Impact of SARS-CoV-2 Pandemic on "Stroke Code" Imaging Utilization and Yield.
Indirect consequences of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic include those related to failure of patients to seek or receive timely medical attention for seemingly unrelated disease. We report our experience with stroke code imaging during the early pandemic months of 2020. Retrospective review of stroke codes during the 2020 pandemic and both 2020 and matched 2019 prepandemic months was performed. Patient variables were age, sex, hospital location, and severity of symptoms based on the NIHSS. We reviewed the results of CT of the head, CTA, CTP, and MR imaging examinations and classified a case as imaging-positive if any of the imaging studies yielded a result that related to the clinical indication for the study. Both year-to-year and sequential comparisons were performed between pandemic and prepandemic months. A statistically significant decrease was observed in monthly stroke code volumes accompanied by a statistically significant increased proportion of positive imaging findings during the pandemic compared with the same months in the prior year (P < .001) and prepandemic months in the same year (P < .001). We also observed statistically significant increases in average NIHSS scores (P = .045 and P = .03) and the proportion of inpatient stroke codes (P = .003 and P = .03). During our pandemic period, there was a significantly decreased number of stroke codes but simultaneous increases in positivity rates, symptom severity, and inpatient codes. We postulate that this finding reflects the documented reluctance of patients to seek medical care during the pandemic, with the shift toward a greater proportion of inpatient stroke codes potentially reflecting the neurologic complications of the virus itself.


Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations.
Benzodiazepines in micromolar concentrations significantly inhibit depolarization-sensitive Ca2+ uptake in intact nerve-terminal preparations. Benzodiazepine inhibition of Ca2+ uptake is concentration dependent and stereospecific. Micromolar-affinity benzodiazepine receptors have been identified and characterized in brain membrane and shown to be distinct from nanomolar-affinity benzodiazepine receptors. Evidence is presented that micromolar, and not nanomolar, benzodiazepine binding sites mediate benzodiazepine inhibition of Ca2+ uptake. Irreversible binding to micromolar benzodiazepine binding sites also irreversibly blocked depolarization-dependent Ca2+ uptake in synaptosomes, indicating that these compounds may represent a useful marker for identifying the molecular components of Ca2+ channels in brain. Characterization of benzodiazepine inhibition of Ca2+ uptake demonstrates that these drugs function as Ca2+ channel antagonists, because benzodiazepines effectively blocked voltage-sensitive Ca2+ uptake inhibited by Mn2+, Co2+, verapamil, nitrendipine, and nimodipine. These results indicate that micromolar benzodiazepine binding sites regulate voltage-sensitive Ca2+ channels in brain membrane and suggest that some of the neuronal stabilizing effects of micromolar benzodiazepine receptors may be mediated by the regulation of Ca2+ conductance.


In vitro heme and non-heme iron capture from hemoglobin, myoglobin and ferritin by bovine lactoferrin and implications for suppression of reactive oxygen species in vivo.
Lactoferrin (Lf), present in colostrum and milk is a member of the transferrin family of iron-binding glyco-proteins, with stronger binding capacity to ferric iron than hemoglobin, myoglobin or transferrin. Unlike hemoglobin and myoglobin, iron-bound Lf is reasonably stable to gastric and duodenal digestive conditions. Unlike ferrous iron, ferric iron is not directly reactive with oxygen supporting the capacity of Lf capture of heme iron to suppress reactive oxygen species (ROS) production. We therefore hypothesized that bovine Lf could capture and thereby terminate the cycle of ROS production by heme iron. The transfer of heme iron from either intact or digested forms of hemoglobin and myoglobin and from intact ferritin was demonstrated by in vitro methods, monitoring Fe-saturation status of Lf by changes in absorptivity at 465 nm. The results are discussed in the context of new proposed opportunities for orally administered Lf to regulate oxidative damage associated with heme iron. In addition to potentially suppressing oxidative heme-iron-mediated tissue damage in the lumen, Lf is expected to also reverse the overload of ferritin-bound iron, that accompanies chronic inflammation and aging. These new proposed uses of Lf are additional to known host defense functions that include anti-microbial, anti-viral properties, immune and cancer cell growth regulation. The findings and interpretations presented require clinical substantiation and may support important additional protective and therapeutic uses for Lf in the future.


Effects of Vitamin D Receptor Knockout and Vitamin D Deficiency on Corneal Epithelial Wound Healing and Nerve Density in Diabetic Mice.
Diabetic keratopathy occurs in ∼70% of all people with diabetes. This study was designed to examine the effects of vitamin D receptor knockout (VDR-/-) and vitamin D deficiency (VDD) on corneal epithelial wound healing and nerve density in diabetic mice. Diabetes was induced using the low-dose streptozotocin method. Corneal epithelial wounds were created using an Algerbrush, and wound healing was monitored over time. Corneal nerve density was measured in unwounded mice. VDR-/- and VDD diabetic mice (diabetic for 8 and 20 weeks, respectively) had slower healing ratios than wild-type diabetic mice. VDR-/- and VDD diabetic mice also showed significantly decreased nerve density. Reduced wound healing ratios and nerve densities were not fully rescued by a supplemental diet rich in calcium, lactose, and phosphate. We conclude that VDR-/- and VDD significantly reduce both corneal epithelial wound healing and nerve density in diabetic mice. Because the supplemental diet did not rescue wound healing or nerve density, these effects are likely not specifically related to hypocalcemia. This work supports the hypothesis that low vitamin D levels can exacerbate preexisting ophthalmic conditions, such as diabetes.


Associations between genetic variants in the ACE, AGT, AGTR1 and AGTR2 genes and renal function in the Multi-ethnic Study of Atherosclerosis.
Some studies suggest that polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AGTR1) and angiotensin II type II receptor (AGTR2) genes may contribute to renal function variation. Genotyping for single nucleotide polymorphisms (SNPs) in these candidate genes was performed in 2,847 participants from four racial/ethnic groups (African American, Chinese, White and Hispanic) without known cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. SNP and haplotype analyses were performed to determine associations between genotypes and cross-sectional renal function measurements, including urine albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C. Twenty-four ACE SNPs, 10 AGT SNPs, 15 AGTR1 SNPs and 6 AGTR2 SNPs were typed successfully. After adjusting for ancestry, age and gender, 3 SNPs (AGT M235T, AGT rs2148582 and AGTR1 rs2131127) showed associations with an empiric p value <0.05 with the same phenotype in multiple racial/ethnic groups, suggesting replication. The AGT M235T SNP has been shown previously to be associated with diabetic and hypertensive nephropathy. These data suggest that genetic polymorphisms in the renin-angiotensin system are associated with renal phenotypes in the general population, but that many associations differ across racial/ethnic groups.


Strategies for Proximal Femoral Nailing of Unstable Intertrochanteric Fractures: Lateral Decubitus Position or Traction Table.
The aim of this prospective randomized study was to compare the traction table and lateral decubitus position techniques in the management of unstable intertrochanteric fractures. Eighty-two patients with unstable intertrochanteric fractures between 2011 and 2013 were included in this study. All patients were treated surgically with the Proximal Femoral Nail Antirotation implant (DePuy Synthes). Patients were randomized to undergo the procedure in the lateral decubitus position (42 patients) or with the use of a traction table (40 patients). Patients whose procedure was not performed entirely with a semi-invasive method or who required the use of additional fixation materials, such as cables, were excluded from the study. The groups were compared on the basis of the setup time, surgical time, fluoroscopic exposure time, tip-to-apex distance, collodiaphyseal angle, and modified Baumgaertner criteria for radiologic reduction. The setup time, surgical time, and fluoroscopic exposure time were lower and the differences were statistically significant in the lateral decubitus group compared with the traction table group. The collodiaphyseal angles were significantly different between the groups in favor of the lateral decubitus method. The tip-to-apex distance and the classification of reduction according to the modified Baumgaertner criteria did not demonstrate a statistically significant difference between the groups. The lateral decubitus position is used for most open procedures of the hip. We found that this position facilitates exposure for the surgical treatment of unstable intertrochanteric fractures and has advantages over the traction table in terms of set up time, surgical time and fluoroscopic exposure time.


Risk of high dietary calcium for arterial calcification in older adults.
Concern has recently arisen about the potential adverse effects of excessive calcium intakes, i.e., calcium loading from supplements, on arterial calcification and risks of cardiovascular diseases (CVD) in older adults. Published reports that high calcium intakes in free-living adults have relatively little or no beneficial impact on bone mineral density (BMD) and fracture rates suggest that current recommendations of calcium for adults may be set too high. Because even healthy kidneys have limited capability of eliminating excessive calcium in the diet, the likelihood of soft-tissue calcification may increase in older adults who take calcium supplements, particularly in those with age or disease-related reduction in renal function. The maintenance of BMD and bone health continues to be an important goal of adequate dietary calcium consumption, but eliminating potential risks of CVDs from excessive calcium intakes needs to be factored into policy recommendations for calcium by adults.


