Are There Gaps in Current Thoracic Surgery Residency Training Programs?
Cardiothoracic surgery is rapidly evolving to adapt to a changing health care environment and a wider application of innovative techniques. The Society of Thoracic Surgeons Workforce on Thoracic Surgery Resident Issues Transition to Practice Task Force sought to identify new or existing gaps of training in contemporary thoracic surgery residency training programs. A voluntary survey consisting of 24 questions was distributed to recent graduates of thoracic surgery residency programs in the United States during the 2014 American Board of Thoracic Surgery oral examination application process. Fifty-five of 132 applicants anonymously participated. The majority of respondents admitted that they needed more instruction or lacked confidence with the following specific cardiothoracic procedures: minimally invasive cardiac operations (25/52, 48%), robotic cardiac operations (29/52, 55.8%), endovascular operations (28/52, 53.8%), robotic pulmonary operations (29/52, 55.8%), minimally invasive esophageal operations (24/52, 46.2%), robotic esophageal operations (32/52, 61.5%), and operations on congenital cardiac conditions (31/52, 59.6%). The respondents further declared either a need for more instruction or lack of confidence in employment contracting (17/21, 81.0%), negotiating terms of employment (17/21, 81.0%), and professional service agreements (16/21, 76.2%). Further exposure to minimally invasive robotic procedures, operations on congenital conditions, and issues of practice management appear to be needed in contemporary cardiothoracic training in the United States. These identified gaps may assist cardiothoracic surgery residency programs to optimally prepare future graduates for our evolving specialty.


Chlorophyll degradation and formation of colorless chlorophyll derivatives during soybean (Glycine max L. Merill) seed maturation.
The natural chlorophyll degradation results in noncolored chlorophyll catabolites (NCCs), but there are controversies if these are the final products. The formation and degradation of NCCs during soybean seed ( Glycine max L. Merrill) maturation and two drying temperatures were investigated. Soybean was harvested at six maturation stages. The effect of postharvest drying at 40 and 60 degrees C on the NCC formation was analyzed by high-performance liquid chromatography (HPLC), and results were expressed as areas under the curve. All samples contained fractions with an absorption maximum at 320 nm, typical for NCC. The amounts of NCC increased until 114 days after planting and were significantly lower in advanced maturation stages. These results indicate that the NCC in soybeans might not be the final products of chlorophyll degradation. Their reduction in advanced maturation stages may be due to further metabolization. Heating soybeans at 40 and 60 degrees C promoted unnatural chlorophyll degradation and impaired the formation of NCC.


[Combined treatment of rectal cancer].
In 15 males and 25 females at the age of 24--70 the authors have studied radiation pathomorphosis, the early and late results in anal and low ampullar cancer following preoperative large fractionation irradiation on a gamma-therapeutic machine "Rokus" with the rotation regime of 400--600 rad daily, a total dosage--2000--3000 rad. The operation was performed 2--3 days following the irradiation. Eighteen patients were followed up over 3 years. Recurrences and metastases were noted in 5 cases (glandular-solid and mucosa forms of cancer). A 3-year survival was 72.2% versus 40.7% (P less than 0.001) while using surgical therapy solely.


Long-term trends in Indigenous deaths from chronic diseases in the Northern Territory: a foot on the brake, a foot on the accelerator.
To examine trends in Northern Territory Indigenous mortality from chronic diseases other than cancer. A comparison of trends in rates of mortality from six chronic diseases (ischaemic heart disease [IHD], chronic obstructive pulmonary disease [COPD], cerebrovascular disease [CVD], diabetes mellitus [DM], renal failure [RF] and rheumatic heart disease [RHD]) in the NT Indigenous population with those of the total Australian population. NT Indigenous and total Australian populations, 1977-2001. Estimated average annual change in chronic disease mortality rates and in mortality rate ratios. Death rates from IHD and DM among NT Indigenous peoples increased between 1977 and 2001, but this increase slowed after 1990. Death rates from COPD rose before 1990, but fell thereafter. There were non-significant declines in death rates from CVD and RHD. Mortality rates from RF rose in those aged > or = 50 years. The ratios of mortality rates for NT Indigenous to total Australian populations from these chronic diseases increased throughout the period. Mortality rates from IHD and DM in the NT Indigenous population have been increasing since 1977, but there is evidence of a slower rise (or even a fall) in death rates in the 1990s. These early small changes give reason to hope that some improvements (possibly in medical care) have been putting the brakes on chronic disease mortality among Aboriginal and Torres Strait Islander peoples.


