Thrombus Volume as a Predictor of Nonrecanalization After Intravenous Thrombolysis in Acute Stroke.
Background and Purpose- We investigated whether measuring the volume and density of a thrombus could predict nonrecanalization after intravenous thrombolysis. Methods- This study included a retrospective cohort to develop a computed tomography marker of thrombus for predicting nonrecanalization after intravenous thrombolysis and a prospective multicenter cohort for validation of this marker. The volume and density of thrombus were measured semiautomatically using 3-dimensional software on a baseline thin-section noncontrast computed tomography (1 or 1.25 mm). Recanalization was assessed on computed tomography angiography or magnetic resonance angiography immediately after intravenous thrombolysis or conventional angiography in patients who underwent further intra-arterial treatment. Nonrecanalization was defined as a modified Thrombolysis in Cerebral Infarction grade 0, 1, 2a. Results- In the retrospective cohort, 162 of 214 patients (76.7%) failed to achieve recanalization. The thrombus volume was significantly larger in patients with nonrecanalization than in those with successful recanalization (149.5±127.6 versus 65.3±58.3 mm3; P<0.001). In the multivariate analysis, thrombus volume was independently associated with nonrecanalization ( P<0.001). The cutoff for predicting nonrecanalization was calculated as 200 mm3. In the prospective multicenter validation study, none of the patients with a thrombus volume ≥200 mm3 among 78 enrolled patients achieved successful recanalization. The positive and negative predictive values were 95.5 and 29.4 in the retrospective cohort 100 and 23.3 in the prospective validation cohort, respectively. The thrombus density was not associated with nonrecanalization. Conclusions- Thrombus volume was predictive of nonrecanalization after intravenous thrombolysis. Measurement of thrombus volume may help in determining the recanalization strategy and perhaps identify patients suitable for direct endovascular thrombectomy.


A paradoxical fall in urine dopamine output when patients with essential hypertension are given added dietary salt.
The effect of dietary sodium on the urine dopamine excretion of eight hypertensive patients and six matched controls was studied under metabolic balance conditions over a 2 week period during which dietary sodium intake was increased from 20 to 220 mmol/day. The control group showed the expected increase in dopamine excretion in response to sodium but the hypertensive patients showed an initial fall followed by a return to baseline values. Neither group showed a rise in blood pressure but the hypertensive patients showed a greater weight gain on salt loading, although this change was not significant. The cumulative sodium balance was greater and more prolonged in the hypertensive patients, although this difference also did not attain statistical significance. This defect in dopamine mobilization may be important in relation to renal sodium handling by patients with essential hypertension.


Persistent marine litter: small plastics and cigarette butts remain on beaches after organized beach cleanups.
Cyprus is an island country in the Eastern Mediterranean whose economy is largely dependent on coastal tourism. It boasts some of the cleanest waters in Europe and has the largest number of Blue Flag awarded beaches per capita in the world. These beaches are managed by local authorities and are regularly cleaned, throughout the year, at least once per day. This paper presents findings from cleanups that were organized over the summers of 2016 and 2017 on nine Blue Flag beaches around the island of Cyprus, after the beaches were cleaned by the responsible authorities. The aim was to answer the following questions: 'Are regular beach cleanups by local authorities efficient?' and 'What is left on a "clean" beach?' The results suggest that local authority cleanup efforts are quite successful at collecting larger pieces of marine litter, leaving the beach seemingly clean. However, small pieces of litter, such as cigarette butts and small pieces of plastic items related to recreational activities, remain on the beach. They likely accumulate or are buried over time, with some items becoming a nuisance to beach goers and a potential source of marine litter.


Type 2 diabetes in children.
The emerging epidemic of type 2 diabetes (T2DM) in young people reflects increasing rates of obesity and parallels the increasing frequency of T2DM in adults. As in adults, T2DM in children is part of the insulin resistance syndrome that includes hyperandrogenism seen as premature adrenarche and polycystic ovary syndrome, hypertension, dyslipidemia, and other atherosclerosis risk factors. Recent studies in children document risk factors for T2DM, and associated cardiovascular risk factors, including obesity, family history, diabetic gestation, and underweight or overweight for gestational age. Genetically determined insulin resistance or limited beta-cell reserve has been demonstrated in high-risk individuals, including first-degree relatives of girls with premature adrenarche. This genetic background, considered advantageous in a feast-and-famine existence (the thrifty genotype), is rendered detrimental with abundant food and physical inactivity, a lifestyle demonstrated to be typical of families of children with T2DM. The increasing incidence of T2DM in children and adolescents threatens to become a major public health problem. Risk factors for cardiovascular disease, hypertension, hyperlipidemia, and microalbuminuria are present at diagnosis of T2DM in Native American adolescents, indicating that insulin resistance has been present for some time before the diagnosis of diabetes was made. Case finding is likely to be beneficial in high-risk youths. Treatment is the same as that of adults. The only data on use of oral hypoglycemic agents in children have been with metformin. Community and governmental efforts to educate all children and their parents about the need for physical activity and dietary modification are essential to control this epidemic.


Depression screening and treatment among nonpregnant women of reproductive age in the United States, 1990-2010.
Whether routine screening for depression among nonpregnant women of reproductive age improves identification and treatment of the disorder remains unclear. We conducted a systematic review of the literature to address 5 key questions specific to this population: 1) What are the current national clinical practice recommendations and guidelines for depression screening; 2) What are the prevalence and predictors of screening; 3) How well do screening tools detect depression; 4) Does screening lead to diagnosis, treatment, and improved outcomes; and 5) What are the most effective treatment methods? We searched bibliographic databases for full-length articles published in English between 1990 and 2010 that addressed at least 1 of our key questions. We identified 5 clinical practice guidelines pertinent to question 1, and 12 systematic reviews or post-hoc analyses of pooled data that addressed questions 3 through 5. No systematic reviews addressed question 2; however, we identified 4 individual studies addressing this question. Current guidelines do not recommend universal screening for depression in adults, unless staff supports are in place to diagnose, treat, and follow up patients. Reported screening rates ranged from 33% to 84% among women. Several validated screening tools for depression exist; however, their performance among this population is unknown. Screening in high-risk populations may improve the patient's receipt of diagnosis and treatment. Effective treatments include exercise, psychotherapy, and pharmacotherapy. More research is needed on whether routine screening for depression among women of reproductive age increases diagnosis and treatment of depression, improves preconception health, and reduces adverse outcomes.


Capsaicin induces apoptosis of cisplatin-resistant stomach cancer cells by causing degradation of cisplatin-inducible Aurora-A protein.
Various chemotherapeutic agents such as cisplatin have been used to treat gastric cancer. However, a substantial number of patients acquire resistance to this treatment, and this is followed by rapid relapse of the disease. We investigated the anticancer effect of capsaicin, the active ingredient in red pepper, in the cisplatin-resistant Korean human gastric cancer cell line SNU-668. We found that treatment of SNU-668 cells with capsaicin in combination with cisplatin induced higher apoptotic cell death than that of treatment with either capsaicin or cisplatin alone. Furthermore, we discovered that Aurora-A protein increased in response to cisplatin and was degraded upon combined treatment with capsaicin with cisplatin, suggesting that the Aurora-A-mediated signaling pathway is responsible for the resistance to cisplatin in cisplatin-resistant gastric cancer cell lines. Combined treatment with capsaicin and cisplatin induced G1/S arrest, whereas cisplatin alone caused accumulation in G2/M. Combined treatment with capsaicin and cisplatin inhibited IκB phosphorylation in a dose-dependent manner, suggesting that Aurora-A directly or indirectly regulates NF-κB translocation. We propose that combined administration of cisplatin and capsaicin may provide a strategy for overcoming cisplatin resistance.


Feeding blueberry diets in early life prevent senescence of osteoblasts and bone loss in ovariectomized adult female rats.
Appropriate nutrition during early development is essential for maximal bone mass accretion; however, linkage between early nutrition, childhood bone mass, peak bone mass in adulthood, and prevention of bone loss later in life has not been studied. In this report, we show that feeding a high quality diet supplemented with blueberries (BB) to pre-pubertal rats throughout development or only between postnatal day 20 (PND20) and PND34 prevented ovariectomy (OVX)-induced bone loss in adult life. This protective effect of BB is due to suppression of osteoblastic cell senescence associated with acute loss of myosin expression after OVX. Early exposure of pre-osteoblasts to serum from BB-fed rats was found to consistently increase myosin expression. This led to maintenance osteoblastic cell development and differentiation and delay of cellular entrance into senescence through regulation of the Runx2 gene. High bone turnover after OVX results in insufficient collagenous matrix support for new osteoblasts and their precursors to express myosin and other cytoskeletal elements required for osteoblast activity and differentiation. These results indicate: 1) a significant prevention of OVX-induced bone loss from adult rats can occur with only 14 days consumption of a BB-containing diet immediately prior to puberty; and 2) the molecular mechanisms underlying these effects involves increased myosin production which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence.


Spatially structured oscillations in a two-dimensional excitatory neuronal network with synaptic depression.
We study the spatiotemporal dynamics of a two-dimensional excitatory neuronal network with synaptic depression. Coupling between populations of neurons is taken to be nonlocal, while depression is taken to be local and presynaptic. We show that the network supports a wide range of spatially structured oscillations, which are suggestive of phenomena seen in cortical slice experiments and in vivo. The particular form of the oscillations depends on initial conditions and the level of background noise. Given an initial, spatially localized stimulus, activity evolves to a spatially localized oscillating core that periodically emits target waves. Low levels of noise can spontaneously generate several pockets of oscillatory activity that interact via their target patterns. Periodic activity in space can also organize into spiral waves, provided that there is some source of rotational symmetry breaking due to external stimuli or noise. In the high gain limit, no oscillatory behavior exists, but a transient stimulus can lead to a single, outward propagating target wave.