[Role of new quinolones in the treatment of mycobacteriosis].
New quinolones (NQs) have acquired potent antimicrobial activity against gram-positive cocci and penetrate well into organs when compared with old quinolones. Their indications were extended to the treatment of respiratory infection caused by gram-negative and gram-positive bacteria, and their possibility of an indication for the treatment of mycobacteriosis has been considered. Mycobacteriosis, against which NQs are expected to be effective, includes tuberculosis, which involves a problem of multiple-drug resistant bacteria, and atypical mycobacteriosis, for which there are few remedies. Since, there has been no established evaluation of NQs against mycobacteriosis, the purpose of the present evening symposium was to evaluate the role of NQs at present in the treatment of mycobacteriosis, as well as to present future prospects. Four speakers made presentations. Dr. Chiaki Sano reported that STFX, GFLX, MXFX, and SPFX had a potent antibacterial activity against various acid-fast bacteria and were particularly effective against M. tuberculosis, M. kansasii, and M. fortuitum. Among these drugs, MXFX had a greater therapeutic effect in experimental mice model of a tuberculosis than SM when used concomitantly with INH + RPT. These results suggested that MXFX might become one of the first-line drugs, taking the place of SM. However, OFLX, SPFX, and STFX are not effective against MAC. Only MXFX exhibited a significant therapeutic effect when administered alone and potent therapeutic effect when used concomitantly with EB, in experimental mice model of MAC infection. These results suggested that 8-methoxy quinolone might be effective. Dr. Yuka Sasaki reported the results of a questionnaire survey among national sanatoriums, as well as the current status of administration of NQs for the treatment of pulmonary tuberculosis based on the results of her study. The ATS recommended in 2002 that LVFX, MXFX, and GFLX be second-line drugs, which should be used alternatively only when first-line drugs cannot be used due to drug-resistant M. tuberculosis or adverse reactions. She reported that LVFX, MXFX, and GFLX were used in a similar manner also in Japan and that they achieved therapeutic results equivalent to those by first-line drugs. She stated that there were some urgent problems, for example, these drugs are not listed in the Tuberculosis Control Law of Japan or in health insurance, and no testing system for sensitivity to NQs has been established. Dr. Atsuyuki Kurashima reported the results of a study conducted in other countries and his study on atypical acid-fast bacteria. He indicated the position of NQs in the treatment of pulmonary atypical mycobacteriosis. However, the significance of concomitant use of CPFX with RFP + EB in the treatment of MAC disease associated with AIDS has already been recognized. He was of the opinion that atypical acid-fast bacteria against which NQs were useful were M. kansasii and M. fortuitum alone at present and that NQs had a very limited effect in the treatment of pulmonary MAC infection, although there were only an insufficient number of studies on pulmonary MAC disease. Dr. Koichi Wada reported on the advisability of administration of NQs in the treatment of mycobacteriosis as a whole and prospects for NQs. His conclusion was similar to those by the two former speakers: he stated that NQs are important for the treatment of tuberculosis as alternative drugs and that they should be used in sufficient doses when first-line drugs could not be used due to drug resistance or adverse reactions. He also stated that use of NQs, including duration of administration, should be discussed after the testing method for drug sensitivity has been established and that long-term use of NQs should be avoided in the treatment of atypical mycobacteriosis at present, although significant results have not been obtained in atypical acid-fast bacteria, mainly MAC. In the last part of the symposium, an active discussion was held. Many opinions similar to those of the speakers were expressed also from the floor. Lastly, President Dr. Matsushima summarized the role of NQs in the treatment of mycobacteriosis at present and future prospects for NQs and confirmed the significance of having held the present symposium.


Radiation damping at clinical field strength: Characterization and compensation in quantitative measurements.
In any MR experiment, the bulk magnetization acts on itself, caused by the induced current in the RF receiver circuit that generates an oscillating damping field. This effect, known as "radiation damping" (RD), is usually weak and, therefore, unconsidered in MRI, but can affect quantitative studies performed with dedicated coils that provide a high SNR. The current work examined RD in a setup for investigations of small tissue specimens including a quantitative characterization of the spin-coil system. A custom-made Helmholtz coil (radius and spacing 16 mm) was interfaced to a transmit-receive (Tx/Rx) switch with integrated passive feedback for modulation or suppression of RD similar to preamplifier decoupling. Pulse sequences included pulse-width arrays to demonstrate the absence/ presence of RD and difference techniques employing gradient pulses or composite RF pulses to quantify RD effects during free precession and transmission, respectively. Experiments were performed at 3T in small samples of MnCl2 solution. Significant RD effects may impact RF pulse application and evolution periods. Effective damping time constants were comparable to typical T2 * times or echo spacings in multi-echo sequences. Measurements of the phase relation showed that deviations from the commonly assumed 90° angle between the damping field and the transverse magnetization may occur. Radiation damping may affect the accuracy of quantitative MR measurements performed with dedicated RF coils. Efficient mitigation can be achieved hardware-based or by appropriate consideration in the pulse sequence.


Conditional analysis of mixed Poisson processes with baseline counts: implications for trial design and analysis.
The design of clinical trials is typically based on marginal comparisons of a primary response under two or more treatments. The considerable gains in efficiency afforded by models conditional on one or more baseline responses has been extensively studied for Gaussian models. The purpose of this article is to present methods for the design and analysis of clinical trials in which the response is a count or a point process, and a corresponding baseline count is available prior to randomization. The methods are based on a conditional negative binomial model for the response given the baseline count and can be used to examine the effect of introducing selection criteria on power and sample size requirements. We show that designs based on this approach are more efficient than those proposed by McMahon et al. (1994).


Predictors of C-reactive protein in the national social life, health, and aging project.
Inflammation plays an important role in many chronic degenerative diseases associated with aging, and social, economic, and behavioral factors that contribute to inflammation may lead to differential burdens of morbidity and mortality in later life. This study examines socioeconomic status and race/ethnicity as predictors of C-reactive protein (CRP) among older adults in the United States and considers the degree to which health behaviors, medical conditions and medication use, and psychosocial factors account for these associations. Multiple linear regression analysis of survey data for 1,580 participants, 57-85 years of age, in a population-based nationally representative sample of community-residing older adults in the United States. Educational attainment, household wealth, and race/ethnicity were independently associated with CRP, with limited evidence for interactions with age. Health-related behaviors and usage of medications related to inflammation accounted for substantial proportions of these associations. These results highlight the fundamental causes of inflammation among older adults and suggest pathways through which social disparities in inflammation may be reduced.


A complementary study to "toward scatter-free phosphors in white phosphor-converted light-emitting diodes:" comment.
In a recent paper, Park et al. [Opt. Express 20(9), 10218 (2012)] demonstrated that large micro-size cube phosphors are an outstanding potential candidate for scatter-free phosphors in white phosphor-converted light-emitting diodes (pc-LEDs). They found that large micro-size cube phosphors can lead to higher luminous efficiency (LE), higher packaging efficiency (PE), and reduced influences of ambient temperature and applied current. In this comment, we further discussed the large micro-size phosphors on the angular color uniformity (ACU). It is found that when the phosphor particle size increases from 30 μm to 100 μm, the ACU decreases from 0.91 to 0.86.


[Smoking cessation in patients with COPD: the status of routine care in Germany].
Almost every second heavy-smoker (> 20 Cig./day) develops a COPD after long-term tobacco use. Cigarette smoking is not only the leading cause of COPD, but also the most important predictor for an unfavourable prognosis. Inversely, quitting smoking can enhance the disease course as well as the lung function of patients suffering from COPD more effectively than any other treatment. Currently, a wide range of evidence-based psychological and pharmacological smoking cessation treatments exists including disease-specific therapy approaches. However, professional smoking cessation treatments are used only rarely in health-care routine. This fact is due to persisting deficits in the German health-care system: With the exception of pharmacological therapy approaches and some telephone or online counselling programmes, smoking cessation treatments are not generally available. In the future, one should keep a sharp eye on the permanent motivation of COPD patients to quit smoking totally and to establish disease-specific smoking cessation programmes in routine care.


Favored use of immunoglobulin V(H)4 Genes in AIDS-associated B-cell lymphoma.
We examined the lg heavy chain variable region genes (Ig V(H) genes) expressed in biopsy specimens of 10 patients with acquired immunodeficiency syndrome (AIDS)-associated lymphoma. Eight expressed Ig V(H) genes of the V(H)4 group, indicating a bias toward expression of Ig V(H) genes of this subgroup. Sequence analyses of Ig V(H) genes isolated from any one lymphoma did not reveal evidence for intraclonal diversity. However, some lymphomas express Ig V(H) genes that apparently have undergone somatic diversification and selection. In addition, we found that the sequence encoding each examined third complementarity determining region most likely resulted from D-D fusion, a process that ordinarily contributes to the generation of a relatively small proportion of the Ig heavy chain genes expressed by normal adult B cells. The noted restriction in the use of Ig V(H) genes by AIDS-associated B-cell lymphomas suggests that antigenic stimulation contributes to lymphomagenesis in patients with AIDS.


[Epidemiological study on rotavirus-borne diarrhea in infants and children in different areas].
To analyze and compare the epidemiological features of rotavirus diarrhea among infants in the different areas so as to provide data for rotavirus vaccine research. From Sep. 2001 through Sep. 2003, sentinel sites were set up in Suzhou Children's Hospital and Maanshan Hospital. Fecal samples from children (< 5 years) with acute diarrheal were collected and enzyme linked immunosorbent assay was used to detect rotavirus antigen. Reverse transcription-polymerase chain reaction was used to determine the G serotypes and P genotypes of rotavirus strains. The features of strains in the two places and other areas of China were analyzed and compared. (1) Rotavirus infection appeared in autumn and winter, but the peaks varied. In Suzhou the peaks were from December to next February in 2001, and November to next January in 2002. But in Maanshan, it was November to next January for both two years. (2) Rate of rotavirus infection in Suzhou was much higher than that in Maanshan, infective rates of Inpatient Department and Outpatient Department are 47.28%, 28.39% and 30.38%, 14.77% respectively in the two hospitals. (3) Rates of infection in two hospitals showed age difference but the highest group was in 6 - 35 month-olds. No gender difference was found. (4) Secular distribution of G-typing and P-typing of rotavirus strain was different in Suzhou and Maanshan. G3 was mainly found in Suzhou and G1 in Maanshan. From 2002-2003 on, G3 became dominant in Maanshan. Rotavirus caused diarrhea among infant and children were different in terms of areas, period and types, suggesting that the introduction of rotavirus vaccine should be adjusted according to different strains with specific types and optimal timeline.


Connected-sea partons.
According to the path-integral formalism of the hadronic tensor, the nucleon sea contains two distinct components called the connected sea (CS) and the disconnected sea (DS). We discuss how the CS and DS are accessed in the lattice QCD calculation of the moments of the parton distributions. We show that the CS and DS components of ū(x) + d(x) can be extracted by using recent data on the strangeness parton distribution, the CT10 global fit, and the lattice result of the ratio of the strange to u(d) moments in the disconnected insertion. The extracted CS and DS for ū(x) + d(x) have a distinct Bjorken x dependence in qualitative agreement with expectation. The analysis also shows that the momentum fraction of ū(x) + d(x) is about equally divided between the CS and DS at Q(2) = 2.5 GeV(2). Implications for the future global analysis of parton distributions are presented.