Role of modified nucleosides in tRNA: effect of modification of the 2-thiouridine derivative located at the 5'-end of the anticodon of yeast transfer RNA Lys2.
Yeast tRNA Lys2 codes preferentially for AAA and contains a 2-thiouridine derivative (U) at the 5'-position of the anticodon. Removal of the 2-thio group from U by treatment with CNBr did not affect the amino acid accepting activity of the modified tRNA Lys2. CNBr treated tRNA Lys2 was active in protein synthesis but with a much reduced efficiency. Although the modified tRNA Lys2 was recognized by elongation factor (EF) T, the EFT dependent binding to ribosomes to tRNA Lys2 (CNBr) was markedly decreased.


Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice.
The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In the present work, we investigated the physiological role of microglia in the remodeling of perineuronal nets (PNNs), predominantly associated with parvalbumin-immunopositive (PV+) interneurons, and the perisynaptic ECM around pyramidal neurons in the hippocampus. Adult mice were treated with PLX3397 (pexidartinib), as the inhibitor of colony-stimulating factor 1 receptor (CSF1-R), to deplete microglia. Then, confocal analysis of the ECM and synapses was performed. Although the elimination of microglia did not alter the overall number or intensity of PNNs in the CA1 region of the hippocampus, it decreased the size of PNN holes and elevated the expression of the surrounding ECM. In the neuropil area in the CA1 str. radiatum, the depletion of microglia increased the expression of perisynaptic ECM proteoglycan brevican, which was accompanied by the elevated expression of presynaptic marker vGluT1 and the increased density of dendritic spines. Thus, microglia regulate the homeostasis of pre- and postsynaptic excitatory terminals and the surrounding perisynaptic ECM as well as the fine structure of PNNs enveloping perisomatic-predominantly GABAergic-synapses.


Trends in healthcare resource use and expenditure before and after ischaemic stroke. A population-based study.
Despite improved survival rates, stroke represents an increasing healthcare and socioeconomic burden. We describe the main characteristics of patients with ischaemic stroke and resource use and associated expenditure one year before and 3 years after stroke, using a population-based dataset. The information technology systems of the Catalan Health Service were used to identify patients with ischaemic strokes occurring between January 2012 and December 2016. For each patient, information from one year before the stroke and up to 3 years thereafter was linked across databases. We describe annual and monthly resource use and healthcare expenditure per patient. We identified 36 044 patients with ischaemic stroke (mean age, 74.7 ± 13.3 years). The survival rate at 3 years was 63%. Average expenditure per patient was €3230 the year before stroke, €11 060 for year 1 after stroke, €4104 for year 2, and €3878 for year 3. The greatest determinants of cost in year 1 were hospitalisation (including initial hospitalisation), representing 45% of the difference in expenditure compared to the previous year, and convalescence and rehabilitation services, representing 33% of this difference. After year one, the increase in expenditure was mainly determined by additional hospital admissions and drug treatment. After ischaemic stroke, healthcare expenditure increases primarily because of initial hospitalisation. After year one, the expenditure decreases but remains above baseline values. Information from population-based datasets is useful for improving the planning of stroke services.


Women's experiences of maternity care: satisfaction or passivity?
This study is a first attempt to describe Lebanese women's responses to the medical management of their pregnancy and delivery. A qualitative approach in data collection and analysis was adopted to gain an in-depth view of women's perceptions. Women of any parity undergoing a normal vaginal delivery during the three months preceding the interview were interviewed in different areas in Lebanon: one urban, one semi-rural and two remote rural. Childbirth for all the women interviewed was managed within the medical system. Findings show that women accord total trust to their physicians, and very rarely question the usefulness of many routinely applied procedures, even those which the literature shows are unnecessary. When probed, women report that many aspects of the technical care are intimidating and that they experience discomfort with these procedures. Women are more vocal about patient-provider communication and value good interaction with their provider. The extent of passivity and feelings of discontent women have varies according to their social class and the amount of psychosocial support they receive throughout the process of childbirth.


High levels of mRNA encoding IL-4 in unstimulated peripheral blood mononuclear cells from tuberculosis patients revealed by quantitative nested reverse transcriptase-polymerase chain reaction; correlations with serum IgE levels.
The dominant view has been that there is little or no activation of Type 2 cytokine production in human tuberculosis. A novel approach to quantitative nested reverse transcriptase-polymerase chain reaction has revealed that this conclusion was based on technical inadequacies of earlier studies, particularly the failure to discriminate between IL-4 and the IL-4 splice variant, IL4delta2. A new approach reveals that the largest cytokine change in tuberculosis is a 1-2 log increase in copy number for mRNAs encoding IL-4 and IL-13, accompanied by a small decrease in expression of mRNA encoding interferon-gamma. The increased IL-4 level correlates with disease severity and with serum levels of IgE and soluble CD30, and may be attributable to the recently observed increase in conversion of cortisone into cortisol in tuberculous lesions. The implications of these findings for pathogenesis, vaccine design and immunotherapy are discussed, as effective reagents will need to downregulate this inappropriate Th2 component.


