Single-Session Therapy by Appointment for the Treatment of Anxiety Disorders in Youth and Adults: A Systematic Review of the Literature.
Purpose: This systematic review provides a summary of the available evidence of the efficacy of single-session therapy (SST) on anxiety disorders in both youth and adults. Methods: PubMed, Scopus, Medline, and Google Scholar databases were search for relevant articles, and the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials was used for transparent reporting of the methodological quality of each selected study. Results: The search of electronic databases identified 18 reports based on rigorous inclusion criteria. Single-session therapy was found superior to no treatment in reducing anxiety symptoms, and similar results were observed while comparing SST to multi-treatment sessions. Discussion: The findings support the benefits of SST in enhancing cognitive, behavioral, and psychological outcomes in both youth and adults suffering from anxiety disorders across treatment conditions and approaches, SST thus appears to be a promising way of providing access to both private and public therapeutic services efficiently and cost-effectively. Conclusions: Single-session therapy is effective in treating anxiety disorders. Further research is required to quantify its cost-effectiveness and deepen the knowledge of effective treatment ingredients for both young people and the adult population suffering from diverse anxiety disorders. Systematic Review Registration: PROSPERO, identifier [CRD42021232024].


Utilization of health care services before and after media attention about fatal side effects of the AstraZeneca vaccine: a nation-wide register-based event study.
Survey studies have found that vaccinated persons tend to report more side effects after being given information about side effects rather than benefits. However, the impact of high media attention about vaccine-related side effects on the utilization of health care is unknown. We aimed to assess whether utilization of health care services for newly vaccinated health care workers changed after media attention about fatal side effects of the AstraZeneca vaccine on March 11th, 2021, and whether changes differed by age, sex, or occupation. We utilized individual-level data on health care use, vaccination, employment, and demographics available in the Norwegian emergency preparedness register Beredt C19. In all 99,899 health care workers in Norway who were vaccinated with AstraZeneca between February 11th and March 11th, we used an event-study design with a matched comparison group to compare the change in primary and inpatient specialist care use from 14 days before to 14 days after the information shock on March 11th, 2021. Primary health care use increased with 8.2 daily consultations per 1000 health care workers (95% CI 7.51 to 8.89) the week following March 11th for those vaccinated with AstraZeneca (n = 99,899), compared with no increase for the unvaccinated comparison group (n = 186,885). Utilization of inpatient care also increased with 0.8 daily hospitalizations per 1000 health care workers (95% CI 0.37 to 1.23) in week two after March 11th. The sharpest increase in daily primary health care use in the first week after March 11th was found for women aged 18-44 (10.6 consultations per 1000, 95% CI 9.52 to 11.68) and for cleaners working in the health care sector (9.8 consultations per 1000, 95% CI 3.41 to 16.19). Health care use was higher after the media reports of a few cases of fatal or severe side effects of the AstraZeneca vaccine. Our results suggest that the reports did not only lead vaccinated individuals to contact primary health care more, but also that physicians referred and treated more cases to specialist care after the new information.


TET1 regulates stem cell properties and cell cycle of Cancer stem cells in triple-negative breast cancer via DNA demethylation.
The role of cancer stem cells in metastasis, recurrence, and resistance to conventional therapies is significant. Addressing these cells could potentially decrease cancer reoccurrences and mortality rates. TET1, a crucial gene involved in stem cell self-renewal and potency, may also play a part in cancer stem cells, which warrants further research. To explore the role of TET1 in cancer stem cells, we conducted experiments involving loss and gain. We then analyzed factors such as migration, invasion, cell cycle, cell viability, mammosphere formation, and the CD44+/CD24- subpopulation of cancer cells. We also investigate the influence of TET1 on CCNB1, CDK1, and OCT4. Our study reveals that TET1 can regulate the phenotype of cancer stem cells via OCT4. Additionally, it can control the cell cycle by increasing CDK1 and CCNB1 levels. These findings suggest that targeting DNA methylation and TET1 could be an effective strategy to overcome obstacles posed by Cancer stem cells. Our research also indicates that TET1 can influence the phenotype of cancer stem cells and the cell cycle of breast cancer cells potentially through OCT4, CCNB1, and CDK1. This highlights the importance of TET1 in breast cancer cases and suggests a potential therapeutic approach through DNA methylation and modulation of TET1.


Sex differences in age at first hospital admission for schizophrenia: fact or artifact?
Reports that men develop schizophrenia earlier than women could be a clue to major factors in the pathological processes of schizophrenia or they could be diagnostic artifacts. The authors evaluated the effect of alternative diagnostic systems on age at first admission for schizophrenia, depression, and personality disorder. They found that the age-sex disproportion is specific to schizophrenia and occurs irrespective of the diagnostic system. An unexpected relationship between diagnostic system and sex differences in the rate of schizophrenia obtained, however: the broadest and narrowest sets of criteria yielded approximately equal proportions of females and males, but intermediate systems yielded a significantly greater proportion of males than females.


Nanoscale hydrodynamics near solids.
Density Functional Theory (DFT) is a successful and well-established theory for the study of the structure of simple and complex fluids at equilibrium. The theory has been generalized to dynamical situations when the underlying dynamics is diffusive as in, for example, colloidal systems. However, there is no such a clear foundation for Dynamic DFT (DDFT) for the case of simple fluids in contact with solid walls. In this work, we derive DDFT for simple fluids by including not only the mass density field but also the momentum density field of the fluid. The standard projection operator method based on the Kawasaki-Gunton operator is used for deriving the equations for the average value of these fields. The solid is described as featureless under the assumption that all the internal degrees of freedom of the solid relax much faster than those of the fluid (solid elasticity is irrelevant). The fluid moves according to a set of non-local hydrodynamic equations that include explicitly the forces due to the solid. These forces are of two types, reversible forces emerging from the free energy density functional, and accounting for impenetrability of the solid, and irreversible forces that involve the velocity of both the fluid and the solid. These forces are localized in the vicinity of the solid surface. The resulting hydrodynamic equations should allow one to study dynamical regimes of simple fluids in contact with solid objects in isothermal situations.


Responses of dorsal cochlear nucleus neurons to signals in the presence of modulated maskers.
The detection of a signal in noise is enhanced when the masking noise is coherently modulated over a wide range of frequencies. This phenomenon, known as comodulation masking release (CMR), has been attributed to across-channel processing; however, the relative contribution of different stages in the auditory system to such across-channel processing is unknown. It has been hypothesized that wideband or lateral inhibition may underlie a physiological correlate of CMR. To further test this hypothesis, we have measured the responses of single units from the dorsal cochlear nucleus in which wideband inhibition is particularly pronounced. Using a sinusoidally amplitude-modulated tone at the best frequency of each unit as a masker, a pure-tone signal was added in the dips of the masker modulation. Flanking bands (FBs, also amplitude-modulated pure tones) were positioned to fall within the inhibitory sidebands of the receptive field of the unit. The FBs were either in phase (comodulated) or out of phase (codeviant) with the on-frequency masker. For the majority of units, the addition of the comodulated FBs produced a strong reduction in the response to the masker modulation, making the signal more salient in the post stimulus time histograms. The change in spike rate in response to the signal between the masker and signal-plus-masker conditions was greatest for the comodulated condition for 29 of 45 units. These results are consistent with the hypothesis that wideband inhibition may play a role in across-channel processing at an early stage in the auditory pathway.


Dietary Composition Independent of Weight Loss in the Management of Non-Alcoholic Fatty Liver Disease.
Poor dietary composition is an important factor in the progression of non-alcoholic fatty liver disease (NAFLD). The majority of NAFLD patients follow diets with overconsumption of simple carbohydrates, total and saturated fat, with reduced intake of dietary fiber and omega-3 rich foods. Although lifestyle modifications including weight loss and exercise remain the keystone of NAFLD management, modifying dietary composition with or without a calorie-restricted diet may also be a feasible and sustainable strategy for NAFLD treatment. In the present review article, we highlight the potential therapeutic role of a "high quality healthy diet" to improve hepatic steatosis and metabolic dysfunction in patients with NAFLD, independent of caloric restriction and weight loss. We provide a literature review evaluating the evidence behind dietary components including fiber-, meat- and omega-3-rich diets and, pending further evidence, we concur with the EASL-EASD-EASO Clinical Guidelines recommendation of the Mediterranean diet as the diet of choice in these patients.


Medicare Compensation Rates for Hand and Shoulder/Elbow Surgery by Operative Time: A Comparative Analysis.
There is a high demand for shoulder/elbow experience among hand-fellowship trainees due to the perception that this exposure will improve their professional "marketability" in a subspecialty they perceive as having higher compensation. Using Medicare data, we investigated the most common surgeries from these fields and determined which have the highest compensation [work relative value unit (wRVU), payment, charge, and reimbursement (payment-to-charge percentage] rates per operative time. We then determined whether the overall non-weighted and weighted (by surgical frequency/volume) compensation rates of shoulder/elbow surgery are greater than that of hand surgery. Among 30 shoulder/elbow procedures, arthroplasty and arthroscopic rotator cuff repair had the highest payment and wRVU assignments. Among 83 hand procedures, upper-extremity flaps, carpal stabilization, distal radius open reduction internal fixation (ORIF), both-bone ORIF, and interposition arthroplasty had the greatest wRVU assignments with correspondingly high payments. A non-weighted comparison of the two subspecialties showed that hand surgery has a higher mean payment/min ($10.46±3.22 vs. $7.52±2.89), charge/min ($51.02±17.11 vs. $41.96±11.32), and reimbursement (21±4.7% vs. 18±5.1%) compared with shoulder/elbow surgery (all, P<0.01). Non-weighted mean wRVUs/min were similar (0.12±0.03 vs. 0.13±0.03, P = 0.12). When weighted by procedure frequency, hand surgery had greater wRVUs/min (0.15±0.036 vs. 0.13±0.032), payments/min ($14.17±4.50 vs. $6.97±2.26), charges/min ($75.68±30.47 vs. $42.61±7.83), and reimbursement (20±5.0% vs. 17±6.0%) (all, P<0.01). According to Medicare compensation, and when weighted by procedure frequency, hand procedures are associated with greater overall mean wRVUs/min, payments/min, charges/min, and reimbursement compared with shoulder and elbow procedures. Hand-surgery fellowship applicants should be aware that subspecialty compensation is complex in nature but should seek shoulder/elbow elective experience to acquire an additional surgical skill-set as opposed to primarily monetary reason.