Synergistic administration of photothermal therapy and chemotherapy to cancer cells using polypeptide-based degradable plasmonic matrices.
Resistance of cancer cells to hyperthermic temperatures and spatial limitations of nanoparticle-induced hyperthermia necessitates the identification of effective combination treatments that can enhance the efficacy of this treatment. Here we show that novel polypeptide-based degradable plasmonic matrices can be employed for simultaneous administration of hyperthermia and chemotherapeutic drugs as an effective combination treatment that can overcome cancer cell resistance to hyperthermia. Novel gold nanorod elastin-like polypeptide matrices were generated and characterized. The matrices were also loaded with the heat-shock protein (HSP)90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), currently in clinical trials for different malignancies, in order to deliver a combination of hyperthermia and chemotherapy. Laser irradiation of cells cultured over the plasmonic matrices (without 17-AAG) resulted in the death of cells directly in the path of the laser, while cells outside the laser path did not show any loss of viability. Such spatial limitations, in concert with expression of prosurvival HSPs, reduce the efficacy of hyperthermia treatment. 17-AAG-gold nanorod-polypeptide matrices demonstrated minimal leaching of the drug to surrounding media. The combination of hyperthermic temperatures and the release of 17-AAG from the matrix, both induced by laser irradiation, resulted in significant (>90%) death of cancer cells, while 'single treatments' (i.e., hyperthermia alone and 17-AAG alone) demonstrated minimal loss of cancer cell viability (<10%). Simultaneous administration of hyperthermia and HSP inhibitor release from plasmonic matrices is a powerful approach for the ablation of malignant cells and can be extended to different combinations of nanoparticles and chemotherapeutic drugs for a variety of malignancies.


Seasonal variation in the abundance of microplastics in three commercial bivalves from Bandon Bay, Gulf of Thailand.
This study investigated the abundance of microplastics in three commercial bivalves found at Bandon Bay. Spatial-temporal differences in the concentration of microplastics were evaluated during the dry and wet seasons. The results showed that the highest abundance of microplastics in oysters, blood cockles, and green mussels was observed in fishery and aquaculture areas during the dry season, with 1.42 particles/g (w/w), 1.01 particles/g (w/w) and 0.87 particles/g (w/w), respectively. Microplastics were more abundant during the dry season compared to the wet season (p < 0.05), with fibre being the predominant shape and black being the major colour of particles. Cellophane was the most common type of polymer in all bivalves. This result is an important reference for understanding the status of microplastics in three commercial bivalves during different seasons and in different human activities, which should aid in understanding the sources of microplastics in Bandon Bay.


Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF.
Arterial blood flow enhances glycoprotein Ibalpha (GPIbalpha) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIbalpha/vWF bonds first prolonged ("catch") and then shortened ("slip") bond lifetimes. Two type 2B vWD A1 domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIbalpha dissociating from the A1 domain suggested mechanisms for catch bonds and their conversion by the A1 domain mutations. Catch bonds caused platelets and GPIbalpha-coated microspheres to roll more slowly on WT vWF and WT A1 domains as flow increased from suboptimal levels, explaining flow-enhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant A1 domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant A1 domains, but not WT A1 domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif-13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIbalpha on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding.


Neighborhood-Level Socioeconomic Status and Prescription Fill Patterns Among Patients With Heart Failure.
Medication nonadherence is common among patients with heart failure with reduced ejection fraction (HFrEF) and can lead to increased hospitalization and mortality. Patients living in socioeconomically disadvantaged areas may be at greater risk for medication nonadherence due to barriers such as lower access to transportation or pharmacies. To examine the association between neighborhood-level socioeconomic status (nSES) and medication nonadherence among patients with HFrEF and to assess the mediating roles of access to transportation, walkability, and pharmacy density. This retrospective cohort study was conducted between June 30, 2020, and December 31, 2021, at a large health system based primarily in New York City and surrounding areas. Adult patients with a diagnosis of HF, reduced EF on echocardiogram, and a prescription of at least 1 guideline-directed medical therapy (GDMT) for HFrEF were included. Patient addresses were geocoded, and nSES was calculated using the Agency for Healthcare Research and Quality SES index, which combines census-tract level measures of poverty, rent burden, unemployment, crowding, home value, and education, with higher values indicating higher nSES. Medication nonadherence was obtained through linkage of health record prescription data with pharmacy fill data and was defined as proportion of days covered (PDC) of less than 80% over 6 months, averaged across GDMT medications. Among 6247 patients, the mean (SD) age was 73 (14) years, and majority were male (4340 [69.5%]). There were 1011 (16.2%) Black participants, 735 (11.8%) Hispanic/Latinx participants, and 3929 (62.9%) White participants. Patients in lower nSES areas had higher rates of nonadherence, ranging from 51.7% in the lowest quartile (731 of 1086 participants) to 40.0% in the highest quartile (563 of 1086 participants) (P < .001). In adjusted analysis, patients living in the lower 2 nSES quartiles had significantly higher odds of nonadherence when compared with patients living in the highest nSES quartile (quartile 1: odds ratio [OR], 1.57 [95% CI, 1.35-1.83]; quartile 2: OR, 1.35 [95% CI, 1.16-1.56]). No mediation by access to transportation and pharmacy density was found, but a small amount of mediation by neighborhood walkability was observed. In this retrospective cohort study of patients with HFrEF, living in a lower nSES area was associated with higher rates of GDMT nonadherence. These findings highlight the importance of considering neighborhood-level disparities when developing approaches to improve medication adherence.


Comparison of stochastic parametrization approaches in a single-column model.
We discuss and test the potential usefulness of single-column models (SCMs) for the testing of stochastic physics schemes that have been proposed for use in general circulation models (GCMs). We argue that although single-column tests cannot be definitive in exposing the full behaviour of a stochastic method in the full GCM, and although there are differences between SCM testing of deterministic and stochastic methods, SCM testing remains a useful tool. It is necessary to consider an ensemble of SCM runs produced by the stochastic method. These can be usefully compared with deterministic ensembles describing initial condition uncertainty and also with combinations of these (with structural model changes) into poor man's ensembles. The proposed methodology is demonstrated using an SCM experiment recently developed by the GCSS (GEWEX Cloud System Study) community, simulating transitions between active and suppressed periods of tropical convection.


[Serotonin in genetically determined types of defensive behavior].
A review of the data concerning the role of 5-hydroxytriptamine (5HT) in genetically defined defensive behavior. 5HT-ergic system of the brain is involved in the expression of the genetic predisposition of rodents to defensive behavior--both aggression and freezing. The results suggest that the density of 5HT1A receptors in the frontal cortex is related to the expression of aggressive behavior of both types, while functional state of the brain 5HT system is involved in mechanisms determining the strategy of choice of type of defensive behavior--freezing or aggression.


Serum glycerophosphate levels are increased in Japanese men with type 2 diabetes.
To identify metabolites showing changes in serum levels among Japanese male with diabetes. We performed metabolite profiling by coupling capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry using fasting serum samples from Japanese male subjects with diabetes (n=17), impaired glucose tolerance (IGT; n=5) and normal glucose tolerance (NGT; n=14). Other than the expected differences in characteristics related to abnormal glucose metabolism, the percent body fat was significantly different among subjects with diabetes, IGT and NGT (27.3±6.2, 22.2±4.5 and 19.2±6.0%, respectively, p=0.0022). Therefore, percent body fat was considered as a possible confounding factor in subsequent analyses. Of 560 metabolites detected using our platform, the levels of 74 metabolites were quantified in all of the serum samples. Significant differences between diabetes and NGT were observed for 24 metabolites. The top-ranked metabolite was glycerol-3-phophate (glycerophosphate), which was significantly higher in subjects with diabetes than in those with NGT, even after Bonferroni correction for multiple testing (11.7±3.6 vs. 6.4±1.9 µM, respectively; corrected p=0.0222). Stepwise multiple regression analyses revealed that serum glycerophosphate levels were significantly correlated with 2-h plasma glucose after a 75-g oral glucose tolerance test (r=0.553, p=0.0005), independently of other characteristics, including FPG and HbA1c. Serum glycerophosphate levels were found to be elevated in Japanese men with diabetes, and correlated with 2-h PG, independent of FPG and HbA1c. Namely, serum glycerophosphate level at fasting condition can be a marker for predicting glucose intolerance. These results warrant further studies to evaluate the relevance of glycerophosphate in the pathophysiology of diabetes.


The molecular structure of microtubule-associated protein 1A (MAP1A) in vivo and in vitro. An immunoelectron microscopy and quick-freeze, deep-etch study.
We studied the distribution of microtubule-associated protein 1A (MAP1A) in Purkinje cell dendrites by means of electronmicroscopic immunocytochemistry, using a monoclonal antibody (McAb) against MAP1A; this was combined with the observation of the 3-dimensional cytoskeletal ultrastructure in dendrites via the quick-freeze, deep-etch technique (QF-DE). We prepared a McAb against rat brain MAP1. This McAb recognized MAP1A on a nitrocellulose filter through use of the immunoblotting method, and stained immunofluorescently Purkinje cell perikarya, dendrites, and axons. Using the McAb, we labeled rat cerebellum extracted with Triton X-100 and simultaneously fixed with aldehyde, followed by gold-labeled rabbit anti-mouse IgG. Gold particles were attached to the filamentous, fuzzy materials, mostly those connected to microtubules (MTs), but were hardly localized on those attached to neurofilaments (NFs). The 3-dimensional cytoskeletal ultrastructure of fresh Purkinje cell dendrites was revealed by QF-DE. In Purkinje cell dendrites, MT was a predominant cytoskeletal element, whereas only a few NFs were found. Fine, elaborate cross-bridges filled up the interstices among MTs, and between MTs and other cellular components. Cross-bridges linking MTs to one another were composed mainly of a fine filamentous structure, frequently branching and anastomosing at several sites, and appeared somewhat granular. We ensured that the cross-bridges observed in saponin-extracted tissues were not a result of artifactual condensations or precipitations of soluble proteins during deep etching. The molecular structure of MAP1A was further investigated by the rotary shadowing technique. The affinity-purified MAP1A was a long, thin, filamentous, and very flexible molecule.(ABSTRACT TRUNCATED AT 250 WORDS)