What are the barriers to implementation of cardiopulmonary resuscitation training in secondary schools? A qualitative study.
Cardiopulmonary resuscitation (CPR) training in schools is recommended to increase bystander CPR and thereby survival of out-of-hospital cardiac arrest, but despite mandating legislation, low rates of implementation have been observed in several countries, including Denmark. The purpose of the study was to explore barriers to implementation of CPR training in Danish secondary schools. A qualitative study based on individual interviews and focus groups with school leadership and teachers. Thematic analysis was used to identify regular patterns of meaning both within and across the interviews. 8 secondary schools in Denmark. Schools were selected using strategic sampling to reach maximum variation, including schools with/without recent experience in CPR training of students, public/private schools and schools near to and far from hospitals. The study population comprised 25 participants, 9 school leadership members and 16 teachers. School leadership and teachers considered it important for implementation and sustainability of CPR training that teachers conduct CPR training of students. However, they preferred external instructors to train students, unless teachers acquired the CPR skills which they considered were needed. They considered CPR training to differ substantially from other teaching subjects because it is a matter of life and death, and they therefore believed extraordinary skills were required for conducting the training. This was mainly rooted in their insecurity about their own CPR skills. CPR training kits seemed to lower expectations of skill requirements to conduct CPR training, but only among those who were familiar with such kits. To facilitate implementation of CPR training in schools, it is necessary to have clear guidelines regarding the required proficiency level to train students in CPR, to provide teachers with these skills, and to underscore that extensive skills are not required to provide CPR. Further, it is important to familiarise teachers with CPR training kits.


High-dose epinephrine is not superior to standard-dose epinephrine in pediatric in-hospital cardiopulmonary arrest.
To compare the efficacy of high-dose epinephrine (HDE) with that of standard-dose epinephrine (SDE) for resuscitation from in-hospital pediatric cardiopulmonary arrest (CPA). Fifty-four-month retrospective study of all pediatric patients who had a CPA while hospitalized at a tertiary care children's hospital. Standard pediatric advanced life support techniques were used for all patients. Patients received HDE or SDE in accordance with physician orders and standard protocols at the time of CPA. Primary outcome measures were the return of spontaneous circulation (ROSC), the duration of survival after resuscitation, survival to hospital discharge, and Pediatric Overall Performance Category scores at the time of discharge. During the study period, 51 patients met entry criteria and had a total of 58 CPAs. Twenty-one patients received HDE during resuscitation from 24 arrests, at a dose of 0.12 +/- 0.05 mg/kg (mean +/- SD); 30 patients received SDE during resuscitation from 34 arrests, at a dose of 0.01 +/- 0.01 mg/kg (mean +/- SD). The HDE and SDE groups were not significantly different in terms of gender, initial cardiac rhythm, location of CPA, primary diagnoses at the time of CPA, initial pH, or additional resuscitation medications received; the SDE group had a significantly higher mean age, although the median ages were not different. Fourteen of 24 resuscitations using HDE resulted in ROSC (58%) with a mean time to ROSC of 19 minutes; 7 (29%) of 24 led to survival for 24 hours, and 6 (26%) of 23 patients survived to hospital discharge, all with moderate to severe neurologic and functional impairment. Twenty-four of 34 resuscitations using SDE resulted in ROSC (71%) with a mean time to ROSC of 12 minutes; 17 (50%) of 34 led to survival for 24 hours; and 7 (23%) of 30 patients survived to hospital discharge, 4 with mild to moderate neurologic impairment. No significant differences in rates of ROSC, survival rates, or Pediatric Overall Performance Category scores of survivors were found between the two groups. The mean time to ROSC was significantly longer in the HDE group. In this study, the use of HDE did not improve the rates of ROSC, short-term survival, or long-term survival after pediatric in-hospital CPA, nor did it improve overall outcome scores. Given the conflicting evidence surrounding possible detrimental effects of HDE use, a large, blinded, prospective trial of HDE use in this setting is necessary to clarify the appropriate role for HDE in pediatric resuscitation.