Thoracic pheochromocytoma: computerized tomographic characteristics.
We have reported a typical case of extra-adrenal pheochromocytoma. The tumor, located in the posterior mediastinum was diagnosed five years after onset of classic symptoms and signs. Our case illustrated the usefulness of computerized tomography in locating pheochromocytomas. A high index of suspicion is required to detect such a unique tumor and avoid unnecessary delays in diagnosis and treatment.


The Science of Absent Evidence: Is There Such Thing as an Effective Responsible Drinking Message?
To review the effectiveness of responsible drinking messages (RDMs). We searched PsycINFO, MEDLINE and Google Scholar to June 2016 for studies evaluating the effectiveness of RDMs. Only eight studies met the inclusion/exclusion criteria. Due to a small number of search results and broad inconsistency in methods and outcome measures, quantitative synthesis was not possible so a narrative summary of findings was conducted. A review of findings from these articles suggested a disjointed approach in terms of the format and content of RDMs evaluated, as well as the dependent variables used to judge their effectiveness. An overall pattern emerged suggesting that RDMs may have beneficial effects across various outcome measures, including reducing prospective alcohol use. However, due to the inconsistent approach to both the development and evaluation of RDMs, it was not possible to draw any clear conclusions in terms of effectiveness, or indeed the potential size of any effects. A systematic approach to the development and evaluation of RDMs is recommended to ensure that a clearer evidence base is established in this area, particularly in light of the substantial public funds which are often spent on RDM campaigns. A systematic review of studies evaluating the effectiveness of responsible drinking message campaigns reveals an inconsistent approach to message design and evaluation. Findings of the review suggest the need for a more consistent approach to aid in the development of a clearer evidence base in this area.


Surgical repair of cytomegalovirus-related retinal detachment without silicone oil in patients with AIDS.
To analyze visual and anatomic results following surgical repair of cytomegalovirus (CMV)-related retinal detachment (RD) without silicone oil permanent tamponade. We analyzed five consecutive patients (six eyes) with acquired immunodeficiency syndrome and CMV-related RD that were repaired with pars plana vitrectomy with peeling of the posterior hyaloid, laser photocoagulation, encircling scleral buckle, and intraocular gas tamponade. Preoperative vision ranged from 20/40 to hand motion. Total retinal reattachment was achieved in five of six eyes (83%). Macular reattachment was achieved in all eyes. Mean postoperative visual acuity was 20/40 (range 20/30-20/60). Mean postoperative follow-up was 12 months (range 7-19 months). All patients in this series presented with low preoperative CD4+ T-lymphocyte counts (mean, 24 cells per microL) and received highly active antiretroviral therapy. One retina (Patient 1) redetached 7 months after initial repair and was successfully reattached without using silicone oil. Postoperatively, visual acuity remains 20/30, and total retinal reattachment has been maintained for 16 months. Good anatomic and visual success can be achieved and maintained in CMV-related RD without the use of silicone oil.


Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell.
Characterization of epigenetic events in carcinogenesis has led to the discovery of a new class of oncogenes and thereby a new class of therapeutic targets. Among the new therapeutic approaches are modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). HDACs deacetylate histones as well as transcription factors and can modulate gene expression through both these mechanisms in normal and malignant cells. Furthermore, acetylation is an important posttranslational modulation of several proteins involved in the regulation of cell proliferation, differentiation and apoptosis in normal as well as cancer cells. Even though several HDAC inhibitors have been characterized in vitro, only a limited number of these agents are in clinical trials. Various HDAC inhibitors differ in their toxicity profile when comparing the side effects described in the available clinical studies of HDAC inhibition in the treatment of cancer. These drugs may also affect normal hematopoiesis; hematologic toxicity is common to many drugs but stimulation of hematopoiesis seems to occur for others. HDAC inhibitors usually affect <10% of the genes in cancer cells. Divergent effects of HDAC inhibition on the global gene expression profiles have been described when testing various cancer cells, and this is further complicated by altered HDAC expression induced by HDAC inhibitors. However, increased p21 expression seems to be a common characteristic for most studies, suggesting an important role of this molecule during HDAC inhibitory treatment. Even though the initial studies are encouraging, additional in vitro and in vivo pharmacological characterization is definitely needed.


Priority strategies for India's family planning programme.
Strategies to accelerate progress of India's family planning programme are discussed and the importance of improving the quality and reach of services to address unmet contraceptive need by providing method choice is emphasized. Although there is a growing demand for both limiting and spacing births, female sterilisation, is the dominant method in the national programme and use of spacing methods remains very limited. Fertility decline has been slower in the empowered action group (EAG) states which contribute about 40 per cent of population growth to the country and also depict gloomy statistics for other socio-development indicators. It is, therefore, important to intensify efforts to reduce both fertility and mortality in these states. arationale has been provided for implementing integrated programmes using a gender lens because the lack of women's autonomy in reproductive decision-making, compounded by poor male involvement in sexual and reproductive health matters, is a fundamental issue yet to be addressed. The need for collaboration between scientists developing contraceptive technologies and those implementing family planning services is underscored. If contraceptive technologies are developed with an understanding of the contexts in which they will be delivered and an appreciation of end-users' needs and perspectives, they are more likely to be accepted by service providers and used by clients.


Bisphosphonates in breast cancer: clinical activity and implications of preclinical data.
Breast cancer is the most frequently diagnosed and second deadliest cancer among women. Bisphosphonates are stable pyrophosphate analogues used to treat skeletal-related events resulting from bone metastases. In the adjuvant setting, they have been shown to prevent aromatase inhibitor-associated and chemotherapy-induced bone loss. There is a growing body of evidence that bisphosphonates have direct and indirect anticancer activity in the preclinical and clinical settings. These include the inhibition of tumor growth; induction of apoptosis; synergism with chemotherapy; inhibition of tumor migration, invasion, and metastasis; reduction in disseminated tumor cells; inhibition of angiogenesis; stimulation of immune surveillance; and suppression of bone-derived growth factors. In addition to reducing the risk of breast cancer, bisphosphonate therapy has been shown to improve outcomes of early and metastatic breast cancer treatment. This review provides a brief overview of the current role of bisphosphonates in clinical practice and discusses their potential as anticancer agents.


Cortical inhibition on TMS-EEG: interstimulus interval effect on short-interval paired-pulse.
In mental disorders, paired-pulse (PP) transcranial magnetic stimulation and electroencephalography (TMS-EEG) recordings usage is increasing to directly evaluate the cortical inhibition of motor and nonmotor regions. One of the most common measures to assess the inhibition is the short-interval cortical inhibition (SICI), which depends on the interstimulus interval (ISI). This measure has been widely used in the motor cortex. However, the number of studies that evaluate other nonmotor regions, such as the dorsolateral prefrontal cortex (DLPFC), are increasing and there is still little knowledge on how the ISI affects those areas.In this pilot study, six subjects underwent a SICI protocol over the DLPFC using ISI values of 2 and 4ms with the aim of comparing them. TMS-EEG signals for both ISIs were characterized regarding the amplitude and latency of the TMS-evoked potentials (TEP) P60 and N100. Whereas the variation of cortical inhibition between ISIs is almost significant for N100, with higher inhibition for an ISI of 2ms, for TEP P60 the variation was not appreciable. Findings are in accordance with the ones in the state-of-the-art obtained in the motor cortex and suggest that a greater inhibition is likely to be produced with an ISI of 2ms.Clinical relevance- This pilot study indicates that cortical inhibition might be better assessed when DLPFC is stimulated with an ISI of 2ms in the SICI protocol.


Autologous stem cell transplantation and IgM amyloidosis.
High dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) is an accepted form of treatment for patients with AL amyloidosis. The purpose of the current study is to review the outcomes of IgM AL amyloidosis patients treated with high dose chemotherapy and autologous stem cell transplant and compare them to the outcomes of all AL amyloidosis subtypes treated similarly. We retrospectively reviewed the pretransplant characteristics, conditioning regimens and response to transplant of all twelve IgM AL amyloidosis patients who were transplanted at the Mayo Clinic between May 1999 and August 2005. Transplant related mortality was low at 8%. The overall hematologic response rate was 89%. The organ response rate was 67%. Overall median survival has not been reached as eleven patients are still alive. IgM AL amyloidosis patients appear to have similar outcomes after HDC and ASCT as other subtypes of AL amyloidosis suggesting that this therapy is an acceptable form of treatment for patients with IgM amyloidosis, and should be considered as a first line treatment option.


Qoala-T: A supervised-learning tool for quality control of FreeSurfer segmented MRI data.
Performing quality control to detect image artifacts and data-processing errors is crucial in structural magnetic resonance imaging, especially in developmental studies. Currently, many studies rely on visual inspection by trained raters for quality control. The subjectivity of these manual procedures lessens comparability between studies, and with growing study sizes quality control is increasingly time consuming. In addition, both inter-rater as well as intra-rater variability of manual quality control is high and may lead to inclusion of poor quality scans and exclusion of scans of usable quality. In the current study we present the Qoala-T tool, which is an easy and free to use supervised-learning model to reduce rater bias and misclassification in manual quality control procedures using FreeSurfer-processed scans. First, we manually rated quality of N = 784 FreeSurfer-processed T1-weighted scans acquired in three different waves in a longitudinal study. Different supervised-learning models were then compared to predict manual quality ratings using FreeSurfer segmented output data. Results show that the Qoala-T tool using random forests is able to predict scan quality with both high sensitivity and specificity (mean area under the curve (AUC) = 0.98). In addition, the Qoala-T tool was also able to adequately predict the quality of two novel unseen datasets (total N = 872). Finally, analyses of age effects showed that younger participants were more likely to have lower scan quality, underlining that scan quality might confound findings attributed to age effects. These outcomes indicate that this procedure could further help to reduce variability related to manual quality control, thereby benefiting the comparability of data quality between studies.