Protein thiol modification by 15-deoxy-Delta12,14-prostaglandin J2 addition in mesangial cells: role in the inhibition of pro-inflammatory genes.
The cyclopentenone prostaglandin and PPARgamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) displays anti-inflammatory effects in several experimental models. Direct modification of protein thiols is arising as an important mechanism of cyclopentenone prostaglandin action. However, little is known about the extent or specificity of this process. Mesangial cells (MC) play a key role in glomerulonephritis. In this work, we have studied the selectivity of protein modification by 15d-PGJ(2) in MC, and the correlation with the modulation of several proinflammatory genes. MC incubation with biotinylated 15d-PGJ(2) results in the labeling of a distinct set of proteins as evidenced by two-dimensional electrophoresis. 15d-PGJ(2) binds to nuclear and cytosolic targets as detected by fluorescence microscopy and subcellular fractionation. The pattern of biotinylated 15d-PGJ(2)-modified polypeptides is readily distinguishable from that of total protein staining or labeling with biotinylated iodoacetamide. 15d-PGJ(2) addition requires the double bond in the cyclopentane ring. 9,10-Dihydro-15d-PGJ(2), a 15d-PGJ(2) analog that shows the same potency as peroxisome proliferator-activated receptor (PPAR) agonist in MC but lacks the cyclopentenone moiety, displays reduced ability to modify proteins and to block 15d-PGJ(2) binding. Micromolar concentrations of 15d-PGJ(2) inhibit cytokine-elicited levels of inducible nitricoxide synthase, cyclooxygenase-2, and intercellular adhesion molecule-1 in MC. In contrast, 9,10-dihydro-15d-PGJ(2) does not reproduce this inhibition. 15d-PGJ(2) effect is not blocked by the PPARgamma antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662). Moreover, compounds possessing an alpha,beta-unsaturated carbonyl group, like 2-cyclopenten-1-one and 2-cyclohexen-1-one, reduce pro-inflammatory gene expression. These observations indicate that covalent modification of cellular thiols by 15d-PGJ(2) is a selective process that plays an important role in the inhibition of MC responses to pro-inflammatory stimuli.


[Odyssey of the iliac. "Mandibular reconstruction by bone free flaps"].
The authors proposed here a retrospective analysis of a surgical procedure they performed for long time. It allows to put into questions some established principles, to find some unkwown datas which could be important to predict complications. It is also interesting to discuss about the use of indication and choice of the flaps along years of reconstructive surgery history in the way to improve protocoles and management of those large reconstruction. During ten years in one maxillofacial surgery departement, more than 200 bone free flaps (essentially fibula and iliac crest) have been used for mandibular reconstruction and analyse with a three years follow-up. The global failure rate is estimated as 28 % included all various complications from fistulas to infections. Five different points are discussed from the ambiguity of the reported studies to the way of doing of such surgery. It is also pointed out the importance of the biological dimension of all surgical procedures and the place of clinical figures regarding of the technical processes which usually forget the main clinical purpose.


Alpha-fetoprotein variants in a case of pancreatoblastoma.
We describe a 6-year-old boy with histologically confirmed pancreatoblastoma and a markedly elevated serum alpha-fetoprotein (AFP) concentration. Due to local tumour invasion, cytotoxic chemotherapy was given to debulk the tumour before attempting surgical resection. Serial serum AFP concentrations were measured on this patient. During chemotherapy there was a > 95% fall in total AFP. Tumour-specific variants of AFP, detected by isoelectric focusing, also disappeared during chemotherapy but recurred when chemotherapy was withdrawn. It is suggested that although there was no change in overall size of the tumour, as assessed by various imaging techniques, the changes in serological markers may indicate that the treatment did in fact cause considerable tumour necrosis, AFP and its variants may be useful markers of tumour response in patients with pancreatoblastoma. The expression of AFP and its variants in pancreatoblastoma may be related to the embryonic origin of the pancreas.


Visual modulation of pleasure in subjects with physical and social anhedonia.
Anhedonia is a personality trait associated with a decrease in the ability to feel pleasure. We investigated the experience of pleasure in individuals with physical and social anhedonia for positive pictures with varying levels of luminance contrast. Photographs with either a sensory or a social content were modified with a contrast-gradation procedure. Participants had to report the intensity of the pleasure they experienced in response to these pictures. Twenty-six subjects with physical anhedonia, 18 with social anhedonia and 34 control subjects completed the task. In controls, high-contrast pictures elicited an intense feeling of pleasure, whereas low contrast pictures elicited little pleasure. Although they were also sensitive to the modulation of contrast, subjects with physical and social anhedonia reported less pleasure than controls, across a larger range of contrast levels for sensory and social pictures, respectively. The findings suggest that the deficit in the experience of positive emotion in anhedonia is associated with a diminished pleasure intensity, fairly selective for the sensory or the social emotion dimension. This study encourages further investigation of the interaction between perceptual encoding and emotional processing in anhedonia.


Toward development and production of human T cells in swine for potential use in adoptive T cell immunotherapy.
Immunotherapy and vaccination for cancer or infection are generally approached by administration of antigen or stimulation of antigen-presenting cells or both. These measures may fail if the treated individual lacks T cells specific for the immunogen(s). We tested another strategy-the generation of new T cells from hematopoietic stem cells that might be used for adoptive immunotherapy. To test this concept, we introduced T cell-depleted human bone marrow cells into fetal swine and tested the swine for human T cells at various times after birth. Human T cells were detected in the thymus and blood of the treated swine. These cells were generated de novo as they contained human T cell receptor excision circles not present in the T cell-depleted bone marrow. The human T cells were highly diverse and included novel specificities capable of responding to antigen presented by human antigen-presenting cells. Our findings constitute a first step in a new promising approach to immunotherapy in which tumor- or virus-specific T cell clones lacking in an individual might be generated in a surrogate host from hematopoietic stem cells of the individual to be treated.


Authentication of pure camellia oil by using near infrared spectroscopy and pattern recognition techniques.
Total of 4 pattern recognition methods for the authentication of pure camellia oil applying near infrared (NIR) spectroscopy were evaluated in this study. Total of 115 samples were collected and their authenticities were confirmed by gas chromatography (GC) in according to China Natl. Standard (GB). A preliminary study of NIR spectral data was analyzed by unsupervised methods including principal component analysis (PCA) and hierarchical cluster analysis (HCA). Total of 2 supervised classification techniques based on discriminant analysis (DA) and radical basis function neural network (RBFNN) were utilized to build calibration model and predict unknown samples. In the wavenumber range of 6000 to 5750 cm⁻¹, correct classification rate of both supervised and unsupervised solutions all can reach 98.3% when smoothing, first derivative, and autoscaling were used. The good performance showed that NIR spectroscopy with multivariate calibration models could be successfully used as a rapid, simple, and nondestructive method to discriminate pure camellia oil.


Determination of glyceryl trinitrate and its two main metabolites in human plasma using a new sensitive gas chromatography method.
The aim of the present study was to determine the concentrations of nitroglycerin (glyceryl trinitrate, GTN, CAS 55-63-0) and its two main stable metabolites; 1,2-dinitroglycerin (1,2-glyceryl dinitrate, GDN, CAS 621-65-8) and 1,3-dinitroglycerin (1,3-GDN, CAS 623-87-0) in human plasma using a capillary gas chromatography method with an electron capture detection. Using the GC conditions, linear calibrations were obtained for 1,3-GDN from 0.14 to 3 ng/mL, for 1,2-GDN from 0.06 to 6 ng/mL, and for GTN from 0.01 to 0.3 ng/mL in plasma samples by the following calibration curve equations: [y = 0.1924x - 0.0088 (r = 0.999)], [y = 0.2273x + 0.0164 (r = 0.995)], [y = 17.434x - 0.0751] for 1,3-GDN, 1,2-GDN, and GTN respectively. The calculated limits of quantification values for GTN, 1,2-GDN, and 1,3-GDN were 0.03 ng/mL, 0.2 ng/mL, and 0.15 ng/mL respectively. This method was verified with a bioequivalence study of an Iranian brand of oral sustained release nitroglycerin with an innovator formulation.


A Quality Improvement Collaborative Program for Neonatal Pain Management in Japan.
Neonatal pain management guidelines have been released; however, there is insufficient systematic institutional support for the adoption of evidence-based pain management in Japan. To evaluate the impact of a collaborative quality improvement program on the implementation of pain management improvements in Japanese neonatal intensive care units (NICUs). Seven Japanese level III NICUs participated in a neonatal pain management quality improvement program based on an Institute for Healthcare Improvement collaborative model. The NICUs developed evidence-based practice points for pain management and implemented these over a 12-month period. Changes were introduced through a series of Plan-Do-Study-Act cycles, and throughout the process, pain management quality indicators were tracked as performance measures. Jonckheere's trend test and the Cochran-Armitage test for trend were used to examine the changes in quality indicator implementations over time (baseline, 3 months, 6 months, and 12 months). Baseline pain management data from the 7 sites revealed substantial opportunities for improvement of pain management, and testing changes in the NICU setting resulted in measurable improvements in pain management. During the intervention phase, all participating sites introduced new pain assessment tools, and all sites developed electronic medical record forms to capture pain score, interventions, and infant responses to interventions. The use of collaborative quality improvement techniques played a key role in improving pain management in the NICUs. Collaborative improvement programs provide an attractive strategy for solving evidence-practice gaps in the NICU setting.


MRI findings of a middle ear cholesteatoma in a dog.
This article describes the MRI features of a middle ear cholesteatoma in an 8 yr old flat-coated retriever. Physical examination revealed pain on opening the jaw, and otoscopic examination showed tympanic membrane rupture associated with hyperplastic tissue at the entrance of the middle ear. Standard MRI sequences allowed for the identification of a severely expanded bulla containing material that was isointense to brain tissue on T1-weighted images and of mixed intensity on T2-weighted and fluid-attenuated inversion recovery sequences. No postcontrast enhancement of the content was present, but the lining of the bulla was partially enhanced. The images allowed evaluation of the surgical margins and the secondary changes due to the expansion of the mass. Surgery was performed and histopathology confirmed the presumptive diagnosis of cholesteatoma. In the present case, MRI appeared to serve as a good alternative to computed tomography for the diagnosis of cholesteatoma.


