Distal Migration and Ectopic Eruption of the Mandibular First Premolar: A Case Report.
Migration describes the movement of an unerupted tooth within the bone when normal eruption is prevented and the tooth leaves its normal site of development. This report describes a case of distal migration and ectopic eruption of the mandibular first premolar in an 8.5-year-old boy. Following early extraction of the primary second molar, the first premolar migrated distally through the extraction site of the primary second molar and erupted into occlusion just mesial of the permanent first molar.


Dementia resulting from traumatic brain injury: what is the pathology?
Traumatic brain injury (TBI) is among the earliest illnesses described in human history and remains a major source of morbidity and mortality in the modern era. It is estimated that 2% of the US population lives with long-term disabilities due to a prior TBI, and incidence and prevalence rates are even higher in developing countries. One of the most feared long-term consequences of TBIs is dementia, as multiple epidemiologic studies show that experiencing a TBI in early or midlife is associated with an increased risk of dementia in late life. The best data indicate that moderate and severe TBIs increase risk of dementia between 2- and 4-fold. It is less clear whether mild TBIs such as brief concussions result in increased dementia risk, in part because mild head injuries are often not well documented and retrospective studies have recall bias. However, it has been observed for many years that multiple mild TBIs as experienced by professional boxers are associated with a high risk of chronic traumatic encephalopathy (CTE), a type of dementia with distinctive clinical and pathologic features. The recent recognition that CTE is common in retired professional football and hockey players has rekindled interest in this condition, as has the recognition that military personnel also experience high rates of mild TBIs and may have a similar syndrome. It is presently unknown whether dementia in TBI survivors is pathophysiologically similar to Alzheimer disease, CTE, or some other entity. Such information is critical for developing preventive and treatment strategies for a common cause of acquired dementia. Herein, we will review the epidemiologic data linking TBI and dementia, existing clinical and pathologic data, and will identify areas where future research is needed.


Resuscitating the elderly: what do the patients want?
To study the resuscitation preferences, choice of decision-maker, views on the seeking of patients' wishes and determinants of these of elderly hospital in-patients. Questionnaire administered on admission and prior to discharge. Two acute geriatric medicine units (Southampton and Poole). Two hundred and fourteen consecutive consenting mentally competent patients admitted to hospital as emergencies. Resuscitation was wanted by 60%, particularly married and functionally independent patients and those who had not already considered it. Not wanted resuscitation was associated with lack of social contacts. Sixty-seven per cent welcomed enquiry about their preferences and 78% wanted participation in decision, 43% as sole decision-maker. Wishing to choose oneself was associated with not wanting resuscitation, prior knowledge of it, and lack of a spouse. Patients' opinions remained stable during their admission. Discussion of resuscitation is practical on hospital admission without causing distress and the views expressed endure through the period of hospitalisation. Elderly patients' attitudes depend partly on personal health and social circumstances. This may assist doctors when patients are unable to participate themselves.


Combination of anti-CD4 with anti-LFA-1 and anti-CD154 monoclonal antibodies promotes long-term survival and function of neonatal porcine islet xenografts in spontaneously diabetic NOD mice.
Type 1 diabetes mellitus (T1DM) is caused by the autoimmune destruction of pancreatic islet beta-cells, which are required for the production of insulin. Islet transplantation has been shown to be an effective treatment option for TIDM; however, the current shortage of human islet donors limits the application of this treatment to patients with brittle T1DM. Xenotransplantation of pig islets is a potential solution to the shortage of human donor islets provided xenograft rejection is prevented. We demonstrated that a short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) was highly effective in preventing rejection of neonatal porcine islet (NPI) xenografts in non-autoimmune-prone B6 mice. However, the efficacy of this therapy in preventing rejection of NPI xenografts in autoimmune-prone nonobese diabetic (NOD) mice is not known. Given that the current application of islet transplantation is for the treatment of T1DM, we set out to determine whether a combination of anti-LFA-1 and anti-CD154 mAbs could promote long-term survival of NPI xenografts in NOD mice. Short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs, which we found highly effective in preventing rejection of NPI xenografts in B6 mice, failed to promote long-term survival of NPI xenografts in NOD mice. However, addition of anti-CD4 mAb to short-term treatment of a combination of anti-LFA-1 and anti-CD154 mAbs resulted in xenograft function in 9/12 animals and long-term graft (>100 days) survival in 2/12 mice. Immunohistochemical analysis of islet grafts from these mice identified numerous insulin-producing beta-cells. Moreover, the anti-porcine antibody as well as autoreactive antibody responses in these mice was reduced similar to those observed in naive nontransplanted mice. These data demonstrate that simultaneous targeting of LFA-1, CD154, and CD4 molecules can be effective in inducing long-term islet xenograft survival and function in autoimmune-prone NOD mice.


Stem cell transplantation in multiple sclerosis.
The recent advances in our understanding of stem cell biology, the availability of innovative techniques that allow large-scale acquisition of stem cells, and the increasing pressure from the multiple sclerosis (MS) patient community seeking tissue repair strategies have launched stem cell treatments as one of the most exciting and difficult challenges in the MS field. Here, we provide an overview of the current status of stem cell research in MS focusing on secured actuality, reasonable hopes and unrealistic myths. Results obtained from small clinical studies with transplantation of autologous hematopoietic stem cells have demonstrated that this procedure is feasible and possibly effective in severe forms of MS but tackles exclusively inflammation without affecting tissue regeneration. Results from preclinical studies with other adult stem cells such as mesenchymal stem cells and neural precursor cells have shown that they may be a powerful tool to regulate pathogenic immune response and foster tissue repair through bystander mechanisms with limited cell replacement. However, the clinical translation of these results still requires careful evaluation. Current experimental evidence suggests that the sound clinical exploitation of stem cells for MS may lead to novel strategies aimed at blocking uncontrolled inflammation, protecting neurons and promoting remyelination but not at restoring the chronically deranged neural network responsible for irreversible disability typical of the late phase of MS.


Oxygen uptake kinetics during supra VO2max treadmill running in humans.
Accurate classification of VO2 kinetics is essential to correctly interpret its control mechanisms. The purpose of this study was to examine VO2 kinetics in severe and supra-maximal intensity running exercise using two modelling techniques. Nine subjects (mean +/- S.D: age, 27 +/- 7 years; mass, 69.8 +/- 9.0 kg; VO2max, 59.1 +/- 1.8 mL x kg x min(-1)) performed a series of "square-wave" exercise transitions to exhaustion at running speeds equivalent to 80% of the difference between the VO2 at LT and VO2max (delta), and at 100%, 110% and 120% VO2max. The VO2 response was modelled with an exponential model and with a semi-logarithmic transformation, the latter assuming a certain steady state VO2. With the exponential model there was a significant reduction in the "gain" of the primary component in supra-maximal exercise (167 +/- 5 mL x kg(-1) x km(-1) at 80% delta to 142 +/- 5 mL x kg(-1) x km(-1) at 120% VO2max, p = 0.005). The time constant of the primary component also reduced significantly with increasing intensity (17.8 +/- 1.1 s at 80% delta to 12.5 +/- 1.2 s at 120% VO2max, p < 0.05). However, in contrast, using the semi-log model, the time constant significantly increased with intensity (30.9 +/- 13.5 s at 80% delta to 72.2 +/- 23.9 s at 120% VO2max, p < 0.05). Not withstanding the need for careful interpretation of mathematically modelled data, these results demonstrate that neither the gain nor the time constant of the VO2 primary component during treadmill running are invariant across the severe and supra-maximal exercise intensity domains when fit with an exponential model. This suggests the need for a reappraisal of the VO2/work rate relationship in running exercise.


Correlation between facial asymmetry, shoulder imbalance, and adolescent idiopathic scoliosis.
We conducted a prospective cross-sectional study to examine the correlation between facial asymmetry, shoulder imbalance, and adolescent idiopathic scoliosis. Sixty-nine adolescent idiopathic scoliosis patients and 29 healthy volunteers were enrolled in this study. All patients underwent whole-spine standing anteroposterior radiographs and frontal cephalograms. Patients were divided into mild, moderate, and severe groups depending on Cobb angle (10°-25°, 25°-40°, and >40°, respectively). Facial measurements included maxilla height difference, ramus length difference, and anterior nasal spine-menton angle. Shoulder measurements included coracoid height difference, clavicular angle, clavicle-rib intersection difference, and radiographic shoulder height.The anterior nasal spine-menton angle in the severe group (>40°) was higher than in the other groups (P<.05), as was the clavicle-rib intersection difference (P<.05). In addition, the magnitude of the curve showed a possible correlation with the anterior nasal spine-menton angle and clavicle-rib intersection difference in scoliosis patients (r=0.433 and r=0.511, respectively). According to different curve patterns, the anterior nasal spine-menton angle and clavicle-rib intersection difference were significantly higher in the double thoracic group than in the other groups (P<.05). In the correlation analysis, the ramus length difference and anterior nasal spine-menton angle had a possible correlation with the coracoid height difference, clavicular angle, radiographic shoulder height, and clavicle-rib intersection difference (P<.05).