Distress among hospitalized patients with acute coronary syndrome.
Previous studies have demonstrated that those suffering from acute coronary syndrome (ACS) experience various physical and psychological symptoms. Few studies have investigated the multi-factorial, holistic, unpleasant experience of distress that includes physical, psychological, social, and spiritual factors among this patient population while still hospitalized. To describe the level of distress among patients hospitalized with ACS and its association with demographic and clinical factors and mortality. The study conducted a descriptive, cross-sectional survey. The Acute Coronary Syndrome Israel Study is a national, biennial registry, enrolling all patients with ACS admitted to cardiac intensive care or cardiology wards in Israel within a 2-month period. Demographic and clinical data were retrieved from an electronic database. Distress was measured by the Distress Thermometer. Nurses collected distress data directly from patients before discharge. Nine hundred ninety participants (50.6% response rate) were surveyed. Mean age was 62.8 (SD = 12.5). Mean distress level was 4.8 (SD = 3.45) out of 10. The most frequently reported area of distress was physical, followed by emotional. Practical and family problems were less frequent. Emotional distress was found to differ based on educational level, marital status, smoking history, and previous medical history. Distress did not predict 7- or 30-day mortality. Respondents with ACS were in moderate distress. It is recommended that those at increased risk receive increased monitoring of emotional distress while still in hospital. Further studies should investigate this holistic view of distress among the ACS population using a variety of methods and methodologies.


Is oral indomethacin effective in treatment of preterm infants with patent ductus arteriosus?
Twenty-one preterm infants (with a mean gestational age and birth weight of 29.3 weeks and 1288.6 g) and nine pretem infants (with a mean gestational age and birth weight of 29.6 weeks and 1153.1 g) were treated with an enteral preparation of indomethacin and with intravenous indomethacin, respectively, for the closure of hemodynamically significant ductus arteriosus. The patients received three doses of either oral indomethacin capsule (Endol, Deva, Turkey) or intravenous indomethacin (Confortid, Dumex GmBH, Germany) in a dose of 0.2 mg/kg at 12-hour intervals. The ductus was closed in 17 (81%) and 7 (77%) of the babies in the orally and intravenously treated groups, respectively (p > 0.05). There was no significant difference in blood urea nitrogen, creatinine levels or thrombocyte counts in either group before and after treatment with indomethacin (p > 0.05). No side effect was reported in the oral indomethacin group. Oral indomethacin may be an alternative to the intravenous preparation in developing countries if the intravenous form is not available or not affordable.


Genetic plasticity of the Shigella virulence plasmid is mediated by intra- and inter-molecular events between insertion sequences.
Acquisition of a single copy, large virulence plasmid, pINV, led to the emergence of Shigella spp. from Escherichia coli. The plasmid encodes a Type III secretion system (T3SS) on a 30 kb pathogenicity island (PAI), and is maintained in a bacterial population through a series of toxin:antitoxin (TA) systems which mediate post-segregational killing (PSK). The T3SS imposes a significant cost on the bacterium, and strains which have lost the plasmid and/or genes encoding the T3SS grow faster than wild-type strains in the laboratory, and fail to bind the indicator dye Congo Red (CR). Our aim was to define the molecular events in Shigella flexneri that cause loss of Type III secretion (T3S), and to examine whether TA systems exert positional effects on pINV. During growth at 37°C, we found that deletions of regions of the plasmid including the PAI lead to the emergence of CR-negative colonies; deletions occur through intra-molecular recombination events between insertion sequences (ISs) flanking the PAI. Furthermore, by repositioning MvpAT (which belongs to the VapBC family of TA systems) near the PAI, we demonstrate that the location of this TA system alters the rearrangements that lead to loss of T3S, indicating that MvpAT acts both globally (by reducing loss of pINV through PSK) as well as locally (by preventing loss of adjacent sequences). During growth at environmental temperatures, we show for the first time that pINV spontaneously integrates into different sites in the chromosome, and this is mediated by inter-molecular events involving IS1294. Integration leads to reduced PAI gene expression and impaired secretion through the T3SS, while excision of pINV from the chromosome restores T3SS function. Therefore, pINV integration provides a reversible mechanism for Shigella to circumvent the metabolic burden imposed by pINV. Intra- and inter-molecular events between ISs, which are abundant in Shigella spp., mediate plasticity of S. flexneri pINV.


[Magnetic resonance imaging (MRI) of the bursa around the knee joint].
Since fluid filled bursae lead to visible structures on MR images it is important to establish criteria to recognize them and to differentiate them from tumorous fluid-like structures. With this study the bursae around the knee joint were analyzed for potential differential diagnostic criteria such as localisation, size and shape. In a retrospective study of 133 MR exams the frequency, localization and morphology were registered. The frequency of occurrence was correlated with the frequency of an effusion by means of the chi 2 test. The most frequently recognized bursae were bursa subtendinea musculi gastrocnemii medialis (54.9%), bursa musculi semimembranosi (21%), and bursa infrapatellaris profunda (18.8%). 8 different bursae were identified in complete. Size roanged from 2 to 18 mm. The shape was round and ovoid. The bursa subtendinea musculi gastrocnemii medialis and bursa musculi semimembranosi correlated with the occureance of an effusion. Bursae around the knee are frequently visualized as asymptomatic fluid like structures. Knowledge of the typical localization, size and contour is important for identification and differentiation diagnosis against ganglia, cysts or joint recesses.


Hyperuricemia and coronary heart disease: a systematic review and meta-analysis.
The role of serum uric acid as an independent risk factor for cardiovascular disease remains unclear, although hyperuricemia is associated with cardiovascular disease such as coronary heart disease (CHD), stroke, and hypertension. A systematic review and meta-analysis using a random-effects model was conducted to determine the risk of CHD associated with hyperuricemia in adults. Studies of hyperuricemia and CHD were identified by searching major electronic databases using the medical subject headings and keywords without language restriction (through February 2009). Only prospective cohort studies were included if they had data on CHD incidences or mortalities related to serum uric acid levels in adults. Twenty-six eligible studies of 402,997 adults were identified. Hyperuricemia was associated with an increased risk of CHD incidence (unadjusted risk ratio [RR] 1.34, 95% confidence interval [95% CI] 1.19-1.49) and mortality (unadjusted RR 1.46, 95% CI 1.20-1.73). When adjusted for potential confounding, the pooled RR was 1.09 (95% CI 1.03-1.16) for CHD incidence and 1.16 (95% CI 1.01-1.30) for CHD mortality. For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR for CHD mortality was 1.12 (95% CI 1.05-1.19). Subgroup analyses showed no significant association between hyperuricemia and CHD incidence/mortality in men, but an increased risk for CHD mortality in women (RR 1.67, 95% CI 1.30-2.04). Hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors. A more pronounced increased risk for CHD mortality in women should be investigated in future research.


MedSpanish: a language tool for the emergency department.
Language barriers frequently impede the ability of the health care professional to provide the highest quality health care to his or her patients. Spanish speaking people are rapidly becoming the largest minority population in the United States. In order to facilitate access to appropriate medical care that would not be inhibited by miscommunication or lack of a trained translator, the MedSpanish Web Site was developed for use in the Emergency Department. The site contains common Spanish vocabularies, including translations and audio clips, that would be used in such a setting. The various sections are formatted so that they could easily become pocket cards rather than relying on the availability of a computer in a medical emergency. While MedSpanish is not designed to replace a trained translator, it does offer an effective alternative if such translations services are not available.


The molecular structure of TE146 and its derivatives in Drosophila melanogaster.
TE146 is a giant transposon of Drosophila melanogaster. It carries two copies of the white and roughest genes, normally found on the X chromosome. The structure of this transposon has been studied at the molecular level. TE146 may transpose to new chromosome positions, excise and be lost from the genome or undergo internal rearrangements. The termini of TE146 are foldback DNA elements (FB); the transposon also carries two internal FB elements. Loss or internal rearrangement of TE146 involves recombination between different FB elements. These events have been mapped molecularly, by taking advantage of the fact that the FB sequences are composed largely of a regular 155-bp repeat sequence that is cut by the restriction enzyme TaqI, and are shown to be nonrandom. We suggest that these FB-FB exchange events occur by mitotic sister-chromatid exchange in the premeiotic germ line.


Chimpanzee bipedalism: cineradiographic analysis and implications for the evolution of gait.
Bipedal chimpanzees reorient the pelvis to achieve an upright posture but retain the same pattern of femoral flexion and extension as in quadrupedal walking. Major differences from human gait are the abducted, relatively more flexed excursion of the femur and the timing of pelvic tilt, which raises during the swing phase. The femoral head morphology in the fossil hominid Australopithecus robustus is evidence of an approximately vertical excursion of the femur in contrast to the adducted pattern of modern man and the abducted pattern of chimpanzees.


