peer-like social robot: rapport. We explore connections between preschool children's learning, rapport, and emulation of the robot's language during a storytelling intervention. We performed a long-term field study in a preschool with 17 children aged 4-6 years. Children played a storytelling game with a social robot for 8 sessions over two months. For some children, the robot matched the level of its stories to the children's language ability, acting as a slightly more advanced peer (Matched condition); for the others, the robot did not match the story level (Unmatched condition). We examined children's use of target vocabulary words and key phrases used by the robot, children's emulation of the robot's stories during their own storytelling, and children's language style matching (LSM-a measure of overlap in function word use and speaking style associated with rapport and relationship) to see whether they mirrored the robot more over time. We found that not only did children emulate the robot more over time, but also, children who emulated more of the robot's phrases during storytelling scored higher on the vocabulary posttest. Children with higher LSM scores were more likely to emulate the robot's content words in their stories. Furthermore, the robot's personalization in the Matched condition led to increases in both children's emulation and their LSM scores. Together, these results suggest first, that interacting with a more advanced peer is beneficial for children, and second, that children's emulation of the robot's language may be related to their rapport and their learning. This is the first study to empirically support that rapport may be a modulating factor in children's peer learning, and furthermore, that a social robot can serve as an effective intervention for language development by leveraging this insight.


Effects of global system for mobile communications 1800 MHz radiofrequency electromagnetic fields on gene and protein expression in MCF-7 cells.
Despite many studies over a decade, it still remains ambiguous as to the real biological effects induced by radiofrequency electromagnetic fields (RF EMF) utilized in mobile telephony. Here we investigated global gene and protein responses to RF EMF simulating the Global System for Mobile Communications (GSM) 1800 MHz signal in human breast cancer cell line MCF-7 using genomic and proteomic approaches. GeneChip analysis identified a handful of consistent changed genes after exposure to RF EMF at specific absorption rates (SAR) of up to 3.5 W/kg for 24 h. However, these differentially transcribed genes could not be further confirmed by real-time RT-PCR assay. Meanwhile, systematic proteome analysis of the MCF-7 cells revealed that a few but different proteins were differentially expressed under continuous or intermittent RF EMF exposure at SAR of 3.5 W/kg for 24 h or less, implying that the observed effects might have occurred by chance. Overall, the present study does not provide convincing evidence that RF EMF exposure under current experimental conditions can produce distinct effects on gene and protein expression in the MCF-7 cells.


Nutrition labelling: a review of research on consumer and industry response in the global South.
To identify peer-reviewed research on consumers' usage and attitudes towards the nutrition label and the food industry's response to labelling regulations outside Europe, North America, and Australia and to determine knowledge gaps for future research. Narrative review. This review identified nutrition labelling research from 20 countries in Asia, Africa, the Middle East, and Latin America. Consumers prefer that pre-packaged food include nutrition information, although there is a disparity between rates of use and comprehension. Consumer preference is for front-of-pack labelling and for information that shows per serving or portion as a reference unit, and label formats with graphics or symbols. Research on the food and beverage industry's response is more limited but shows that industry plays an active role in influencing legislation and regulation. Consumers around the world share preferences with consumers in higher income countries with respect to labelling. However, this may reflect the research study populations, who are often better educated than the general population. Investigation is required into how nutrition labels are received in emerging economies especially among the urban and rural poor, in order to assess the effectiveness of labelling policies. Further research into the outlook of the food and beverage industry, and also on expanded labelling regulations is a priority. Sharing context-specific research regarding labelling between countries in the global South could be mutually beneficial in evaluating obesity prevention policies and strategies.


MUS81 encodes a novel helix-hairpin-helix protein involved in the response to UV- and methylation-induced DNA damage in Saccharomyces cerevisiae.
The gene MUS81 p6ethyl methansulfonate, UV sensitive) was identified as clone 81 in a two-hybrid screen using the Saccharomyces cerevisiae Rad54 protein as a bait. It encodes a novel protein with a predicted molecular mass of 72,316 (632 amino acids) and contains two helix-hairpin-helix motifs, which are found in many proteins involved in DNA metabolism in bacteria, yeast, and mammals. Mus81p also shares homology with motifs found in the XPF endonuclease superfamily. Deletion of MUS81 caused a recessive methyl methansulfonate- and UV-sensitive phenotype. However, mus81delta cells were not significantly more sensitive than wild-type to gamma-radiation or double-strand breaks induced by HO endonuclease. Double mutant analysis suggests that Rad54p and Mus81p act in one pathway for the repair of, or tolerance to, UV-induced DNA damage. A complex containing Mus81p and Rad54p was identified in immunoprecipitation experiments. Deletion of MUS81 virtually eliminated sporulation in one strain background and reduced sporulation and spore viability in another. Potential homologs of Mus81p have been identified in Schizosaccharomyces pombe, Caenorhabditis elegans and Arabidopsis thaliana. We hypothesize that Mus81p plays a role in the recognition and/or processing of certain types of DNA damage (caused by UV and MMS) during repair or tolerance processes involving the recombinational repair pathway.