Pharmacist medication therapy management in home health care: Investigation of a sustainable practice model.
The objective of this study was to quantify the financial impact of a pharmacist-driven pilot medication therapy management (MTM) program within a visiting nurse service (VNS) and identify types of medication-related problems affecting the home health care population. Patients were contacted to schedule a home visit with the primary investigator. At the appointment, a comprehensive medication review (CMR) was completed, and data collected included primary reason for VNS care, comorbid diagnoses, number of prescription and nonprescription medications at time of visit, and type of pharmacist-identified medication therapy intervention(s). The VNS is a nonprofit independent home health care agency serving patients of all ages and health conditions. Patients admitted with primary insurance coverage through Blue Cross Blue Shield (BCBSRI) Blue Chip for Medicare and 65 years of age and older were eligible for inclusion. Intervention categories were aligned to coordinate with current billable OutcomesMTM claim categories. Dollar allocation for each intervention severity level was assigned according to the predetermined Medicare cost savings predicted value from BCBSRI. Interventions were assigned cost-saving value by the severity level to estimate savings. Twenty-five patients received CMRs. Patients averaged 5.92 chronic health conditions, 8.48 Part D drugs, and 3.88 over-the-counter medications. Two hundred eighteen medication-related problems were identified spanning 13 intervention categories. Intervention severity level was assigned to the medication-related problems, with calculated cost savings from pharmacist interventions totaling $124,352. This pilot study demonstrated the positive economic impact of a pharmacist-run MTM program at VNS for patients with multiple chronic conditions and medication-related problems. Potential societal benefits include that community members admitted to VNS will continue to have access to a pharmacist as a standard of care with the continuation of this MTM program.


Surgery for low back pain: a review of the evidence for an American Pain Society Clinical Practice Guideline.
Systematic review. To systematically assess benefits and harms of surgery for nonradicular back pain with common degenerative changes, radiculopathy with herniated lumbar disc, and symptomatic spinal stenosis. Although back surgery rates continue to increase, there is uncertainty or controversy about utility of back surgery for various conditions. Electronic database searches on Ovid MEDLINE and the Cochrane databases were conducted through July 2008 to identify randomized controlled trials and systematic reviews of the above therapies. All relevant studies were methodologically assessed by 2 independent reviewers using criteria developed by the Cochrane Back Review Group (for trials) and Oxman (for systematic reviews). A qualitative synthesis of results was performed using methods adapted from the US Preventive Services Task Force. For nonradicular low back pain with common degenerative changes, we found fair evidence that fusion is no better than intensive rehabilitation with a cognitive-behavioral emphasis for improvement in pain or function, but slightly to moderately superior to standard (nonintensive) nonsurgical therapy. Less than half of patients experience optimal outcomes (defined as no more than sporadic pain, slight restriction of function, and occasional analgesics) following fusion. Clinical benefits of instrumented versus noninstrumented fusion are unclear. For radiculopathy with herniated lumbar disc, we found good evidence that standard open discectomy and microdiscectomy are moderately superior to nonsurgical therapy for improvement in pain and function through 2 to 3 months. For symptomatic spinal stenosis with or without degenerative spondylolisthesis, we found good evidence that decompressive surgery is moderately superior to nonsurgical therapy through 1 to 2 years. For both conditions, patients on average experience improvement either with or without surgery, and benefits associated with surgery decrease with long-term follow-up in some trials. Although there is fair evidence that artificial disc replacement is similarly effective compared to fusion for single level degenerative disc disease and that an interspinous spacer device is superior to nonsurgical therapy for 1- or 2-level spinal stenosis with symptoms relieved with forward flexion, insufficient evidence exists to judge long-term benefits or harms. Surgery for radiculopathy with herniated lumbar disc and symptomatic spinal stenosis is associated with short-term benefits compared to nonsurgical therapy, though benefits diminish with long-term follow-up in some trials. For nonradicular back pain with common degenerative changes, fusion is no more effective than intensive rehabilitation, but associated with small to moderate benefits compared to standard nonsurgical therapy.


Questionnaire discrimination: (re)-introducing coefficient delta.
Questionnaires are used routinely in clinical research to measure health status and quality of life. Questionnaire measurements are traditionally formally assessed by indices of reliability (the degree of measurement error) and validity (the extent to which the questionnaire measures what it is supposed to measure). Neither of these indices assesses the degree to which the questionnaire is able to discriminate between individuals, an important aspect of measurement. This paper introduces and extends an existing index of a questionnaire's ability to distinguish between individuals, that is, the questionnaire's discrimination. Ferguson (1949) 1 derived an index of test discrimination, coefficient delta, for psychometric tests with dichotomous (correct/incorrect) items. In this paper a general form of the formula, deltaG, is derived for the more general class of questionnaires allowing for several response choices. The calculation and characteristics of deltaG are then demonstrated using questionnaire data (GHQ-12) from 2003-2004 British Household Panel Survey (N = 14761). Coefficients for reliability (alpha) and discrimination (deltaG) are computed for two commonly-used GHQ-12 coding methods: dichotomous coding and four-point Likert-type coding. Both scoring methods were reliable (alpha > 0.88). However, deltaG was substantially lower (0.73) for the dichotomous coding of the GHQ-12 than for the Likert-type method (deltaG = 0.96), indicating that the dichotomous coding, although reliable, failed to discriminate between individuals. Coefficient deltaG was shown to have decisive utility in distinguishing between the cross-sectional discrimination of two equally reliable scoring methods. Ferguson's delta has been neglected in discussions of questionnaire design and performance, perhaps because it has not been implemented in software and was restricted to questionnaires with dichotomous items, which are rare in health care research. It is suggested that the more general formula introduced here is reported as deltaG, to avoid the implication that items are dichotomously coded.


Nutrition and depression at the forefront of progress.
Depression is a debilitating disorder estimated to become the second cause of morbidity worldwide by the year 2020. The limited efficacy of antidepressant therapy, as well as the major negative consequences of this disorder, has stimulated additional research in order to determine possible adjunctive treatments. There is mounting evidence linking dietary patterns to major depression development. This article presents some of the most significant findings concerning the role of nutrition in major depressive disorder. Although more focused and clear results are needed, the correlation between nutrition and mental health is gaining attention. Now, there is evidence supporting the importance of nutrition in maintaining good mental health. We emphasize multiple findings that support adherence to healthy dietary patterns, taking into account that the production of neurotransmitters need, among others, right amounts of nutrients, a lot of which can only be supplied through diet. Not only certain nutrients are needed for proper brain functioning, but also others can be harmful, promoting depression. The Mediterranean diet has been linked to a low prevalence of depression while fast-food consumption has been found to increase the risk of developing and aggravating this disorder, hence the need for nutritional interventions. From the perspective of discovering modifiable risk factors, the role of nutrition in psychiatry could be more important than it was initially considered.


Efficacy and Safety of Triazavirin Therapy for Coronavirus Disease 2019: A Pilot Randomized Controlled Trial.
No therapeutics have been proven effective yet for the treatment of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the efficacy and safety of Triazavirin therapy for COVID-19, we conducted a randomized, double-blinded controlled trial involving hospitalized adult patients with COVID-19. Participants were enrolled from ten sites, and were randomized into two arms of the study with a ratio of 1:1. Patients were treated with Triazavirin 250 mg versus a placebo three or four times a day for 7 d. The primary outcome was set as the time to clinical improvement, defined as normalization of body temperature, respiratory rate, oxygen saturation, cough, and absorption of pulmonary infection by chest computed tomography (CT) until 28 d after randomization. Secondary outcomes included individual components of the primary outcome, the mean time and proportion of inflammatory absorption in the lung, and the conversion rate to a repeated negative SARS-CoV-2 nucleic acid test of throat swab sampling. Concomitant therapeutic treatments, adverse events, and serious adverse events were recorded. Our study was halted after the recruitment of 52 patients, since the number of new infections in the participating hospitals decreased greatly. We randomized 52 patients for treatment with Triazavirin (n = 26) or a placebo (n = 26). We found no differences in the time to clinical improvement (median, 7 d versus 12 d; risk ratio (RR), 2.0; 95% confidence interval (CI), 0.7-5.6; p = 0.2), with clinical improvement occurring in ten patients in the Triazavirin group and six patients in the placebo group (38.5% versus 23.1%; RR, 2.1; 95% CI, 0.6-7.0; p = 0.2). All components of the primary outcome normalized within 28 d, with the exception of absorption of pulmonary infection (Triazavirin 50.0%, placebo 26.1%). Patients in the Triazavirin group used less frequent concomitant therapies for respiratory, cardiac, renal, hepatic, or coagulation supports. Although no statistically significant evidence was found to indicate that Triazavirin benefits COVID-19 patients, our observations indicated possible benefits from its use to treat COVID-19 due to its antiviral effects. Further study is required for confirmation.


BMP9 stimulates joint regeneration at digit amputation wounds in mice.
A major goal of regenerative medicine is to stimulate tissue regeneration after traumatic injury. We previously discovered that treating digit amputation wounds with BMP2 in neonatal mice stimulates endochondral ossification to regenerate the stump bone. Here we show that treating the amputation wound with BMP9 stimulates regeneration of a synovial joint that forms an articulation with the stump bone. Regenerated structures include a skeletal element lined with articular cartilage and a synovial cavity, and we demonstrate that this response requires the Prg4 gene. Combining BMP2 and BMP9 treatments in sequence stimulates the regeneration of bone and joint. These studies provide evidence that treatment of growth factors can be used to engineer a regeneration response from a non-regenerating amputation wound.