Factors influencing participation in worksite smoking cessation and weight loss programs: the Healthy Worker Project.
Worksite intervention for health behavior change has attracted much recent interest as a potentially cost-effective way to promote healthier behaviors in the general population. In evaluating the impact of health promotion activities, it is essential to consider the entire work force rather than just self-selected participants. Overall, recruitment results reported to date have varied widely. There are a large number of factors pertaining to both employee and worksite characteristics that could contribute to variability in how well worksite health promotion programs attract employees. A critical issue that has received little research attention is the dynamics of participation in employee health promotion programs as they are offered repeatedly over time. The present study examined participation rates and contributing factors in worksite health promotion programs for weight loss and smoking cessation in the Healthy Worker Project, a randomized trial of worksite intervention conducted among 16 intervention and 16 control worksites in the Minneapolis/St. Paul metropolitan area between 1987 and 1990. Data analyses focused on characterizing individuals enrolling in worksite health promotion programs in comparison to those in the worksite population as a whole who would be considered in need of such programs.


An up-down Bayesian, defibrillation efficacy estimator.
In both the clinic and the laboratory, efficacy estimators are used to estimate the shock strength required to achieve a given defibrillation success rate. In the clinic, efficacy estimators are used to estimate highly effective doses (i.e., the shock strength that defibrillates 95% of the time), in order to choose the setting for an ICD. Efficacy estimators are used in the laboratory to compare defibrillation techniques and configurations. Current efficacy estimators are inadequate because they are either difficult to use, can only estimate the shock strength that defibrillates 50% of the time, or do not yield desirable accuracy (low RMS error). This article presents a Bayesian estimation technique that forces the difference between successive test shock strengths (step-size) to be a fixed value after each measurement. Constraining the difference dramatically reduces the computational complexity of the up-down Bayesian method. This new, up-down Bayesian protocol can be used with up to 15 measurements to estimate the shock strength for any given success rate. Simulations show that the added constraint (fixed step-size) only slightly increases the rms error, as compared to the optimum Bayesian protocol. Our simulations also show that protocols can be generated for shock strengths rounded to the nearest 1, 10, or 50 V. without a great increase in RMS error. Experimental results from a subset of all the simulations are reported from six animals, showing a < -2.4% difference between the simulated and measured errors.


Spatial offset of test field elements from surround elements affects the strength of motion aftereffects.
Static movement aftereffects (MAEs) were measured after adaptation to vertical square-wave luminance gratings drifting horizontally within a central window in a surrounding stationary vertical grating. The relationship between the stationary test grating and the surround was manipulated by varying the alignment of the stationary stripes in the window and those in the surround, and the type of outline separating the window and the surround [no outline, black outline (invisible on black stripes), and red outline (visible throughout its length)]. Offsetting the stripes in the window significantly increased both the duration and ratings of the strength of MAEs. Manipulating the outline had no significant effect on either measure of MAE strength. In a second experiment, in which the stationary test fields alone were presented, participants judged how segregated the test field appeared from its surround. In contrast to the MAE measures, outline as well as offset contributed to judged segregation. In a third experiment, in which test-stripe offset was systematically manipulated, segregation ratings rose with offset. However, MAE strength was greater at medium than at either small or large (180 degrees phase shift) offsets. The effects of these manipulations on the MAE are interpreted in terms of a spatial mechanism which integrates motion signals along collinear contours of the test field and surround, and so causes a reduction of motion contrast at the edges of the test field.


Calls for reform of medical education by the Carnegie Foundation for the Advancement of Teaching: 1910 and 2010.
The Carnegie Foundation for the Advancement of Teaching, which in 1910 helped stimulate the transformation of North American medical education with the publication of the Flexner Report, has a venerated place in the history of American medical education. Within a decade following Flexner's report, a strong scientifically oriented and rigorous form of medical education became well established; its structures and processes have changed relatively little since. However, the forces of change are again challenging medical education, and new calls for reform are emerging. In 2010, the Carnegie Foundation will issue another report, Educating Physicians: A Call for Reform of Medical School and Residency, that calls for (1) standardizing learning outcomes and individualizing the learning process, (2) promoting multiple forms of integration, (3) incorporating habits of inquiry and improvement, and (4) focusing on the progressive formation of the physician's professional identity. The authors, who wrote the 2010 Carnegie report, trace the seeds of these themes in Flexner's work and describe their own conceptions of them, addressing the prior and current challenges to medical education as well as recommendations for achieving excellence. The authors hope that the new report will generate the same excitement about educational innovation and reform of undergraduate and graduate medical education as the Flexner Report did a century ago.


Rare nasosinusal tumors: case series and literature review.
Tumors of the nasal cavity and paranasal sinuses are unusual pathologies found in clinical practice. Approximately 0.8% of all human cancers are located in this area. Despite being rare, nasosinusal neoplasms usually manifest through nonspecific symptoms that are common to numerous inflammatory pathologies. The aim of this study is to describe a series of rare nasosinusal tumors, including esthesioneuroblastomas, central giant cell granulomas, extramedullary plasmocytomas, nasosinusal hemangiopericytomas, neurofibromas and cemento-ossifying fibromas, diagnosed at the Fortaleza General Hospital. We, hereby, briefly review each of the aforementioned pathologies, stressing the need for a precise histological diagnosis for proper treatment in each case.


Increasing incidence of Plasmodium knowlesi malaria following control of P. falciparum and P. vivax Malaria in Sabah, Malaysia.
The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo and threatens the prospect of malaria elimination. However, little is known about the emergence of P. knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each malaria species over time. Reporting of microscopy-diagnosed malaria cases in Sabah is mandatory. We reviewed all available Department of Health malaria notification records from 1992-2011. Notifications of P. malariae and P. knowlesi were considered as a single group due to microscopic near-identity. From 1992-2011 total malaria notifications decreased dramatically, with P. falciparum peaking at 33,153 in 1994 and decreasing 55-fold to 605 in 2011, and P. vivax peaking at 15,857 in 1995 and decreasing 25-fold to 628 in 2011. Notifications of P. malariae/P. knowlesi also demonstrated a peak in the mid-1990s (614 in 1994) before decreasing to ≈ 100/year in the late 1990s/early 2000s. However, P. malariae/P. knowlesi notifications increased >10-fold between 2004 (n = 59) and 2011 (n = 703). In 1992 P. falciparum, P. vivax and P. malariae/P. knowlesi monoinfections accounted for 70%, 24% and 1% respectively of malaria notifications, compared to 30%, 31% and 35% in 2011. The increase in P. malariae/P. knowlesi notifications occurred state-wide, appearing to have begun in the southwest and progressed north-easterly. A significant recent increase has occurred in P. knowlesi notifications following reduced transmission of the human Plasmodium species, and this trend threatens malaria elimination. Determination of transmission dynamics and risk factors for knowlesi malaria is required to guide measures to control this rising incidence.


Experiences of participation in activities among girls with juvenile idiopathic arthritis: A qualitative study.
This study aimed to describe how girls with juvenile idiopathic arthritis (JIA) experience participation in activities in relation to their disease. Semi-structured interviews of eight girls with JIA in ages 12-15 were recorded and transcribed as a whole. Data have been analysed with qualitative content analysis. Participation was influenced by disease symptoms, which could result in absence and exclusion from participation in activities. The experience of participation was affected by the participant's choice of using strategies and making adjustments during activities. Social environment could both increase and decrease participation through treatment and type of knowledge about the disease. Also the physical environment could affect participation due to the climate or road and ground conditions. We could conclude that the experience of participation among girls with JIA was affected by disease symptoms, perceptions of selves, disease and the use of strategies, and also the social and physical environment. This indicates the need to address participation in clinical practice and the importance to include different health professionals, teachers and other personnel involved in the child's schooling.


Automated monitoring of early neurobehavioral changes in mice following traumatic brain injury.
Traumatic brain injury often causes a variety of behavioral and emotional impairments that can develop into chronic disorders. Therefore, there is a need to shift towards identifying early symptoms that can aid in the prediction of traumatic brain injury outcomes and behavioral endpoints in patients with traumatic brain injury after early interventions. In this study, we used the SmartCage system, an automated quantitative approach to assess behavior alterations in mice during an early phase of traumatic brain injury in their home cages. Female C57BL/6 adult mice were subjected to moderate controlled cortical impact (CCI) injury. The mice then received a battery of behavioral assessments including neurological score, locomotor activity, sleep/wake states, and anxiety-like behaviors on days 1, 2, and 7 after CCI. Histological analysis was performed on day 7 after the last assessment. Spontaneous activities on days 1 and 2 after injury were significantly decreased in the CCI group. The average percentage of sleep time spent in both dark and light cycles were significantly higher in the CCI group than in the sham group. For anxiety-like behaviors, the time spent in a light compartment and the number of transitions between the dark/light compartments were all significantly reduced in the CCI group than in the sham group. In addition, the mice suffering from CCI exhibited a preference of staying in the dark compartment of a dark/light cage. The CCI mice showed reduced neurological score and histological abnormalities, which are well correlated to the automated behavioral assessments. Our findings demonstrate that the automated SmartCage system provides sensitive and objective measures for early behavior changes in mice following traumatic brain injury.


Relationship between sex hormones, myocardial infarction, and occlusive coronary disease.
An alteration in sex hormones has been considered a risk factor for myocardial infarction. In this study, estradiol (E2) and testosterone (T) levels were evaluated in healthy firefighters, patients with myocardial infarction acutely and during their convalescence, patients with no evidence of occlusive coronary artery disease on arteriography, and patients with chronic angina pectoris in whom there was at least one vessel that indicated 50% occlusive coronary artery disease. Although T levels were similar in all groups, E2 levels were substantially higher in patients with myocardial infarction and in patients with chronic angina pectoris. These results support the hypothesis that elevated estrogen levels may be a risk factor for myocardial infarction and coronary artery disease, possibly by promoting clotting or coronary spasm.