First Report of Black Spot Disease Caused by Alternaria alternata on Cherry Fruits in China.
Cherry (Cerasus pseudocerasus) has become an economically important fruit in China in recent years. In June 2010, fruit spots were discovered on fruit grown in Dalian City, Liaoning Province, China and 30% of local-orchard trees were infected with the disease, reducing yield and fruit quality. Disease incidence increased up to 75% in 2011. At the initial stage of the infection, some small, light brown spots appeared on the fruit that gradually became round or irregular and dark brown, and a black-brown concentric ring formed in the advanced stage of the infection. As disease progressed, the lesions expanded, causing the fruit surface to become pitted, withered, and dead. The pathogen was isolated from infected fruit of four orchards by a tissue isolation method (1) and cultured on potato dextrose agar (PDA) at 25°C in the dark for one week. Colonies on PDA were initially white and became grayish brown over time. Conidiophores were single or fasciculate, straight or knee curved, gray-brown with regular septa, branched or unbranched, and 12.5 to 90.0 × 2.0 to 5.0 μm. Conidia were oval, obclavate, or obpyriform, brown or dark brown, surface smooth or spinulose with short columnar beaks, and 20.0 to 42.0 × 7.5 to 14.5 μm with three to eight transverse septa and zero to three longitudinal or oblique septa. The sporulation pattern appeared in bush branches. According to the morphology, the pathogen was identified as Alternaria alternata (Fr:Fr.) Keissler (2,3). The internal transcribed spacer (ITS) region of rDNA was amplified using the primers ITS1/ITS4 and the ITS sequence was 99% identical to A. alternata (GenBank Accession No. FJ228163). Pathogenicity tests were performed on detached, asymptomatic fruit. Six fruit were inoculated by placing a PDA plug containing mycelia on the upper surface of the fruit. Another six fruit received sterile PDA plugs. Fruit were cultured in petri dishes with a 12-h photoperiod at 25°C and 90% relative humidity. Black spot symptoms were observed on inoculated fruit but not control fruit after 5 days. The pathogen was reisolated from inoculated fruit and confirmed to be A. alternata. The pathogenicity test was repeated once. A. alternata has a broad host range, but to our knowledge, this is the first report of A. alternata infecting cherries in China. References: (1) Z. D. Fang. Research Methods of Plant Disease, 124, 1998. (2) E. G. Simmons. Alternaria themes and variations. Mycotaxon 37: 79, 1990. (3) T. Y. Zhang et al. Fungi Notes-Genera Alternaria in China, 16:32, 2003.


Protocol for a population-based molecular epidemiology study of tuberculosis transmission in a high HIV-burden setting: the Botswana Kopanyo study.
Mycobacterium tuberculosis (Mtb) is transmitted from person to person via airborne droplet nuclei. At the community level, Mtb transmission depends on the exposure venue, infectiousness of the tuberculosis (TB) index case and the susceptibility of the index case's social network. People living with HIV infection are at high risk of TB, yet the factors associated with TB transmission within communities with high rates of TB and HIV are largely undocumented. The primary aim of the Kopanyo study is to better understand the demographic, clinical, social and geospatial factors associated with TB and multidrug-resistant TB transmission in 2 communities in Botswana, a country where 60% of all patients with TB are also infected with HIV. This manuscript describes the methods used in the Kopanyo study. The study will be conducted in greater Gaborone, which has high rates of HIV and a mobile population; and in Ghanzi, a rural community with lower prevalence of HIV infection and home to the native San population. Kopanyo aims to enrol all persons diagnosed with TB during a 4-year study period. From each participant, sputum will be cultured, and for all Mtb isolates, molecular genotyping (24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats) will be performed. Patients with matching genotype results will be considered members of a genotype cluster, a proxy for recent transmission. Demographic, behavioural, clinical and social information will be collected by interview. Participant residence, work place, healthcare facilities visited and social gathering venues will be geocoded. We will assess relationships between these factors and cluster involvement to better plan interventions for reducing TB transmission. Ethical approval from the Independent Review Boards at the University of Pennsylvania, US Centers for Disease Control and Prevention, Botswana Ministry of Health and University of Botswana has been obtained.


Factors Influencing the Flavour of Bovine Milk and Cheese from Grass Based versus Non-Grass Based Milk Production Systems.
There has been a surge in interest in relation to differentiating dairy products derived from pasture versus confined systems. The impact of different forage types on the sensory properties of milk and cheese is complex due to the wide range of on farm and production factors that are potentially involved. The main effect of pasture diet on the sensory properties of bovine milk and cheese is increased yellow intensity correlated to β-carotene content, which is a possible biomarker for pasture derived dairy products. Pasture grazing also influences fat and fatty acid content which has been implicated with texture perception changes in milk and cheese and increased omega-3 fatty acids. Changes in polyunsaturated fatty acids in milk and cheese due to pasture diets has been suggested may increase susceptibility to lipid oxidation but does not seem to be an issue to due increased antioxidants and the reducing environment of cheese. It appears that pasture derived milk and cheese are easier to discern by trained panellists and consumers than milk derived from conserved or concentrate diets. However, milk pasteurization, inclusion of concentrate in pasture diets, cheese ripening time, have all been linked to reducing pasture dietary effects on sensory perception. Sensory evaluation studies of milk and cheese have, in general, found that untrained assessors who best represent consumers appear less able to discriminate sensory differences than trained assessors and that differences in visual and textural attributes are more likely to be realized than flavour attributes. This suggests that sensory differences due to diet are often subtle. Evidence supports the direct transfer of some volatiles via inhalation or ingestion but more so with indirect transfer post rumen metabolism dietary components. The impact of dietary volatiles on sensory perception of milk and dairy products obviously depends upon their concentration and odour activity, however very little quantitative studies have been carried out to date. Some studies have highlighted potential correlation of pasture with enhanced "barny" or "cowy" sensory attributes and subsequently linked these to accumulation of p-cresol from the metabolism of β-carotene and aromatic amino acids or possibly isoflavones in the rumen. p-Cresol has also been suggested as a potential biomarker for pasture derived dairy products. Other studies have linked terpenes to specific sensory properties in milk and cheese but this only appears to be relevant in milk and cheese derived from unseeded wild pasture where high concentrations accumulate, as their odour threshold is quite high. Toluene also a product of β-carotene metabolism has been identified as a potential biomarker for pasture derived dairy products but it has little impact on sensory perception due to its high odour threshold. Dimethyl sulfone has been linked to pasture diets and could influence sensory perception as its odour threshold is low. Other studies have linked the presence of maize and legumes (clover) in silage with adverse sensory impacts in milk and cheese. Considerably more research is required to define key dietary related impacts on the flavour of milk and cheese.


Task-related activity in sensorimotor cortex in Parkinson's disease and essential tremor: changes in beta and gamma bands.
In Parkinson's disease patients in the OFF medication state, basal ganglia local field potentials exhibit changes in beta and gamma oscillations that correlate with reduced voluntary movement, manifested as rigidity and akinesia. However, magnetoencephalography and low-resolution electrocorticography (ECoG) studies in Parkinson's patients suggest that changes in sensorimotor cortical oscillations differ from those of the basal ganglia. To more clearly define the role of sensorimotor cortex oscillatory activity in Parkinson's, we performed intraoperative, high-resolution (4 mm spacing) ECoG recordings in 10 Parkinson's patients (2 females, ages 47-72) undergoing deep brain stimulation (DBS) lead placement in the awake, OFF medication state. We analyzed ECoG potentials during a computer-controlled reaching task designed to separate movement preparation from movement execution and compared findings to similar invasive recordings in eight patients with essential tremor (3 females, ages 59-78), a condition not associated with rigidity or akinesia. We show that (1) cortical beta spectral power at rest does not differ between Parkinson's and essential tremor patients (p = 0.85), (2) early motor preparation in Parkinson's patients in the OFF medication state is associated with a larger beta desynchronization compared to patients with essential tremor (p = 0.0061), and (3) cortical broadband gamma power is elevated in Parkinson's patients compared to essential tremor patients during both rest and task recordings (p = 0.004). Our findings suggest an oscillatory profile in sensorimotor cortex of Parkinson's patients that, in contrast to the basal ganglia, may act to promote movement to oppose the anti-kinetic bias of the dopamine-depleted state.


Bayesian covariance selection in generalized linear mixed models.
The generalized linear mixed model (GLMM), which extends the generalized linear model (GLM) to incorporate random effects characterizing heterogeneity among subjects, is widely used in analyzing correlated and longitudinal data. Although there is often interest in identifying the subset of predictors that have random effects, random effects selection can be challenging, particularly when outcome distributions are nonnormal. This article proposes a fully Bayesian approach to the problem of simultaneous selection of fixed and random effects in GLMMs. Integrating out the random effects induces a covariance structure on the multivariate outcome data, and an important problem that we also consider is that of covariance selection. Our approach relies on variable selection-type mixture priors for the components in a special Cholesky decomposition of the random effects covariance. A stochastic search MCMC algorithm is developed, which relies on Gibbs sampling, with Taylor series expansions used to approximate intractable integrals. Simulated data examples are presented for different exponential family distributions, and the approach is applied to discrete survival data from a time-to-pregnancy study.


Four responsibilities of the tuberculosis nurse, circa 1919.
Specialization in public health nursing practice was beginning to occur early in the 20th century. In a 1919 paper published in The Public Health Nurse, Mary Van Zile argued that there were four essential functions of the tuberculosis nurse. Later that year, Janet Scott reported on the results of a partnership between the tuberculosis dispensary, the Lions Club, and other Oklahoma City community organizations, which illustrated the application of Van Zile's principles, and the expanding scope of public health nursing practice.