Ruthenium based antimicrobial theranostics - using nanoscopy to identify therapeutic targets and resistance mechanisms in Staphylococcus aureus.
In previous studies we reported that specific dinuclear RuII complexes are particularly active against pathogenic Gram-negative bacteria and, unusually for this class of compounds, appeared to display lowered activity against Gram-positive bacteria. With the aim of identifying resistance mechanisms specific to Gram-positive bacteria, the uptake and antimicrobial activity of the lead complex against Staphylococcus aureus SH1000 and other isolates, including MRSA was investigated. This revealed differential, strain specific, sensitivity to the complex. Exploiting the inherent luminescent properties of the RuII complex, super-resolution STED nanoscopy was used to image its initial interaction with S. aureus and confirm its cellular internalization. Membrane damage assays and transmission electron microscopy confirm that the complex disrupts the bacterial membrane structure before internalization, which ultimately results in a small amount of DNA damage. A known resistance mechanism against cationic antimicrobials in Gram-positive bacteria involves increased expression of the mprF gene as this results in an accumulation of positively charged lysyl-phosphatidylglycerol on the outer leaflet of the cytoplasmic membrane that electrostatically repel cationic species. Consistent with this model, it was found that an mprF deficient strain was particularly susceptible to treatment with the lead complex. More detailed co-staining studies also revealed that the complex was more active in S. aureus strains missing, or with altered, wall teichoic acids.


Hematologic, plasma biochemistry, and acid-base analysis of adult Negev Desert tortoises (Testudo werneri) in Israel.
The Negev Desert tortoise (Testudo werneri) is one of the smallest tortoise species in the Mediterranean region. This is a critically endangered species (CITES I) in its native habitat, which includes the Saharo-Arabian sands of northern Egypt, Sinai, and the Negev Desert in Israel. Great efforts have been invested in captive breeding and reintroduction of this tortoise to the wild. The purpose of this study was to collect blood samples from healthy Negev Desert tortoises kept in well-managed zoologic collections in order to describe hematologic, plasma biochemistry, and acid-base analytes for this species. Data of 36 different blood analytes were collected using the Abaxis Vetscan bench-top analyzer and i-STAT handheld analyzer, and a significant difference was observed between males and females in 13 of the measured analytes. To the authors' knowledge, this is the first report of blood analytes for the Negev Desert tortoise; however, the data do not fully meet the strict ASVCP guidelines required for reference range determination and thus can only provide a rough estimate for evaluating the health status of Negev Desert tortoises using similar testing methodology.


Near-field investigation of THz surface-wave emission from optically excited graphite flakes.
THz emission from an unbiased graphite flake after optical sub-ps pulse inter-band excitation is measured using a novel micro-machined photoconductive probe-tip. Oscillatory behavior of the measured THz near-field emission is shown to originate from electromagnetic eigenmode resonances of the laterally limited graphite flake. The excitation efficiency of the lowest order eigenmode resonances strongly dependents on optical pump location. From this data a radial symmetric charge carrier translocation at the pump location is revealed as the dominating THz surface-wave emission effect. Measurements show good agreement with numerical field simulations of the eigenmode center frequencies and the spectral response expected for THz emission through basal plane oriented radial current surge excitation.


The selection of chief residents across residency programs at a large academic medical center.
Chief residents have a unique role in graduate medical education (GME). They not only connect residents with program and hospital leadership, but also advocate for the wellbeing and educational priorities of trainees. Previous studies have focused on describing the characteristics of chief residents (CRs), however little is known about how CRs are selected across GME programs. One-on-one semi-structured interviews with all (n = 21) GME program directors at the Johns Hopkins University School of Medicine were conducted from January to March 2022. Investigators independently coded the transcripts using an inductive approach to categorize meaningful segments of text; this culminated in the identification of explanatory themes. From discussions with 21 program directors, four themes were identified: (1) identifying candidates: timing, recruitment, nominations, as well as desirable attributes and data considered; (2) applications: expression of intent and participation in interviews; (3) selections: voting, discussions leading to consensus, and program director intimately involved in the choice(s); and (4) confidence in processes and outcomes. Our results provide a deeper understanding of the nuances associated with the selection of CRs. It is hoped that the descriptions of the similarities and differences across GME programs will prompt reflection about what is done at one institution such that all programs can consider what are the best practices to serve their individual goals and needs.


Internet-based continuing medical education in otolaryngology: a survey of Canadian otolaryngologists.
To assess the readiness of the Canadian otolaryngology community for an on-line continuing medical education (CME) program. Data were obtained through surveys mailed to members of the Canadian Society of Otolaryngology-Head and Neck Surgery. Two hundred and eight of 321 (65%) surveys were returned. Seventy-six percent of the respondents indicated that they would be interested in participating in an on-line CME course. A greater proportion of younger otolaryngologists and those with community-based practices were interested in participating. A greater number of those with an academic practice were found to have convenient access to the Internet, the ability to post images on-line, and encountered cases they felt worthy of discussion and were willing to instruct/facilitate future on-line CME. Ninety-three percent of respondents described having easy access to the Internet, but only 32% said that they have the equipment necessary to post computed tomographic scans/audiograms on-line. Twenty-three percent had previous computer-based CME experience. Sinusitis and related topics were of greatest interest, with hearing loss/ear surgery and oncology following respectively. The data suggest that on-line CME would be welcomed and are feasible in the Canadian otolaryngology community.