Influence of lean and fat mass on bone mineral density and on urinary stone risk factors in healthy women.
The role of body composition (lean mass and fat mass) on urine chemistries and bone quality is still debated. Our aim was therefore to determine the effect of lean mass and fat mass on urine composition and bone mineral density (BMD) in a cohort of healthy females. 78 female volunteers (mean age 46 ± 6 years) were enrolled at the Stone Clinic of Parma University Hospital and subdued to 24-hour urine collection for lithogenic risk profile, DEXA, and 3-day dietary diary. We defined two mathematical indexes derived from body composition measurement (index of lean mass-ILM, and index of fat mass-IFM) and the cohort was split using the median value of each index, obtaining groups differing only for lean or fat mass. We then analyzed differences in urine composition, dietary intakes and BMD. The women with high values of ILM had significantly higher excretion of creatinine (991 ± 194 vs 1138 ± 191 mg/day, p = 0.001), potassium (47 ± 13 vs 60 ± 18 mEq/day, p < 0.001), phosphorus (520 ± 174 vs 665 ± 186 mg/day, p < 0.001), magnesium (66 ± 20 vs 85 ± 26 mg/day, p < 0.001), citrate (620 ± 178 vs 807 ± 323 mg/day, p = 0.002) and oxalate (21 ± 7 vs 27 ± 11 mg/day, p = 0.015) and a significantly better BMD values in limbs than other women with low values of ILM. The women with high values of IFM had similar urine composition to other women with low values of IFM, but significantly better BMD in axial sites. No differences in dietary habits were found in both analyses. Lean mass seems to significantly influence urine composition both in terms of lithogenesis promoters and inhibitors, while fat mass does not. Lean mass influences bone quality only in limb skeleton, while fat mass influences bone quality only in axial sites.


Apoptotic death of renal tubular cells in experimental sepsis.
Renal dysfunction attributable to sepsis was long considered a result of hemodynamic instability and subsequent local ischemia. Recent data show that apoptosis may be implicated also. The purpose of this study was to evaluate the role of apoptosis and the expression of the bax, bcl-2, caspase-8, and cytochrome c proteins in the renal parenchymal cells of rats with sepsis. Sepsis was induced using cecal ligation and puncture (CLP) in 62 male Wistar rats, which were euthanized 6, 12, 24, 36, 48, or 60 h later. Ten sham-treated animals served as a control group. Another group of 50 animals were subjected to CLP and then supervised for 60 h. Renal apoptosis was evaluated using light and transmission electron microscopy, in situ nick-end labeling (TUNEL), and flow cytometry using 7-amino-actinomycin D (7-AAD). Caspase-mediated apoptosis was assessed using M30 antibody. The expression of the apoptosis-regulator proteins B-cell lymphoma 2 (bcl-2), bcl-2-associated x protein (bax), caspase-8, and cytochrome c was detected immunohistochemically. Sepsis increased inflammatory infiltration (p < 0.001) and necrosis (p < 0.001) in renal parenchyma. Apoptosis was significantly more common than in the kidneys of control animals (p = 0.02). Nuclei stained by the TUNEL technique were predominant in the tubular cells of non-survivors (p = 0.05). The time distribution of all types of cell death was increased significantly 6 h after the induction of sepsis, and declined subsequently. Caspase-generated cytokeratin 18 (CK18) new epitope (M30) was significantly more abundant in the kidneys of animals with sepsis than in control rats, with peaks at 6 h and 60 h post-procedure (p < 0.001). In addition, cells initiating apoptosis were significantly more common at 6 h than at 48 h post-CLP (p = 0.014). Caspase-8 protein immunodetection followed the same time pattern as cell death, increasing as early as 6 h post-CLP and decreasing thereafter (p = 0.013). Bax protein expression was elevated significantly early in the course of sepsis (p = 0.037), whereas the other members of the mitochondrial-dependent pathway remained constant. Animals dying from sepsis had a significantly greater prevalence of bax- (p = 0.037) and caspase-8- (p = 0.031) immunoreactive renal cells. Apoptosis in renal tissue was significantly more common in animals with sepsis than in controls. The time distribution of cell death markers showed a consistent pattern, making early sepsis the likely initiator of the apoptotic events.


Two living species of coelacanths?
During the period of September 1997 through July 1998, two coelacanth fishes were captured off Manado Tua Island, Sulawesi, Indonesia. These specimens were caught almost 10,000 km from the only other known population of living coelacanths, Latimeria chalumnae, near the Comores. The Indonesian fish was described recently as a new species, Latimeria menadoensis, based on morphological differentiation and DNA sequence divergence in fragments of the cytochrome b and 12S rRNA genes. We have obtained the sequence of 4,823 bp of mitochondrial DNA from the same specimen, including the entire genes for cytochrome b, 12S rRNA, 16S rRNA, four tRNAs, and the control region. The sequence is 4.1% different from the published sequence of an animal captured from the Comores, indicating substantial divergence between the Indonesian and Comorean populations. Nine morphological and meristic differences are purported to distinguish L. menadoensis and L. chalumnae, based on comparison of a single specimen of L. menadoensis to a description of five individuals of L. chalumnae from the Comores. A survey of the literature provided data on 4 of the characters used to distinguish L. menadoensis from L. chalumnae from an additional 16 African coelacanths; for all 4 characters, the Indonesian sample was within the range of variation reported for the African specimens. Nonetheless, L. chalumnae and L. menadoensis appear to be separate species based on divergence of mitochondrial DNA.


Comparison of the effects of high doses of rosuvastatin versus atorvastatin on the subpopulations of high-density lipoproteins.
Atorvastatin and rosuvastatin are both highly effective in decreasing low-density lipoprotein cholesterol and triglyceride levels. However, rosuvastatin was shown to be more effective in increasing high-density lipoprotein (HDL) cholesterol levels. The purpose of the study is to compare the effects of daily doses of rosuvastatin 40 mg with atorvastatin 80 mg during a 6-week period on HDL subpopulations in 306 hyperlipidemic men and women. We previously showed that increased levels of large alpha-1 and alpha-2 HDLs decrease the risk of coronary heart disease and protect against progression of coronary atherosclerosis (superior to HDL cholesterol). In this study, both statins caused significant increases in large alpha-1 (p <0.001) and alpha-2 (p <0.001 for rosuvastatin, p <0.05 for atorvastatin) and significant (p <0.001) decreases in small pre-beta-1 HDL levels; however, increases in the 2 large HDL particles were significantly higher for rosuvastatin than atorvastatin (alpha-1, 24% vs 12%; alpha-2, 13% vs 4%; p <0.001). Statin-induced increases in alpha-1 and alpha-2 correlated with increases in HDL cholesterol, whereas decreases in pre-beta-1 were associated with decreases in triglycerides. In subjects with low HDL cholesterol (<40 mg/dl for men, <50 mg/dl for women, n = 99), increases in alpha-1 were 32% versus 11%, and in alpha-2, 21% versus 5% for rosuvastatin and atorvastatin, respectively. In conclusion, our data show that both statins, given at their maximal doses, favorably alter the HDL subpopulation profile, but also that rosuvastatin is significantly more effective in this regard than atorvastatin.


Adaptation of retrovirus producer cells to serum deprivation: Implications in lipid biosynthesis and vector production.
The manufacture of enveloped virus, particularly retroviral (RV) and lentiviral (LV) vectors, faces the challenge of low titers that are aggravated under serum deprivation culture conditions. Also, the scarce knowledge on the biochemical pathways related with virus production is still limiting the design of rational strategies for improved production yields. This work describes the adaptation to serum deprivation of two human RV packaging cell lines, 293 FLEX and Te Fly and its effects on lipid biosynthetic pathways and infectious vector production. Total lipid content as well as cellular cholesterol were quantified and lipid biosynthesis was assessed by (13)C-NMR spectroscopy; changes in gene expression of lipid biosynthetic enzymes were also evaluated. The effects of adaptation to serum deprivation in lipid biosynthesis were cell line specific and directly correlated with infectious virus titers: 293 FLEX cells faced severe lipid starvation-up to 50% reduction in total lipid content-along with a 68-fold reduction in infectious vector titers; contrarily, Te Fly cells were able to maintain identical levels of total lipid content by rising de novo lipid biosynthesis, particularly for cholesterol-50-fold increase-with the consequent recovery of infectious vector productivities. Gene expression analysis of lipid biosynthetic enzymes further confirmed cholesterol production pathway to be prominently up-regulated under serum deprivation conditions for Te Fly cells, providing a genotype-phenotype validation for enhanced cholesterol synthesis. These results highlight lipid metabolism dynamics and the ability to activate lipid biosynthesis under serum deprivation as an important feature for high retroviral titers. Mechanisms underlying virus production and its relationship with lipid biosynthesis, with special focus on cholesterol, are discussed as potential targets for cellular metabolic engineering.


Acute Toxicity From Intravenous Use of the Tricyclic Antidepressant Tianeptine.
Tianeptine (7-[([3-chloro-6,11]-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl) amino] heptanoic acid S, S dioxide) is a tricyclic compound prescribed as an antidepressant in European countries, but is not currently approved for use in the United States. There are few published case reports of tianeptine intoxication. Presented is the first case of acute toxicity associated with the intravenous use of tianeptine. A 36-year-old male intentionally injected tianeptine powder intravenously to "help him see into the future". He became unresponsive and a bystander called emergency medical services. Upon arrival to the Emergency Department, excessive constriction of the pupils, sedation, and a respiratory rate of 6 respirations per minute (rpm) were noted. Blood and urine were collected ~2 h post admission. The patient's serum ethanol concentration was 133 mg/dL. His toxicity was successfully reversed with two doses of naloxone 0.4 mg IV. He was started on a naloxone infusion at 0.2 mg/h and discharged 13 h after admittance awake, alert and oriented. The patient's urine sample screened negative for common drugs of abuse and total tricyclic antidepressants. A high performance liquid chromatography tandem mass spectrometry method was developed and validated to quantify tianeptine in urine. The calibration range was 1-100 ng/mL with linear regression correlation (r2) of 0.9996 or greater. The limit of quantitation was administratively set at 1 ng/mL. The bias of the assay was determined to be within ±20% of the target value for each quality control specimen. The intra-day and inter-day precision did not exceed 15% coefficient of variation for each quality control specimen. Matrix effects, absolute recovery, carryover and specificity were also evaluated. The patient's tianeptine urine concentration was determined to be 2 ng/mL.