Symptomatic intracerebral hemorrhage following thrombolytic therapy for acute ischemic stroke: a review of the risk factors.
Symptomatic intracerebral hemorrhage (SICH) following thrombolytic therapy for acute ischemic stroke is associated with a high rate of morbidity and mortality. Knowledge of the risk factors associated with SICH following thrombolyitc therapy may provide insight into the pathophysiological mechanisms underlying the development of SICH, lead to the development of treatments that reduce the risk of SICH and have implications for the design of future stroke trials. Relevant studies were identified through a search in Pubmed. Included studies used multivariate analyses to identify independent risk factors for SICH following thrombolytic therapy. For each variable that was found to have a significant association with SICH, a secondary literature search was conducted to identify additional reports on the specific relationship between that variable and SICH. Twelve studies met inclusion criteria for the systematic review. Extent of hypoattenuated brain parenchyma on pretreatment CT and elevated serum glucose or history of diabetes were independent risk factors for thrombolysis-associated SICH in six of the twelve studies. Symptom severity was an independent risk factor in three of the studies and advanced age, increased time to treatment, high systolic blood pressure, low platelets, history of congestive heart failure and low plasminogen activator inhibitor levels were found to be independent risk factors for SICH in a single study. Although these data should not alter the current guidelines for the use of rt-PA in acute stroke, they may help develop future strategies aimed at reducing the rate of thrombolysis-associated SICH.


Nicotine Attenuates Disruption of Blood-Brain Barrier Induced by Saturated-Fat Feeding in Wild-Type Mice.
Emerging evidence suggests that integrity of blood-brain barrier (BBB) is pivotal to pathology and pathogenesis of vascular-based neurodegenerative disorders. We have recently reported BBB protective effects of nutraceutical agents with anti-inflammatory properties in an established dietary-induced BBB dysfunction model. Studies also reported that nicotine exhibits anti-oxidative/-inflammatory effects and improve cognitive impairment in Alzheimer's disease. However there has been no studies reporting the effect of nicotine on high-fat-induced BBB dysfunction. In the present study, we investigated the effect of nicotine on BBB integrity and neuro-inflammation in an established mouse model of BBB disruption induced by a diet enriched in saturated fatty acids (SFA). Wild-type C57BL/6J mice were fed chow enriched in SFA (23% w/w) with/without nicotine for 10 weeks. Compared to mice maintained on SFA-free and low-fat (LF) chow (4% w/w), capillary permeability indicated by the parenchymal extravasation of plasma derived IgG, was significantly greater in the SFA treatment group. Nicotine provided concomitantly with the SFA diet significantly attenuated IgG extravasation, however it remained significantly greater than LF-controls. Markers of neurovascular inflammation glial fibrillary acidic protein, cyclooxygenase-2, and glucose regulated protein 78 remained exaggerated in SFA+nicotine treated mice compared to LF-controls. Nicotine did however modestly, but not significantly, improve plasma total anti-oxidative status in SFA fed mice. Nicotine moderately attenuated BBB disruption induced by chronic ingestion of high-SFA diet, but had no significant effect on neuroinflammation per se.


Physiotherapy based on the Bobath concept in stroke rehabilitation: a survey within the UK.
The Bobath concept is one of the most widely used approaches in stroke rehabilitation within Europe. This survey aimed to provide an expert consensus view of the theoretical beliefs underlying current Bobath practise in the UK. Questionnaires (with sections related to: therapist background, physiotherapy management, theoretical beliefs and gait re-education strategies used) were posted to all senior level physiotherapists working in stroke care (n = 1,022). The majority of respondents had more than 10 year's experience overall and at least 5 years experience in stroke care. The Bobath concept was the preferred approach (n = 67%) followed by an 'eclectic' approach (n = 31%). Despite a high level of consensus between groups, there were 13 significant differences highlighted between Bobath and 'eclectic' groups related to recovery, control of tone, the analysis and facilitation of normal movement and function. In summary. Bobath therapists considered that patients needed to have normal tone and use normal movement patterns in order to perform functional tasks. They would delay patients from performing tasks independently if abnormal tone and movement would be reinforced by task practice. They were not opposed to the use of walking aids and orthotics. This survey has raised several issues for debate within physiotherapy such as the automatic translation of movement into function, carry over outside therapy, and the way in which tasks should be practiced. The dominance of the Bobath concept needs to be justified by establishing that it is both effective and efficient at achieving its treatment aims of: normalizing tone, improving intrinsic recovery of the affected side and function within everyday tasks.


Clinical outcome after bone metastasis (BM) surgery in patients with differentiated thyroid carcinoma (DTC): a retrospective study of 40 cases.
The purpose of this study is to identify factors that affect survival of patients with differentiated thyroid carcinoma with bone metastases and to optimize surgical treatment modality for bone metastatic lesion by comparing duration of patient survival and local control. We examined 52 bone metastatic lesions from 40 patients with differentiated thyroid carcinoma who were treated surgically between 1994 and 2008 at Keio University Hospital. Median follow-up time was 46 months (range: 4-233 months). Patients' disease-specific survival, local control duration and factors that potentially affected disease-specific survival after bone metastasis surgery were statistically analyzed. The 2-, 5- and 10-year disease-specific survival rates were 77.2, 64.3 and 45.7%, respectively. Factors that were significantly associated with poor survival rates in multivariate analyses included age at bone metastasis surgery ≥65 years (P = 0.0068), time from diagnosis of primary cancer to bone metastasis surgery ≥5 years (P = 0.0018) and presence of visceral metastases (P = 0.0092). The 2-, 5- and 10-year local control rates in our series were 91.4, 72.7 and 63.6%, respectively. The 5-year local control rates for radical and palliative surgery were 84.4 and 55.3%, respectively, and differed significantly (P = 0.019). Because disease-specific survival of patients with differentiated thyroid carcinoma is fairly good, inadequate treatment of bone metastatic lesions can result in severe disabilities. Therefore, radical surgery for bone metastatic lesions should be considered, especially for those with favorable prognostic factors.


Clinical and Pathologic Features of Hispanic Endometrial Cancer Patients With Loss of Mismatch Repair Expression.
Approximately 3% to 5% of endometrial cancers (EC) are associated with Lynch syndrome (LS). The clinical characteristics and prevalence of LS have not been well studied in the US Hispanic population. Hispanics are the largest and fastest growing ethnic minority group in the United States. We sought to characterize the demographics, tumor characteristics, and prevalence of loss of mismatch repair (MMR) protein expression in a large Hispanic population with EC. From January 1, 2005, to August 1, 2012, 83 women of Hispanic ethnicity diagnosed with EC 50 years and younger were identified. Clinical and pathologic data were abstracted from the electronic medical record. Tumor studies included immunohistochemistry of MLH1, MSH2, MSH6, and PMS2 and methylation of the MLH1 promoter. Ninety-five percent of patients were overweight or obese. The mean body mass index was 40.1 kg/m, 75% had irregular menses, 36% had diabetes, 46% were nulliparous, and 95% had endometrioid histology. Thirteen patients (15.7%) had tumor MMR deficiency due to a presumed germline mutation (9 MSH6, 3 MSH2, and 1 MLH1). The pattern of MMR protein loss was consistent with the expected binding properties of the MMR heterodimer complexes. No significant difference was found in clinical or pathological variables between patients with and without MMR deficient tumors. The prevalence of molecular findings consistent with LS was at least as high as other populations of varied geography, race, and ethnicity. We found no reliable factors to include body mass index, family history, synchronous tumors, or pathologic tumor features to serve as triage markers for which ECs should be screened for MMR protein loss. Our findings support a recommendation for universal screening of ECs utilizing 2-antibody testing with MLH1 promoter methylation testing as indicated up to 60 years or older. Our recommendations should be generalizable to other Hispanic populations in the Southern United States.


Relative contribution of individual versus combined functional imaging studies in predicting seizure freedom in pediatric epilepsy surgery: an area under the curve analysis.
The goal of this study was to evaluate the predictive value and relative contribution of noninvasive presurgical functional imaging modalities based on the authors' institutional experience in pursuing seizure-free surgical outcomes in children with medically refractory epilepsy. This was a retrospective, single-institution, observational cohort study of pediatric patients who underwent evaluation and surgical treatment for medically refractory partial epilepsy between December 2003 and June 2016. During this interval, 108 children with medically refractory partial epilepsy underwent evaluation for localization and resective epilepsy surgery. Different noninvasive functional imaging modalities, including ictal SPECT, FDG-PET, and magnetoencephalography-magnetic source imaging, were utilized to augment a standardized paradigm (electroencephalography/semiology, MRI, and neuropsychology findings) for localization. Outcomes were evaluated at a minimum of 2 years (mean 7.5 years) utilizing area under the receiver operating characteristic curve analysis. Localizing modalities and other clinical covariates were examined in relation to long-term surgical outcomes. There was variation in the contribution of each test, and no single presurgical workup modality could singularly and reliably predict a seizure-free outcome. However, concordance of presurgical modalities yielded a high predictive value. No difference in long-term outcomes between inconclusive (normal or diffusely abnormal) and abnormal focal MRI results were found. Long-term survival analyses revealed a statistically significant association between seizure freedom and patients with focal ictal EEG, early surgical intervention, and no history of generalized convulsions. Comprehensive preoperative evaluation utilizing multiple noninvasive functional imaging modalities is not redundant and can improve pediatric epilepsy surgical outcomes.


Gene-environment interactions in human health: case studies and strategies for developing new paradigms and research methodologies.
THE SYNERGISTIC EFFECTS OF GENES AND THE ENVIRONMENT ON HEALTH ARE EXPLORED IN THREE CASE STUDIES: adult lactase persistence, autism spectrum disorders, and the metabolic syndrome, providing examples of the interactive complexities underlying these phenotypes. Since the phenotypes are the initial targets of evolutionary processes, understanding the specific environmental contexts of the genetic, epigenetic, and environmental changes associated with these phenotypes is essential in predicting their health implications. Robust databases must be developed on the local scale to deconstruct both the population substructure and the unique components of the environment that stimulate geographically specific changes in gene expression patterns. To produce these databases and make valid predictions, new, locally focused, and information-dense models are needed that incorporate data on evolutionary ecology, environmental complexity, local geographic patterns of gene expression, and population substructure.