Neoplasms of the shoulder girdle.
The author has briefly discussed radiation therapy, immunotherapy, and chemotherapy in the treatment of some of the more commonly encountered disease entities affecting the shoulder girdle. Specific operations and their indications are discussed. However, utilizing physical and x-ray examination, arteriography, lymphangiography, and bone scan information, the surgeon may decide that the routine operation is not indicated for a particular tumor problem. He should be able to be flexible and to modify the operation according to the specific presenting problem and not be bound by routine fixed rules. In this way the patient can be assured of the very best treatment.


Decomposing perseverative errors among undergraduates scoring high on the Schizotypal Personality Questionnaire.
Cognitive control (CC), the capacity to flexibly direct resources to a goal by selecting and integrating relevant contextual information, is impaired among persons with schizophrenia-spectrum disorders. CC is achieved, in part, through shifting one's cognitive set towards stimuli of task relevance. Set-shifting deficits typically result in perseverative errors, like those captured by the Wisconsin Card Sorting Test (WCST). However, a disadvantage of the WCST is that it confounds the potential sources of perseverative errors. The Dimensional Change Card Sorting Task (DCCS), in contrast, allows for the decomposition of perseverative errors by systematically varying the shape and/or color of stimuli across pre-switch, switch and post-switch trials. Using these techniques previous research has evaluated the separable contributions of negative priming, positive priming, and extra dimensional shifting to the production of perseverative errors. In the current study, college students scoring high on the Schizotypal Personality Questionnaire (High-SPQ; Raine, A., 1991. The SPQ: a scale for the assessment of schizotypal personality based on DSM-III-R criteria. Schizophr. Bull. 17 (4), 555-564.) and average scoring individuals (Ave-SPQ) were administered the DCCS to investigate schizotypal-related mechanisms underlying set-shifting abnormalities. Relative to Ave-SPQ, High-SPQ participants showed more perseverative responses that were restricted to the positive priming post-switch condition. Possible mechanisms of this impairment, including depletion of cognitive resources and differences in strategy commitment, are discussed.


Community health assessment following mercaptan spill: Eight Mile, Mobile County, Alabama, September 2012.
In 2008, a lightning strike caused a leak of tert-butyl mercaptan from its storage tank at the Gulf South Natural Gas Pumping Station in Prichard, Alabama. On July 27, 2012, the Alabama Department of Public Health requested Centers for Disease Control and Prevention epidemiologic assistance investigating possible health effects resulting from airborne exposure to mercaptan from a contaminated groundwater spring, identified in January 2012. To assess the self-reported health effects in the community, to determine the scope of the reported medical services received, and to develop recommendations for prevention and response to future incidents. In September 2012, we performed a representative random sampling design survey of households, comparing reported exposures and health effects among residents living in 2 circular zones located within 1 and 2 miles from the contaminated source. Eight Mile community, Prichard, Alabama. We selected 204 adult residents of each household (≥ 18 years) to speak for all household members. Self-reported mercaptan odor exposure, physical and mental health outcomes, and medical-seeking practices, comparing residents in the 1- and 2-mile zones. In the past 6 months, 97.9% of respondents in the 1-mile zone and 77.6% in the 2-mile zone reported mercaptan odors. Odor severity was greater in the 1-mile zone, in which significantly more subjects reported exposures aggravating their physical and mental health including shortness of breath, eye irritations, and agitated behavior. Overall, 36.5% sought medical care for odor-related symptoms. Long-term odorous mercaptan exposures were reportedly associated with physical and psychological health complaints. Communication messages should include strategies to minimize exposures and advise those with cardiorespiratory conditions to have medications readily available. Health care practitioners should be provided information on mercaptan health effects and approaches to prevent exacerbating existing chronic diseases.


Novel probiotic approach to counter Paenibacillus larvae infection in honey bees.
American foulbrood (AFB) is a highly virulent disease afflicting honey bees (Apis mellifera). The causative organism, Paenibacillus larvae, attacks honey bee brood and renders entire hives dysfunctional during active disease states, but more commonly resides in hives asymptomatically as inactive spores that elude even vigilant beekeepers. The mechanism of this pathogenic transition is not fully understood, and no cure exists for AFB. Here, we evaluated how hive supplementation with probiotic lactobacilli (delivered through a nutrient patty; BioPatty) affected colony resistance towards a naturally occurring AFB outbreak. Results demonstrated a significantly lower pathogen load and proteolytic activity of honey bee larvae from BioPatty-treated hives. Interestingly, a distinctive shift in the microbiota composition of adult nurse bees occurred irrespective of treatment group during the monitoring period, but only vehicle-supplemented nurse bees exhibited higher P. larvae loads. In vitro experiments utilizing laboratory-reared honey bee larvae showed Lactobacillus plantarum Lp39, Lactobacillus rhamnosus GR-1, and Lactobacillus kunkeei BR-1 (contained in the BioPatty) could reduce pathogen load, upregulate expression of key immune genes, and improve survival during P. larvae infection. These findings suggest the usage of a lactobacilli-containing hive supplement, which is practical and affordable for beekeepers, may be effective for reducing enzootic pathogen-related hive losses.