Alisertib induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt/mTOR- and p38 MAPK-mediated pathways in human glioblastoma cells.
Glioblastoma (GBM) is the most common brain tumor with poor response to current therapeutics. Alisertib (ALS), a second-generation selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects on solid tumors in animal studies. This study aimed to investigate the killing effect of ALS on GBM cell line DAOY and the possible underlying mechanisms using both bioinformatic and cell-based approaches. Our molecular docking showed that ALS preferentially bound AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS also bound key regulating proteins of cell cycle, apoptosis and autophagy, such as cyclin-dependent kinase 1 (CDK1/CDC2), CDK2, cyclin B1, p27 Kip1, p53, cytochrome C, cleaved caspase 3, Bax, Bcl-2, Bcl-xl, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 5'-adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (MAPK), beclin 1, phosphatase and tensin homolog (PTEN), and microtubule-associated protein light chain 3 (LC3). ALS exhibited potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects on DAOY cells in a concentration-dependent manner. Notably, ALS remarkably induced G2/M arrest mainlyvia regulating the expression of CDK1/CDC2, CDK2, cyclin B1, p27 Kip1, and p53 in DAOY cells. ALS significantly induced the expression of mitochondria-mediated pro-apoptotic proteins such as Baxbut inhibited the expression of anti-apoptotic proteins such as Bcl-2 and Bcl-xl, with a significant increase in the release of cytochrome C and the activation of caspases 3 and 9. ALS also induced PI3K/Akt/mTOR and p38 MAPK signaling pathways while activating the AMPK signaling pathway. Taken together, these findings indicate that ALS exerts a potent inhibitory effect on cell proliferation and induces mitochondria-dependent apoptosis and autophagy with the involvement of PI3K/Akt/mTOR- and p38 MAPK-mediated signaling pathways in DAOY cells. ALS is a promising anticancer agent for GBM treatment.


Molecular defect-containing bilayer graphene exhibiting brightened luminescence.
The electronic structure of bilayer graphene can be altered by creating defects in its carbon skeleton. However, the natural defects are generally heterogeneous. On the other hand, rational bottom-up synthesis offers the possibility of building well-defined molecular cutout of defect-containing bilayer graphene, which allows defect-induced modulation with atomic precision. Here, we report the construction of a molecular defect-containing bilayer graphene (MDBG) with an inner cavity by organic synthesis. Single-crystal x-ray diffraction, mass spectrometry, and nuclear magnetic resonance spectroscopy unambiguously characterize the structure of MDBG. Compared with its same-sized, defect-free counterpart, the MDBG exhibits a notable blue shift of optical absorption and emission, as well as a 9.6-fold brightening of its photoluminescence, which demonstrates that a single defect can markedly alter the optical properties of bilayer graphene.


Two-phase synthesis of shape-controlled colloidal zirconia nanocrystals and their characterization.
We have developed a two-phase approach for the synthesis of shape-controlled colloidal zirconia nanocrystals, including spherical-, teardrop-, rod-, and rice grain-shaped particles. We found that the key factors for controlling the shape were the reaction time, the nature of the capping agent, and the monomer concentration. We have analyzed the morphologies, crystallinity, optical properties, and structural features of the as-prepared ZrO2 nanoparticles by using transmission electron microscopy (TEM), high-resolution TEM, X-ray powder diffraction, and UV-vis absorption and fluorescence spectroscopy. The possible nucleation and growth process is also discussed.


Discussion: DMARDs and biologic therapies in the management of inflammatory joint diseases.
Therapy for inflammatory joint diseases, such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, includes various conventional disease-modifying antirheumatic drugs (DMARDs). These therapeutic agents are termed DMARDs because they have the potential to reduce or prevent joint damage and preserve joint integrity and function. Conventional DMARDs are used as monotherapy or in combination and include methotrexate, leflunomide, azathioprine, ciclosporin, hydroxychloroquine, sulfasalazine, gold and minocycline. Biologic response modifiers, which are based on proteins made by living cells, are newer agents available for the treatment of various inflammatory joint diseases. Biologic therapies now approved for use in inflammatory joint diseases are TNF inhibitors, T-cell modulators and B-cell depleters. They have all been shown to have clinical efficacy and are able to retard structural damage. However, all current immune-modulating therapies also have potential side effects, and the decision to use a particular agent for treatment should be based on a thorough discussion of the benefits and risks with the patient. Newer biologic response modifiers and other immunologic therapies are currently being developed for the treatment of inflammatory joint diseases and are discussed in this review.


Use of 'Omic' technologies to study humans exposed to benzene.
'Omic' technologies include genomics, transcriptomics (gene expression profiling), proteomics and metabolomics. We are utilizing these new technologies in an effort to develop novel biomarkers of exposure, susceptibility and response to benzene. Advances in genomics allow one to study hundreds to thousands of single nucleotide polymorphisms simultaneously on small quantities of DNA using array-based technologies. We are currently utilizing these technologies to examine genetic variation in pathways relating to biotransformation, DNA repair, folate metabolism and immune response with the goal of finding biomarkers of susceptibility to benzene hematotoxicity. Transcriptomics is used to measure the full complement of activated genes, mRNAs or transcripts in a particular tissue at a particular time typically using microarray technology. We have applied microarrays to the study of global gene expression in the peripheral blood cells of benzene-exposed workers. More than 100 genes were identified as being potentially differentially expressed, with genes related to apoptosis and immune function being the most significantly affected. Initial studies employing proteomics have also shown that several proteins are altered in the serum of exposed compared to control subjects and these proteins are potential biomarkers of benzene exposure. Omic technologies therefore have significant potential in generating novel biomarkers of exposure, susceptibility and response to benzene.


Clonality and micro-diversity of a nationwide spreading genotype of Mycobacterium tuberculosis in Japan.
Mycobacterium tuberculosis transmission routes can be estimated from genotypic analysis of clinical isolates from patients. In Japan, still a middle-incidence country of TB, a unique genotype strain designated as 'M-strain' has been isolated nationwide recently. To ascertain the history of the wide spread of the strain, 10 clinical isolates from different areas were subjected to genome-wide analysis based on deep sequencers. Results show that all isolates possessed common mutations to those of referential strains. The greatest number of accumulated single nucleotide variants (SNVs) from the oldest coalescence was 13 nucleotides, indicating high clonality of these isolates. When an SNV common to the isolates was used as a surrogate marker of the clone, authentic clonal isolates with variation in a reliable subset of variable number of tandem repeat (VNTR) genotyping method can be selected successfully from clinical isolates populations of M. tuberculosis. When the authentic clones can also be assigned to sub-clonal groups by SNVs derived from the genomic comparison, they are classifiable into three sub-clonal groups with a bias of geographical origins. Feedback from genomic analysis of clinical isolates of M. tuberculosis to genotypic markers will be an efficient strategy for the big data in various settings for public health actions against TB.


Structural and optical properties of disc-in-wire InGaN/GaN LEDs.
This study examines the role of the microstructure and optical properties of InGaN/GaN nanowire LED structures on Si(111) having different nanowire coverages. Cathodoluminescence (CL) measurements show that all samples exhibit broad emission around the intended energy, 1.95 eV (635 nm). While the absolute emission intensity is hard to compare for CL measurement, the bandgap emission (∼3.4 eV) coming from the GaN root is more pronounced as coverage of nanowires decreases, which has less coalescence formation. The width of the emission peak is likely due to variations in the morphology of the InGaN discs within the wires, as faceted layers with different thicknesses and quantum dots are observed by transmission electron microscopy. Nonepitaxial six-fold symmetric lateral branching, called "nanocrowns," emanate from stacking faults within the active regions. These features likely reduce optical emission as a result of grain boundaries between the nanocrown and nanowire.


[Differential diagnosis of pancreatic head cancer].
The results of clinical, instrumental and laboratory examinations were analyzed for 99 patients. 59 of them had pancreatic head cancer, 40--chronic pseudotumorous pancreatitis. The importance of complex ultrasonic diagnosis in detection of pancreatic diseases (98%), in true diagnosis of unresectable tumors (96.7%), and also in determination of bile ducts lesion level in obstructive jaundice is shown. It was revealed that spiral computed tomography (SCT) had an advantage over computed tomography in diagnosis of pancreatic tumors and in assessment of their resectability. Sensitivity of combined use of US, SCT and tumor marker CA 19-9 in pancreatic cancer diagnosis increases to 95.2%. High diagnostic value of laparoscopy with laparoscopic ultrasonic examination as a method of final assessment of tumor resectability is shown.


The proliferative activity of carcinomas of the cervix after radiation therapy.
The findings obtained so far from 15 patients with advanced non-keratinizing squamous cell carcinoma of the cervix uteri show a growing fall in 3H-thymidine incorporation at different intervals during radiation therapy under the application of 2,000 to 5,000 rad. The radiogenic reduction of S-phase nuclei occurs at lower radiation doses than do changes in the histopathological structure; this reduction is however ambiguous, since it is no more than just a rough indication of the decreasing proliferative intensity.


Evaluating Accelerometry Thresholds for Detecting Changes in Levels of Moderate Physical Activity and Resulting Major Mobility Disability.
An important decision with accelerometry is the threshold in counts per minute (CPM) used to define moderate to vigorous physical activity (MVPA). We explore the ability of different thresholds to track changes in MVPA due to a physical activity (PA) intervention among older adults with compromised function: 760 CPM, 1,041 CPM, and an individualized threshold. We also evaluate the ability of change in accelerometry and self-reported PA to attenuate treatment effects on major mobility disability (MMD). Data from a week of hip worn accelerometers and self-reported PA data (30-day recall) were examined from baseline, 6-, 12-, and 24-months of follow-up on 1,528 older adults. Participants were randomized to either PA or Health Education (HE). MMD was objectively defined by loss of ability to walk 400 m during the follow-up. The three thresholds yielded similar and higher levels of MVPA for PA than HE (p < .001), however, this difference was significantly attenuated in participants with lower levels of physical function. Self-reported PA that captured both walking and strength training totally attenuated the intervention effect for MMD, an 18% reduction to a 3% increase. Accelerometer CPMs showed less attenuation of the intervention effect. Accelerometry assessment within the LIFE study was not sensitive to change in level in physical activity for older adults with very low levels of physical function. A combination of self-report and objective measures are recommended for use in physical activity intervention studies of the elderly; limitations of accelerometry deserve closer attention.