Mucinous adenocarcinoma in an ovarian remnant.
The ovarian remnant syndrome, a complication of bilateral salpingo-oophorectomy, is progressively receiving more attention in the gynecological surgery literature. The syndrome is manifested by pelvic pain and a palpable or sonographic finding of a pelvic mass. However, in rare cases, patients can present with large masses and radiographic suggestion of malignancy. We present the case of a 76-year-old white female, 23 months after bilateral salpino-oophorectomy at the same institution, complaining of 3.5 months of right flank and abdominal pain. Clinical and radiological evidence of a right ovarian remnant was discovered. Subsequent laparoscopic resection was consistent with a well-encapsulated mucinous adenocarcinoma in a right ovarian remnant. Curiously, this patient had no history of endometriosis, dense pelvic adhesions, pelvic inflammatory disease, or difficulty encountered during the original hysterectomy. This is the seventh published case report in the international literature about carcinoma developing in an ovarian remnant. However, this case differs in that the patient had no preexisting gynecologic conditions at the time of hysterectomy and bilateral salpingo-oophorectomy to account for residual ovarian tissue. Additionally, the oophorectomy was performed vaginally, in contrast to multiple previous case reports.


Role of endosomal escape for disulfide-based drug delivery from colloidal mesoporous silica evaluated by live-cell imaging.
Redox-driven intracellular disulfide-cleavage is a promising strategy to achieve stimuli-responsive and controlled drug release. We synthesized colloidal mesoporous silica (CMS) nanoparticles with ATTO633-labeled cysteine linked to the inner particle core via disulfide-bridges and characterized their cysteine release behavior after internalization into HuH7 cells by high-resolution fluorescence microscopy. Our study revealed that endosomal escape is a bottleneck for disulfide-linkage based drug release. Photochemical opening of the endosome leads to successful delivery of fluorescently labeled cysteine to the cytosol.


Parent-child aggression: association with child abuse potential and parenting styles.
The present investigation predicted that greater use of corporal punishment as well as physical maltreatment would be associated with child abuse potential and selected parenting styles. Three independent studies were examined, two with community samples and a third with a clinical at-risk sample of parents. Parents across all studies anonymously completed the Child Abuse Potential Inventory, the Parent-Child Conflict Tactics Scale to assess physical discipline and maltreatment, as well as the Parenting Scale to measure dysfunctional parenting styles. Findings support that overall parent-child aggression, as well as physical maltreatment behaviors specifically, were associated with child abuse potential. Parent-child aggression was also related to dysfunctional parenting styles, particularly an overreactive, authoritarian parenting style. Permissive parenting was also identified as potentially associated with physical maltreatment, although the findings regarding such lax parenting styles are less clear. Intriguing findings emerged regarding the connection of psychological aggression to both child abuse potential and dysfunctional parenting style. Child abuse potential was also associated with dysfunctional parenting style, particularly harsh, overreactive approaches. Recommendations for future study with at-risk samples and additional research on permissive parenting and psychological aggression are discussed.


Experiences of the quality of care of women with near-miss maternal morbidities in the UK.
We undertook a qualitative interview study of women's and their partners' experiences of severe pregnancy complications. Across the care pathway, women identified a number of examples of good practice that made an important difference to their recovery. There were some areas where women felt the quality of care could be improved, for example during points of transition between higher level and routine care or from hospital to the community. Longer-term support and counselling were felt to be particularly valuable, and yet not always universally available. These results emphasise the importance of integrated quality care across the whole patient pathway.


Road proximity, air pollution, noise, green space and neurologic disease incidence: a population-based cohort study.
Emerging evidence links road proximity and air pollution with cognitive impairment. Joint effects of noise and greenness have not been evaluated. We investigated associations between road proximity and exposures to air pollution, and joint effects of noise and greenness, on non-Alzheimer's dementia, Parkinson's and Alzheimer's disease and multiple sclerosis within a population-based cohort. We assembled administrative health database cohorts of 45-84 year old residents (N ~ 678,000) of Metro Vancouver, Canada. Cox proportional hazards models were built to assess associations between exposures and non-Alzheimer's dementia and Parkinson's disease. Given reduced case numbers, associations with Alzheimer's disease and multiple sclerosis were evaluated in nested case-control analyses by conditional logistic regression. Road proximity was associated with all outcomes (e.g. non-Alzheimer's dementia hazard ratio: 1.14, [95% confidence interval: 1.07-1.20], for living < 50 m from a major road or < 150 m from a highway). Air pollutants were associated with incidence of Parkinson's disease and non-Alzheimer's dementia (e.g. Parkinson's disease hazard ratios of 1.09 [1.02-1.16], 1.03 [0.97-1.08], 1.12 [1.05-1.20] per interquartile increase in fine particulate matter, Black Carbon, and nitrogen dioxide) but not Alzheimer's disease or multiple sclerosis. Noise was not associated with any outcomes while associations with greenness suggested protective effects for Parkinson's disease and non-Alzheimer's dementia. Road proximity was associated with incidence of non-Alzheimer's dementia, Parkinson's disease, Alzheimer's disease and multiple sclerosis. This association may be partially mediated by air pollution, whereas noise exposure did not affect associations. There was some evidence of protective effects of greenness.


Blinking and tear break-up during four visual tasks.
This study investigates the relationship between blinking, tear film break-up, and ocular symptoms for normal and dry eye subjects performing four different visual tasks. Sixteen control and sixteen dry eye subjects performed four visual tasks (looking straight ahead, watching a movie, identifying rapidly changing letters, and playing a computer game) while blink patterns and fluorescein images of the tear film were videotaped. Pre and posttesting symptom questionnaires, querying the intensity of nine symptoms of ocular irritation, were completed by all subjects. Blink rate and blink amplitude were computed from digitized videos. The percentage of tear film break-up before the blink was calculated. Dry eye subjects had a significantly higher blink rate (p = 0.017, t-test). Both groups blinked significantly less during the game and letter tasks (p < 0.04, t-test). Partial blinks were common as were clusters or "flurries" of rapid blinks, but there was no significant difference in blink amplitude for control and dry eye subjects. Tear film break-up in normal subjects was typically inferior; whereas dry eye subjects showed more tear break-up centrally and superiorly. Real-time video recording of tear break-up and blink behavior pointed to complex interaction between the two. Dry eye subjects shifted more toward intense ocular symptoms at posttesting (p < 0.05, Wilcoxon signed rank) than controls. Both groups showed a shift toward more corneal staining at posttesting (p < 0.05, Wilcoxon signed rank), which was typically inferior. Reduced and incomplete blinking along with increased tear film break-up during normal visual tasks may explain the increased level of ocular discomfort symptoms reported at the end of the day, particularly in dry eye patients.


Non-invasive carotid imaging using optoacoustic tomography.
The high prevalence of atherosclerosis and the corresponding derived morbidity drives the investigation of novel imaging tools for disease diagnosis and assessment. Multi-spectral optoacoustic tomography (MSOT) can resolve structural, hemodynamic and molecular parameters that relate to cardiovascular disease. Similarly to ultrasound imaging, optoacoustic (photoacoustic) imaging can be implemented as a handheld arrangement which further brings dissemination potential to point of care applications. Correspondingly, we experimentally investigate herein the performance of non-invasive optoacoustic scanning developed for carotid imaging, in phantoms and humans. The results demonstrate that traditional transducers employed in ultrasound imaging do not offer optimal MSOT imaging. Instead, feasibility to detect human carotids and carotid-sized vessels in clinically-relevant depths is better demonstrated with curved arrays and tomographic approaches.


Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology.
Novel therapeutic agents and strategies have been introduced into the management of myelodysplastic syndromes (MDS) in the last years. This has led to more treatment options and a better chance of long-term survival for MDS patients, but also to uncertainty regarding the optimal use and possible side effects of these treatments. The Italian Society of Hematology commissioned a project to develop guidelines for the therapy of MDS using evidence-based knowledge and consensus-formation techniques. An Advisory Council (AC) shaped the project around a series of key clinical questions, performed a systematic search for evidence and graded the available evidence according to the Scottish Intercollegiate Guidelines Network (SIGN). A list of clinical questions was mailed to each of 10 senior hematologists composing the Expert Panel (EP): the panelists were asked to rank the most relevant questions, and to formulate answers to the questions according to the tables of evidence. A scenario phase followed, so as to reach a consensus on the three top ranked questions. The EP was asked to score patient profiles as appropriate or not appropriate for the therapeutic strategy under scrutiny, according to the RAND technique. Finally, from September 2001 to January 2002, four Consensus Conferences conducted according to the Nominal Group Technique were held in Milan, Italy. The overall goal of the conferences was to take a final decision upon the appropriateness of the uncertain scenarios and of the uncertain responses to the clinical questions. Evidence was judged sufficient for providing recommendations on the use of allogeneic stem cell transplantation, leukemia-like chemotherapy, autologous stem cell transplantation, low-dose chemotherapy, danazol, immunosuppressive therapy, hypomethylating agents and hematopoietic growth factors. Specific recommendations for supportive therapy, including iron chelation, were issued. Allogeneic stem cell transplantation was unanimously considered as the only curative treatment for MDS patients, and recommendations on its use were agreed based on patient's age, risk, clinical features and donor availability. AML-like chemotherapy was also considered a valuable therapeutic option for subsets of MDS patients. Autologous stem cell transplantation was recommended for patients who lack an HLA identical donor and have achieved complete remission with AML-like chemotherapy. Decitabine, recombinant human erythropoietin and immunosuppressive therapy were judged valuable therapeutic options for subsets of MDS patients whereas low-dose cytarabine was not. Specific therapeutic strategies for those subjects younger than 18 years or older than 75 years and the strategy of watchful waiting were decided by patient-oriented questions. Using evidence and consensus, recommendations for the treatment of MDS were issued. Statements were graded according to the strength of the supporting evidence and uncertainty was explicitly declared.


Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection.
Human immunodeficiency virus type 1 (HIV) infection is characterized by progressive immunodeficiency despite of an overwhelming cellular immune activation. Patients show highly elevated serum/plasma concentrations of the proinflammatory cytokine interferon-gamma (IFN-gamma), which induces human monocytes to form neopterin, to produce reactive oxygen species (ROS) and in parallel, to degrade tryptophan. Enhanced tryptophan degradation by the enzyme indoleamine-2, 3-dioxygenase (IDO) contributes importantly to disease progression and "complications" of HIV infection: By a subsequent impairment of protein metabolism and serotonin formation, the development of neuropsychiatric disorders and weight loss in HIV infected patients can be enforced. Furthermore, increased IDO-activation efficiently suppresses the growth and proliferation of pathogens as well as host T-cells. IDO and other IFN-gamma-mediated pathways are strongly induced in patients with HIV infection and are also linked with disease progression: Neopterin formation by GTP-cyclohydrolase I sensitively reflects the stage of the disease, and determination of the pteridine in body fluids is useful to monitor the efficacy of antiretroviral therapy. Neopterin is an independent prognostic factor for the outcome of disease, and well suited to estimate the degree of immune activation in vivo and the responsiveness of immunocompetent cells to stimulation in vitro. ROS formation may contribute to the development of oxidative stress in HIV infection, resulting in depletion of antioxidants. The cause-effective role of an overwhelming Th1-type immune response together with the activation of IDO and other IFN-gamma-mediated biochemical pathways for the course of HIV infection, the development of immunodeficiency, anemia and weight loss in HIV patients is discussed.


Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials.
Randomized trials that studied clinical outcomes after percutaneous coronary intervention (PCI) with bare metal stenting versus coronary artery bypass grafting (CABG) are underpowered to properly assess safety end points like death, stroke, and myocardial infarction. Pooling data from randomized controlled trials increases the statistical power and allows better assessment of the treatment effect in high-risk subgroups. We performed a pooled analysis of 3051 patients in 4 randomized trials evaluating the relative safety and efficacy of PCI with stenting and CABG at 5 years for the treatment of multivessel coronary artery disease. The primary end point was the composite end point of death, stroke, or myocardial infarction. The secondary end point was the occurrence of major adverse cardiac and cerebrovascular accidents, death, stroke, myocardial infarction, and repeat revascularization. We tested for heterogeneities in treatment effect in patient subgroups. At 5 years, the cumulative incidence of death, myocardial infarction, and stroke was similar in patients randomized to PCI with stenting versus CABG (16.7% versus 16.9%, respectively; hazard ratio, 1.04, 95% confidence interval, 0.86 to 1.27; P=0.69). Repeat revascularization, however, occurred significantly more frequently after PCI than CABG (29.0% versus 7.9%, respectively; hazard ratio, 0.23; 95% confidence interval, 0.18 to 0.29; P<0.001). Major adverse cardiac and cerebrovascular events were significantly higher in the PCI than the CABG group (39.2% versus 23.0%, respectively; hazard ratio, 0.53; 95% confidence interval, 0.45 to 0.61; P<0.001). No heterogeneity of treatment effect was found in the subgroups, including diabetic patients and those presenting with 3-vessel disease. In this pooled analysis of 4 randomized trials, PCI with stenting was associated with a long-term safety profile similar to that of CABG. However, as a result of persistently lower repeat revascularization rates in the CABG patients, overall major adverse cardiac and cerebrovascular event rates were significantly lower in the CABG group at 5 years.


Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation.
Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.


Cardiac computed tomographic angiography for detection of cardiac sources of embolism in stroke patients.
We assessed the diagnostic performance of 2-phase 64-slice cardiac computed tomographic angiography (CCTA) for the detection of a cardiac source of embolism in stroke patients using transesophageal echocardiography (TEE) as the reference standard. We selected 137 patients who had experienced a recent episode of stroke and had undergone both 2-phase 64-slice CCTA and TEE within a period of 5 days. A potential cardiac source of embolism detected at both CCTA and TEE was recorded, and echocardiographic findings were categorized into high- and medium-risk sources based on the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Of 137 patients, 100 abnormal findings in 91 patients were found on TEE, and 46 patients had no abnormal finding on TEE. The overall sensitivity, specificity, positive predictive value, and negative predictive value of the 64-slice CCTA for detecting cardiac sources of embolism were 89% (95% CI, 82%, 95%), 100% (95% CI, 90%, 100%), 100% (95% CI, 95%, 100%), and 81% (95% CI, 70%, 92%), respectively. TEE detected a total of 47 high-risk sources of embolism, whereas CT detected 44 lesions. For medium-risk sources of cardiac embolic stroke, TEE detected a total of 53 abnormal findings, whereas CT detected 44 abnormal findings. Of 53 lesions, there were 8 false-negative results on CT (5 patent foramen ovale and 3 atrial septal aneurysm). Two-phase 64-slice CCTA is a noninvasive and useful modality for detecting high-risk cardiac sources of embolism in stroke patients.


Localization of epitopes recognized by monoclonal antibodies that neutralized the H3N2 influenza viruses in man.
Through extensive isolation of neutralizing mAbs against H3N2 influenza viruses representing the in vivo repertoire in a human donor, we examined the relationships between antigenic drift of influenza virus and protective antibodies generated in an infected individual. The majority of mAbs isolated from a donor born in 1960 were divided into three major groups with distinct strain specificity: 1968-1973, 1977-1993 and 1997-2003. In the present study, we developed a new method that allowed us to comprehensively determine the location of epitopes recognized by many mAbs. Original haemagglutinins (HAs) of several strains and chimaeric variants, in which one of the seven sites (A, B1, B2, C1, C2, D or E) was replaced by some other strain-derived sequence, were artificially expressed on the cell surface. The binding activity of mAbs to the HAs was examined by flow cytometry. By using this method, we determined the location of epitopes recognized by 98 different mAbs. Clones that neutralize the 1968-1973 strains bind to site B2/D, A or A/B1. While sites C, E and B were recognized by clones that neutralized the 1977-1993 strains, the majority of these clones bind to site C. Clones that neutralize the 1997-2003 strains bind to site B, A/B1, A/B2 or E/C2.


Mitomycin-C in corneal surface excimer laser ablation techniques: a report by the American Academy of Ophthalmology.
To review the published literature assessing the efficacy and safety of mitomycin-C (MMC) as an adjunctive treatment in corneal surface excimer laser ablation procedures. Literature searches of the PubMed and Cochrane Library databases were last conducted on August 19, 2014, without language or date limitations. The searches retrieved a total of 239 references. Of these, members of the Ophthalmic Technology Assessment Committee Refractive Management/Intervention Panel selected 26 articles that were considered to be of high or medium clinical relevance, and the panel methodologist rated each article according to the strength of evidence. Ten studies were rated as level I evidence, 5 studies were rated as level II evidence, and the remaining 11 studies were rated as level III evidence. The majority of the articles surveyed in this report support the role of MMC as an adjunctive treatment in surface ablation procedures. When MMC is applied in the appropriate concentration and confined to the central cornea, the incidence of post-surface ablation haze is decreased. Although a minority of studies that evaluated endothelial cell density (ECD) reported an MMC-related decrease in ECD, no clinical adverse outcomes were reported. Over the past 15 years, the use of MMC during surgery in surface ablation has become widespread. There is good evidence of the effectiveness of MMC when used intraoperatively as prophylaxis against haze in higher myopic ablations. Although there are reports of decreased endothelial counts after the administration of MMC during surgery, the clinical significance of this finding remains uncertain, because no adverse outcomes were reported with as much as 5 years of follow-up. Optimal dosage, effectiveness as prophylaxis in lower myopic and hyperopic ablations, and long-term safety, particularly in eyes with reduced corneal endothelial cell counts from prior intraocular surgery, have yet to be established.


Marker-free detection of progenitor cell differentiation by analysis of Brownian motion in micro-wells.
The kinetics of stem and progenitor cell differentiation at the single-cell level provides essential clues to the complexity of the underlying decision-making circuits. In many hematopoietic progenitor cells, differentiation is accompanied by the expression of lineage-specific markers and by a transition from a non-adherent to an adherent state. Here, using the granulocyte-macrophage progenitor (GMP) as a model, we introduce a label-free approach that allows one to follow the course of this transition in hundreds of single cells in parallel. We trap single cells in patterned arrays of micro-wells and use phase-contrast time-lapse movies to distinguish non-adherent from adherent cells by an analysis of Brownian motion. This approach allowed us to observe the kinetics of induced differentiation of primary bone-marrow-derived GMPs into macrophages. The time lapse started 2 hours after addition of the cytokine M-CSF, and nearly 80% of the population had accomplished the transition within the first 20 h. The analysis of Brownian motion proved to be a sensitive and robust tool for monitoring the transition, and thus provides a high-throughput method for the study of cell differentiation at the single-cell level.


Visual Categorization with Random Projection.
Humans learn categories of complex objects quickly and from a few examples. Random projection has been suggested as a means to learn and categorize efficiently. We investigate how random projection affects categorization by humans and by very simple neural networks on the same stimuli and categorization tasks, and how this relates to the robustness of categories. We find that (1) drastic reduction in stimulus complexity via random projection does not degrade performance in categorization tasks by either humans or simple neural networks, (2) human accuracy and neural network accuracy are remarkably correlated, even at the level of individual stimuli, and (3) the performance of both is strongly indicated by a natural notion of category robustness.