Smoking and erectile dysfunction: findings from a representative sample of Australian men.
To examine whether there is an association between smoking and erectile dysfunction in a representative sample of Australian men. Secondary analysis of cross-sectional survey data from the Australian Study of Health and Relationships. 8367 Australian men aged 16-59 years. Erectile dysfunction was identified in men who reported having had trouble keeping an erection when they wanted to, a problem which persisted for at least one month over the previous year. Variables examined in multivariate logistic regression analyses included age, education, presence of cardiovascular disease and diabetes, and current alcohol and tobacco consumption. Almost one in 10 of the respondents (9.1%) reported erectile dysfunction that lasted for at least one month over the previous year. More than a quarter (27.2%) of respondents were current smokers, with 20.9% smoking < or = 20 cigarettes per day, and 6.3% smoking > 20 cigarettes per day. Compared with non-smokers, the adjusted odds ratios for erectile dysfunction were 1.24 (95% confidence interval (CI) 1.01 to 1.52, p = 0.04) for those smoking < or = 20 cigarettes per day and 1.39 (95% CI 1.05 to 1.83, p = 0.02) for those smoking > 20 cigarettes per day, after adjusting for other confounding factors. Older age, low level of education, and taking medications for cardiovascular disease were also independently and positively associated with erectile dysfunction. In contrast, moderate alcohol consumption (1-4 drinks per day) significantly reduced the likelihood of having erectile dysfunction. Erectile dysfunction is a significant health concern affecting around one in 10 Australian men aged 16-59 years. Current smoking is significantly associated with erectile dysfunction in Australian males. This association was strengthened as the number of cigarettes smoked increased. Health promotion programmes could use the link between smoking and erectile dysfunction to help reduce smoking levels among men.


Effects of light and presence of fish on lure display and larval release behaviours in two species of freshwater mussels.
We investigated how two sympatric species of freshwater mussels transmit their parasitic larvae to fish hosts. We found that Villosa nebulosa and V. vibex both display large mantle lures to attract potential host fish, but V. nebulosa displayed only at night and V. vibex displayed mostly by day. Display periods were similar in the laboratory and in the field. In two laboratory experiments, we found that the frequency of lure display in both mussel species was unrelated to the presence of fish or to the species of fish present. However, both species released more larvae in the presence of a suitable host fish (Micropterus spp.) and a nonhost species (Cyprinella camura) than in the absence of fish. In all treatments, females released low numbers of larvae on a daily basis throughout the experiment. We also observed several, irregularly occurring major release events in which numbers of larvae released were from one to three orders of magnitude larger than minor, daily releases. In V. nebulosa, major releases occurred with suitable and nonsuitable host species; in V. vibex major releases occurred mostly with suitable host species. In an additional laboratory experiment, we found that V. vibex released large numbers of larvae only when the host fish was able to make physical contact with the mussel. Few larvae were released when no fish were present or when host fish were present but physical access to the mussel was restricted. These results show that, in mussel species that display lures, physical interaction with a fish is necessary to stimulate large releases of larvae and suggest that interactions with a suitable host species stimulate larger and more frequent releases than with nonhosts. Copyright 2000 The Association for the Study of Animal Behaviour.


ssDNA aptamer-based surface plasmon resonance biosensor for the detection of retinol binding protein 4 for the early diagnosis of type 2 diabetes.
Retinol binding protein 4 (RBP4) is a useful biomarker in the diagnosis of type 2 diabetes since its level in the serum is higher in insulin-resistant states. Accurate measurement of the serum RBP4 levels is hampered by conventional immunologic methods, such as enzyme-linked immunosorbent assay (ELISA). In this study, therefore, we have developed an aptamer-based surface plasmon resonance (SPR) biosensor that can be used to sense for RBP4 in serum samples. A single-stranded DNA (ssDNA) aptamer that showed high affinity (Kd = 0.2 +/- 0.03 microM) and specificity to RBP4 was selected. This RBP4-specific aptamer was immobilized on a gold chip and used in a label-free RBP4 detection using SPR. Analysis of RBP4 in artificial serum using SPR was compared with ELISA and Western blot analysis. Our results indicated that the RBP4-specific aptamer-based SPR biosensor gave better dose-dependent responses and was more sensitive than ELISA assays. As such, this RBP4 aptamer-based SPR biosensor can be potentially used to monitor the RBP4 levels within the serum as an indicator of type 2 diabetes.


Prospective evaluation of intrahisian conduction delay.
We prospectively evaluated 46 patients who had intrahisian conduction delay. Twenty-three had a split His potential and 23 had a prolonged HV interval with a normal QRS complex. In those with a split His, the interval between the two His potentials averaged 32.7 msec (range 9--90 msec); in nine patients this split His was demonstrated only by atrial pacing. The 20 patients from this group with 1:1 atrioventricular conduction have been followed for an average of 18.1 months (range 2--48 months). All are alive. Three have had syncope, but Holter monitoring revealed no bradyarrhythmias. In the 23 patients with a narrow QRS and prolonged HV interval, the HV interval averaged 73.7 msec (range 57--180 msec). Twelve of these patients received pacemakers at the time of the His bundle study, six had symptomatic atrioventricular block and five had symptomatic sinus pauses. The 11 patients who did not receive pacemakers have been followed for an average of 15.1 months (range 2--44 months). In three with recurrent syncope and five with dizziness, monitoring has revealed no bradyarrhythmias. One patient died from a myocardial infarction without arrhythmias. Further prospective evaluation of patients with intrahisian conduction delay without documented bradyarrhythmias is needed, but with follow-up averaging 17 months and up to 4 years, patients with intrahisian conduction delay and without documented bradyarrhythmias appear not to require prophylactic permanent pacemakers to decrease morbidity or mortality.


Single-dose pharmacokinetics of orally administered metronidazole and intravenously administered imipenem in healthy horses and computer-based simulation of pleural fluid concentrations with multiple dosing.
To determine plasma pharmacokinetics of metronidazole and imipenem following administration of a single dose PO (metronidazole, 15 mg/kg) or IV (imipenem, 10 mg/kg) in healthy Thoroughbreds and simulate pleural fluid concentrations following multiple dose administration every 8 hours. 4 healthy Thoroughbreds. Metronidazole and imipenem were administered, and samples of plasma and pleural fluid were collected at predetermined time points. Minimum concentrations of metronidazole and imipenem that inhibited growth of 90% of isolates (MIC90), including 22 clinical Bacteroides isolates from horses with pleuropneumonia, were calculated. For the computer simulation, the target ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was > 70, and the target percentage of time per day that the pleural fluid concentration of imipenem exceeded the MIC90 was > 50%. Mean ± SD pleural fluid concentrations of metronidazole and imipenem were 12.7 ± 3.3 μg/mL and 12.1 ± 0.9 μg/mL, respectively, 1 hour after administration and 4.9 ± 0.85 μg/mL and 0.3 ± 0.08 μg/mL, respectively, 8 hours after administration. For both antimicrobials, concentrations in the pleural fluid and plasma were similar. The ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was 84.9, and the percentage of time per day the pleural fluid concentration of imipenem exceeded the MIC90 was 70.9%. Results suggested that administration of metronidazole (15 mg/kg, PO, q 8 h) or imipenem (10 mg/kg, IV, q 8 h) resulted in their accumulation in the pleural fluid in healthy horses and concentrations were likely to be effective for the treatment of pneumonia and pleuropneumonia caused by Bacteroides spp.


Conceptualizing, Contextualizing, and Operationalizing Race in Quantitative Health Sciences Research.
Differences in health outcomes across racial groups are among the most commonly reported findings in health disparities research. Often, these studies do not explicitly connect observed disparities to mechanisms of systemic racism that drive adverse health outcomes among racialized and other marginalized groups in the United States. Without this connection, investigators inadvertently support harmful narratives of biologic essentialism or cultural inferiority that pathologize racial identities and inhibit health equity. This paper outlines pitfalls in the conceptualization, contextualization, and operationalization of race in quantitative population health research and provides recommendations on how to appropriately engage in scientific inquiry aimed at understanding racial health inequities. Race should not be used as a measure of biologic difference, but rather as a proxy for exposure to systemic racism. Future studies should go beyond this proxy use and directly measure racism and its health impacts.VISUAL ABSTRACTAppeared as Annals "Online First" article.


Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review).
Prostate cancer is one of the most commonly diagnosed cancers in men. The number of affected men is expected to rapidly increase as the population of males over the age of 50 grows worldwide. For patients who are not cured by local treatment and experience metastatic disease, neither androgen ablation nor chemotherapy can abrogate progression and death from androgen-independent/hormone-refractory disease. Therefore, finding strategies for the prevention of prostate cancer initiation and disease progression is a medical challenge. Consumption of cruciferous vegetables has been reported to be associated with reduced incidence of prostate cancer cases. The isothiocyanates, including phenethyl isothiocyanate (PEITC), from cruciferous vegetables have been demonstrated as active components responsible for chemoprevention. In this review, we summarize the recent findings of PEITC on prostate cancer prevention with an emphasis on epigenetic mechanisms. Studies have indicated that PEITC mediates gene regulation, such as downregulation of androgen receptor expression and induction of endogenous cyclin-dependent kinase inhibitors, p21 and p27. The gene for detoxifying enzyme pi-class glutathione S-transferase (GSTP1), silenced in the vast majority of prostate tumor cells, could be reactivated and the enzymatic function recovered. This may be through epigenetic mechanisms as PEITC is a dual inhibitor of histone deacetylases and aberrant CpG island methylation of various genes. The epigenetic regulation may play a critical role, along with interactive mechanisms including the disruption of microtubule polymerization, in prostate cancer prevention by PEITC. These mechanisms target and correct the aberrations fundamental to the initiation and progression of carcinogenesis in cells, and restoring the cells to a more normal state. Inhibiting and eliminating cancer cells forms the basis of cancer prevention.