A Comparison of Methods for Analyzing Viral Load Data in Studies of HIV Patients.
HIV RNA viral load (VL) is a pivotal outcome variable in studies of HIV infected persons. We propose and investigate two frameworks for analyzing VL: (1) a single-measure VL (SMVL) per participant and (2) repeated measures of VL (RMVL) per participant. We compared these frameworks using a cohort of 720 HIV patients in care (4,679 post-enrollment VL measurements). The SMVL framework analyzes a single VL per participant, generally captured within a "window" of time. We analyzed three SMVL methods where the VL binary outcome is defined as suppressed or not suppressed. The omit-participant method uses a 8-month "window" (-6/+2 months) around month 24 to select the participant's VL closest to month 24 and removes participants from the analysis without a VL in the "window". The set-to-failure method expands on the omit-participant method by including participants without a VL within the "window" and analyzes them as not suppressed. The closest-VL method analyzes each participant's VL measurement closest to month 24. We investigated two RMVL methods: (1) repeat-binary classifies each VL measurement as suppressed or not suppressed and estimates the proportion of participants suppressed at month 24, and (2) repeat-continuous analyzes VL as a continuous variable to estimate the change in VL across time, and geometric mean (GM) VL and proportion of participants virally suppressed at month 24. Results indicated the RMVL methods have more precision than the SMVL methods, as evidenced by narrower confidence intervals for estimates of proportion suppressed and risk ratios (RR) comparing demographic strata. The repeat-continuous method had the most precision and provides more information than other considered methods. We generally recommend using the RMVL framework when there are repeated VL measurements per participant because it utilizes all available VL data, provides additional information, has more statistical power, and avoids the subjectivity of defining a "window."


Charcot foot in diabetes and an update on imaging.
Charcot neuroarthropathy (CN) is a serious complication of diabetes mellitus that can cause major morbidity including limb amputation. Since it was first described in 1883, and attributed to diabetes mellitus in 1936, the diagnosis of CN has been very challenging even for the experienced practitioners. Imaging plays a central role in the early and accurate diagnosis of CN, and in distinction of CN from osteomyelitis. Conventional radiography, computed tomography, nuclear medicine scintigraphy, magnetic resonance imaging, and positron emission tomography are the imaging techniques currently in use for the evaluation of CN but modalities other than magnetic resonance imaging appeared to be complementary. This study focuses on imaging findings of acute and chronic neuropathic osteoarthropathy in diabetes and discrimination of infected vs. non-infected neuropathic osteoarthropathy.


Fecal microbiota transplantation for gastrointestinal disorders.
The importance of the gut microbiome in human health is being increasingly recognized. The purpose of this review is to examine the existing literature pertaining to alterations in the gut microbiome and the utility of microbiome restoration therapies in gastrointestinal disorders. Imbalance and maladaptation of the microbiome, termed dysbiosis, has been associated with several disease states such as irritable bowel syndrome, Clostridium difficile infection, inflammatory bowel diseases, nonalcoholic fatty liver disease, and obesity among others. The possibility of restoration of normal microbiota has become an attractive concept for diseases in which the normal microbiome is perturbed. The rationale of using fecal microbiota transplantation to treat disease has been validated by its successful use in treating recurrent Clostridium difficile infection, which occurs as a result of decreased microbial diversity in the gut, most often in the setting of recent antibiotic treatment. Similar strategies may be applicable to other disorders. Alterations in the gut microbiome are associated with several disorders, and microbiome restoration based therapies such as fecal microbiota transplantation may be an adjunct to conventional treatments but more investigation is needed.


Sensitive Detection of an Erbium Isotope in an Atomic Beam Using Cavity Ring-Down Spectroscopy.
We have applied cavity ring-down spectroscopy (CRDS) to the study of the 166Er isotope in an atomic beam. These measurements were realized with an external cavity diode laser tuned to the 400.9 nm atomic transition of erbium and a customized high-finesse ring-down optical cavity under vacuum. Erbium atomic beams of different number densities were generated in a tantalum foil micro-crucible within the cavity. Absorbance values of the 166Er isotope between 3 × 10-6 and 7 × 10-5 were measured with a best-case precision on the order of 10-6, which is remarkable when considering the extreme temperatures at which the measurements were conducted, and the short detection path which is characteristic of collimated atomic beams. Number densities of erbium atoms were inferred to be between 2 × 106 and 6 × 107 cm-3. This work demonstrates for the first time the ability of studying dilute atomic beams of refractory materials with high accuracy utilizing CRDS. In these initial studies, we used erbium as a model system, but we expect to extend the proposed approach to the measurement of isotopes of uranium and plutonium for nuclear non-proliferation applications.


Desmoplastic ameloblastoma in the mandible.
The desmoplastic variant of ameloblastoma (DA) is characterized by unique histological and radiographic features. It is histologically characterized by an abundance of densely collagenous stroma with small nests and strands of likely compressed odontogenic epithelium. Although radiographic examination of ameloblastomas usually reveals unilocular or multilocular radiolucency, DA may appear as a mixed radiopaque-radiolucent lesion. In this case report, a 68-year-old man who had a complaint of a mass in his right mental region is presented. The patient was unable to wear his prosthesis because of an underlying swelling. An incisional biopsy was performed. Microscopic examination of the surgical specimen revealed large epithelial islands of ameloblast-like cells within increased, dense, collagenous desmoplastic stroma. Histopathologically, it was diagnosed as DA. Under local anesthesia, the lesion was enucleated. There was no recurrence after 32 months of follow-up.