Angiotensin II stimulates phosphorylation of an ectodomain-truncated platelet-derived growth factor receptor-beta and its binding to class IA PI3K in vascular smooth muscle cells.
PI3K (phosphoinositide 3-kinase) activity is involved in Ang (angiotensin) II-stimulated VSMC (vascular smooth muscle cell) growth and hypertrophy. In the present study, we demonstrate that the inhibition of PI3K in VSMCs by expression of a dominant-negative p85alpha mutant lacking the p110-binding domain (Deltap85), or by treatment of cells with LY294002, inhibited Ang II-stimulated PAI-1 (plasminogen activator inhibitor-1) mRNA expression. Using a GST (glutathione S-transferase) fusion protein containing the p85 N-terminal SH2 (Src homology 2) domain as 'bait' followed by MS/MS (tandem MS), we identified a 70 kDa fragment of the p70 PDGFR-beta (platelet-derived growth factor receptor-beta) as a signalling adapter that is phosphorylated and recruits the p85 subunit of PI3K after Ang II stimulation of AT1 (Ang II subtype 1) receptors on VSMCs. This fragment of the PDGFR-beta, which has a truncation of its extracellular domain, accounted for approx. 15% of the total PDGFR-beta detected in VSMCs with an antibody against its cytoplasmic domain. Stimulation of VSMCs with Ang II increased tyrosine-phosphorylation of p70 PDGFR-beta at Tyr751 and Tyr1021 and increased its binding to p85. PDGF also induced phosphorylation of p70 PDGFR-beta, a response inhibited by the PDGF tyrosine kinase selective inhibitor, AG1296. By contrast, Ang II-induced phosphorylation of the 70 kDa receptor was not affected by AG1296. Ang II-stimulated phosphorylation of the p70 PDGFR-beta was blocked by the AT1 receptor antagonist, candesartan (CV 11974) and was partially inhibited by PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine}, an Src family kinase inhibitor. Our result suggests that the p70 PDGFR-beta functions as an adapter that recruits PI3K to the membrane upon AT1 receptor stimulation.


Trypanosomiasis in domestic livestock in the Lambwe Valley area and a field evaluation of various diagnostic techniques.
A preliminary survey of 2 073 domestic animals in the Lambwe Valley, Kenya, showed a 7.4% rate of infection with Trypanosoma congolense and T. vivax. In comprehensive surveys covering 6 384 domestic stock, pathogenic trypanosomes were found in 17.0% of cattle, 5.0% of sheep, and 2.1% of goats. Adults were more often infected than young animals, and males more often than females. T. congolense was the trypanosome most frequently diagnosed, followed by T. vivax and the T. brucei subgroup. T. theileri was also found. The examination of wet blood films in the field as a means of diagnosing trypanosome infections was shown to be valueless. More infections were detected in peripheral blood films than in systemic blood films, but both should be examined. An examination of smears of glandular fluid is essential for the diagnosis of T. vivax in cattle, while mouse-inoculation tests are necessary for the diagnosis of the T. brucei subgroup. The detection of T. vivax was improved by the high-speed centrifugation of blood samples in capillary tubes.


Drug-induced rhabdomyolysis: from systems pharmacology analysis to biochemical flux.
The goal of this study was to integrate systems pharmacology and biochemical flux to delineate drug-induced rhabdomyolysis by leveraging prior knowledge and publicly accessible data. A list of 211 rhabdomyolysis-inducing drugs (RIDs) was compiled and curated from multiple sources. Extended pharmacological network analysis revealed that the intermediators directly interacting with the pharmacological targets of RIDs were significantly enriched with functions such as regulation of cell cycle, apoptosis, and ubiquitin-mediated proteolysis. A total of 78 intermediators were shown to be significantly connected to at least five RIDs, including estrogen receptor 1 (ESR1), synuclein gamma (SNCG), and janus kinase 2 (JAK2). Transcriptomic analysis of RIDs profiled in Connectivity Map on the global scale revealed that multiple pathways are perturbed by RIDs, including ErbB signaling and lipid metabolism pathways, and that carnitine palmitoyl transferase 2 (CPT2) was in the top 1 percent of the most differentially perturbed genes. CPT2 was downregulated by nine drugs that perturbed the genes significantly enriched in oxidative phosphorylation and energy-metabolism pathways. With statins as the use case, biochemical pathway analysis on the local scale implicated a role for CPT2 in statin-induced perturbation of energy homeostasis, which is in agreement with reports of statin-CPT2 interaction. Considering the complexity of human biology, an integrative multiple-approach analysis composed of a biochemical flux network, pharmacological on- and off-target networks, and transcriptomic signature is important for understanding drug safety and for providing insight into clinical gene-drug interactions.


Pilot and Repeat Trials as Development Tools Associated with Demonstration of Bioequivalence.
The purpose of this work is to use simulated trials to study how pilot trials can be implemented in relation to bioequivalence testing, and how the use of the information obtained at the pilot stage can influence the overall chance of showing bioequivalence (power) or the chance of approving a truly bioinequivalent product (type I error). The work also covers the use of repeat pivotal trials since the difference between a pilot trial followed by a pivotal trial and a pivotal trial followed by a repeat trial is mainly a question of whether a conclusion of bioequivalence can be allowed after the first trial. Repeating a pivotal trial after a failed trial involves dual or serial testing of the bioequivalence null hypothesis, and the paper illustrates how this may inflate the type I error up to almost 10%. Hence, it is questioned if such practice is in the interest of patients. Tables for power, type I error, and sample sizes are provided for a total of six different decision trees which allow the developer to use either the observed geometric mean ratio (GMR) from the first or trial or to assume that the GMR is 0.95. In cases when the true GMR can be controlled so as not to deviate more from unity than 0.95, sequential design methods ad modum Potvin may be superior to pilot trials. The tables provide a quantitative basis for choosing between sequential designs and pivotal trials preceded by pilot trials.


Inhaled isobutyl nitrite inhibited macrophage inducible nitric oxide by blocking NFkappaB signaling and promoting degradation of inducible nitric oxide synthase-2.
We previously reported that inhaled isobutyl nitrite inhibited macrophage tumoricidal activity by inhibiting inducible nitric oxide (NO) production. In the present study, a much shorter inhalant exposure regimen (five daily exposures) inhibited inducible NO and the NO synthase (NOS2). One of the ways in which NO and NOS2 are regulated is by ubiquitin-dependent NOS2 degradation. Immunoprecipitated NOS2 showed increased poly-ubiquitination, following exposure to the inhalant. In addition, Western blots of macrophage nuclear extracts for the NFkappaB subunit, p65, showed that exposure to the inhalant inhibited NFkappaB signaling, necessary for induction of NOS2. The inhalant blocked phosphorylation of the NFkappaB inhibitor, IkappaBalpha. The inhibition of NFkappaB signaling following inhalant exposure was confirmed using mice transgenic for the kappaB-dependent promoter of the HIV 5' LTR linked to luciferase. The data suggested that inhalant exposure likely inhibited macrophage NO production by blocking NFkappaB-mediated activation signaling and promoting poly ubiquitination of NOS2.


Differential Regulation of Kernel Set and Potential Kernel Weight by Nitrogen Supply and Carbohydrate Availability in Maize Genotypes Contrasting in Nitrogen Use Efficiency.
Sub-optimal nitrogen (N) conditions reduce maize yield due to a decrease in two sink components: kernel set and potential kernel weight. Both components are established during the lag phase, suggesting that they could compete for resources during this critical period. However, whether this competition occurs or whether different genotypic strategies exist to optimize photoassimilate use during the lag phase is not clear and requires further investigation. We have addressed this knowledge gap by conducting a nutrient solution culture experiment that allows abrupt changes in N level and light intensity during the lag phase. We investigated plant growth, dry matter partitioning, non-structural carbohydrate concentration, N concentration, and 15N distribution (applied 4 days before silking) in plant organs at the beginning and the end of the lag phase in two maize hybrids that differ in grain yield under N-limited conditions: one is a nitrogen-use-efficient (EFFI) genotype and the other is a control (GREEN) genotype that does not display high N use efficiency. We found that the two genotypes used different mechanisms to regulate kernel set. The GREEN genotype showed a reduction in kernel set associated with reduced dry matter allocation to the ear during the lag phase, indicating that the reduced kernel set under N-limited conditions was related to sink restrictions. This idea was supported by a negative correlation between kernel set and sucrose/total sugar ratios in the kernels, indicating that the capacity for sucrose cleavage might be a key factor defining kernel set in the GREEN genotype. By contrast, the kernel set of the EFFI genotype was not correlated with dry matter allocation to the ear or to a higher capacity for sucrose cleavage; rather, it showed a relationship with the different EFFI ear morphology with bigger kernels at the apex of the ear than in the GREEN genotype. The potential kernel weight was independent of carbohydrate availability but was related to the N flux per kernel in both genotypes. In conclusion, kernel set and potential kernel weight are regulated independently, suggesting the possibility of simultaneously increasing both sink components in maize.


Cultural investment and urban socio-economic development: a geosocial network approach.
Being able to assess the impact of government-led investment onto socio-economic indicators in cities has long been an important target of urban planning. However, owing to the lack of large-scale data with a fine spatio-temporal resolution, there have been limitations in terms of how planners can track the impact and measure the effectiveness of cultural investment in small urban areas. Taking advantage of nearly 4 million transition records for 3 years in London from a popular location-based social network service, Foursquare, we study how the socio-economic impact of government cultural expenditure can be detected and predicted. Our analysis shows that network indicators such as average clustering coefficient or centrality can be exploited to estimate the likelihood of local growth in response to cultural investment. We subsequently integrate these features in supervised learning models to infer socio-economic deprivation changes for London's neighbourhoods. This research presents how geosocial and mobile services can be used as a proxy to track and predict socio-economic deprivation changes as government financial effort is put in developing urban areas and thus gives evidence and suggestions for further policymaking and investment optimization.


Analysis of the stable levels of messenger RNA derived from different polymorphic alleles in the vitamin D receptor gene.
The association between polymorphisms in the vitamin D receptor (VDR) gene and bone mineral density (BMD) has been studied by many investigators. However, the question of how polymorphisms in the gene modulate the function of the VDR remains to be answered. To address this issue, we examined the mRNA levels of the VDR in relation to polymorphisms. First, we compared the levels of mRNA between the allele with the polymorphic TaqI-digestive site (t) and nondigestive site (T) located at exon 9 of the VDR gene determined by reverse transcription-polymerase chain reaction (RT-PCR). Total RNA was extracted from peripheral mononuclear cells in volunteers whose genotype is Tt. After the amplification of cDNA by PCR, the amplified fragments were digested by TaqI. The digested (t) and undigested (T) fragments were visualized by ethidium bromide and semiquantified by an image analyzer. In 24 subjects, the mRNA levels of allele t were significantly higher than those of allele T (1.35 fold, P < 0.001). Second, the VDR mRNA levels were estimated by competitive RT-PCR in 60 healthy subjects (35TT, 24Tt, 1 tt). The competitive template was 47 bases shorter than the product of the wild-type gene. After RT-PCR, the mRNA level was determined by a comparison with the competitive fragments. No significant difference in the mRNA level was observed between two groups (1.75 +/- 0.84 and 1.65 +/- 0.99 10(-13)mol/g total RNA in TT and Tt, respectively). In addition, no significant relationship was observed between the VDR mRNA levels and BMD in the 23 subjects whose BMD data were available. In conclusion, higher mRNA levels of allele t than T were detected, but the difference did not result in higher levels of VDR mRNA in subjects with the Tt genotype compared to those with the TT genotype.