Transcriptomic Analysis of Streptococcus pyogenes Colonizing the Vaginal Mucosa Identifies hupY, an MtsR-Regulated Adhesin Involved in Heme Utilization.
Streptococcus pyogenes (group A streptococcus [GAS]) is a serious human pathogen with the ability to colonize mucosal surfaces such as the nasopharynx and vaginal tract, often leading to infections such as pharyngitis and vulvovaginitis. We present genome-wide transcriptome sequencing (RNASeq) data showing the transcriptomic changes GAS undergoes during vaginal colonization. These data reveal that the regulon controlled by MtsR, a master metal regulator, is activated during vaginal colonization. This regulon includes two genes highly expressed during vaginal colonization, hupYZ Here we show that HupY binds heme in vitro, affects intracellular concentrations of iron, and is essential for proper growth of GAS using hemoglobin or serum as the sole iron source. HupY is also important for murine vaginal colonization of both GAS and the related vaginal colonizer and pathogen Streptococcus agalactiae (group B streptococcus [GBS]). These data provide essential information on the link between metal regulation and mucosal colonization in both GAS and GBS.IMPORTANCE Colonization of the host requires the ability to adapt to an environment that is often low in essential nutrients such as iron. Here we present data showing that the transcriptome of the important human pathogen Streptococcus pyogenes shows extensive remodeling during in vivo growth, resulting in, among many other differentially expressed genes and pathways, a significant increase in genes involved in acquiring iron from host heme. Data show that HupY, previously characterized as an adhesin in both S. pyogenes and the related pathogen Streptococcus agalactiae, binds heme and affects intracellular iron concentrations. HupY, a protein with no known heme binding domains, represents a novel heme binding protein playing an important role in bacterial iron homeostasis as well as vaginal colonization.


Correlates of Future Violence in People Being Treated for Schizophrenia.
Violent behavior is infrequent among individuals with schizophrenia but is clinically important. The purpose of this study was to provide data on the correlates of violence, which may allow better risk assessment and care. A total of 1,435 individuals with schizophrenia who participated in the National Institute of Mental Health's Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and were followed for 18 months were examined. The dependent variables were self-reported injurious and noninjurious violence during follow-up. The independent variables, assessed at study entry, comprised participants' recent injurious and noninjurious violence, demographic and background variables, childhood risk factors, clinical condition, current circumstances, and recent contact with hospitals and prisons. Proportional hazards models of time to first injurious violence were used to generate bivariable and multivariable hazard ratios for all participants and, separately, for participants with no injurious violence at study entry. Seventy-seven participants (5.4%) reported engaging in injurious violence during follow-up, and 119 (8.3%) reported engaging in exclusively noninjurious violence. In the multivariable analysis, baseline injurious violence (hazard ratio=4.02), recent violent victimization (hazard ratio=3.52), severity of drug use (hazard ratio=2.93), baseline noninjurious violence (hazard ratio=2.72), childhood sexual abuse (hazard ratio=1.85), and medication nonadherence (hazard ratio=1.39) were associated with future injurious violence. For participants with no history of injurious violence at study entry, baseline noninjurious violence was the strongest predictor (hazard ratio=3.02). Recent violent victimization was no longer a significant correlate. The remaining correlates and the strength of their association with future injurious violence were similar to those for all participants. This is the first longitudinal multivariable analysis of predictors of injurious violence in a large cohort of patients with schizophrenia followed over 18 months. The results revealed simultaneous strong effects of baseline injurious violence and recent violent victimization on future injurious violent behavior. Among clinical variables, poor medication adherence, but not baseline symptoms of psychosis or depression, significantly predicted injurious violence. Treatment strategies to reduce risk should emphasize medication adherence.


Trial of Galcanezumab in Prevention of Episodic Cluster Headache.
Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache. We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed. Recruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain. Galcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).


Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis.
Prostate-specific antigen (PSA) evaluation leads to the early detection of both prostate cancer and recurrences following primary treatment. Prostate-specific antigen outcome information on patients 5 or more years following treatment is limited and available mainly as single-institution reports. To assess the likelihood and durability of tumor control using PSA evaluation 5 or more years after radical external beam radiation therapy and to identify pretreatment prognostic factors in men with early prostate cancer treated since 1988, the PSA era. Retrospective, nonrandomized, multi-institutional pooled analysis of patients treated with external beam radiation therapy alone between 1988 and 1995 at 6 US medical centers. Follow-up lasted up to a maximum of 9 years. Outcome data were analyzed using Cox regression and recursive partitioning techniques. A total of 1765 men with stage T1b, T1c, and T2 tumors treated between 1988 and 1995 with external beam radiation. The majority (58%) of patients were older than 70 years and 24.2% had initial PSA values of 20 ng/mL or higher. A minimum of 2 years of subsequent follow-up was required for participation. Actuarial estimates of freedom from biochemical failure. The 5-year estimates of overall survival, disease-specific survival, and the freedom from biochemical failure are 85.0% (95% confidence interval [CI], 82.5%-87.6%), 95.1% (95% CI, 94.0%-96.2%), and 65.8% (95% CI, 62.8%-68.0%), respectively. The PSA failure-free rates 5 and 7 years after treatment for patients presenting with a PSA of less than 10 ng/mL were 77.8% (95% CI, 74.5%-81.3%), and 72.9% (95% CI, 67.9%-78.2%). Recursive partitioning analysis of initial PSA level, palpation stage, and the Gleason score groupings yielded 4 separate prognostic groups: group 1, included patients with a PSA level of less than 9.2 ng/mL; group 2, PSA level of at least 9.2 but less than 19.7 ng/mL; group 3, PSA level at least 19.7 ng/mL and a Gleason score of 2 to 6; and group 4, PSA level of at least 19.7 ng/mL and a Gleason score of 7 to 10. The estimated rates of survival free of biochemical failure at 5 years are 81 % for group 1, 69% for group 2, 47% for group 3, and 29% for group 4. Of the 302 patients followed up beyond 5 years who were free of biochemical disease, 5.0% relapsed from the fifth to the eighth year. Estimated PSA control rates in this pooled analysis are similar to those of single institutions. These rates indicate the probability of success for subsets of patients with tumors of several prognostic category groupings. These results represent a multi-institutional benchmark for evidence-based counseling of prostate cancer patients about radiation treatment.


COVID-19 vaccine research focusses on safety, efficacy, immunoinformatics, and vaccine production and delivery: a bibliometric analysis based on VOSviewer.
Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has affected tens of millions of people globally since it was declared a pandemic by the World Health Organization (WHO) on March 11, 2020. There is an urgent need for safe and effective preventive vaccines to curb this pandemic. A growing amount of related research has been published. This study aimed to provide the current status of COVID-19 vaccine using bibliometric analysis. We searched Embase.com and MEDLINE comprehensively and included articles, articles in press, reviews, short surveys, conference abstracts and conference papers about COVID-19 vaccine. VOSviewer1.6.11 (Leiden University, Leiden, Netherlands) was applied to perform the bibliometric analysis of these papers. A total of 1,312 papers were finally included. The BMJ has been the most popular journal in this field. The United States maintained a top position worldwide and has provided a pivotal influence, followed by China, India and United Kingdom. Among all the institutions, Harvard University was regarded as a leader for research collaboration. We analyzed the keywords and identified seven COVID-19 vaccine research hotspot clusters. COVID-19 vaccine research hotspots focus on clinical trials on vaccine safety and efficacy, research on vaccine immunology and immunoinformatics, and vaccine hesitancy. Our analysis results demonstrated that cooperation between countries, institutions, and authors were insufficient. The results suggested that clinical trials on vaccine safety, efficacy, immunology, immunoinformatics, production and delivery are research hotspots. Furthermore, we can predict that there will be a lot of research focusing on vaccine adverse reactions.


Breast cancer among women in Michigan following exposure to brominated flame retardants.
In this updated follow-up, we investigated the breast cancer experience among women in Michigan exposed to brominated flame retardants, some 30 years following exposure. Michigan residents were enrolled in a study cohort after exposure to polybrominated biphenyls (PBBs) through the consumption of contaminated food products. PBB concentrations were measured in serum at the time of enrolment. Cancer experience was determined by linkage to the Michigan Cancer Registry. We conducted a nested case-control study that included 51 women diagnosed with breast cancer during 1974-2004 and 202 age-matched controls. While the data suggest an increase in breast cancer risk with higher PBB exposure, this did not reach statistical significance. The OR of having breast cancer among women with PBB concentrations ≥10 ng/mL compared to women with PBB concentrations at or below the limit of detection of 1 ng/mL was 2.60, 95% CI 0.93 to 7.27, (p=0.07), when adjusted for age and family history of cancer in a first-degree female relative. It remains important to examine exposure to brominated chemicals and possible health effects, and to continue following the cancer experience of participants in this study.


Serial biomarker measurements in ambulatory patients with chronic heart failure: the importance of change over time.
Cardiac troponin T (cTnT) and B-type natriuretic peptide (BNP) have been used to estimate prognosis in heart failure; however, most studies have evaluated decompensated patients with single measurements. To determine if there are advantages to serial measurements, we evaluated stable chronic heart failure patients every 3 months for 2 years. A cohort of 190 New York Heart Association class III-IV heart failure patients was prospectively enrolled from June 2001 to January 2004. Primary end points were death, cardiac transplantation, or hospitalization. At study enrollment cTnT was < 0.01 ng/mL in 87 (45.8%) patients, 0.01 to 0.03 ng/mL in 50 (26.3%) patients, and > 0.03 ng/mL in 53 (27.9%) patients. An increase in cTnT above normal (< 0.01 ng/mL) carried a 3.4-fold increased risk (P=0.019). Further increases (> or = 20%) from an elevated level worsened the overall risk (hazard ratio, 5.09; P<0.001). BNP was elevated (> 95th percentile for age and gender normal population) in 122 (64.2%) patients. An elevation of BNP from normal at any time during the study was associated with a poor outcome, but, once elevated, further changes in BNP (increases or decreases) remained associated with the same risk (hazard ratio, 5.09; P<0.001). Combined elevations of cTnT (> 0.03 ng/mL) and BNP defined the highest risk group (hazard ratio, 8.58; P<0.001). Elevations of cTnT or BNP from normal detected at any time during clinical follow-up in ambulatory patients with chronic heart failure are highly associated with an increased risk of events. Further increases in cTnT contribute to additional risk. Combined elevations of cTnT and BNP contribute the highest risk. The ability to monitor changes by serial measurements adds substantially to the assessment of risk in this patient population.


Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia.
To investigate the serum levels of insulin-like growth factor-I (IGF-I) in patients with fibromyalgia (FM) compared to healthy controls and patients with other rheumatic diseases, and to explore possible etiologic mechanisms of low IGF-I levels in patients with FM. Five hundred patients with FM and 152 controls (74 healthy blood donors, 26 myofascial pain patients and 52 patients with other rheumatic diseases) were studied. All had measurements of acid extracted serum IGF-I. A subset of 90 patients with FM were evaluated for clinical features that might explain low IGF-I levels. Twenty-five patients with FM underwent growth hormone (GH) provocation testing with l-dopa and clonidine. The mean serum IGF-I level in patients with FM was 138 +/- 56 ng/ml and in controls 215 +/- 86 ng/ml (p = 0.00000000001). Low levels of IGF-I were not due to depression, tricyclic medications, nonsteroidal antiinflammatory drugs, poor aerobic conditioning, obesity, or pain level. Patients with focal myofascial pain syndromes had normal IGF-I levels (236 +/- 68), as did most patients with other rheumatic disorders, unless they had concomitant FM. Patients with FM with initially normal levels often had a rapid decline of IGF-I over 1 to 2 years. Most patients with FM with low IGF-I levels failed to secrete GH after stimulation with clonidine and l-dopa. Many, but not all, patients with FM have low levels of IGF-I that cannot be explained by clinical associations. These results suggest that low IGF-I levels in patients with FM are a secondary phenomenon due to hypothalamic-pituitary-GH axis dysfunction.


How can Doctors Improve their Communication Skills?
The process of curing a patient requires a holistic approach which involves considerations beyond treating a disease. It warrants several skills in a doctor along with technical expertise. Studies have shown that good communication skill in a doctor improve patient's compliance and overall satisfaction. There are certain basic principles of practicing good communication. Patient listening, empathy, and paying attention to the paraverbal and non verbal components of the communication are the important ones that are frequently neglected. Proper information about the nature, course and prognosis of the disease is important. Besides, patients and attendants should always be explained about the necessity and yield of expensive investigations and risks/benefits involved in invasive procedures. One should be extremely cautious while managing difficult encounters and breaking bad news. Formal training of the doctors in improving communication skills is necessary and has proven to improve overall outcome. The authors recommend inclusion of formal training in communication skills in medical curriculum and training of practising doctors in the form of CMEs and CPEs.


Proangiogenic hydrogels within macroporous scaffolds enhance islet engraftment in an extrahepatic site.
The transplantation of allogeneic islets in recent clinical trials has shown substantial promise as a therapy for type 1 diabetes; however, long-term insulin independence remains inadequate. This has been largely attributed to the current intravascular, hepatic transplant site, which exposes islets to mechanical and inflammatory stresses. A highly macroporous scaffold, housed within an alternative transplant site, can support an ideal environment for islet transplantation by providing three-dimensional distribution of islets, while permitting the infiltration of host vasculature. In the present study, we sought to evaluate the synergistic effect of a proangiogenic hydrogel loaded within the void space of a macroporous poly(dimethylsiloxane) (PDMS) scaffold on islet engraftment. The fibrin-based proangiogenic hydrogel tested presents platelet derived growth factor (PDGF-BB), via a fibronectin (FN) fragment containing growth factor and major integrin binding sites in close proximity. The combination of the proangiogenic hydrogel with PDMS scaffolds resulted in a significant decrease in the time to normoglycemia for syngeneic mouse islet transplants. This benefit was associated with an observed increase in competent vessel branching, as well as mature intraislet vessels. Overall, the addition of the proangiogenic factor PDGF-BB, delivered via the FN fragment-functionalized hydrogel, positively influenced the efficiency of engraftment. These characteristics, along with its ease of retrieval, make this combination of a biostable macroporous scaffold and a degradable proangiogenic hydrogel a supportive structure for insulin-producing cells implanted in extrahepatic sites.


Basophil/mast cell precursors in mast cell proliferative disorders.
Mast cell proliferative disorders include urticaria pigmentosa, localized to the skin, and systemic mastocytosis, with progression from urticaria pigmentosa to systemic mastocytosis in some adults. We have evaluated the presence of basophil/mast cell precursors in urticaria pigmentosa and systemic mastocytosis using an in vitro assay for cells which form histamine-positive peripheral blood granulocyte colonies in methylcellulose. In 17 cultures from 10 patients with mast cell proliferative disorders (6 urticaria pigmentosa, 4 systemic mastocytosis), the frequency of histamine-positive granulocyte colonies was significantly higher in systemic mastocytosis (40% colonies picked) than in urticaria pigmentosa (15%, p less than 0.002). The mean histamine content per cell of urticaria pigmentosa patient colonies was less than or equal to 0.1 pg compared to 0.7 +/- 0.1 pg in systemic mastocytosis patient colonies. Precursor assays done serially at different times in individual patients appeared to reflect clinical extent of disease. In one patient with urticaria pigmentosa, a repeatedly normal number of histamine-positive colonies paralleled no change in clinical course, while in 2 others (1 systemic mastocytosis, 1 urticaria pigmentosa) increasing skin lesions, leukopenia, increased urinary histamine or refractoriness to therapy was accompanied by an increase in the frequency of basophil/mast cell precursors. Using an index of disease activity, the frequency of histamine-positive colonies was significantly higher in active, versus inactive, mast cell proliferative disorders (p less than 0.0001). These studies confirm the biologic relevance of mast cell proliferation in mast cell proliferative disorders, and suggest that precursor assays using histamine content of granulocyte colonies may be useful in predicting extent of disease.


Lasing and waveguiding in smectic A liquid crystal optical fibers.
We demonstrate a new class of soft matter optical fibers, which are self-assembled in a form of smectic-A liquid crystal microtubes grown in an aqueous surfactant dispersion of a smectic-A liquid crystal. The diameter of the fibers is highly uniform and the fibers are highly birefringent. They are characterized by a line topological defect in the core of the fiber with an optical axis pointing from the defect core towards the surface. We demonstrate guiding of light along the fiber and Whispering Gallery Mode (WGM) lasing in a plane perpendicular to the fiber. The light guiding as well as the lasing threshold are significantly dependent on the polarization of the excitation beam. The observed threshold for WGM lasing is very low (≈ 75μJ/cm(2)) when the pump beam polarization is perpendicular to the direction of the laser dye alignment and is similar to the lasing threshold in nematic droplets. The smectic-A fibers are soft and flexible and can be manipulated with laser tweezers demonstrating a promising approach for realization of soft photonic circuits.


An urban outbreak of leptospirosis in Mumbai, India.
An outbreak of leptospirosis occurred during the rainy season in the city of Mumbai, India. Out of 169 suspected cases, 74 (43.7%) were determined serologically positive by microagglutination test (MAT) carried out with a battery of eight pathogenic serovars, while 78 (46.1%) were shown positive for IgM antibodies to leptospira by enzyme-linked immunosorbent assay. On the basis of MAT, serovar Copenhageni accounted for 66 (89.1%) out of the 74 cases admitted during the period of the outbreak. Myalgia, conjunctival suffusion, cough with hemoptysis, icterus, and oliguria were significantly more common in patients whose samples were determined positive by MAT. The presence of pulmonary signs and symptoms and renal failure were significantly associated with mortality in patients presumed to be suffering from leptospirosis.


Initiation and promotion at different ages and doses in 2200 mice. II. Decrease in promotion by TPA with ageing.
Using the data described in Paper I, we compare the effects of the same treatment timings and doses given at different ages. Initiation with DMBA at 68 weeks of age, followed 3 weeks later by TPA, has a significantly (P less than 0.0001) less rapid effect on subsequent tumour incidence than does initiation at 8 or at 48 weeks of age, followed 3 weeks later by TPA. We suggested that this is chiefly due not to changes in the numbers of cells initiated by DMBA, but rather to a decrease in the promotional efficacy of TPA in ageing mice.


EFNS guidelines on the use of neuroimaging in the management of motor neuron diseases.
These European Federation of Neurological Societies guidelines on neuroimaging of motor neuron diseases (MNDs) are designed to provide practical help for the neurologists to make appropriate use of neuroimaging techniques in patients with MNDs, which ranges from diagnostic and monitoring aspects to the in vivo study of the pathobiology of such conditions. Literature searches were performed before expert members of the Task Force wrote proposal. Then, consensus was reached by circulating drafts of the manuscript to the Task Force members and by discussion of the classification of evidence and recommendations. The use of conventional MRI in patients suspected of having a MND is yet restricted to exclude other causes of signs and symptoms of MN pathology [class IV, level good clinical practice point (GCPP)]. Although the detection of corticospinal tract hyperintensities on conventional MRI and a T2-hypointense rim in the pre-central gyrus can support a pre-existing suspicion of MND, the specific search of these abnormalities for the purpose of making a firm diagnosis of MND is not recommended (class IV, level GCPP). At present, advanced neuroimaging techniques, including diffusion tensor imaging and proton magnetic resonance spectroscopic imaging, do not have a role in the diagnosis or routine monitoring of MNDs yet (class IV, level GCPP). However, it is strongly advisable to incorporate measures derived from these techniques into new clinical trials as exploratory outcomes to gain additional insights into disease pathophysiology and into the value of these techniques in the (longitudinal) assessment of MNDs (class IV, level GCPP).