Time-sequential and Multi-functional 3d Printed Mgo2 /PLGA Scaffold Developed as A Novel Biodegradable and Bioactive Bone Substitute for Challenging Postsurgical Osteosarcoma Treatment.
Osteosarcoma (OS) is the most commonly occurring primary bone malignant tumor. The clinical postsurgical OS treatment faces big challenges for the staged therapeutic requirements of early anti-tumor, anti-bacterial, and long-lasting osteogenesis. Herein, multi-functional bioactive scaffolds with time-sequential functions of prevent tumor recurrence, inhibit bacterial infection and promote bone defect repair have been rationally designed as a novel strategy. Nanocomposite scaffold magnesium peroxide (MgO2 )/poly (lactide-co-glycolide (PLGA) is prepared by low-temperature 3D printing for controllable releasing magnesium ions (Mg2+ ) and ROS in a time-sequential manner. The scaffold with 20 wt% MgO2 (20MP) is verified with desired mechanical properties, as well as exhibits staged release behavior of bioactive elements with hydrogen peroxide (H2 O2 ) release for the first 3 weeks, and long-lasting Mg2+ release for 12 weeks. The released H2 O2 initiates chemodynamic therapy (CDT) to induce apoptosis and ferroptosis in tumor cells, along with activating the anticancer immune microenvironment by M1 polarization of macrophages. The released Mg2+ subsequently enhances bone repair by activating the Wnt3a/GSK-3β/β-catenin signaling pathway to promote osteogenic differentiation of BMSCs and creating osteopromotive immune microenvironment by M2 polarization of macrophages. In conclusion, the multi-functional 20MP scaffold demonstrates time-sequential therapeutic properties as an innovative strategy for OS-associated challenging bone defect treatment. This article is protected by copyright. All rights reserved.


Influence of G1359A polimorphysm of the cannabinoid receptor gene (CNR1) on insulin resistance and adipokines in patients with non alcoholic fatty liver disease.
Considering the evidence that endogenous cannabinoid system plays a role in metabolic aspects of body weight and metabolic syndrome components such as non alcoholic fatty liver disease (NAFLD). The aim of our study was to investigate the influence of this polymorphism on insulin resistance, liver histological changes, anthropometric parameters and adipocytokines in patients with NAFLD. A population of 71 patients with NAFLD was recruited in a cross sectional study. A biochemical analysis of serum was measured. Genotype of G1359A polymorphism of CB1 receptor gene CB1 receptor was studied. Forty one patients (36.9%) had the genotype G1359G (wild type group) and twenty nine (26.1%) patients G1359A or A1359A (mutant type group). Twenty four 24 patients (32,3%) had a Brunt grade > 4 and 12 patients (17%) had a significative fibrosis (F > = 2). HOMA values were higher in wild type group than mutant type group. Adiponectin and visfatin levels were higher in mutant type group. Moreover, TNF-alpha and resistin levels were higher in wild type group than mutant type group. Patients with mutant genotype showed less frequently elevated levels of AST. AST > 40 UI/L was detected in 28.5% of patients in the mutant vs. 53% of patients with wild genotype, p < 0.05. Patients with mutant type group presented a percentage of Brunt grade > = 4 less frequently than patients with wild type group (28.5%vs 7.1%). A variant of the polymorphism G1359A CBR1 is associated with lower levels of HOMA, TNF-alpha, resistin and higher levels of adiponectin than patients with the wild variant of this polymorphism. Besides, patients with A allele variant shown lower Brunt grade in liver biopsy.