The pediatric Internet.
The Internet is a set of rules for computer communications that has created easy access to electronic mail, electronic mailing lists, and the World Wide Web. The "pediatric Internet" consists of a growing collection of Internet resources that deal specifically with the health care of the young. Locating this information, judging its quality, and determining its appropriate use presents difficulties, but the ubiquity of the Internet makes it imperative for child health professionals to learn the skills necessary to access and provide information via this medium. The Internet will be used increasingly for scientific publishing, the original purpose of the World Wide Web. This article presents basic definitions for the Internet, some characteristics of the pediatric Internet, guidance on how to locate information, and what the future of the pediatric Internet holds.


OGEE: an online gene essentiality database.
OGEE is an Online GEne Essentiality database. Its main purpose is to enhance our understanding of the essentiality of genes. This is achieved by collecting not only experimentally tested essential and non-essential genes, but also associated gene features such as expression profiles, duplication status, conservation across species, evolutionary origins and involvement in embryonic development. We focus on large-scale experiments and complement our data with text-mining results. Genes are organized into data sets according to their sources. Genes with variable essentiality status across data sets are tagged as conditionally essential, highlighting the complex interplay between gene functions and environments. Linked tools allow the user to compare gene essentiality among different gene groups, or compare features of essential genes to non-essential genes, and visualize the results. OGEE is freely available at http://ogeedb.embl.de.


Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. (ClinicalTrials.gov number, NCT00329628.)


Tomotherapeutic portal imaging for radiation treatment verification.
In their tomotherapy concept Mackie and co-workers proposed not only a new technique for IMRT but also an appropriate and satisfactory method of treatment verification. This method allows both monitoring of the portal dose distribution and imaging of the patient anatomy during treatment by means of online CT. This would enable the detection of inaccuracies in dose delivery and patient set-up errors. In this paper results are presented showing that a single electronic portal imaging device (EPID) could deliver all data necessary to establish such a complete verification system for tomotherapy and even other IMRT techniques. Consequently it has to be shown that it is able to record both the low-intensity photon fluences encountered in tomographic imaging and the intense photon transmission of each treatment field. The detector under investigation is a video-based EPID, the BIS 710 (manufactured by Wellhöfer Dosimetrie, Schwarzenbruck, Germany). To examine the suitability of the BIS for CT at 6 MV beam quality, different phantoms were scanned and reconstructed. The agreement between a diamond detector and BIS responses is quantitative. Tomographic reconstruction of a complete set of these transmission profiles resulted in images which resolve 3 cm large objects having a (theoretical) contrast to water of less than 9%. Three millimetre objects with a 100% contrast are clearly visible. The BIS signal was shown to measure photon fluence distributions. The reconstructed images possess a spatial and contrast resolution sufficient for accurate imaging of the patient anatomy, needed for treatment verification in many clinical cases.


Transformation of Actinobacillus actinomycetemcomitans by electroporation, utilizing constructed shuttle plasmids.
Actinobacillus actinomycetemcomitans, a periodontal pathogen, has been strongly implicated in human periodontal disease. Advances in the molecular analysis of A. actinomycetemcomitans virulence factors have been limited due to the unavailability of systems for genetic transfer, transposon mutagenesis, and gene complementation. Slow progress can be traced almost exclusively to the lack of gene vector systems and methods for the introduction of DNA into A. actinomycetemcomitans. An electrotransformation system that allowed at least five strains of A. actinomycetemcomitans to be transformed with stable shuttle plasmids which efficiently replicated in both Escherichia coli and A. actinomycetemcomitans was developed. One plasmid, a potential shuttle vector designated pDL282, is 5.7 kb in size, has several unique restriction enzyme sites, and codes for resistance to spectinomycin and ampicillin. E. coli and A. actinomycetemcomitans were transformed with equal efficiencies of approximately 10(5) transformants per micrograms of DNA. Similar transformation efficiencies were obtained whether the plasmid DNA was isolated from A. actinomycetemcomitans or E. coli. In addition, frozen competent cells of A. actinomycetemcomitans yielded comparable efficiencies of transformation. Restriction enzyme analysis of pDL282 isolated after transformation confirmed the presence of intact donor plasmids. A plasmid isolated from A. pleuropneumoniae was also capable of transforming some isolates of A. actinomycetemcomitans, although generally at a lower frequency. The availability of these shuttle plasmids and an efficient transformation procedure should significantly facilitate the molecular analysis of virulence factors of A. actinomycetemcomitans.


Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours.
Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y-DOTA]-TOC or [(177)Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(90)Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [(177)Lu-DOTA]-TOC over [(90)Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [(177)Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). The present results revealed no difference in median overall survival after [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.


The relationship of natural killer cell counts, perforin mRNA and CD2 expression to post-exercise natural killer cell activity in humans.
The aim of this study was to further investigate the mechanism of suppression of natural killer (NK) cell cytotoxic activity in peripheral blood following strenuous exercise. Blood was collected for analysis of NK cell concentration, cytotoxic activity, CD2 surface expression and perforin gene expression from runners (RUN, n=6) and resting controls (CONTROL, n=4) pre-exercise, 0, 1.5, 5, and 24 h following a 60-min treadmill run at 80% of VO2 peak. Natural killer cytotoxic activity, measured using a whole blood chromium release assay, fluctuated minimally in the CONTROL group and increased by 63% and decreased by 43% 0 and 1.5 h post-exercise, respectively, in the RUN group (group x time, P < 0.001). Lytic index (cytotoxic activity per cell) did not change. Perforin mRNA, measured using quantitative real-time polymerase chain reaction (QRT-PCR) decreased from pre- to post-exercise and remained decreased through 24 h. The decrease from pre- to 0 h post-exercise was seen predominately in the RUN group and was inversely correlated (r=- 0.95) to pre-exercise perforin mRNA. The NK cell surface expression of CD2 (lymphocyte function-associated antigen-2) was determined using fluorescent antibodies and flow cytometry. There was no change in the proportion of NK cells expressing CD2 or CD2 density. We conclude that (1) numerical redistribution accounted for most of the change in NK cytotoxic activity following a strenuous run, (2) decrease in perforin gene expression during the run was inversely related to pre-exercise levels but did not parallel changes in cytotoxic activity, and (3) CD2 surface expression was not affected by exercise.


Placentation in the Amazonian manatee (Trichechus inunguis).
Evidence from several sources supports a close phylogenetic relationship between elephants and sirenians. To explore whether this was reflected in similar placentation, we examined eight delivered placentae from the Amazonian manatee using light microscopy and immunohistochemistry. In addition, the fetal placental circulation was described by scanning electron microscopy of vessel casts. The manatee placenta was zonary and endotheliochorial, like that of the elephant. The interhaemal barrier comprised maternal endothelium, cytotrophoblasts and fetal endothelium. We found columnar trophoblast beneath the chorionic plate and lining lacunae in this region, but there was no trace in the term placenta of haemophagous activity. The gross anatomy of the cord and fetal membranes was consistent with previous descriptions and included a four-chambered allantoic sac, as also found in the elephant and other afrotherians. Connective tissue septae descended from the chorionic plate and carried blood vessels to the labyrinth, where they gave rise to a dense capillary network. This appeared to drain into shorter vessels near the chorionic plate. The maternal vasculature could not be examined in the same detail, but maternal capillaries ran rather straight and roughly parallel to the fetal ones. Overall, there is a close resemblance in placentation between the manatee and the elephant.


Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression.
Quantitation of huntingtin protein in the brain is needed, both as a marker of Huntington disease (HD) progression and for use in clinical gene silencing trials. Measurement of huntingtin in cerebrospinal fluid could be a biomarker of brain huntingtin, but traditional protein quantitation methods have failed to detect huntingtin in cerebrospinal fluid. Using micro-bead based immunoprecipitation and flow cytometry (IP-FCM), we have developed a highly sensitive mutant huntingtin detection assay. The sensitivity of huntingtin IP-FCM enables accurate detection of mutant huntingtin protein in the cerebrospinal fluid of HD patients and model mice, demonstrating that mutant huntingtin levels in cerebrospinal fluid reflect brain levels, increasing with disease stage and decreasing following brain huntingtin suppression. This technique has potential applications as a research tool and as a clinical biomarker.


Distinct mouse models of Stargardt disease display differences in pharmacological targeting of ceramides and inflammatory responses.
Mutations in many visual cycle enzymes in photoreceptors and retinal pigment epithelium (RPE) cells can lead to the chronic accumulation of toxic retinoid byproducts, which poison photoreceptors and the underlying RPE if left unchecked. Without a functional ATP-binding cassette, sub-family A, member 4 (ABCA4), there is an elevation of all-trans-retinal and prolonged buildup of all-trans-retinal adducts, resulting in a retinal degenerative disease known as Stargardt-1 disease. Even in this monogenic disorder, there is significant heterogeneity in the time to onset of symptoms among patients. Using a combination of molecular techniques, we studied Abca4 knockout (simulating human noncoding disease variants) and Abca4 knock-in mice (simulating human misfolded, catalytically inactive protein variants), which serve as models for Stargardt-1 disease. We compared the two strains to ascertain whether they exhibit differential responses to agents that affect cytokine signaling and/or ceramide metabolism, as alterations in either of these pathways can exacerbate retinal degenerative phenotypes. We found different degrees of responsiveness to maraviroc, a known immunomodulatory CCR5 antagonist, and to the ceramide-lowering agent AdipoRon, an agonist of the ADIPOR1 and ADIPOR2 receptors. The two strains also display different degrees of transcriptional deviation from matched WT controls. Our phenotypic comparison of the two distinct Abca4 mutant-mouse models sheds light on potential therapeutic avenues previously unexplored in the treatment of Stargardt disease and provides a surrogate assay for assessing the effectiveness for genome editing.