Predicting postsurgery nasal physiology with computational modeling: current challenges and limitations.
High failure rates for surgical treatment of nasal airway obstruction (NAO) indicate that better diagnostic tools are needed to improve surgical planning. This study evaluates whether computer models based on a surgeon's edits of presurgery scans can accurately predict results from computer models based on postoperative scans of the same patient using computational fluid dynamics. Prospective study. Academic medical center. Three-dimensional nasal models were reconstructed from computed tomographic scans of 10 patients with NAO presurgery and 5 to 8 months postsurgery. To create transcribed-surgery models, the surgeon digitally modified the preoperative reconstruction in each patient to represent physical changes expected from surgery and healing. Steady-state, laminar, inspiratory airflow was simulated in each model under physiologic, pressure-driven conditions. Transcribed-surgery and postsurgery model variables were statistically different from presurgery variables at α = 0.05. Unilateral nasal resistance and airflow were not statistically different between transcribed-surgery and postsurgery models, but bilateral resistance was significantly different. Cross-sectional average pressures in transcribed surgery trended with postsurgery. Transcribed-surgery prediction errors of postsurgery bilateral resistance were within 10% to 20% and 20% to 30% in 5 and 4 subjects, respectively. Prediction errors for unilateral resistance were <10%, 10% to 20%, and 20% to 30% in 1, 2, and 4 subjects, respectively. Computational models with modifications mimicking actual surgery and healing have the potential to predict postoperative outcomes. However, software to effectively translate virtual surgery steps into computational models is lacking. The ability to account for healing factors and the current limited virtual surgery tools are challenges that need to be overcome for greater accuracy.


Large spin-orbit coupling in carbon nanotubes.
It has recently been recognised that the strong spin-orbit interaction present in solids can lead to new phenomena, such as materials with non-trivial topological order. Although the atomic spin-orbit coupling in carbon is weak, the spin-orbit coupling in carbon nanotubes can be significant due to their curved surface. Previous works have reported spin-orbit couplings in reasonable agreement with theory, and this coupling strength has formed the basis of a large number of theoretical proposals. Here we report a spin-orbit coupling in three carbon nanotube devices that is an order of magnitude larger than previously measured. We find a zero-field spin splitting of up to 3.4 meV, corresponding to a built-in effective magnetic field of 29 T aligned along the nanotube axis. Although the origin of the large spin-orbit coupling is not explained by existing theories, its strength is promising for applications of the spin-orbit interaction in carbon nanotubes devices.


Evidence-based point-of-care tests and device designs for disaster preparedness.
To define pathogen tests and device specifications needed for emerging point-of-care (POC) technologies used in disasters. Surveys included multiple-choice and ranking questions. Multiple-choice questions were analyzed with the chi2 test for goodness-of-fit and the binomial distribution test. Rankings were scored and compared using analysis of variance and Tukey's multiple comparison test. Disaster care experts on the editorial boards of the American Journal of Disaster Medicine and the Disaster Medicine and Public Health Preparedness, and the readers of the POC Journal. Vibrio cholera and Staphylococcus aureus were top-ranked pathogens for testing in disaster settings. Respondents felt that disaster response teams should be equipped with pandemic infectious disease tests for novel 2009 H1N1 and avian H5N1 influenza (disaster care, p < 0.05; POC, p < 0.01). In disaster settings, respondents preferred self-contained test cassettes (disaster care, p < 0.05; POC, p < 0.001) for direct blood sampling (POC, p < 0.01) and disposal of biological waste (disaster care, p < 0.05; POC, p < 0.001). Multiplex testing performed at the POC was preferred in urgent care and emergency room settings. Evidence-based needs assessment identifies pathogen detection priorities in disaster care scenarios, in which Vibrio cholera, methicillin-sensitive and methicillin-resistant Staphylococcus aureus, and Escherichia coli ranked the highest. POC testing should incorporate setting-specific design criteria such as safe disposable cassettes and direct blood sampling at the site of care.


Structured surveillance of infantile gastroenteritis in East Anglia, UK: incidence of infection with common viral gastroenteric pathogens.
The aim of this study was to investigate the burden of disease associated with gastroenteric viruses (rotavirus, norovirus, sapovirus, astrovirus and enteric adenovirus) using structured surveillance of children aged <6 years in the community. Faecal samples were collected between 2000 and 2003 from 685 children with symptoms of gastroenteritis. The children comprised three groups; 223 in the structured surveillance cohort, 203 in a community cohort and 259 in a cohort of hospitalized children. All samples were tested for the presence of viral pathogens using molecular methods. Questionnaires were sent to the parents/carers of the children recruited to the structured surveillance cohort in order to collect data that would allow an estimation of the severity of illness by means of the Vesikari score, and of the cost associated with gastrointestinal disease in this age group. A viral aetiological agent was detected in 53.5% of samples tested. Rotavirus was the most common pathogen found in all three cohorts followed by norovirus and enteric adenoviruses. Multiple viruses were found in 8% of the samples, and commonly involved rotavirus and any other virus. G1P[8] was the most commonly detected rotavirus strain and there was no significant difference in the distribution of rotavirus genotypes among the three cohorts. Analysis of the questionnaires indicated that rotavirus infections were likely to be more severe than any other virus infection, and children from whom a viral pathogen was identified were more likely to require rehydration therapy.