Uncertainties of potentials and recent changes in global yields of major crops resulting from census- and satellite-based yield datasets at multiple resolutions.
Global agriculture is under pressure to meet increasing demand for food and agricultural products. There are several global assessments of crop yields, but we know little about the uncertainties of their key findings, as the assessments are driven by the single best yield dataset available when each assessment was conducted. Recently, two different spatially explicit, global, historical yield datasets, one based on agricultural census and the other largely based on satellite remote sensing, became available. Using these datasets, we compare the similarities and differences in global yield gaps, trend patterns, growth rates and changes in year-to-year variability. We analyzed maize, rice, wheat and soybean for the period of 1981 to 2008 at four resolutions (0.083°, 0.5°, 1.0° and 2.0°). Although estimates varied by dataset and resolution, the global mean annual growth rates of 1.7-1.8%, 1.5-1.7%, 1.1-1.3% and 1.4-1.6% for maize, rice, wheat and soybean, respectively, are not on track to double crop production by 2050. Potential production increases that can be attributed to closing yield gaps estimated from the satellite-based dataset are almost twice those estimated from the census-based dataset. Detected yield variability changes in rice and wheat are sensitive to the choice of dataset and resolution, but they are relatively robust for maize and soybean. Estimates of yield gaps and variability changes are more uncertain than those of yield trend patterns and growth rates. These tendencies are consistent across crops. Efforts to reduce uncertainties are required to gain a better understanding of historical change and crop production potential to better inform agricultural policies and investments.


African Swine Fever: Fast and Furious or Slow and Steady?
Since the introduction of African swine fever (ASF) into Georgia in 2007, the disease has been spreading in an unprecedented way. Many countries that are still free from the disease fear the emergence of ASF in their territory either in domestic pigs or in wild boar. In the past, ASF was often described as being a highly contagious disease with mortality often up to 100%. However, the belief that the disease might enter a naïve population and rapidly affect the entire susceptible population needs to be critically reviewed. The current ASF epidemic in wild boar, but also the course of ASF within outbreaks in domestic pig holdings, suggest a constant, but relatively slow spread. Moreover, the results of several experimental and field studies support the impression that the spread of ASF is not always fast. ASF spread and its speed depend on various factors concerning the host, the virus, and also the environment. Many of these factors and their effects are not fully understood. For this review, we collated published information regarding the spreading speed of ASF and the factors that are deemed to influence the speed of ASF spread and tried to clarify some issues and open questions in this respect.


Mesenchymal stem cells attenuate systemic lupus erythematosus by inhibiting NLRP3 inflammasome activation through Pim-1 kinase.
The inflammatory response runs through the whole pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSC) have exhibited a positive therapeutic effect on SLE. This study aimed to ascertain the pathogenic role of inflammasome activation in SLE and whether MSC alleviate SLE by suppressing it. The results showed that the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome was activated in macrophages from MRL/lpr mice and patients with SLE, correlating with disease activity. After MSC transplantation, the disease severity in MRL/lpr mice was alleviated, and NLRP3 inflammasome activation was inhibited with decreased levels of NLRP3 and caspase-1 in macrophages. Furthermore, lower serum levels of interleukin (IL)-1β and IL-18 were observed in patients with SLE who underwent MSC transplantation. In vitro and in vivo studies indicated that MSC suppressed NLRP3 inflammasome activation by inhibiting Pim-1 expression. The findings provide an updated view of inflammasome signaling in SLE. Additionally, MSC ameliorated SLE by inhibiting NLRP3 inflammasome activation, implying a possible molecular mechanism for the clinical application of MSC and a potential therapeutic target in patients with SLE.


International co-operation through the Interpol system to counter illicit drug trafficking.
The International Criminal Police Organization (ICPO/Interpol), whose main aim is the prevention and suppression of ordinary crime, has 135 member countries. The Government of each of these countries has designated an Interpol National Central Bureau to co-operate and liaise within the framework of Interpol. The Drugs Sub-Division of Interpol's General Secretariat monitors and responds to incoming communications on drug enforcement matters, conducts intelligence analysis of information and produces tactical and strategic intelligence reports as well as statistical and other specialized reports. It received 33,181 and dispatched 6,741 drug-enforcement-related communications in 1982, which was over 60 per cent of the entire communications of the General Secretariat. The Drugs Sub-Division participates in drug training and drug strategy seminars world-wide. Interpol also carries out drug liaison officer programmes in five regions of the world.


Prenatal exposure to the herbicide 2,4-dichlorophenyl-p-nitrophenyl ether destroys the rodent Harderian gland.
Exposure of mice to the herbicide 2,4-dichlorophenyl-p-nitrophenyl ether during gestation produces abnormalities that are not readily apparent at birth but become obvious as the pups mature. By 2 weeks after birth there are severe intraorbital defects resulting from destruction of the Harderian glands behind the eyes. This effect is noticeable only postnatally because the Harderian gland does not grow or function until after birth.


Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite.
In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death. Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD. Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons. Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.