Evaluation of a human monocytic cell line THP-1 model for assay of the intracellular activities of antimicrobial agents against Legionella pneumophila.
We examined the intracellular activities of 11 antimicrobial agents against Legionella pneumophila using a human monocyte-derived cell line, THP-1. Colony counting and microscopic examination of L. pneumophila co-incubated with THP-1 cells (5 x 105 cells/well) were performed. Both extra- and intra-cellular multiplication of L. pneumophila were observed and were dependent on the inoculum of L. pneumophila in the culture; L. pneumophila did not grow in the cell culture medium alone. Light microscopic examination confirmed that extracellular L. pneumophila originated from THP-1 cells disrupted by bacterial multiplication. L. pneumophila multiplied by 3-4 logs after 24 h incubation with THP-1 cells and their number remained stable at 106-107 cfu/mL until 72 h. The results of viability studies using four antimicrobial agents-ciprofloxacin, erythromycin, minocycline and rifampicin-demonstrated that our system was suitable for the intracellular activity assay. We used a concept of 'minimum extracellular concentration inhibiting intracellular multiplication' (MIEC) to evaluate the intracellular activity of antimicrobial agents. The MIECs of three beta-lactams were markedly higher than their conventional MICs while those of macrolides, quinolones, rifampicin and minocycline were similar to their MICs. Our results suggest that evaluation of the clinical efficacy of drugs against L. pneumophila should include determination of their intracellular activity against the bacteria, which could be measured using our assay system in THP-1 cells.


Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer.
Several G protein-coupled receptors have been shown to exist as homo-and hetero-oligomeric complexes in living cells. However, the link between ligand-induced receptor activation and its oligomerization state as well as the proportion of the total receptor population that can engage in oligomeric complexes remain open questions. Here, the closely related human MT1 and MT2 melatonin receptors (MT1R, MT2R) were used to address these issues. Bioluminescence resonance energy transfer (BRET) experiments in living HEK 293 cells revealed that these receptors form homo- and hetero-oligomers. Constitutive energy transfer was observed for all receptor combinations at physiological expression levels and could be detected in single cell BRET experiments. Inhibition of the energy transfer by dilution of the BRET partners identified MT1R and MT2R dimers as the predominant receptor species, and this oligomerization state did not change upon agonist and antagonist binding. Agonists, neutral antagonists, and inverse agonists all promoted increases in BRET values for MT2R but not for MT1R homodimers in living cells and isolated plasma membranes. This indicates that no correlation could be inferred between the receptor activation state and the dimerization state of the receptor. This also suggests that ligand-promoted BRET increases represent specific ligand-induced conformational changes of pre-existing dimers rather then increased dimerization. The observation that ligands favored the energy transfer within the hetero-oligomer from MT1R to MT2R but not in the reverse orientation, from MT2R to MT1R, supports this view.


Tolerance in intestinal inflammation and cancer.
In the human body, mucosal surfaces of the intestinal tract are the largest and one of the most complex parts of the immune system. These surfaces are covered by a layer of epithelial cells which allows efficient absorption of nutrients but also serves to separate the intestine from an environment loaded with potential harmful agents. Discrimination between beneficial commensal bacteria, harmless antigens and pathogenic microorganisms is a central issue in the role that gut immune cells play in maintaining the balance between immune response and tolerance. However, the basis of this discrimination in the mucosal immune system, where this occurs and how it can affect both local and systemic responses is not yet well understood. Nevertheless, antigen uptake and presentation seems to be a crucial factor in this issue. In this review, we will discuss the key role of immune intestinal cells in the development of mucosal immunity, tolerance and disease.


Bronchospasm and its biophysical basis in airway smooth muscle.
Airways hyperresponsiveness is a cardinal feature of asthma but remains unexplained. In asthma, the airway smooth muscle cell is the key end-effector of bronchospasm and acute airway narrowing, but in just the past five years our understanding of the relationship of responsiveness to muscle biophysics has dramatically changed. It has become well established, for example, that muscle length is equilibrated dynamically rather than statically, and that non-classical features of muscle biophysics come to the forefront, including unanticipated interactions between the muscle and its time-varying load, as well as the ability of the muscle cell to adapt rapidly to changes in its dynamic microenvironment. These newly discovered phenomena have been described empirically, but a mechanistic basis to explain them is only beginning to emerge.


Optimum wavelength combinations for retinal vessel oximetry.
Several investigators have demonstrated techniques for noninvasive measurement of the oxygen saturation of blood in retinal arteries and veins. These techniques have been based on measuring the optical density of a retinal vessel at multiple wavelengths and on calculating the oxygen saturation on the basis of the known absorption coefficients of hemoglobin and oxyhemoglobin. A technique is presented for determining the optimum wavelengths for retinal oximetry measurements. What is believed to be a novel wavelength combination of 488, 635, and 905 nm is found to provide excellent oxygen sensitivity across a broad range of typical vessel diameters and saturations. The use of this wavelength combination should allow for the most accurate retinal saturation measurements made to date.


Statistical approach for avoiding pseudoreplication and increasing power in wound-healing studies.
Many animal wound-healing models measure the progression of healing over time, resulting in counts of fully healed wounds from different treatments at several time points. Data from these models are usually analyzed using contingency table methods. However, pooling data from multiple animals without appropriate correction for animal-to-animal variability results in pseudoreplication. Kaiser and colleagues, overcame pseudoreplication by adjusting the estimate of healing variation to account for the interanimal covariance. This solution nevertheless is limited by the ability to accurately estimate the adjustment factor due to the small number of animals used. An improved method is described that both overcomes pseudoreplication and increases power. It involves estimating the time for half of the wounds within each animal to be completely healed (TCH(50)), rather than a pooled estimate for all animals (HT(50)). Subsequent ANOVA testing of the individual TCH(50) values, using a model with fixed treatments and random animals, generates unbiased estimates of treatment means and differences between means, and accurate p-values for these differences and for the overall model. This method has sufficient power to detect treatment differences with fewer animals. Furthermore, it is fully applicable to analyses of results from human trials having similar data organization.


Voice outcomes following the gray minithyrotomy.
Most practitioners have limited treatment options for vocal fold scar and sulcus vocalis. The Gray minithyrotomy (GMT) is a surgical procedure for the treatment of these conditions, although limited objective data exist regarding voice outcomes. This study compares the quantified subjective and visual perceptual outcomes following GMT for the treatment of vocal fold scar and sulcus vocalis. We performed a retrospective review of patients who underwent GMT in a single institution. Patient-reported satisfaction, Voice Handicap Index-10 scores, results of video perceptual analysis, and complications were recorded. Sixteen patients underwent GMT for phonotraumatic or postoperative scar (11), radiation-induced scar (3), or sulcus vocalis (2). Seven underwent bilateral operations. Follow-up data were available for 12 patients. Eight patients had 2 or more failed surgical interventions before GMT. Seven of the 13 procedures resulted in a self-reported improvement. Although the mean preoperative Voice Handicap Index-10 score (30.6) across all patients did not decrease after the operation, 6 of the 13 GMT procedures resulted in improvement (mean decrease, 7.5). Complications, encountered in 5 patients, included ecchymosis, neck abscess, tongue numbness, wound dehiscence, and aspiration pneumonia. The GMT is a viable treatment for severe vocal fold scar and sulcus vocalis. Our results show improvement in half of a cohort that was marked by previous failures at improving voice. These results point to the recalcitrant nature of voice difficulties in treating vocal fold scar and sulcus, and may properly guide clinicians and patients in their expectations following this infrequently used technique.


Serological detection of phage infection in Chlamydia psittaci recovered from ducks.
Antiserum prepared against a phage which infects a Chlamydia psittaci isolate recovered from domestic ducks was used to screen other recent avian C psittaci isolates by indirect immunofluorescence. Two more phage infected strains from ducks were discovered. However, phage was not detected in every isolate examined from common source ducks, although such birds are likely to be infected with the same C psittaci strain. Moreover, phage could not always be demonstrated by indirect immunofluorescence in McCoy cell monolayers infected with the phage-containing strain. The results suggest that phage infection is probably an integral part of duck chlamydiosis in the United Kingdom at present, but that the infection is often cryptic.


Loss of sleep spindle frequency deceleration in Obstructive Sleep Apnea.
Sleep spindles have been suggested as surrogates of thalamo-cortical activity. Internal frequency modulation within a spindle's time frame has been demonstrated in healthy subjects, showing that spindles tend to decelerate their frequency before termination. We investigated internal frequency modulation of slow and fast spindles according to Obstructive Sleep Apnea (OSA) severity and brain topography. Seven non-OSA subjects and 21 patients with OSA contributed with 30min of Non-REM sleep stage 2, subjected to a Matching pursuit procedure with Gabor chirplet functions for automatic detection of sleep spindles and quantification of sleep spindle internal frequency modulation (chirp rate). Moderate OSA patients showed an inferior percentage of slow spindles with deceleration when compared to Mild and Non-OSA groups in frontal and parietal regions. In parietal regions, the percentage of slow spindles with deceleration was negatively correlated with global apnea-hypopnea index (rs=-0.519, p=0.005). Loss of physiological sleep spindle deceleration may either represent a disruption of thalamo-cortical loops generating spindle oscillations or some compensatory mechanism, an interesting venue for future research in the context of cognitive dysfunction in OSA. Quantification of internal frequency modulation (chirp rate) is proposed as a promising approach to advance description of sleep spindle dynamics in brain pathology.