Management of insulin pump therapy in children with type 1 diabetes.
Insulin pump therapy is a current treatment option for children and adolescents with type 1 diabetes. Insulin pumps can provide a greater flexibility in insulin administration and meal planning, as compared with multiple insulin injections, and they may be particularly suitable for the paediatric age group. Many young people with diabetes have integrated insulin pumps into their daily practice. The use of insulin pumps can also be supplemented by the information retrieved from continuous glucose monitoring in the sensor-augmented pump therapy, which may improve glycaemic control. In this review, we describe the principles of pump therapy and summarise features of commercially available insulin pumps, with focus on practical management and the advantages and disadvantages of this technology.


ENA/VASP downregulation triggers cell death by impairing axonal maintenance in hippocampal neurons.
Neurodegenerative diseases encompass a broad variety of motor and cognitive disorders that are accompanied by death of specific neuronal populations or brain regions. Cellular and molecular mechanisms underlying these complex disorders remain largely unknown. In a previous work we searched for novel Drosophila genes relevant for neurodegeneration and singled out enabled (ena), which encodes a protein involved in cytoskeleton remodeling. To extend our understanding on the mechanisms of ENA-triggered degeneration we now investigated the effect of silencing ena ortholog genes in mouse hippocampal neurons. We found that ENA/VASP downregulation led to neurite retraction and concomitant neuronal cell death through an apoptotic pathway. Remarkably, this retraction initially affected the axonal structure, showing no effect on dendrites. Reduction in ENA/VASP levels blocked the neuritogenic effect of a specific RhoA kinase (ROCK) inhibitor, thus suggesting that these proteins could participate in the Rho-signaling pathway. Altogether these observations demonstrate that ENA/VASP proteins are implicated in the establishment and maintenance of the axonal structure and that a change on their expression levels triggers neuronal degeneration.


Adaptive adjustment of offspring sex ratio and maternal reproductive effort in an iteroparous mammal.
Large mammals in seasonal environments have a pattern of high-reproductive synchrony in spring, but how the timing of reproduction affects resource allocation decisions at different stages of the reproductive cycle remains largely unexplored. By manipulating the timing of conception in reindeer (Rangifer tarandus), we tested how the timing of conception affected sex ratio, gestation length and weight development of mother and offspring. Females that conceived at their first ovulation within the rut had a 60.5% probability of producing a male; in contrast, females that conceived a cycle later had a 31.3% probability of producing a male. Late conceiving females had gestation times that were 10 days shorter and the calves were 0.6 kg (9.2%) lighter at birth and 7.4 kg (14.7%) lighter in autumn. Over the year, female weight changes was similar between the groups suggesting reindeer follow a bet-hedging strategy; reducing the quality of this year's offspring to ensure their own future reproduction and survival. Harvesting is often selective leading to skewed sex ratios and age structure, which may influence the timing of reproduction due to females hesitation to mate with young males. Whenever this hesitation is strong enough to increase the frequency of recycling, harvesting is likely to have profound life history consequences.


[Clinical experiences with extracorporeal shockwave lithotripsy].
Clinical experience with 2738 patients treated by extracorporeal shock wave lithotripsy between March 1985 and December 1988 is reported. All treatments were performed with the Dornier HM-3 lithotriptor. 34% of the patients needed auxiliary measures, consisting primarily of urological manipulation to improve urinary drainage or for better localization and/or focussing of the stones. Severe complications were rare; urosepticemia occurred in 0.3%, 2 patients had to undergo nephrectomy because of abscessing pyelonephritis, and there was one death due to recurrent pulmonary embolism in a patient with polycythemia vera. ESWL was used for stones in the entire upper urinary tract. The stone free rate for pelvic calculi smaller than 2 cm was 79% three months after treatment; a further 16% showed desintegrated material smaller than 5 mm, augmenting the success rate to 95%. The success rate dropped to 74% for very large renal stones of more than 4 cm. A stone free rate of 84-96% was ascertained for ureteral calculi 3 months after ESWL. Absolute contraindications for ESWL are acute pyelonephritis, coagulation disorders and pregnancy. The patients must tolerate anesthesia, as most treatments with this lithotriptor must be carried out under peridural or general anesthesia and only in a few exceptional cases is treatment in sedoanalgesia possible. ESWL is now generally accepted in view of its negligible invasiveness, low morbidity and the high success rate. Modern treatment of urinary calculi is inconceivable without considering ESWL.


Carriage of Streptococcus pneumoniae 3 years after start of vaccination program, the Netherlands.
To evaluate the effectiveness of the 7-valent pneumococcal conjugate vaccine (PCV7) program, we conducted a cross-sectional observational study on nasopharyngeal carriage of Streptococcus pneumoniae 3 years after implementation of the program in the Netherlands. We compared pneumococcal serotypes in 329 prebooster 11-month-old children, 330 fully vaccinated 24-month-old children, and 324 parents with age-matched pre-PCV7 (unvaccinated) controls (ages 12 and 24 months, n = 319 and n = 321, respectively) and 296 of their parents. PCV7 serotype prevalences before and after PCV7 implementation, respectively, were 38% and 8% among 11-month-old children, 36% and 4% among 24-month-old children, and 8% and 1% among parents. Non-PCV7 serotype prevalences were 29% and 39% among 11-month-old children, 30% and 45% among 24-month-old children, and 8% and 15% among parents, respectively; serotypes 11A and 19A were most frequently isolated. PCV7 serotypes were largely replaced by non-PCV7 serotypes. Disappearance of PCV7 serotypes in parents suggests strong transmission reduction through vaccination.


Sipuleucel-T for the Treatment of Patients With Metastatic Castrate-resistant Prostate Cancer: Considerations for Clinical Practice.
Sipuleucel-T treatment is associated with a significant and consistent survival benefit in patients with metastatic castrate-resistant prostate cancer. Most adverse events are infusion related, manageable, and of short duration. Early screening and diagnosis of metastatic disease is important, as the greatest survival benefit may occur in patients with a lower disease burden. The short duration of sipuleucel-T treatment facilitates the use of subsequent therapies. Sipuleucel-T is now being used in the clinic for patients with a lower disease burden. We present our own experience with the use of sipuleucel-T in the setting of a large urology practice.


Australopithecine enamel prism patterns.
Following a recent suggestion that tooth enamel prism shape differs within Hominoidea, the teeth of a number of extinct and extant hominoid species were analyzed by scanning electron microscopy. The enamel prism patterns of some gracile and robust australopithecine specimens from Sterkfontein, Swartkrans, and Kromdraai are recorded. The characteristic arrangements of enamel prisms in all modern and extinct hominoid species were found to be essentially similar. The implications of enamel prisms for phylogenetic deduction in Hominoidea are discussed.


Validation of the Knee Injury and Osteoarthritis Outcome Score subscales for patients with articular cartilage lesions of the knee.
The Knee Injury and Osteoarthritis Outcome Score (KOOS) assesses acute and chronic knee injuries or early-onset osteoarthritis in young, active patients. The United States Food and Drug Administration guidelines recommend that patient-reported outcome instruments used to support clinical trial label claims should demonstrate content validity using patient input and have acceptable psychometric properties in the target population. To use the KOOS subscales in safety and efficacy trials assessing new treatments for patients with articular cartilage lesions, additional validation work, using input from patients with articular cartilage lesions, was necessary. Qualitative and quantitative evaluations of the KOOS subscales' validity among patients with articular cartilage lesions were conducted to support their use as clinically meaningful end points in clinical trials. Cohort study (diagnosis); Level of evidence, 2. For qualitative analysis, cognitive interviews involving concept elicitation and cognitive debriefing with the KOOS items were conducted with 15 participants aged 25 to 52 years. Participants either were candidates for cartilage repair or had undergone cartilage repair 6 months or more before the study. For the quantitative analysis, a psychometric evaluation of the KOOS was conducted with clinical trial data from 54 patients, aged 18 to 55 years, evaluating the Cartilage Autograft Implantation System in the United States (n = 29) and the European Union (n = 25). Data were collected before surgery and at 7 postsurgical visits up to 12 months. Internal consistency and test-retest reliability, construct validity, responsiveness, and estimates of the minimal detectable change (MDC) were assessed. Test-retest reliability was assessed using data from months 2 and 3 on a subset of stable patients. Qualitative research confirmed that concepts measured on the KOOS are important to patients with articular cartilage lesions. Most participants reported the KOOS was comprehensive and appropriate. In the quantitative research, KOOS subscales showed excellent internal consistency reliability (range, .74-.97 at baseline) and test-retest reliability (range, .78-.82). Construct validity results supported hypothesized relationships, with significant correlations (r ≥ .50) in the expected directions. Responsiveness analyses demonstrated excellent sensitivity to change; standardized response means ranged from 0.8 to 1.2, and MDC estimates ranged from 7.4 to 12.1. The study results support the use of the KOOS subscales among patients with articular cartilage lesions.


Novel mononuclear and 1D-polymeric derivatives of lanthanides and (η6-benzoic acid)tricarbonylchromium: synthesis, structure and magnetism.
Two series of novel heteroleptic derivatives of lanthanides and (η6-benzoic acid)tricarbonylchromium (benchrotrenecarboxylic acid) were synthesized and characterized: mononuclear complexes [Ln(BcrCOO)(acac)2(H2O)2] (Ln = Eu (1), Gd (2), Tb (3a), Dy (4a), Ho (5a)) and 1D-polymeric ones [Ln(BcrCOO)(acac)2(H2O)]n (Ln = Tb (3b), Dy (4b), Ho (5b), Er (6), Tm (7), Yb (8) and Y (9)), Bcr = (η6-C6H5)Cr(CO)3. The molecular and crystal structures of the obtained compounds were determined. Complexes 3a, 4a, 4b, 6 and 8 were found to exhibit SMM properties. Two maxima were observed on χ''(ν) dependencies (LF and HF) for 4a, 4b and 6. For 4a, the anisotropy barriers are Δeff/kB = 100 K and 118 K in zero dc-field (128 K and 143 K in 2000 Oe field) for the LF (low frequency) and HF (high frequency) signals, respectively. These values are the highest ones for Ln carboxylate complexes. The nature of the appearance of two maxima in the system is discussed.