Status of NCRP Scientific Committee 1-23 Commentary on Guidance on Radiation Dose Limits for the Lens of the Eye.
Previous National Council on Radiation Protection and Measurements (NCRP) publications have addressed the issues of risk and dose limitation in radiation protection and included guidance on specific organs and the lens of the eye. NCRP decided to prepare an updated commentary intended to enhance the previous recommendations provided in earlier reports. The NCRP Scientific Committee 1-23 (SC 1-23) is charged with preparing a commentary that will evaluate recent studies on the radiation dose response for the development of cataracts and also consider the type and severity of the cataracts as well as the dose rate; provide guidance on whether existing dose limits to the lens of the eye should be changed in the United States; and suggest research needs regarding radiation effects on and dose limits to the lens of the eye. A status of the ongoing work of SC 1-23 was presented at the Annual Meeting, "Changing Regulations and Radiation Guidance: What Does the Future Hold?" The following represents a synopsis of a few main points in the current draft commentary. It is likely that several changes will be forthcoming as SC 1-23 responds to subject matter expert review and develops a final document, expected by mid 2016.


Liquid nitrogen cryo-impacting: a new concept for cell disruption.
High-efficiency disruption of bacteria can be accomplished in 2 or more min by the new procedure of liquid nitrogen cryo-impacting. Release of the dipicolinic acid-Ca2+ chelate paralleled the breakage of Bacillus megaterium endospores. Lactate dehydrogenase activity was much better in supernates from liquid nitrogen cryo-impacting-broken Escherichia coli cells than in those from sonically treated and broken E. coli cells.


Study on differentiation factors for main disease identification of intermittent claudication.
Intermittent Claudication is a walking symptom. After a short time walking, patients suffer from pains at lower limbs. But if taking a rest, the pains can be relieved and they can walk again. Unfortunately, it arises from not one but mainly two kinds of diseases: LSS (lumber spinal canal stenosis) and PAD (peripheral arterial disease). Additionally, it is reported that symptom is similar and LSS groups is furthermore divided into two main groups: L4 and L5 groups. Therefore, it is clinically very important to differentiate which diseases the patients suffer from, PAD, L4 or L5. We aims at developing the system to differentiate them from short walking motion data. In our previous paper, we derived differentiation factors, but did not consider the difference between L4 and L5 and the results are limited. This paper focuses on biarticular muscles associated with the diseases, and derive new and effective differentiation factors. The results supports their effectiveness and validity.


[Prospects of the anti-cytokine therapy in rheumatoid arthritis].
The development and introduction of the anti-cytokine therapy applicable to rheumatoid arthritis (RA) is a most significant achievement in RA therapy. A high degree of purpose-orientation and selectivity of the mentioned method ensuring a high therapeutic effect and providing, simultaneously, for defining a number of important chains in RA pathogenesis is an essential advantage of the discussed approach. The clinical use of neutralization of key cytokines TNF-alpha, IL-1 and IF-gamma is a serious progress within this trend. Possibilities of developing new directions of the cytokines therapy are preconditioned, to a great extent, by the role of new, including little-studied cytokines, in the evolution of immune inflammation. A search for more simple low-molecular inhibitors of cytokines, which do not cause any tolerance-related problems, is another important trend. Hopefully, a further study of anti-cytokines and of their application in combination with other antirheumatic drugs will improve the general treatment results and outline new opportunities in antirheumatic therapy.


Lithobates catesbeianus (American Bullfrog) oocytes: a novel heterologous expression system for aquaporins.
Xenopus laevis oocytes are a valuable tool for investigating the function of membrane proteins. However, regulations around the world, specifically in Brazil, render the import of Xenopus laevis frogs impractical, and, in some cases, impossible. Here, as an alternative, we evaluate the usefulness of the North American aquatic bullfrog Lithobates catesebeianus, which is commercially available in Brazil, for the heterologous expression of aquaporin (AQP) proteins. We have developed a method that combines a brief collagenase treatment and mechanical defolliculation for isolating individual oocytes from Lithobates ovaries. We find that they have a similar size, shape, and appearance to Xenopus oocytes and can tolerate and survive following injections with cRNA or water. Furthermore, surface biotinylation, western blot analysis, and measurements of osmotic water permeability (Pf) show that Lithobates oocytes can express AQPs to the plasma membrane and significantly increase the Pf of the oocytes. In fact, the Pf values are similar to historical values gathered from Xenopus oocytes. Due to the presence of a mercury sensitive cysteine (Cys or C) in the throat of the water channel, the Pf of oocytes expressing human (h) AQP1, hAQP1FLAG [FLAG, short protein tag (DYKDDDDK) added to the N-terminus of AQP1], hAQP8, and rat (r) AQP9 was inhibited with the mercurial compound p-chloromercuribenzene sulfonate (pCMBS), whereas AQPs lacking this Cys - hAQP1C189S mutant [residue Cys 189 was replaced by a serine (Ser or S)] and hAQP7 - were mercury insensitive. Contrary to previous studies with Xenopus oocytes, rAQP3 was also found to be insensitive to mercury, which is consistent with the mercury-sensitive Cys (Cys 11) being located intracellularly. Thus, we consider Lithobates oocytes to be a readily accessible system for the functional expression and study of membrane proteins for international researchers who do not currently have access to Xenopus oocytes.


Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers.
Platinum drugs and PARP inhibitors ("PARPis") are considered to be effective in BRCA-associated cancers with impaired DNA repair. These agents cause stalled and collapsed replication forks and create double-strand breaks effectively in the absence of repair mechanisms, resulting in arrest of the cell cycle and induction of cell death. However, recent studies have shown failure of these chemotherapeutic agents due to emerging drug resistance. In this study, we developed a stochastic model of BRCA-associated cancer progression in which there are four cancer populations: those with (i) functional BRCA, (ii) dysfunctional BRCA, (iii) functional BRCA and a growth advantage, and (iv) dysfunctional BRCA and a growth advantage. These four cancer populations expand from one cancer cell with normal repair function until the total cell number reaches a detectable amount. We derived formulas for the probability and expected numbers of each population at the time of detection. Furthermore, we extended the model to consider the tumor dynamics during treatment. Results from the model were validated and showed good agreement with clinical and experimental evidence in BRCA-associated cancers. Based on the model, we investigated conditions in which drug resistance during the treatment course originated from either a pre-existing drug-resistant population or a de novo population, due to secondary mutations. Finally, we found that platinum drugs and PARPis were effective if (i) BRCA inactivation is present, (ii) the cancer was diagnosed early, and (iii) tumor growth is rapid. Our results indicate that different types of cancers have a preferential way of acquiring resistance to platinum drugs and PARPis according to their growth and mutational characteristics.


Menstrual-cycle-dependent expression of keratan sulphate in human endometrium.
Immunochemical methods have been used to detect and characterize two classes of polypeptide-associated keratan sulphate (KS) in epithelial secretions from human endometrium. Monoclonal antibody D9B1 binds to a hormonally regulated sialylated epitope associated with KS in a high relative molecular mass (250,000-350,000) component that bands as a doublet in SDS/PAGE. These KS chain(s) are sensitive to keratanase, endo-beta-galactosidase and N-glycanase. A second, more highly sulphated, type of KS is also present, that is resistant to all three enzymes. This can be detected using monoclonal antibody 5D4. It is present throughout the menstrual cycle and is associated principally with a component of Mr 140,000. Thus secretory KS contributes to the environment of the implanting embryo, may be used as a molecular index of endometrial function and could be important in the establishment of pregnancy.


Neuroimaging craving: urge intensity matters.
Functional neuroimaging has become an increasingly common tool for studying drug craving. Furthermore, functional neuroimaging studies, which have addressed an incredibly diverse array of questions regarding the nature and treatment of craving, have had a substantial impact on theoretical models of addiction. Here, we offer three points related to this sizeable and influential body of research. First, we assert that the craving most investigators seek to study represents not just a desire but a strong desire to use drugs, consistent with prominent theoretical and clinical descriptions of craving. Secondly, we highlight that, despite the clear conceptual and clinical emphasis on craving as an intense desire, brain imaging studies often have been designed explicitly in a way that reduces the ability to generate powerful cravings. We illustrate this point by reviewing the peak urge levels endorsed by participants in functional magnetic resonance imaging (fMRI) studies of cigarette craving in nicotine-deprived versus non-deprived smokers. Thirdly, we suggest that brain responses measured during mild states of desire (such as following satiety) differ in fundamental ways from those measured during states of overpowering desire (i.e. craving) to use drugs. We support this position by way of a meta-analysis revealing that fMRI cue exposure studies using nicotine-deprived smokers have produced different patterns of brain activation to those using non-deprived smokers. Regarding brain imaging studies of craving, intensity of the urges matter, and more explicit attention to urge intensity in future work has the potential to yield valuable information about the nature of craving.


Ancestral TSH mechanism signals summer in a photoperiodic mammal.
In mammals, day-length-sensitive (photoperiodic) seasonal breeding cycles depend on the pineal hormone melatonin, which modulates secretion of reproductive hormones by the anterior pituitary gland [1]. It is thought that melatonin acts in the hypothalamus to control reproduction through the release of neurosecretory signals into the pituitary portal blood supply, where they act on pituitary endocrine cells [2]. Contrastingly, we show here that during the reproductive response of Soay sheep exposed to summer day lengths, the reverse applies: Melatonin acts directly on anterior-pituitary cells, and these then relay the photoperiodic message back into the hypothalamus to control neuroendocrine output. The switch to long days causes melatonin-responsive cells in the pars tuberalis (PT) of the anterior pituitary to increase production of thyrotrophin (TSH). This acts locally on TSH-receptor-expressing cells in the adjacent mediobasal hypothalamus, leading to increased expression of type II thyroid hormone deiodinase (DIO2). DIO2 initiates the summer response by increasing hypothalamic tri-iodothyronine (T3) levels. These data and recent findings in quail [3] indicate that the TSH-expressing cells of the PT play an ancestral role in seasonal reproductive control in vertebrates. In mammals this provides the missing link between the pineal melatonin signal and thyroid-dependent seasonal biology.