Selecting long-term care facilities with high use of acute hospitalisations: issues and options.
This paper considers approaches to the question "Which long-term care facilities have residents with high use of acute hospitalisations?" It compares four methods of identifying long-term care facilities with high use of acute hospitalisations by demonstrating four selection methods, identifies key factors to be resolved when deciding which methods to employ, and discusses their appropriateness for different research questions. OPAL was a census-type survey of aged care facilities and residents in Auckland, New Zealand, in 2008. It collected information about facility management and resident demographics, needs and care. Survey records (149 aged care facilities, 6271 residents) were linked to hospital and mortality records routinely assembled by health authorities. The main ranking endpoint was acute hospitalisations for diagnoses that were classified as potentially avoidable. Facilities were ranked using 1) simple event counts per person, 2) event rates per year of resident follow-up, 3) statistical model of rates using four predictors, and 4) change in ranks between methods 2) and 3). A generalized mixed model was used for Method 3 to handle the clustered nature of the data. 3048 potentially avoidable hospitalisations were observed during 22 months' follow-up. The same "top ten" facilities were selected by Methods 1 and 2. The statistical model (Method 3), predicting rates from resident and facility characteristics, ranked facilities differently than these two simple methods. The change-in-ranks method identified a very different set of "top ten" facilities. All methods showed a continuum of use, with no clear distinction between facilities with higher use. Choice of selection method should depend upon the purpose of selection. To monitor performance during a period of change, a recent simple rate, count per resident, or even count per bed, may suffice. To find high-use facilities regardless of resident needs, recent history of admissions is highly predictive. To target a few high-use facilities that have high rates after considering facility and resident characteristics, model residuals or a large increase in rank may be preferable.


HemoPDB: Hematopoiesis Promoter Database, an information resource of transcriptional regulation in blood cell development.
Hematopoiesis describes the process of the normal formation and development of blood cells, involving both proliferation and differentiation from stem cells. Abnormalities in this developmental program yield blood cell diseases, such as leukemia. Although, in recent years, extensive molecular research in normal hematopoietic development has characterized transcription factors and their binding sites in the target gene promoters, the information generated is highly fragmented. In order to integrate this important regulatory information with the corresponding genomic sequences, we have developed a new database called Hematopoiesis Promoter Database (HemoPDB). HemoPDB is a comprehensive resource focused on transcriptional regulation during hematopoietic development and associated aberrances that result in malignancy. HemoPDB (version 1.0) contains 246 promoter sequences and 604 experimentally known cis-regulatory elements of 187 different transcription factors, with links to published references. Orthologous promoters from different species are linked with each other and displayed in the same database record, accompanied by a visual image of the promoters and corresponding annotations of cis-regulatory elements. HemoPDB may be searched for the promoter of a specific gene, transcription factors and target genes, and genes that are expressed in a certain cell type or lineage, through a user-friendly web interface at http://bioinformatics.med.ohio-state.edu/HemoPDB. Links to the documentation and other technical details are provided on this website.


Placental stress and pre-eclampsia: a revised view.
In pre-eclampsia, poor placentation causes both oxidative and endoplasmic reticulum stress of the placenta. It is believed placental hypoxia stimulates excessive production of soluble fms-like tyrosine kinase 1 (sFlt-1), which binds and deactivates circulating vascular endothelial growth factor (VEGF). When maternal endothelium is deprived of VEGF it becomes dysfunctional hence leading to the clinical syndrome of the mother. In this paper the previous claim that poor placentation may predispose more to placental oxidative stress than hypoxia is reiterated. We show why pre-eclampsia is not only an endothelial disease, but also a disorder of systemic inflammation. We question that hypoxia is the only or indeed the main stimulus to release of sFlt-1; and emphasise the role of inflammatory mechanisms. Hypoxia cannot be assumed simply because hypoxia-inducible transcription factors (HIF) are upregulated. Concurrent assessments of nuclear factor-kappaB (NF-kappaB), a transcription factor for inflammatory responses are desirable to obtain a more complete picture. We point out that the pre-eclampsia placenta is the source of bioactive circulating factors other than sFlt-1 in concentrations that are much higher than in normal pregnancy. These may also contribute to the final inflammatory syndrome. We propose a modified version of the two-stage model for pre-eclampsia.


Solophenols B-D and solomonin: new prenylated polyphenols isolated from propolis collected from the Solomon Islands and their antibacterial activity.
Three new prenylated flavonoids, namely, solophenols B (1), C (2), and D (3), as well as a new prenylated stilbene, solomonin (4), were isolated from propolis collected from the Solomon Islands. In addition, 17 known compounds were identified. The structures of the new compounds were determined by a combination of methods, including mass spectrometry and NMR. These new compounds and several known compounds were tested for antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa. Most of them exhibited potent antibacterial activity. These findings may indicate that propolis from the Solomon Islands has potential applications as an ingredient in food additives or pharmaceuticals.


Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene.
The CACNA1A gene encodes the pore-forming α1 subunit of voltage-gated P/Q type Ca2+ channels (Cav2.1). Mutations in this gene, among others, have been described in patients and rodents suffering from absence seizures and episodic ataxia type 2 with/without concomitant seizures. In this study, we aimed for the first time to assess phenotypic and behavioral alterations in larval zebrafish with partial cacna1aa knockdown, placing special emphasis on changes in epileptiform-like electrographic discharges in larval brains. Whole-mount in situ hybridization analysis revealed expression of cacna1aa in the optic tectum and medulla oblongata of larval zebrafish at 4 and 5 days post-fertilization. Next, microinjection of two antisense morpholino oligomers (individually or in combination) targeting all splice variants of cacna1aa into fertilized zebrafish eggs resulted in dose-dependent mortality and decreased or absent touch response. Over 90% knockdown of cacna1aa on protein level induced epileptiform-like discharges in the optic tectum of larval zebrafish brains. Incubation of morphants with antiseizure drugs (sodium valproate, ethosuximide, lamotrigine, topiramate) significantly decreased the number and, in some cases, cumulative duration of epileptiform-like discharges. In this context, sodium valproate seemed to be the least effective. Carbamazepine did not affect the number and duration of epileptiform-like discharges. Altogether, our data indicate that cacna1aa loss-of-function zebrafish may be considered a new model of absence epilepsy and may prove useful both for the investigation of Cacna1a-mediated epileptogenesis and for in vivo drug screening.


Genetic rescue of a lethal "null" activity allele of 6-phosphogluconate dehydrogenase in Drosophila melanogaster.
While a null activity mutant allele of the structural gene for 6-phosphogluconate dehydrogenase in Drosophila melanogaster is lethal, a similar mutation for glucose-6-phosphate dehydrogenase is not. Double mutant combinations lacking both enzyme activities, obtained either by recombination or by mutagen treatment of a chromosome bearing the lethal allele, result in a restoration of viability. The indispensability of the pentose phosphate shunt in Drosophila appears to depend upon the specific position of the block within the pathway.


First documented case of BK nephropathy in kidney transplant recipient in Croatia: usage of urine cytology in evaluation process.
BK virus associated nephropathy (BKVAN) in transplanted kidney, although recognized as a distinct entity in the 1970-es, continues to represent a challenge in kidney transplantation, mainly because the optimal treatment approach has not been determined yet. The fact that about 10-20% of patients have simultaneously some stage of acute rejection, complicate the treatment even more. Herein we present a case of BK nephropathy in the patient, one year after combined liver and kidney transplantation, complicated by episode of acute T-cell mediated rejection. Identification of decoy cells by cytology urine exam in patient with acute kidney graft function deterioration, raised suspicion of BKVAN. Diagnosis has been made by histological examination and confirmed with immunohistochemical staining for BK virus in kidney graft biopsy. One month after he had been treated for BKVAN with intravenous immunoglobulin, leflunomide and overall immunosuppression therapy reduction, there was further deterioration of graft function due to an episode of acute T-cell mediated rejection (Banff classification IA). He received 500 mg of metilprednisolon intravenously and mycophenolate mofetil had been reintroduced, which resulted in slow partial recovery of the graft function, but never to the baseline values. For the past two years his renal graft function has been stable, maintaining lower levels of immunosuppressive therapy. According to our knowledge this is the first documented case of BK virus associated nephropathy, diagnosed and confirmed with immunohistochemical staining of tissue from kidney biopsy in Croatia.


Global population genetic structure and male-mediated gene flow in the green turtle (Chelonia mydas): RFLP analyses of anonymous nuclear loci.
We introduce an approach for the analysis of Mendelian polymorphisms in nuclear DNA (nDNA), using restriction fragment patterns from anonymous single-copy regions amplified by the polymerase chain reaction, and apply this method to the elucidation of population structure and gene flow in the endangered green turtle, Chelonia mydas. Seven anonymous clones isolated from a total cell DNA library were sequenced to generate primers for the amplification of nDNA fragments. Nine individuals were screened for restriction site polymorphisms at these seven loci, using 40 endonucleases. Two loci were monomorphic, while the remainder exhibited a total of nine polymorphic restriction sites and three size variants (reflecting 600-base pair (bp) and 20-bp deletions and a 20-bp insertion). A total of 256 turtle specimens from 15 nesting populations worldwide were then scored for these polymorphisms. Genotypic proportions within populations were in accord with Hardy-Weinberg expectations. Strong linkage disequilibrium observed among polymorphic sites within loci enabled multisite haplotype assignments. Estimates of the standardized variance in haplotype frequency among global collections (FST = 0.17), within the Atlantic-Mediterranean (FST = 0.13), and within the Indian-Pacific (FST = 0.13), revealed a moderate degree of population substructure. Although a previous study concluded that nesting populations appear to be highly structured with respect to female (mitochondrial DNA) lineages, estimates of Nm based on nDNA data from this study indicate moderate rates of male-mediated gene flow. A positive relationship between genetic similarity and geographic proximity suggests historical connections and/or contemporary gene flow between particular rookery populations, likely via matings on overlapping feeding grounds, migration corridors or nonnatal rookeries.