Transfusion-associated microchimerism: a new complication of blood transfusions in severely injured patients.
Microchimerism, the stable persistence of an allogeneic cell population, can result from allogeneic exposures including blood transfusion. Transfusion-associated microchimerism (TA-MC) appears to be a common but newly recognized complication of blood transfusion. Thus far TA-MC has been detected when severely injured patients are transfused. Injury induces an immunosuppressive and inflammatory milieu in which fresh blood products with replication-competent leukocytes can sometimes cause TA-MC. TA-MC is present in approximately half of transfused severely injured patients at hospital discharge and is not affected by leukoreduction. In approximately 10% of patients, the chimerism from a single blood donor may increase in magnitude over months to years, reaching as much as 2% to 5% of all circulating leukocytes. In this review, we discuss recent studies of TA-MC in the civilian trauma population and the potential for study of TA-MC in the military population, where the severity of injury and freshness of blood products suggest that TA-MC may be even more prominent. We also discuss the need for future studies to address the immunology of TA-MC, its stem cell biology, and its clinical manifestations that have the potential to be either pathologic (autoimmunity, graft-versus-host disease) or therapeutic (tolerance induction, various cell and gene therapies).


Evidence of D-phenylglycine as delivering tool for improving L-dopa absorption.
L-dopa has been used for Parkinson's disease management for a long time. However, its wide variety in the rate and the extent of absorption remained challenge in designing suitable therapeutic regime. We report here a design of using D-phenylglycine to guard L-dopa for better absorption in the intestine via intestinal peptide transporter I (PepT1). D-phenylglycine was chemically attached on L-dopa to form D-phenylglycine-L-dopa as a dipeptide prodrug of L-dopa. The cross-membrane transport of this dipeptide and L-dopa via PepT1 was compared in brush-boarder membrane vesicle (BBMV) prepared from rat intestine. The intestinal absorption was compared by in situ jejunal perfusion in rats. The pharmacokinetics after i.v. and p.o. administration of both compounds were also compared in Wistar rats. The striatal dopamine released after i.v. administration of D-phenylglycine-L-dopa was collected by brain microdialysis and monitored by HPLC. Anti-Parkinsonism effect was determined by counting the rotation of 6-OHDA-treated unilateral striatal lesioned rats elicited rotation with (+)-methamphetamine (MA). The BBMV uptake of D-phenylglycine-L-dopa was inhibited by Gly-Pro, Gly-Phe and cephradine, the typical PepT1 substrates, but not by amino acids Phe or L-dopa. The cross-membrane permeability (Pm*) determined in rat jejunal perfusion of D-phenylglycine-L-dopa was higher than that of L-dopa (2.58 ± 0.14 vs. 0.94 ± 0.10). The oral bioavailability of D-phenylglycine-L-dopa was 31.7 times higher than that of L-dopa in rats. A sustained releasing profile of striatal dopamine was demonstrated after i. v. injection of D-phenylglycine-L-dopa (50 mg/kg), indicated that D-phenylglycine-L-dopa might be a prodrug of dopamine. D-phenylglycine-L-dopa was more efficient than L-dopa in lowering the rotation of unilateral striatal lesioned rats (19.1 ± 1.7% vs. 9.9 ± 1.4%). The BBMV uptake studies indicated that D-phenylglycine facilitated the transport of L-dopa through the intestinal PepT1 transporter. The higher jejunal permeability and the improved systemic bioavailability of D-phenylglycine-L-dopa in comparison to that of l-dopa suggested that D-phenylglycine is an effective delivery tool for improving the oral absorption of drugs like L-dopa with unsatisfactory pharmacokinetics. The gradual release of dopamine in brain striatum rendered this dipeptide as a potential dopamine sustained-releasing prodrug.


Gray matter heritability in family-based and population-based studies using voxel-based morphometry.
The combination of genetics and imaging has improved their understanding of the brain through studies of aggregate measures obtained from high-resolution structural imaging. Voxel-wise analyses have the potential to provide more detailed information of genetic influences on the brain. Here they report a large-scale study of the heritability of gray matter at voxel resolution (1 × 1 × 1 mm). Validated voxel-based morphometry (VBM) protocols were applied to process magnetic resonance imaging data of 3,239 unrelated subjects from a population-based study and 491 subjects from two family-based studies. Genome-wide genetic data was used to estimate voxel-wise gray matter heritability of the unrelated subjects and pedigree-structure was used to estimate heritability in families. They subsequently associated two genetic variants, known to be linked with subcortical brain volume, with most heritable voxels to determine if this would enhance their association signals. Voxels significantly heritable in both estimates mapped to subcortical structures, but also voxels in the language areas of the left hemisphere were found significantly heritable. When comparing regional patterns of heritability, family-based estimates were higher than population-based estimates. However, regional consistency of the heritability measures across study designs was high (Pearson's correlation coefficient = 0.73, P = 2.6 × 10-13 ). They further show enhancement of the association signal of two previously discovered genetic loci with subcortical volume by using only the most heritable voxels. Gray matter voxel-wise heritability can be reliably estimated with different methods. Combining heritability estimates from multiple studies is feasible to construct reliable heritability maps of gray matter voxels. Hum Brain Mapp 38:2408-2423, 2017. © 2017 Wiley Periodicals, Inc.


Supervised exercise to reduce agitation in severely cognitively impaired persons.
Several studies have shown an improvement in depression, activities of daily living, and agitation in cognitively impaired subjects who undergo a long-term exercise program. These studies have not considered the short-term effects of exercise. The purpose of this study was to investigate the short-term effects of a limited, supervised exercise program on agitation, depression, and activities of daily living in cognitively impaired patients residing in the special needs unit of a nursing home. This study was a prospective comparative study. A 3-week exercise program was implemented at the special needs units of 2 nursing homes. The exercise program involved 30 minutes of exercise (15 minutes of aerobic and 15 minutes of resistance), 3 days per week. There were 50 residents in this study (76% female, 24% male) and they had a mean age of 79.2 +/- 9.7 years. The subjects had a mean SLUMS (Saint Louis Mental Status Examination) score of 1.5 +/- 2.1 (SLUM score range 0-30, 30 meaning full cognitive faculty). Each subject had his or her depression, agitation, activities of daily living, and 6-meter walk time measured before and after the 3-week exercise program. The Cornell Scale for Depression, Pittsburgh Agitation Scale (PAS)/Cohen-Mansfield Agitation Inventory, and ADCS-ADL (Alzheimer's disease cooperative study-activities of daily living) were used to measure depression, agitation, and activities of daily living, respectively. Multiple paired t tests were calculated for each outcome measurement. The post-study scales showed an improvement in the 6-meter walk test and, using the PAS (0-16, 0 meaning no agitation), an improvement in agitation. The improvement in agitation in the entire population was P less than .05; mean PAS pre-study scores were 5.8 +/- 4.8 and mean PAS poststudy scores were 4.5 +/- 3.7 . Among the patients with PAS Pre-Exercise Program Scores greater than 3, thus categorized as agitated, there was a greater decrease in agitation; PAS Pre-Study Scores were 9.1 +/- 3.4 and PAS Study Scores were 6.1 +/- 3.4 (P < .001). There was also an improvement in 6-meter walk times; pre-study times were 12.5 +/- 5.2 and post-exercise program times were 10.1 +/- 4.4 (P < .001). There was an improvement in agitation scores and the 6-meter walk times in the subjects after their engagement in the 3-week exercise program. Further study is needed in order to expand on these results.


The use of assessment scales in Old Age Psychiatry Services in England and Northern Ireland.
Implementation of the Single Assessment Process in the UK is designed to ensure that more standardized assessment procedures are in place across all areas and agencies, that practice improves and older people's needs are comprehensively assessed. This study provides a unique picture of the range and prevalence of standardized scales used within Old Age Psychiatry Services in England and Northern Ireland, reported by 73% of old age psychiatrists. Most services (64%) used three or more standardized assessment scales (range 1-12). Sixty-two separate instruments were identified. The six most used measures were the Mini Mental State Examination (95%), the Geriatric Depression Scale (52%) and the Clock Drawing (50%), the Clifton Assessment Procedures for the elderly (26%), the Barthel Index (18%) and the Health of the Nation Outcome Scales (HoNOS) 65 + (18%). A number of factors were associated with greater use of certain standardized assessment scales. Shared documentation, along with other indicators of integration between health and social care were associated with greater use of standardized scales. The provision of a memory clinic was associated with greater use of neuropsychiatric scales and lower levels of use of cognitive scales. These results provide key material for shaping the provision of psychiatric services for older people


Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons.
Successful development of antiobesity agents requires detailed knowledge of neural pathways controlling body weight, eating behavior, and peripheral metabolism. Genetic ablation of FoxO1 in selected hypothalamic neurons decreases food intake, increases energy expenditure, and improves glucose homeostasis, highlighting the role of this gene in insulin and leptin signaling. However, little is known about potential effects of FoxO1 in other neurons. To address this question, we executed a broad-based neuronal ablation of FoxO1 using Synapsin promoter-driven Cre to delete floxed Foxo1 alleles. Lineage-tracing experiments showed that NPY/AgRP and POMC neurons were minimally affected by the knockout. Nonetheless, Syn-Cre-Foxo1 knockouts demonstrated a catabolic energy homeostatic phenotype with a blunted refeeding response, increased sensitivity to leptin and amino acid signaling, and increased locomotor activity, likely attributable to increased melanocortinergic tone. We confirmed these data in mice lacking the three Foxo genes. The effects on locomotor activity could be reversed by direct delivery of constitutively active FoxO1 to the mediobasal hypothalamus, but not to the suprachiasmatic nucleus. The data reveal that the integrative function of FoxO1 extends beyond the arcuate nucleus, suggesting that central nervous system inhibition of FoxO1 function can be leveraged to promote hormone sensitivity and prevent a positive energy balance.