Clinical significance of serum PSA in breast cancer patients.
Recent preclinical data suggest that androgen receptor (AR) signaling plays a significant role in subsets of breast cancer. Clinical trials testing AR-targeting therapies in breast cancer have been conducted. Assessment of AR-signal in breast cancer tissue maybe useful for treatment selections. Prostate specific antigen (PSA) is the product of an androgen-responsive gene. Serum PSA (sPSA) can be detected in women by a highly sensitive assay although the concentration is much lower than that observed in males. We investigated if sPSA reflects tumor biology, including AR signaling in breast cancer patients. In this study, 132 healthy controls and 144 breast cancer patients were enrolled. sPSA was evaluated by the chemiluminescent enzyme immunoassay (CLEIA) method. Correlations between sPSA and the various clinicopathological factors were analyzed. In post-menopausal state, sPSA detection rate was significantly higher in breast cancer patients compared with controls (27.4% vs 11.3%: p = 0.0090), but not in the whole cohort (29.2% vs 25.8%: p = 0.5265) or pre-menopausal subgroup (37.0% vs 42.6%: p = 0.6231). In post-menopausal breast cancer cases, higher sPSA value was associated with clinic-pathological factors including the expression of AR protein in primary legion. In a correlation analysis of quantitative data limited to post-menopausal metastatic breast cancer (MBC), sPSA was positively, albeit weakly correlated with clinic-pathological features including serum testosterone levels and AR positivity. Our data suggest that sPSA may reflect tumor biological properties including AR activity in post-menopausal breast cancer.


Prevalence of abnormal cervical cytology by liquid based cytology in the antenatal care clinic, Thammasat University Hospital.
To determine the prevalence of abnormal cervical cytology by liquid based cytology (LBC) in pregnant women who attended the antenatal care clinic at Thammasat University Hospital. LBC was performed on specimens from the collecting vial containing preserved cell solution (Cytyc, Boxborough, MA) in pregnant women who attended antenatal care at the antenatal care clinic, Thammasat University Hospital between March and July 2010. One hundred forty three pregnant women were recruited in the present study. All cytological reports were reviewed by senior cytopathologists for accurate diagnosis using the Bethesda System 2001 criteria. Patients with abnormal results as "abnormal squamous/glandular cells of undetermined significant" or more over were referred for colposcopic examination. One hundred forty three pregnant women participated in the present study. The average age was 27.09 years. There were 10 abnormal Pap smear results with four, five, and one cases of ASC-US, LSIL and HSIL respectively The prevalence of abnormal cervical cytology in this investigation was 7% with 0.7% high-grade cervical intraepithelial neoplacia. Only 6% of participants had the correct understanding of the necessity of Pap smear testing. Thirty-one percent of multiparous pregnant women in the present study had no previous Pap smear screening. The majority of participants had coitarche before the age of 20. The prevalence of abnormal cervical cytology in pregnant patients attending the antenatal care clinic at Thammasat University Hospital was 7%. The cervical cytology and related education were highly recommended in antenatal care clinic to increase cervical cancer screening coverage among reproductive age women.


Procaine in malignant hyperpyrexia.
The caffeine contracture of normal human muscle, which has been used as a model for malignant hyperpyrexia, is greatly potentiated by halothane. Prior administration of procaine markedly reduces the halothane-potentiated caffeine contracture, and procaine given at the height of the contracture induces relaxation. Lignocaine, on the other hand, produces a variable response and sometimes increases the contracture.The muscle from a patient with an inherited susceptibility to malignant hyperpyrexia contracted spontaneously with halothane alone, and this contracture was reversed by procaine.These experiments support the therapeutic use of procaine in malignant hyperpyrexia.


Anti-ERBb4 targeted therapy combined with radiation therapy in prostate cancer. Results of in vitro and in vivo studies.
To evaluate the efficiency of anti ErbB4 targeted therapy combined with irradiation (XRT) over each modality alone in prostate cancer. Clones with high ErbB4 expression grew faster than those with low ErbB4 expression. XRT inhibited the growth of both expressive and non-expressive ErbB4 cells, while mAb inhibited only high ErbB4-expressing cells. The combination of XRT and mAb resulted in a 30% reduction of the survival of high ErbB4 expressing cells over XRT alone (p = 0.013). In tumor bearing mice the tumor size in the combined arm was 1 mm at 4 weeks compared to 2-3 mm and 4-5 mm in the radiation and mAb arms (p' value of 0.02 and 0.087 respectively). Clones with low and high expression of ErbB4 isolated by a limited dilution technique from an androgen-independent Cl-1 cell line were used. The cells from these clones were exposed to XRT (single dose of 2-6 Gy) and to anti-ErbB4 monoclonal antibody (mAb). The XTT test was used to measure cell survival. In addition, tumor-bearing nude mice were treated either by XRT, mAb or by a combined treatment. Tumor sizes were recorded at given time points. Anti ErbB4 combined with XRT is possibly more effective than each modality alone in prostate cancer.