In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium.
Significant differences exist in the sensitivity of mice and rats to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot be explained by differences in exposure to or uptake of 1-methyl-4-phenylpyridinium (MPP(+)) into dopamine (DA) neurons. MPP(+) is also a substrate for the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP(+) toxicity. A greater sequestration of MPP(+) into vesicles of DA neurons in rats versus mice could explain the lower vulnerability of DA neurons in the rat to MPP(+) toxicity. To test this hypothesis, the kinetics of uptake for [(3)H]MPP(+) and [(3)H]DA as well as [(3)H]dihydrotetrabenazine binding to VMAT2 were compared in vesicles isolated from the striata of rats and mice. The K(m) value of [(3)H]MPP(+) transport was similar in the two species. In contrast, the maximal transport rate (V(max)) was 2-fold greater in vesicles from rats than in those from mice. Likewise, the K(m) value for [(3)H]DA transport was similar in both preparations, but the V(max) value was 2-fold greater in rat than in mouse vesicles. The B(max) value for [(3)H]dihydrotetrabenazine binding was also 2-fold greater in striatal vesicles from rats than in those from mice. Electron micrographs demonstrated that vesicles isolated from rats and mice were approximately the same size. Based on these observations, we propose that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the reduced vulnerability of rat DA neurons to MPP(+) neurotoxicity.


Enhancing sorafenib-mediated sensitization to gemcitabine in experimental pancreatic cancer through EMAP II.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and tends to be relatively resistant to conventional therapies. Activated Ras oncogene mutations are found in up to 90% of PDAC, leading to activation of the Ras/Raf/MEK/ERK signaling pathway. Sorafenib is a multikinase inhibitor of the Ras/Raf/MEK/ERK pathway and of tumor angiogenesis. Endothelial monocyte activating polypeptide II (EMAP) enhances gemcitabine effects in PDAC. Antitumor activity of sorafenib was evaluated in combination with gemcitabine (Gem) and the antiangiogenic agent EMAP in experimental PDAC. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Animal survival studies were performed in murine PDAC xenografts. Sorafenib decreased phospho-MEK, phospho-ERK1/2, phospho-p70S6K and phospho-4EBP-1 expression in PDAC cells. Sorafenib inhibited in vitro proliferation of all four PDAC cell lines tested. Additive effects on cell proliferation inhibition were observed in the gemcitabine-sorafenib combination in PDAC cells, and in combinations of sorafenib or EMAP with gemcitabine in endothelial (HUVEC) and fibroblast (WI-38) cells. Sorafenib, alone or in combination with gemcitabine and EMAP, induced apoptosis in HUVECs and WI-38 cells as observed via increased expression of cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and caspase-3 proteins. Compared to controls (median survival: 22 days), animal survival increased after Gem therapy (29 days) but not in sorafenib (23 days) or EMAP therapy alone (25 days). Further increases in survival occurred in combination therapy groups Gem+sorafenib (30 days, p=0.004), Gem+EMAP (33 days, p=0.002), and Gem+sorafenib+EMAP (36 days, p=0.004), but not after the sorafenib+EMAP combination (24 days). These findings demonstrate that the addition of a polymechanistic antiangiogenic agent such as EMAP can enhance the combination treatment effects of sorafenib and cytotoxic PDAC therapy.


Studies in Zebrafish Demonstrate That CNNM2 and NT5C2 Are Most Likely the Causal Genes at the Blood Pressure-Associated Locus on Human Chromosome 10q24.32.
Background: Globally, high blood pressure (BP) is the most important risk factor for cardiovascular disease. Several genome-wide association studies (GWAS) have identified variants associated with BP traits at more than 535 chromosomal loci with genome-wide significance. The post-GWAS challenge is to annotate the most likely causal gene(s) at each locus. Chromosome 10q24.32 is a locus associated with BP that encompasses five genes: CYP17A1, BORCS7, AS3MT, CNNM2, and NT5C2 and warrants investigation to determine the specific gene or genes responsible for the phenotype. Aim: To identify the most likely causal gene(s) associated with BP at the 10q24.32 locus using zebrafish as an animal model. Results: We report significantly higher blood flow, increased arterial pulse, and elevated linear velocity in zebrafish larvae with cnnm2 and nt5c2 knocked down using gene-specific splice modification transcriptional morpholinos, compared with controls. No differences in blood-flow parameters were observed after as3mt, borcs7, or cyp17a1 knockdown. There was no effect on vessel diameter in animals with any of the four genes knocked down. At the molecular level, expression of hypertension markers (crp and ace) was significantly increased in cnnm2 and nt5c2 knockdown larvae. Further, the results obtained by morpholino knockdown were validated using zebrafish knockout (KO) lines with cnnm2 and nt5c2 deficiency, again resulting in higher blood flow, increased arterial pulse, and elevated linear velocity. Analysis of nt5c2a KO larvae demonstrated that lack of this gene resulted in reduced expression of cnnm2a, with reciprocal downregulation of nt5c2a in cnnm2a KO larvae. Staining of whole-blood smears from nt5c2 mutants revealed that KO of this gene might be associated with an acute lymphoblastic leukemia phenotype, consistent with literature reports. Additional experiments were designed based on previous literature on cnnm2a mutant zebrafish revealed impaired renal function, high levels of renin, and significantly increased expression of the ren gene, leading us to hypothesize that the observed elevated blood-flow parameters may be attributable to triggering of the renin-angiotensin-aldosterone signaling pathway. Conclusion: Our zebrafish data establish CNNM2 and NT5C2 as the most likely causal genes at the 10q24.32 BP locus and indicate that they trigger separate downstream mechanistic pathways.