Pointwise shape-adaptive DCT for high-quality denoising and deblocking of grayscale and color images.
The shape-adaptive discrete cosine transform ISA-DCT) transform can be computed on a support of arbitrary shape, but retains a computational complexity comparable to that of the usual separable block-DCT (B-DCT). Despite the near-optimal decorrelation and energy compaction properties, application of the SA-DCT has been rather limited, targeted nearly exclusively to video compression. In this paper, we present a novel approach to image filtering based on the SA-DCT. We use the SA-DCT in conjunction with the Anisotropic Local Polynomial Approximation-Intersection of Confidence Intervals technique, which defines the shape of the transform's support in a pointwise adaptive manner. The thresholded or attenuated SA-DCT coefficients are used to reconstruct a local estimate of the signal within the adaptive-shape support. Since supports corresponding to different points are in general overlapping, the local estimates are averaged together using adaptive weights that depend on the region's statistics. This approach can be used for various image-processing tasks. In this paper, we consider, in particular, image denoising and image deblocking and deringing from block-DCT compression. A special structural constraint in luminance-chrominance space is also proposed to enable an accurate filtering of color images. Simulation experiments show a state-of-the-art quality of the final estimate, both in terms of objective criteria and visual appearance. Thanks to the adaptive support, reconstructed edges are clean, and no unpleasant ringing artifacts are introduced by the fitted transform.


Superconducting qubit to optical photon transduction.
Conversion of electrical and optical signals lies at the foundation of the global internet. Such converters are used to extend the reach of long-haul fibre-optic communication systems and within data centres for high-speed optical networking of computers. Likewise, coherent microwave-to-optical conversion of single photons would enable the exchange of quantum states between remotely connected superconducting quantum processors1. Despite the prospects of quantum networking2, maintaining the fragile quantum state in such a conversion process with superconducting qubits has not yet been achieved. Here we demonstrate the conversion of a microwave-frequency excitation of a transmon-a type of superconducting qubit-into an optical photon. We achieve this by using an intermediary nanomechanical resonator that converts the electrical excitation of the qubit into a single phonon by means of a piezoelectric interaction3 and subsequently converts the phonon to an optical photon by means of radiation pressure4. We demonstrate optical photon generation from the qubit by recording quantum Rabi oscillations of the qubit through single-photon detection of the emitted light over an optical fibre. With proposed improvements in the device and external measurement set-up, such quantum transducers might be used to realize new hybrid quantum networks2,5 and, ultimately, distributed quantum computers6,7.


Traction microscopy with integrated microfluidics: responses of the multi-cellular island to gradients of HGF.
Collective cellular migration plays a central role in development, regeneration, and metastasis. In these processes, mechanical interactions between cells are fundamental but measurement of these interactions is often hampered by technical limitations. To overcome some of these limitations, here we describe a system that integrates microfluidics with traction microscopy (TM). Using this system we can measure simultaneously, and in real time, migration speeds, tractions, and intercellular tension throughout an island of confluent Madin-Darby canine kidney (MDCK) cells. The cell island is exposed to hepatocyte growth factor (HGF) at a controlled gradient of concentrations; HGF is known to elicit epithelial-to-mesenchymal transition (EMT) and cell scattering. As expected, the rate of expansion of the cell island was dependent on the concentration of HGF. Higher concentrations of HGF reduced intercellular tensions, as expected during EMT. A novel finding, however, is that the effects of HGF concentration and its gradient were seen within an island. This integrated experimental system thus provides an integrated tool to better understand cellular forces during collective cellular migration under chemical gradients.


Development of two Barthel Index-based Supplementary Scales for patients with stroke.
The Barthel Index (BI) assesses actual performance of activities of daily living (ADL). However, comprehensive assessment of ADL functions should include two other constructs: self-perceived difficulty and ability. The aims of this study were to develop two BI-based Supplementary Scales (BI-SS), namely, the Self-perceived Difficulty Scale and the Ability Scale, and to examine the construct validity of the BI-SS in patients with stroke. The BI-SS was first developed by consultation with experts and then tested on patients to confirm the clarity and feasibility of administration. A total of 306 participants participated in the construct validity study. Construct validity was investigated using Mokken scale analysis and analyzing associations between scales. The agreement between each pair of the scales' scores was further examined. The Self-perceived Difficulty Scale consisted of 10 items, and the Ability Scale included 8 items (excluding both bladder and bowel control items). Items in each individual scale were unidimensional (H ≥ 0.5). The scores of the Self-perceived Difficulty and Ability Scales were highly correlated with those of the BI (rho = 0.78 and 0.90, respectively). The scores of the two BI-SS scales and BI were significantly different from each other (p<.001). These results indicate that both BI-SS scales assessed unique constructs. The BI-SS had overall good construct validity in patients with stroke. The BI-SS can be used as supplementary scales for the BI to comprehensively assess patients' ADL functions in order to identify patients' difficulties in performing ADL tasks, plan intervention strategies, and assess outcomes.


Tradition and change in the Northern Alberta Woodlands Cree: implications for infant feeding practices.
Using anthropological, ethnographic methods of participant observation and interactive, unstructured interviews, we compared traditional and present-day infant feeding practices of the Northern Alberta Woodland Cree. Twelve elderly multigravidae who used traditional ways of childbearing and rearing and 12 women who used present-day practices served as informants. The major change in childbearing was the removal of childbirth from the household to the hospital. This has resulted in the loss of social support and doulas for mothers, who feel insecure and afraid at this time. Infant feeding methods have changed from breastfeeding to the widespread use of canned milk and, if present-day infants are breastfed, it is only for a short time. Both the traditional and present-day mothers introduced solid foods relatively early, but the traditional mothers premasticated the infants' food rather than using commercial baby food or a blender. Following the traditional practices, mothers felt it was important to keep the breasts warm when lactating, and they were reluctant to feed the infant colostrum immediately after delivery. The importance of understanding the cultural context of infant feeding practices is discussed.


Triple grouping and period-three oscillations in minority-game dynamics.
Dynamical systems based on the minority game (MG) have been a paradigm for gaining significant insights into a variety of social and biological behaviors. Recently, a grouping phenomenon has been unveiled in MG systems of multiple resources (strategies) in which the strategies spontaneously break into an even number of groups, each exhibiting an identical oscillation pattern in the attendance of game players. Here we report our finding of spontaneous breakup of resources into three groups, each exhibiting period-three oscillations. An analysis is developed to understand the emergence of the striking phenomenon of triple grouping and period-three oscillations. In the presence of random disturbances, the triple-group/period-three state becomes transient, and we obtain explicit formula for the average transient lifetime using two methods of approximation. Our finding indicates that, period-three oscillation, regarded as one of the most fundamental behaviors in smooth nonlinear dynamical systems, can also occur in much more complex, evolutionary-game dynamical systems. Our result also provides a plausible insight for the occurrence of triple grouping observed, for example, in the U.S. housing market.


Medical pluralism, Pentecostal healing and contests over healing power in Papua New Guinea.
This paper is based on long-term ethnographic fieldwork among the Lelet of New Ireland Province, Papua New Guinea. It draws on qualitative interviews with Pentecostal Christians intended to examine their understanding of Christianity and how this relates to their cultural practices - in this case, how their Pentecostalism affects their therapeutic beliefs and practices. The frequent observation that therapeutic repertoires are becoming less discrete is substantiated by the Lelet case, for in their search for therapy, the Lelet often cross the borders of different repertoires, seeing no contradiction, for example, between combining a vernacular therapy with biomedicine. With the advent of Pentecostalism, the issue has become far more complex. The Lelet therapeutic culture remains pluralist, but the research shows that Lelet Pentecostals are increasingly viewing their own Christian-based forms of healing as in competition with other therapies, especially vernacular therapies. This competitive outlook has brought a demonization of vernacular therapies, which are labelled 'satanic' and their use discouraged. In fact, Pentecostalism is refashioning the realm of therapy: rather than border crossing and mixing of therapeutic repertoires, the situation is increasingly dominated by notions of mutual exclusivity. In order to comprehend the full complexity of medical pluralism, it is now necessary not only to examine how the borders of the different therapeutic repertoires are blurred, destabilized or reconfigured but also how they may be demarcated and policed. In other words, we argue that medical pluralism is being eroded by its interaction with Pentecostalism.