Vasoactive intestinal peptide synergizes with TNF-alpha in inducing human dendritic cell maturation.
We investigated the effects of different neuropeptides on human dendritic cells (DC) maturation. Immature DC, derived from monocytes cultured for 6 days with IL-4 plus GM-CSF, have been exposed to somatostatin, substance P, or vasoactive intestinal peptide (VIP). Among these neuropeptides, only VIP induces the production of bioactive IL-12 and the neoexpression of CD83 on a fraction of the DC population, with an effect significant at 100 and 10 nM, respectively. These effects of VIP are dose-dependent, unaffected by polymixin B, and partly prevented by a VIP receptor antagonist. Although the effects of VIP alone remain modest, it synergizes with TNF-alpha to induce DC maturation. In the presence of a suboptimal concentration of TNF-alpha, which has no detectable effect on DC by itself, VIP induces the production of high levels of bioactive IL-12, the neoexpression of CD83 on almost all the DC population (with an effect significant at 10 and 0.1 nM, respectively), and the up-regulation of various adhesion and costimulatory molecule expression. Moreover, DC exposed to VIP plus a suboptimal concentration of TNF-alpha are as potent as mature DC obtained by treatment with an optimal concentration of TNF-alpha in stimulating allogenic T cell proliferation. Our data suggest that, in inflammatory sites, VIP may cooperate with proinflammatory mediators, such as TNF-alpha, to induce DC maturation.


Simultaneous intra-operative sclerotherapy and surgical resection of cervicofacial venous malformations.
To review simultaneous intra-operative sclerotherapy (IOS) with immediate surgical resection for the treatment of cervicofacial venous malformations (VMs) at a single institution. While pre-operative sclerotherapy (POS) has been reported in the literature, simultaneous intra-operative sclerotherapy and surgery in the operating room has not. The database from the Hemangioma and Vascular Birthmarks Clinic was reviewed. All patients in both groups had biopsy-proven VMs. IOS was used in 11 surgical patients with average age 17 years. Sclerotherapy was performed with sodium tetradecyl sulfate 3%, absolute alcohol or bleomycin. Immediately after IOS, and under the same anesthetic, all patients had either complete resection or debulking of the VMs. Eight patients had complete resolution of their VM and 3 had improvement. Average duration of the combined procedures done under a single anesthetic was 121 min. The POS approach was used for 6 surgical patients with average age 7 years. Sclerotherapy agents used were absolute alcohol or sodium tetradecyl sulfate 3%. All patients underwent complete resection of the VM 24-72 h after sclerotherapy under a separate surgical session. Five patients experienced complete resolution of their VM and one has had further sclerotherapy for recurrent disease. Interventional Radiology suite sclerotherapy times were on average 70 min. Surgical times were on average 142 min. Total combined anesthesia times for the two procedures added together were 212 min. Treatment time was significantly shorter in the IOS group (p = 0.0015). Simultaneous IOS at the time of surgical resection has been successful in our hands. IOS has the advantage of a single procedure and decreased cost to the patient. In the era of reducing pediatric exposure to anesthesia, this approach is especially attractive in the pediatric population. As well, at approximately $100/minute cost to the patient to be in either the Interventional Radiology Suite or in the operating room, the reduced length of the procedures seen in the IOS approach results in lower overall cost to the patient.


Allosteric regulation of PKCθ: understanding multistep phosphorylation and priming by ligands in AGC kinases.
Protein kinases play critical roles in cellular activation and differentiation, and are involved in numerous pathophysiological processes. As a critical component of the regulatory circuitry of the cell, the kinase domain has the ability to integrate multiple signals, yielding a predetermined output. In PKC and other protein kinases of the AGC family, several phosphorylation sites control the activity, but these are in turn influenced by the presence of ligands in the binding pocket, which promotes phosphorylation. Here, we take PKC-theta as a prototypical member of the family and use molecular dynamics simulations to investigate the cross-talk that exists between regulatory and functional sites. We first show how the apo-unphosphorylated form of the kinase is populating a conformational space in which access to the ATP binding site and to the activation loop (AL) are simultaneously hindered. This could explain why the inactive state is not only catalytically incompetent but also resistant to activation. AL phosphorylation induces ATP binding site opening, which can then readily accept the cofactor. But the signal transmission mechanism works both ways, and if ligand binding to the unphosphorylated form occurs first, the AL is de-protected and becomes exposed to phosphorylation, thus providing an explanation for the paradoxical activation of PKCs by their inhibitors.


δ-Cells: The Neighborhood Watch in the Islet Community.
Somatostatin-secreting δ-cells have aroused great attention due to their powerful roles in coordination of islet insulin and glucagon secretion and maintenance of glucose homeostasis. δ-cells exhibit neuron-like morphology with projections which enable pan-islet somatostatin paracrine regulation despite their scarcity in the islets. The expression of a range of hormone and neurotransmitter receptors allows δ-cells to integrate paracrine, endocrine, neural and nutritional inputs, and provide rapid and precise feedback modulations on glucagon and insulin secretion from α- and β-cells, respectively. Interestingly, the paracrine tone of δ-cells can be effectively modified in response to factors released by neighboring cells in this interactive communication, such as insulin, urocortin 3 and γ-aminobutyric acid from β-cells, glucagon, glutamate and glucagon-like peptide-1 from α-cells. In the setting of diabetes, defects in δ-cell function lead to suboptimal insulin and glucagon outputs and lift the glycemic set-point. The interaction of δ-cells and non-δ-cells also becomes defective in diabetes, with reduces paracrine feedback to β-cells to exacerbate hyperglycemia or enhanced inhibition of α-cells, disabling counter-regulation, to cause hypoglycemia. Thus, it is possible to restore/optimize islet function in diabetes targeting somatostatin signaling, which could open novel avenues for the development of effective diabetic treatments.