Orbital involvement by Wegener's granulomatosis: imaging findings.
The purpose of this study was to define patterns of Wegener's granulomatosis (WG) orbital disease involvement. We evaluated the orbital examinations of 14 WG patients (CT for nine, MR imaging for three, and both CT and MR imaging for two) for the number of involved orbits, intraconal or extraconal location, involvement of the orbital apex, sinus involvement, bony erosion, and optic nerve compression. MR images were analyzed for signal characteristics and enhancement patterns. We found orbital disease to be unilateral in 12 patients (86%) and bilateral in two patients (14%) (total of 16 orbits). In 11 orbits (69%), coexistent orbital and sinus diseases with bony erosion were present. Orbital disease without sinus disease was seen in five orbits (31%). Intraorbital disease distribution was as follows: solely extraconal--seven orbits (44%) (four with involvement of muscle); intraconal with muscular involvement--one orbit (6%); combined intra- and extraconal--seven orbits (44%); and primarily orbital apex--one orbit (6%). Involvement of the apex was seen in six orbits. The WG mass was hypointense relative to orbital fat on three standard T2-weighted MR images. We saw homogeneous MR contrast enhancement in all four orbits studied on enhanced T1-weighted images. Intraorbital WG involvement is usually accompanied by paranasal sinus disease. A hypointense signal on T2-weighted MR images is helpful in suggesting the diagnosis.


Mortality Following Hip Fracture Surgery During COVID-19 Pandemic Compared to Pre-COVID-19 Period: A Case Matched Cohort Series.
This study aims to report on clinical outcomes and 30-day mortality of patients with neck of femur fracture during COVID-19 pandemic and compare the outcomes in a cohort during the same period prior to the pandemic. The study included 66 patients with hip fracture over the age of 60 years, presented between 1st March and 15th May 2020 and matched with the patients with hip fractures (75 patients) managed during the corresponding period in 2019 as control. Data was collected on demographics, comorbidities, COVID-19 status, procedures and mortality and complications. Thirty-day mortality following hip surgery was 13.6% during COVID-19 pandemic with all the mortalities in patients with ASA Grade 3 and 4. Mortality was considerably high for intracapsular fracture (20%) but highest in cemented hemiarthroplasty (20%). One third of the hip fractures operated in COVID-19 designated theatre died within 30 days of surgery. Thirty-day mortality rate for COVID-19 positive hip fracture patients were 55.5%. There has been higher 30-day mortality for hip surgeries during COVID-19 pandemic with positive correlation between patient's COVID-19 test status and 30-day mortality following hip surgeries. There is strong association between 30-day mortality and the designated theatre (Clean/COVID) where the patients were operated on with higher mortality for intracapsular neck of femur fractures with significant mortality associated with cemented hemiarthroplasty particularly among symptomatic or COVID-19 positive patients. Therefore, adoption of a multidisciplinary approach is recommended to optimally balance the risk-benefit ratio for planning of management of hip fractures while considering patient's peri-operative outcomes.


Alternative splice variants of survivin as potential targets in cancer.
Survivin, a member of the IAP family is an attractive target for cancer treatment due to it's over expression in most cancers and low or no expression in most differentiated adult tissues. Survivin expression is a poor prognostic marker in a number of cancers. Clinical trials are currently underway evaluating anti-sense oligonucleotides against Survivin, immunotherapy using Survivin primed dentritic cells and peptide mimics that block interaction of Survivin with Hsp90 resulting in loss of Survivin protein stability. Additional approaches using ribozymes against Survivin mRNA, or dominant-negative cDNA to block Survivin function are in pre-clinical stages. Like many genes, Survivin is alternately spliced and a number of new splice variants have recently been identified. Expression of some of these splice variants correlates with loss of steroid receptors as well as the tumor suppressor p53, in some cancers, suggesting that like wild-type Survivin, at least some of these splice variants may also have prognostic relevance. This review will focus on the current understanding of the function of Survivin splice variants and their expression and sub-cellular localization in normal and neoplastic tissues as well as critically evaluating the potential toxicity of the Survivin directed therapies and their predicted effect on the alternatively spliced Survivin isoforms.


Blockade of S100A8 and S100A9 suppresses neutrophil migration in response to lipopolysaccharide.
Recently, proinflammatory activities had been described for S100A8 and S100A9, two proteins found at inflammatory sites and within the neutrophil cytoplasm. In this study, we investigated the role of these proteins in neutrophil migration in vivo in response to LPS. LPS was injected into the murine air pouch, which led to the release of S100A8, S100A9, and S100A8/A9 in the pouch exudates that preceded accumulation of neutrophils. Passive immunization against S100A8 and S100A9 led to a 52% inhibition of neutrophil migration in response to LPS at 3 h postinjection. Injection of LPS was also associated with an increase in peripheral blood neutrophils and the presence in serum of S100A9 and S100A8/A9. Intravenous injection of S100A8, S100A9, or S100A8/A9 augmented the number of circulating neutrophils and diminished the number of neutrophils in the bone marrow, demonstrating that S100A8 and S100A9 induced the mobilization of neutrophils from the bone marrow to the blood. Finally, passive immunization with anti-S100A9 inhibited the neutrophilia associated with LPS injection in the air pouch. These results suggest that S100A8 and S100A9 play a role in the inflammatory response to LPS by inducing the release of neutrophils from the bone marrow and directing their migration to the inflammatory site.


Seasonality, shelf life and storage atmosphere are main drivers of the microbiome and E. coli O157:H7 colonization of post-harvest lettuce cultivated in a major production area in California.
Lettuce is linked to recurrent outbreaks of Shiga toxin-producing Escherichia coli (STEC) infections, the seasonality of which remains unresolved. Infections have occurred largely from processed lettuce, which undergoes substantial physiological changes during storage. We investigated the microbiome and STEC O157:H7 (EcO157) colonization of fresh-cut lettuce of two cultivars with long and short shelf life harvested in the spring and fall in California and stored in modified atmosphere packaging (MAP) at cold and warm temperatures. Inoculated EcO157 declined significantly less on the cold-stored cultivar with short shelf life, while multiplying rapidly at 24 °C independently of cultivar. Metagenomic sequencing of the lettuce microbiome revealed that the pre-storage bacterial community was variable but dominated by species in the Erwiniaceae and Pseudomonadaceae. After cold storage, the microbiome composition differed between cultivars, with a greater relative abundance (RA) of Erwiniaceae and Yersiniaceae on the cultivar with short shelf life. Storage at 24 °C shifted the microbiome to higher RAs of Erwiniaceae and Enterobacteriaceae and lower RA of Pseudomonadaceae compared with 6 °C. Fall harvest followed by lettuce deterioration were identified by recursive partitioning as important factors associated with high EcO157 survival at 6 °C, whereas elevated package CO2 levels correlated with high EcO157 multiplication at 24 °C. EcO157 population change correlated with the lettuce microbiome during 6 °C storage, with fall microbiomes supporting the greatest EcO157 survival on both cultivars. Fall and spring microbiomes differed before and during storage at both temperatures. High representation of Pantoea agglomerans was a predictor of fall microbiomes, lettuce deterioration, and enhanced EcO157 survival at 6 °C. In contrast, higher RAs of Erwinia persicina, Rahnella aquatilis, and Serratia liquefaciens were biomarkers of spring microbiomes and lower EcO157 survival. The microbiome of processed MAP lettuce evolves extensively during storage. Under temperature abuse, high CO2 promotes a lettuce microbiome enriched in taxa with anaerobic capability and EcO157 multiplication. In cold storage, our results strongly support a role for season and lettuce deterioration in EcO157 survival and microbiome composition, suggesting that the physiology and microbiomes of fall- and spring-harvested lettuce may contribute to the seasonality of STEC outbreaks associated with lettuce grown in coastal California.


An epidemiological survey using the Treatment Priority Index (TPI).
The purpose of this study was to evaluate the prevalence of malocclusion and to assess the need for orthodontic treatment among 6-10 year old Turkish primary school children. The Treatment Priority Index (TPI) was used to record and measure the malocclusions. The findings were that 40.38 per cent of the observed population showed normal occlusion, 21.85 per cent had minor manifestations of malocclusion and treatment need was slight, 25.17 per cent of the subjects showed definite malocclusion, 7.54 per cent had severe malocclusion and 5.06 per cent had a very severe handicap with a mandatory treatment requirement. Orthodontic treatment need increased between 6 and 10 years of age. No statistically significant difference was found between the mean TPI values of male and female subjects.


Sustained Engraftment of Cryopreserved Human Bone Marrow CD34(+) Cells in Young Adult NSG Mice.
Hematopoietic stem cells (HSCs) are defined by their ability to repopulate the bone marrow of myeloablative conditioned and/or (lethally) irradiated recipients. To study the repopulating potential of human HSCs, murine models have been developed that rely on the use of immunodeficient mice that allow engraftment of human cells. The NSG xenograft model has emerged as the current standard for this purpose allowing for engraftment and study of human T cells. Here, we describe adaptations to the original NSG xenograft model that can be readily implemented. These adaptations encompass use of adult mice instead of newborns and a short ex vivo culture. This protocol results in robust and reproducible high levels of lympho-myeloid engraftment. Immunization of recipient mice with relevant antigen resulted in specific antibody formation, showing that both T cells and B cells were functional. In addition, bone marrow cells from primary recipients exhibited repopulating ability following transplantation into secondary recipients. Similar results were obtained with cryopreserved human bone marrow samples, thus circumventing the need for fresh cells and allowing the use of patient derived bio-bank samples. Our findings have implications for use of this model in fundamental stem cell research, immunological studies in vivo and preclinical evaluations for HSC transplantation, expansion, and genetic modification.