A Drosophila receptor tyrosine phosphatase expressed in the embryonic CNS and larval optic lobes is a member of the set of proteins bearing the "HRP" carbohydrate epitope.
Recent studies have defined several cell surface glycoproteins expressed in the developing nervous system of insect embryos that may be involved in axon outgrowth and guidance processes. These glycoproteins include the fasciclins and a group of receptor-linked protein tyrosine phosphatases (R-PTPs). In embryos, the fasciclins are localized to axonal subsets, while the R-PTPs appear to be expressed on most or all CNS axons. To identify other neuronal cell surface glycoproteins in the Drosophila embryo, we have taken a biochemical approach. This is based on the observation that antisera against horseradish peroxidase (HRP) recognize a carbohydrate epitope that is selectively expressed in the insect nervous system. A large number of neuronal glycoproteins (denoted "HRP proteins") apparently bear the HRP carbohydrate epitope. We have used polyclonal anti-HRP antibodies to purify these proteins from Drosophila embryos, and have obtained protein sequences from seven HRP protein bands. These data define three major HRP proteins as neurotactin, fasciclin I, and an R-PTP, DPTP69D. Western blotting data suggest that fasciclin II, neuroglian, DPTP10D, and DPTP99A are also HRP proteins. We show that DPTP69D, like the previously characterized R-PTPs, is localized to CNS axons in the embryo. In third instar larvae, DPTP69D expression is restricted to subsets of neuronal processes in the brain, ventral nerve cord, and eye disk. In the optic lobes, DPTP69D is localized to the neuropils of the lamina and medulla, and to an array of parallel thick bundles that may be the transmedullary fibers of the developing lobula complex.


Rat growth hormone receptor/growth hormone-binding protein mRNAs with divergent 5'-untranslated regions are expressed in a tissue-specific manner.
In the rat, the growth hormone receptor (GH-R) gene generates two transcripts, one encoding the transmembrane GH-R, and a shorter one encoding the GH-binding protein (GH-BP). These transcripts exhibit a high degree of heterogeneity in their 5'-untranslated regions (5'-UTRs). Some of the exons encoding these 5'-UTR variants may be flanked by distinct promoter regions whose activity would result in the tissue-specific expression of the GH-R gene. To assess this possibility, we used single-sided polymerase chain reaction (PCR) amplification to characterize 5'-UTR variants in rat GH-R cDNAs, and by using 5'-UTR-specific probes, we determined their pattern of expression in several tissues. Besides two previously described variants (V1 and V2), three new 5'-UTR variants were identified, extending 56 nucleotides (V3), 135 nucleotides (V4), and 209 nucleotides (V5) upstream of the ATG translation initiation codon. The expression of GH-R and GH-BP transcripts was clearly tissue specific. In the liver, GH-BP mRNA was the predominant transcript, whereas in other tissues, there was equivalent expression of both transcripts or predominant expression of GH-R mRNA. With respect to the tissue distribution of the 5'-UTR variants in particular, variants V1 and V5 exhibited a pattern of expression closely resembling that seen with an exon 2 probe, with the overall expression of variant V1 being much higher than that of variant V5. The V2 species was exclusively expressed in liver. Variant V3 was expressed at low levels in liver, muscle, heart, and kidney; in muscle and heart, it was preferentially associated with GH-BP transcripts. Variant V4, although present in liver, was more abundant in extrahepatic tissues and predominantly found in GH-R mRNA transcripts. Southern blot analyses were consistent with exon 2 and the exons encoding the V1 and V2 sequences being in proximity, with the other 5'-UTR sequences being encoded by exons located further upstream of exon 2. These findings support the concept that different 5'-UTR variants are the result of the different promoters acting in a tissue-specific manner. The association of specific 5'-UTR variants with either GH-R or GH-BP transcripts raises the possibility that the alternative splicing process that generates GH-BP mRNA in the rat might be controlled by the 5'-flanking region regulating the expression of specific leader exons.


Epidermal T Cell Dendrites Serve as Conduits for Bidirectional Trafficking of Granular Cargo.
Dendritic epidermal T cells (DETCs) represent a prototypical lineage of intraepithelial γδ T cells that participate in the maintenance of body barrier homeostasis. Unlike classical T cells, DETCs do not recirculate and they remain persistently activated through their T cell receptors (TCR) at steady state, i.e., in absence of infection or tissue wounding. The steady state TCR signals sustain the formation of immunological synapse-like phosphotyrosine-rich aggregates located on projections (PALPs) which act to anchor and polarize DETC's long cellular projections toward the apical epidermis while the cell bodies reside in the basal layers. The PALPs are known to contain pre-synaptic accumulations of TCR-containing and lysosomal granules, but how this cargo accumulates there remains unclear. Here, we combined anti-Vγ5 TCR, cholera toxin subunit B (CTB), and LysoTracker (LT)-based intravital labeling of intracellular granules, with high resolution dynamic microscopy and fluorescence recovery after photobleaching (FRAP) to characterize the steady state composition and transport of DETC granules in steady state epidermis. Intradermal fluorescent Vγ5 antibody decorated DETCs without causing cellular depletion, dendrite mobilization or rounding up and became slowly internalized over 48 h into intracellular granules that, after 6 days, colocalized with LAMP-1 and less so with LT or early endosomal antigen-1. Intradermal CTB was likewise internalized predominantly by DETCs in epidermis, labeling a partly overlapping set of largely LAMP-1+ intracellular granules. These as well as LT-labeled granules readily moved into newly forming dendrites and accumulated at the apical endings. FRAP and spatiotemporal tracking showed that the inside tubular lengths of DETC cellular projections supported dynamic trafficking of lysosomal cargo toward and away from the PALPs, including internalized TCR and lipid raft component ganglioside GM1 (labeled with CTB). By contrast, the rate of GM1 granules transport through comparable dendrites of non-DETCs was twice slower. Our observations suggest that DETCs use chronic TCR activation to establish a polarized conduit system for long-range trans-epithelial transport aimed to accumulate mature lysosomes at the barrier-forming apical epidermis. The biological strategy behind the steady state lysosome polarization by DETCs remains to be uncovered.


Design of multifunctional nanomedical systems.
Multifunctional nanoparticles hold great promise for drug/gene delivery and simultaneous diagnostics and therapeutics ("theragnostics") including use of core materials that provide in vivo imaging and opportunities for externally modulated therapeutic interventions. Multilayered nanoparticles can act as nanomedical systems with on-board molecular programming done through the chemistry of highly specialized layers to accomplish complex and potentially decision-making tasks. The targeting process itself is a multi-step process consisting of initial cell recognition through cell surface receptors, cell entry through the membrane in a manner to prevent undesired alterations of the nanomedical system, re-targeting to the appropriate sub-region of the cell where the therapeutic package can be localized, and potentially control of that therapeutic process through feedback systems using molecular biosensors. This paper describes a bionanoengineering design process in which sophisticated nanomedical platform systems can be designed for diagnosis and treatment of disease. The feasibility of most of these subsystems has been demonstrated, but the full integration of these interacting sub-components remains a challenge for the field. Specific examples of sub-components developed for specific applications are described.


How low should you go: novel device for nail trephination.
The most commonly used treatment for subungual hematomas is nail trephination, a technique that is not standardized and that poorly controls for trephination depth. The objective was to test the safety and tolerance of a new device for nail trephination that uses innovative "mesoscission" or microcutting technology to create holes of specific depths in the nail plate without penetrating the nail bed. Fourteen adult subjects with healthy toenails had five holes drilled in a random single-blind fashion at different test settings into their right great toenail with this device and were assessed for pain and pressure tolerance as well as perioperative and postoperative complications. Nail trephination with this device in this small pilot study was controlled and well tolerated. The study population was small (n = 14) and the follow-up evaluation relied on patient self-report, which is not always reliable. The follow-up period was only 1 week and did not allow for evaluation of permanent nail plate deformity. Mesoscission may be a controlled and practical alternative to traditional nail trephining methods.


Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.
X chromosome inactivation involves multiple levels of chromatin modification, established progressively and in a stepwise manner during early development. The chromosomal protein Smchd1 was recently shown to play an important role in DNA methylation of CpG islands (CGIs), a late step in the X inactivation pathway that is required for long-term maintenance of gene silencing. Here we show that inactive X chromosome (Xi) CGI methylation can occur via either Smchd1-dependent or -independent pathways. Smchd1-dependent CGI methylation, the primary pathway, is acquired gradually over an extended period, whereas Smchd1-independent CGI methylation occurs rapidly after the onset of X inactivation. The de novo methyltransferase Dnmt3b is required for methylation of both classes of CGI, whereas Dnmt3a and Dnmt3L are dispensable. Xi CGIs methylated by these distinct pathways differ with respect to their sequence characteristics and immediate chromosomal environment. We discuss the implications of these results for understanding CGI methylation during development.


Targeted screening and health education for Chagas disease tailored to at-risk migrants in Spain, 2007 to 2010.
Chagas disease is endemic in Latin America, but migration has expanded the disease's geographical limits. Spain is the most affected country in Europe. From 2007, a specific Chagas disease programme aimed at at-risk migrants was developed in three Spanish cities (Madrid, Jerez de la Frontera and Alicante). The objectives of the programme were to increase participants' knowledge and decrease their fears about the disease and to encourage them to undergo screening for Trypanosoma cruzi infection. The programme was specially focused on migrants from Bolivia and Latin American women of childbearing age. Culturally tailored interventions were carried out in non-clinical settings. A total of 276 migrants were screened using a rapid immunochromatographic test following talks on the disease: the results were then later confirmed by standard serological tests. Of those tested, 44 (15.9%) were confirmed cases of Chagas disease. All of them came from Bolivia and a quarter were pregnant women. Of the 44 cases, 31 were later followed up at a specialised Chagas disease clinic. We consider that the adaptation of the programme to the target population's needs and collaboration with non-governmental organisations and migrants' associations contributed to the acceptance of the programme and the increasing number of patients seen at a specialised clinic.