Measuring rat kidney glomerular number and size in vivo with MRI.
number is highly variable in humans and is thought to play an important role in renal health. Chronic kidney disease (CKD) is the result of too few nephrons to maintain homeostasis. Currently, nephron number can only be determined invasively or as a terminal assessment. Due to a lack of tools to measure and track nephron number in the living, the early stages of CKD often go unrecognized, preventing early intervention that might halt the progression of CKD. In this work, we present a technique to directly measure glomerular number ( Nglom) and volume in vivo in the rat kidney ( n = 8) using MRI enhanced with the novel contrast agent cationized ferritin (CFE-MRI). Adult male rats were administered intravenous cationized ferritin (CF) and imaged in vivo with MRI. Glomerular number was measured and each glomerulus was spatially mapped in 3D in the image. Mean apparent glomerular volume (a Vglom) and intrarenal distribution of the individual glomerular volume (IGV), were also measured. These metrics were compared between images of the same kidneys scanned in vivo and ex vivo with CFE-MRI. In vivo Nglom and a Vglom correlated to ex vivo metrics within the same kidneys and were within 10% of Nglom and a Vglom previously validated by stereologic methods. This is the first report of direct in vivo measurements of Nglom and a Vglom, introducing an opportunity to investigate mechanisms of renal disease progression and therapeutic response over time.


Metabolic fate of an oral tracer dose of [13C]docosahexaenoic acid triglycerides in the rat.
The appearance of 13C in rat lipoprotein, blood cells, and brain lipids was followed as a function of time after the ingestion of triglycerides (TG) containing [13C]22:6n-3. The time course of 13C abundance in 22:6n-3 of various lipid pools, measured by gas chromatography combustion-isotope mass spectrometry, established precursor-product relationships within lipids. The [13C]22:6n-3 was rapidly incorporated into very low density lipoprotein-chylomicron-TG and unesterified fatty acids bound to albumin, with a concomitant maximal appearance at 3 h and further decline. Lysophosphatidylcholines (lysoPC) bound to albumin were also enriched in [13C]22:6n-3, and their labeling appeared to be mainly due to hepatic secretion at the earliest time points. From 12 h postingestion, the synthesis of [13C]22:6n-3-lysoPC was twice as high as that of unesterified [13C]22:6n-3, making lysoPC a potential source of 22:6n-3 supply for tissues. The labeling of platelets, red blood cells, and brain phospholipids presented different kinetics, presumably involving the two lipid forms of [13C]22:6n-3 bound to albumin, to different extents. We conclude that [13C]22:6n-3 esterified in TG is rapidly redistributed within blood lipoproteins and the albumin fraction and that its incorporation in lipid species bound to albumin influences its uptake by target tissues.


Administrative expenses under OASDI.
Costs of administering old-age, survivors, and disability insurance (OASDI) are of interest both to specialists in income maintenance and to the general public. This article presents a summary of these expenses compared with several important bases: Contribution income, benefit payments, and taxable payroll. An index is developed and used to analyze changes in administrative expense levels from 1960 through 1979. Over the long run, the cost of operate OASDI per unit of work has increased more slowly than for service industries in general, a trend that should continue in the old-age and survivors insurance program (OASI). Although implementing the 1980 Disability Amendments will raise disability insurance (DI) unit costs, these higher expenses are necessary to obtain the more selective benefit payments provided in this cost-saving legislation.


Pathogenesis of transthyretin amyloidosis.
Current dogma for transthyretin (TTR) pathogenesis is that mutations in TTR alter its structure such that the tetramer becomes unstable and prone to release of monomer which then becomes the putative building block of the fibril. This hypothesis is supported by thermodynamic data showing decreased stability of mutant TTR tetrameric proteins and accelerated fibril formation under acidic conditions in vitro. There are, however, a number of questions that are not readily answered by this simplistic model of a very complex disease. Worrisome questions still to be answered include: 1. If the monomer is the precursor of the fibril, why do fibril deposits contain large amounts of wild-type TTR and not just variant? 2. If destabilized tetramers can form fibrils in vitro, why do we consistently find partial proteolysis of fibril subunit proteins? If enzymatic proteolysis is a required step in fibril formation, are the findings of in vitro fibril formation relevant to the true pathogenesis? 3. With some TTR mutations (e.g. 122ΔVal), it would appear that very little TTR is present in the blood (probably due to degradation prior to hepatic secretion). Enough mutant TTR circulates to the heart and nerves to cause pathology but, if the mutant only serves to initiate fibril deposition, why are not the deposits mainly wild-type TTR?4. Since mutated TTR is present from birth, why is TTR amyloidosis of such delayed onset? What is the role of aging factors?5. Do the variations in biochemical analyses of heart and nerve versus choroid and leptomeningeal fibrils tell us something about pathogenesis? These are questions we need to address. Do not expect quick and easy answers. Hopefully, they will generate thought and discussion.


Correlation between severity of ultrasonographic nonalcoholic fatty liver disease and cardiometabolic risk among Filipino wellness patients.
Introduction: Nonalcoholic fatty liver disease (NAFLD) is a prevalent condition which is known to be related to factors that predispose to the development of coronary artery disease as well as development of metabolic syndrome. The study aimed to determine the association between ultrasound-based grading of hepatic steatosis with metabolic profile and estimated cardiovascular risk using the Framingham Risk Score (FRS). Methods: This was a cross-sectional study on 100 Filipino patients without established cardiovascular disease who underwent a general wellness health evaluation. Cases with NAFLD diagnosed on the basis of ultrasound grading were analyzed. Comparison of demographics and metabolic parameters between grades of hepatic steatosis was performed using Kruskal Wallis test. FRS was used to assess cardiovascular risk with Spearman rank test for correlation with the degree of NAFLD. Results: Mean age was 47 ± 9.6 years, with 70% males. Mean body mass index (BMI) was 28.7 ± 5.1. Most patients had grade I NAFLD (53%), 34% were grade II, and 13% were grade III. BMI (P =0.034), liver enzymes (alanine aminotransferase [ALT], P = 0.001; aspartate aminotransferase [AST], P = 0.00), triglycerides (P = 0.047), and fasting blood sugar [FBS] (P = 0.049) were associated with fatty liver grade. No association was noted with total cholesterol (P = 0.569), high density lipoprotein (HDL) (P = 0.220), and low density lipoprotein (LDL) (P = 0.792). Using the FRS 43% were stratified as low (<10% risk), 45% as intermediate (10%-20% risk) and 12% as high risk (>20% risk). Severity of fatty liver was directly correlated with the FRS (Spearman rank 0.741, P = 0.009). Conclusion: Ultrasound-based grading of the severity of NAFLD is associated with abnormalities in the metabolic profile of patients. The FRS is correlated with increasing severity of NAFLD based on ultrasound. These findings suggest that the presence of NAFLD may be a marker for the presence of increased cardiovascular risk and may help identify patients who may benefit from more aggressive therapies to prevent development of adverse cardiovascular events.


Sodium-activated potassium channels moderate excitability in vascular smooth muscle.
We report that a sodium-activated potassium current, IKNa , has been inadvertently overlooked in both conduit and resistance arterial smooth muscle cells. IKNa is a major K+ resting conductance and is absent in cells of IKNa knockout (KO) mice. The phenotype of the IKNa KO is mild hypertension, although KO mice react more strongly than wild-type with raised blood pressure when challenged with vasoconstrictive agents. IKNa is negatively regulated by angiotensin II acting through Gαq protein-coupled receptors. In current clamp, KO arterial smooth muscle cells have easily evoked Ca2+ -dependent action potentials. Although several potassium currents have been reported to play a role in arterial smooth muscle (ASM), we find that one of the largest contributors to membrane conductance in both conduit and resistance ASMs has been inadvertently overlooked. In the present study, we show that IKNa , a sodium-activated potassium current, contributes a major portion of macroscopic outward current in a critical physiological voltage range that determines intrinsic cell excitability; IKNa is the largest contributor to ASM cell resting conductance. A genetic knockout (KO) mouse strain lacking KNa channels (KCNT1 and KCNT2) shows only a modest hypertensive phenotype. However, acute administration of vasoconstrictive agents such as angiotensin II (Ang II) and phenylephrine results in an abnormally large increase in blood pressure in the KO animals. In wild-type animals Ang II acting through Gαq protein-coupled receptors down-regulates IKNa , which increases the excitability of the ASMs. The complete genetic removal of IKNa in KO mice makes the mutant animal more vulnerable to vasoconstrictive agents, thus producing a paroxysmal-hypertensive phenotype. This may result from the lowering of cell resting K+ conductance allowing the cells to depolarize more readily to a variety of excitable stimuli. Thus, the sodium-activated potassium current may serve to moderate blood pressure in instances of heightened stress. IKNa may represent a new therapeutic target for hypertension and stroke.


Quantitative near-infrared spectroscopy discriminates between mitochondrial myopathies and normal muscle.
Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27 healthy controls were examined by near-infrared spectroscopy (NIRS) for the noninvasive and direct quantitative measurement of muscle oxygen consumption and forearm blood flow. NIRS measurements were obtained in rest and during static isometric handgrip exercise at 10% of the maximum voluntary contraction (MVC) force. A significantly decreased oxygen consumption at rest as well as during exercise was found in patients with CPEO. Our results suggest that NIRS is able to discriminate between CPEO patients and healthy controls, which makes NIRS a valuable tool in the diagnostic workup of patients suspected to have a mitochondrial myopathy.