Validation of the arabic version of the epworth sleepiness scale in oman.
The Epworth sleepiness scale is a self-administered eight-item questionnaire that was developed as a tool to measure subjective sleepiness in adults. The validity of the Epworth sleepiness scale has been validated and tested in different populations and ethnic groups. However, it has yet to be validated or tested in an Omani or other Arabic speaking population. Thus, the aim of this study is to test the validity and reproducibility of the Epworth sleepiness scale in an Omani population. Subjects were recruited from the general population and were asked to participate in the study. The study enrolled 97 Omani volunteers and was conducted between May and October 2008. An Arabic version of the original English questionnaire was used. The study was approved by the Research and Ethics committee of the institution. Lin's concordance correlation coefficient along with Bland-Altman plots were used to test the agreement between the Arabic and English versions of the Epworth sleepiness scale. The study included a total of 37 males (38%) and 60 females (62%) with age ranging between 18-75 years. Concordance correlation results revealed a substantial concordance (RhoC) of 0.914, but one that does not approach 1 (95% CI: 0.881, 0.947). This results from both lack of perfect correlation (Pearson's r=0.914) and bias (C_b = 1.000). The Bland and Altman's limits-of-agreement measured at 0.000 (95% CI: -2.684, 2.684), indicating insignificant average departure from agreement between the two versions of the Epworth sleepiness scale. The results indicate agreement between the two versions of ESS (English and the Arabic).


A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family.
A mutation linked to autistic spectrum disorders encodes an Arg to Cys replacement in the C-terminal portion of the extracellular domain of neuroligin-3. The solvent-exposed Cys causes virtually complete retention of the protein in the endoplasmic reticulum when the protein is expressed in transfected cells. An identical Cys substitution was reported for butyrylcholinesterase through genotyping patients with post-succinylcholine apnea. Neuroligin, butyrylcholinesterase, and acetylcholinesterase are members of the alpha,beta-hydrolase fold family of proteins sharing sequence similarity and common tertiary structures. Although these proteins have distinct oligomeric assemblies and cellular dispositions, homologous Arg residues in neuroligin-3 (Arg-451), in butyrylcholinesterase (Arg-386), and in acetylcholinesterase (Arg-395) are conserved in all studied mammalian species. To examine whether an homologous Arg to Cys mutation affects related proteins similarly despite their differing capacities to oligomerize, we inserted homologous mutations in the acetylcholinesterase and butyrylcholinesterase cDNAs. Using confocal fluorescence microscopy and analysis of oligosaccharide processing, we find that the homologous Arg to Cys mutation also results in endoplasmic reticulum retention of the two cholinesterases. Small quantities of mutated acetylcholinesterase exported from the cell retain activity but show a greater K(m), a much smaller k(cat), and altered substrate inhibition. The nascent proteins associate with chaperones during processing, but the mutation presumably restricts processing through the endoplasmic reticulum and Golgi apparatus, because of local protein misfolding and inability to oligomerize. The mutation may alter the capacity of these proteins to dissociate from their chaperone prior to oligomerization and processing for export.


Disturbance Frequency and Community Stability in Native Tallgrass Prairie.
Ecological communities are spatially and temporally variable in response to a variety of biotic and abiotic forces. It is not always clear, however, if spatial and temporal variability leads to instability in communities. Instability may result from strong biotic interactions or from stochastic processes acting on small populations. I used 10-15 yr of annual data from the Konza Prairie Long-Term Ecological Research site to examine whether plant, breeding bird, grasshopper, and small mammal communities in tallgrass prairie exhibit stability or directional change in response to different experimentally induced fire frequencies. Based on ordination and ANOVA, plant and grasshopper communities on annually burned sites differed significantly from plant and grasshopper communities on less frequently burned sites. Breeding birds and small mammals differed among sites as well, but these differences were not clearly related to disturbance frequency. A modified time series analysis indicated that plant communities were undergoing directional change (unstable) on all watersheds, regardless of fire frequency. Contrary to expectations, directional change was greatest on the annually burned sites and lowest on the infrequently burned sites. Unlike the plant communities, breeding bird, grasshopper, and small mammal communities were temporally stable, despite high-compositional variability from 1 yr to the next. Stability among the consumer communities within these dynamic plant communities occurs because three-dimensional vegetation structure does not change over time, despite changes in plant species composition. Evidence suggests that instability in the plant community results from strong biotic interactions among temporally persistent core species and stochastic dynamics among infrequent satellite species. Overall, community stability cannot be assessed if the pattern of temporal dynamics is unknown. Long-term empirical studies of different taxa under different disturbance regimes are needed to determine over what time frames and spatial scales communities may be stable. Such studies are essential for the development of generalities regarding the relationship between disturbance frequency and community stability in terrestrial and aquatic systems.


Altered expression of sialylated glycoproteins in breast cancer using hydrazide chemistry and mass spectrometry.
Sialylation is one of the altered protein glycosylations associated with cancer development. The sialoglycoproteins in cancer cells, however, largely remain unidentified because of the lack of a method for quantitative analysis of sialoglycoproteins. This manuscript presents a high throughput method for quantitative analysis of N-linked sialoglycoproteins using conditional hydrazide chemistry, liquid chromatography, and tandem mass spectrometry. We further applied the sialoglycoproteomic method to the profiling of breast cancer tissues and compared findings with the results from the total glycoproteomic analysis using the original hydrazide chemistry method. We identified altered expression of sialoglycoproteins, as well as the total glycoprotein changes associated with breast cancer. Using lectin and Western blot analysis, we characterized one of the sialoglycoproteins, versican, and confirmed that versican was most sialylated and elevated in breast cancer. Furthermore, we showed that versican was detected in both cancer epithelial cells and peritumoral stromal cells using immunohistochemistry. Tissue microarray analysis revealed that epithelial expression of versican had significant relations to lymph node metastasis and pathological stages. This is the first quantitative sialoglycoproteomic and glycoproteomic analysis of breast cancer and noncancerous tissues. These findings present a significant addition of the method to the identification of altered expression of sialylated glycoproteins associated with breast cancer development.


Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.
Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.


Cellular proliferation in pilocytic and diffuse astrocytomas.
Using quantitative image analysis, we evaluated the MIB-1 labeling index (LI) in a large population of pilocytic (n = 131) and diffuse astrocytomas (n = 140), explored its significance as a prognostic predictor of survival, and compared it to other commonly accepted predictors, including grade and its histologic determinants, atypia, mitoses, endothelial proliferation, and necrosis. Diffuse astrocytomas were graded according to the St Anne-Mayo scheme and included 45 grade 2, 50 grade 3, and 45 grade 4 astrocytomas. In pilocytic astrocytomas, mean, median, and range of MIB-1 LIs were 1.1, 0.9, and 0-3.9%, respectively. In diffuse astrocytomas, these values were 2.3, 2, and 0-7.6% in grade 2; 6, 4.4, and 0.1-25.7% in grade 3; 9.1, 6, and 0.3-36% in grade 4. There was a significant difference in the distribution of MIB-1 LIs between pilocytic and diffuse grade 2 astrocytomas (p < 0.001), between grade 2 and grade 3 (p < 0.001), and between tumors of grade 3 and 4 (p = 0.014). Among pilocytic astrocytomas there was no association between survival and MIB-1 LI or any histologic parameter. In diffuse astrocytomas, MIB-1 LI was significantly correlated with grade as well as with mitotic activity (<0.001) and survival. While in diffuse astrocytomas of all grades, necrosis was the strongest factor associated with survival, in tumors of grades 2 and 3 the MIB-1 LI preceded other histologic parameters and, on multivariate analysis, remained the only feature predictive of survival. Grade 3 astrocytomas with a single "solitary" mitosis had a significantly lower MIB-I LI than did grade 3 tumors with >1 mitosis and, compared to the latter, had a significantly longer survival (p = 0.013), one not significantly different from patients with grade 2 astrocytomas. These findings suggest that the cutoff point between grade 2 and 3 in the St. Anne-Mayo scheme may not be optimal and may need to be revised.


Kinetic analysis of erythrocyte Na+-K+ pump and cotransport in essential hypertension.
Alterations in red blood cell (RBC) Na+-K+ pump and Na+-K+ cotransport have been described in essential hypertension. We evaluated Na+-K+ pump and cotransport in 30 hypertensive and 26 normotensive subjects subdivided by race and family history of hypertension using an improved method to examine the kinetics of Na and K effluxes. RBCs were Na-loaded by the nystatin method to five different levels of internal Na with pump determined as ouabain-sensitive Na efflux and cotransport as furosemide-sensitive Na and K efflux. Two kinetic parameters were determined for both transport systems: the apparent affinity for Na (K0.5) and the velocity of efflux at saturating internal Na concentration (Vmax). Mean intracellular Na content in fresh RBCs (mmol/L cells) was higher in black hypertensive (12.6 +/- 1.8 mmol/L cells) and normotensive subjects (10.9 +/- 1.2 mmol/L cells) than in white hypertensive (8.7 +/- 1.0 mmol/L cells) or normotensive subjects (8.5 +/- 0.8 mmol/L cells). The Vmax and K0.5 for pump were not significantly different between study groups. The Vmax for cotransport was elevated in white hypertensive compared with normotensive subjects, but the K0.5 values were similar. Black normotensive and hypertensive subjects displayed a lower Vmax and increased K0.5 for cotransport compared with the white groups. A family history of hypertension had no influence on cotransport kinetics in blacks but did predict white normotensive and hypertensive subjects with low cotransport. The reduction in intracellular Na affinity for cotransport in black subjects may explain their higher intracellular Na in fresh RBCs.(ABSTRACT TRUNCATED AT 250 WORDS)


Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis.
In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.


Current Concepts and Treatments of Schizophrenia.
Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.