Enhanced Dopamine Sensitivity Using Steered Fast-Scan Cyclic Voltammetry.
Fast-scan cyclic voltammetry (FSCV) is a technique for measuring phasic release of neurotransmitters with millisecond temporal resolution. The current data are captured by carbon fiber microelectrodes, and non-Faradaic current is subtracted from the background current to extract the Faradaic redox current through a background subtraction algorithm. FSCV is able to measure neurotransmitter concentrations in vivo down to the nanomolar scale, making it a very robust and useful technique for probing neurotransmitter release dynamics and communication across neural networks. In this study, we describe a technique that can further lower the limit of detection of FSCV. By taking advantage of a "waveform steering" technique and by amplifying only the oxidation peak of dopamine to reduce noise fluctuations, we demonstrate the ability to measure dopamine concentrations down to 0.17 nM. Waveform steering is a technique to dynamically alter the input waveform to ensure that the background current remains stable over time. Specifically, the region of the input waveform in the vicinity of the dopamine oxidation potential (∼0.6 V) is kept flat. Thus, amplification of the input waveform will amplify only the Faradaic current, lowering the existing limit of detection for dopamine from 5.48 to 0.17 nM, a 32-fold reduction, and for serotonin, it lowers the limit of detection from 57.3 to 1.46 nM, a 39-fold reduction compared to conventional FSCV. Finally, the applicability of steered FSCV to in vivo dopamine detection was also demonstrated in this study. In conclusion, steered FSCV might be used as a neurochemical monitoring tool for enhancing detection sensitivity.


To what extent does the existence of functional relations in a learning setting change the pattern of differences between younger and older adults' performances?
BACKGROUND/STUDY CONTEXT: The study directly compared the learning performance of younger and older participants in two situations, one in which they had the possibility of detecting functional relations in the learning setting, and one in which they did not. Functional relations were defined as functional correspondences that could be established between abstract properties extracted from the sets of stimulus items and an abstract property extracted from the set of response items. A total of 112 adults (18-90 years old) had to learn to predict the values of a numerical variable (the criterion) on the basis of two words (a plant and an animal) as cues. Five plants and five animals were graded according to size. The plant × animal design was orthogonal. The values of the criterion were obtained using an additive, linear scheme under the functional relations condition, and using random associations under the zero relations condition. The hypothesis was well supported by the data. In the absence of functional relations, the difference between younger and older participants' performances was shown to be practically as great as it could be in the experimental situation that was chosen. When functional relations were present, age differences were significantly reduced, to the extent that the performance of the older participants was almost as good as that achieved by the younger group. The existence of functional relations in a learning setting considerably changes the pattern of differences between younger and older adults' performance. In both the absence and the presence of functional relations, older and younger participants spontaneously approached the learning task in a functional spirit, and conceived a priori the cues and the criterion as directly related. Future studies should examine the way in which participants approach learning tasks, and the characteristics of the tasks that determine participants' spontaneous learning attitudes.


A facile fabrication of upconversion luminescent and mesoporous core-shell structured β-NaYF4:Yb3+, Er3+@mSiO2 nanocomposite spheres for anti-cancer drug delivery and cell imaging.
Upconversion luminescent β-NaYF4:Yb3+, Er3+ nanoparticles (UCNPs) were encapsulated with uniform mesoporous silica shells, which were further modified with poly(ethylene glycol) (PEG) and cancer-targeting ligand folic acid (FA), resulting in the formation of water-dispersible and biologically functionalized core-shell structured UCNPs@mSiO2 nanoparticles with an overall average size of around 80 nm. The obtained multifunctional nanocomposite spheres can be performed as an anti-cancer drug delivery carrier and applied for cell imaging. It is found that anti-cancer drug doxorubicin hydrochloride (DOX) can be absorbed into UCNPs@mSiO2-PEG/FA nanospheres and released in a pH-sensitive pattern. In vitro cell cytotoxicity tests on cancer cells verified that DOX-loaded UCNPs@mSiO2-PEG/FA nanospheres exhibited greater cytotoxicity with respect to free DOX and DOX-loaded UCNPs@mSiO2-PEG at the same concentrations, owing to the increase of cell uptake of anti-cancer drug delivery vehicles mediated by the FA receptor. Moreover, the upconversion luminescence image of UCNPs@mSiO2-PEG/FA taken up by cells shows green emission under 980 nm infrared laser excitation, making the UCNPs@mSiO2-PEG/FA nanocomposite spheres promising candidates as bioimaging agents. These findings highlight the promise of the highly versatile multifunctional nanoparticles for simultaneous imaging and therapeutic applications.


Immunologic and cytochemical cell markers in non-Hodgkin's lymphomas.
Lymph nodes were obtained from 28 patients with non-Hodgkin's lymphoma and 24 patients without hematologic malignancy. Cases of undifferentiated lymphoma, diffuse histiocytic lymphoma, diffuse and nodular mixed histiocytic-lymphocytic lymphoma, nodular poorly differentiated lymphocytic lymphoma, and diffuse well differentiated lymphocytic lymphoma were analyzed. Touch preparations were stained for nonspecific esterases, peroxidase, Sudan black B activity and with periodic acid-Schiff and Wright-Giemsa reagents. Mononuclear cell suspension from lymph nodes and, in some cases, peripheral blood were tested for spontaneous rosette formation with sheep erythrocytes and for the presence of surface immunoglobulin. The remainder of the lymph node was examined after staining with hematoxylin and eosin. Analysis of the lymphocyte surface markers indicated that 15 cases of various histologic types of lymphoma were B cell proliferations. However, three out of four cases of diffuse poorly differentiated lymphocytic lymphoma and one of seven cases of diffuse histiocytic lymphoma appeared to represent T cell neoplasia. Lymph nodes from four cases of lymphoma representing diverse histologic types were replaced by neoplastic cells devoid of discernible cell markers. In five cases, the distribution of cell surface markers in the malignant lymph node failed to differ from data obtained in the analysis of non-neoplastic lymph nodes. The study indicates that the histopathologic entities recognized in the currently employed classification of lymphoreticular malignancies are heterogeneous. Alterations in the distribution of cell surface markers in the peripheral blood from five of 12 patients indicated involvement prior to demonstrable morphologic evidence of peripheral blood involvement in four patients and bone marrow infiltration in two patients.


A Prekindergarten Curriculum Supplement for Enhancing Mainstream American English Knowledge in Nonmainstream American English Speakers.
The purpose of this study was to evaluate the efficacy of a curriculum supplement designed to enhance awareness of Mainstream American English (MAE) in African American English- (AAE-) speaking prekindergarten children. Children in 2 Head Start classrooms participated in the study. The experimental classroom received the Talking and Learning for Kindergarten program (Edwards, Rosin, Gross, & Chen, 2013), which used contrastive analysis to highlight morphological, phonological, and pragmatic differences between MAE and AAE. The control classroom received the Kindness Curriculum (Flook, Goldberg, Pinger, & Davidson, 2014), which was designed to promote mindfulness and emotional self-regulation. The amount of instruction was the same across the 2 programs. Both classrooms participated in pre- and posttest assessments. Children in the experimental classroom, but not the control classroom, showed significant improvement in 3 norm-referenced measures of phonological awareness and in an experimental measure that evaluated comprehension of words that are ambiguous in AAE, but unambiguous in MAE, because of morphological and phonological differences between the 2 dialects. Although more research needs to be done on the efficacy of the Talking and Learning for Kindergarten program, these results suggest that it is possible to enhance AAE-speaking children's awareness of MAE prior to kindergarten entry.


Evaluation of equine fetal growth from day 100 of gestation to parturition by ultrasonography.
Transrectal and transabdominal ultrasonography were performed on normal pregnant mares (n=10) at 2 week intervals from day 100 of gestation to parturition to evaluate fetal growth. Several fetal anatomical regions (head, eye, aorta, abdomen, rib, gonad, kidney and femur) were imaged and measured using standardized scan plans. The results of these analyses indicate that all of the biometric parameters correlate strongly with the day of gestation. Growth charts were developed, which demonstrate that the following variables have linear relationships with the day of gestation on which they were measured: aortic systolic diameter, biparietal diameter, approximate eye volume, femur length and kidney cross-sectional area. The linear regression equation across days was developed for aortic, systolic and biparietal diameter, approximate eye volume, femur length and kidney cross-sectional area, thus allowing assessment of normal equine fetal development after day 100 of gestation. This non-invasive method can be used to estimate fetal age if mating or ovulation dates are unknown, provided the fetus is developing normally. The use of transrectal and transabdominal ultrasonography, as well as different probe frequencies (5.0 or 3.5 MHz), to measure different biometric parameters during gestation is reported.


Adherence to biopsy guidelines increases celiac disease diagnosis.
Celiac disease (CD) is common but underdiagnosed in the United States. A proposed quality guideline recommends that ≥4 specimens be submitted during duodenal biopsy. The degree of adherence to this recommendation in clinical practice is unknown. To measure the number of specimens submitted during duodenal biopsy among patients throughout the United States and to determine the incremental diagnostic yield of adherence to the recommended number of specimens. Retrospective cohort study. This study involved 132,352 patients without known CD who underwent duodenal biopsy. Duodenal biopsy. Duodenal biopsy specimens were submitted to a pathology laboratory operating in 43 states in the United States. We used multivariate logistic regression to identify factors associated with submitting ≥4 specimens. We also compared the prevalence of newly diagnosed CD in biopsies with ≥4 specimens with that in biopsies with <4 specimens. Of the 132,352 patients who underwent biopsy (67% women, mean age 52.9 years), ≥4 specimens were submitted in 45,995 cases (35%). A modest increase in the proportion of biopsies with ≥4 specimens occurred after this guideline was proposed in 2006 (odds ratio for 2009 vs 2006, 1.51; 95% confidence interval, 1.22-1.88), but the rate of adherence in 2009 remained low at 37%. Among patients in whom the indication was malabsorption/suspected CD (n = 3261), adherence to this standard was only 39.5%. The probability of a new diagnosis of CD was increased when ≥4 specimens were submitted (1.8% vs 0.7%; P < .0001). Retrospective analysis lacking clinical follow-up. The guideline publication occurred during the study period, possibly influencing clinical practice and confounding results. Although this proposed standard remains a subject of debate, adherence to submitting ≥4 specimens is low in the United States. Adherence yields a diagnosis rate of 1.8%, a small absolute increase but a doubling of the diagnosis rate of CD. Efforts to increase adherence are warranted.