A comparison of Leydig cell function after unilateral and bilateral cryptorchidism and efferent-duct-ligation.
Surgical induction of cryptorchidism or ligation of the efferent ducts disrupts spermatogenesis. The response of Leydig cells to disrupted gametogenesis was studied in vitro in tissue and collagenase dispersed Leydig cells obtained from the testes of rats that were made unilaterally or bilaterally cryptorchid or had been efferent-duct-ligated. Four wks after surgery, androgen secretion per mg of tissue or per Leydig cell in response to maximal luteinizing hormone (LH) stimulation was greater in tissue from damaged than from sham-operated testes. It was concluded that disruption of spermatogenesis resulted in Leydig cells that were hyperresponsive to LH stimulation in vitro. Unilateral lesions produced different responsiveness of Leydig cells from the testes ipsilateral and contralateral to the lesion, supporting the hypothesis that intragonadal modulation of Leydig cells function occurs when the function of seminiferous tubules is impaired. Stimulated androgen production of Leydig cells from the contralateral nonligated testis did not differ from that of the sham-operated controls. With unilateral cryptorchidism, which is accompanied by an increase in the temperature of the operated testis, Leydig cells from the scrotal testis were also hyperresponsive compared to those from sham-operated controls. This suggests a possible intergonadal influence of aspermatogenesis caused by cryptorchidism.


Topiramate-induced psychotic exacerbation: case report and review of literature.
Background. Topiramate (TPM) is a new antiepileptic drug that is used mainly in the treatment of refractory partial epileptic seizures. There are some studies reporting TPM's effectiveness in the treatment and maintenance of some psychiatric illnesses such as acute mania, some other affective disorders, post-traumatic stress disorder and binge-eating disorder. On the other hand, it has been shown that TPM may cause mild to moderate cognitive impairment and is thought to be responsible for a series of neuro-psychiatric signs and symptoms. Some of the available articles that have mentioned the relationship of psychotic symptoms and topiramate usage are discussed. Objective. The present paper aims to discuss a case of psychotic exacerbation purported to occur after TPM administration and to review specifically the literature on TPM's potential for inducing psychotic symptoms. The patient presented here is thought to be an undiagnosed schizophrenia patient until his admission to our clinic (Department of Psychiatry, Gazi University Medical School) with TPM-exacerbated psychotic symptoms. Conclusions. The current findings are still subject to controversy because of the presence of both individual case reports and case series on the association between appearance of psychotic symptoms and TPM usage.


Fully coherent triple sum frequency spectroscopy of a benzene Fermi resonance.
In this paper we present a new multiresonant coherent multidimensional spectroscopy (CMDS) technique employing a pathway that is both fully coherent and necessarily unique. This technique is based on a Triple Sum Frequency (TSF) coherence pathway with three excitation pulses having frequencies ω1, ω2, and ω3 and the phase matching condition k→1 + k→2 + k→3. Two-dimensional spectra are created by independently tuning the ω1 and ω2 pulses across vibrational resonances while monitoring the intensity of a visible output beam created by a Raman transition induced by the ω3 pulse. Two-dimensional plots of the coherent dynamics are created by independently scanning the τ21 and τ31 delay times between the different frequency excitation pulses over all time orderings. TSF CMDS separates fundamental and overtone/combination band states uniquely onto the ω1 and ω2 axes when τ21 ≠ 0. TSF is valuable in its ability to probe states of complementary parity to those seen in Doubly Vibrationally Enhanced Four-Wave Mixing (DOVE-FWM), the other fully coherent mixed electronic/vibrational CMDS method. This capability is demonstrated through the use of neat benzene as a model system, where the center of inversion imposes strict parity selection rules.


Development and optimization of a self-microemulsifying drug delivery system for atorvastatin calcium by using D-optimal mixture design.
In this study, we developed and optimized a self-microemulsifying drug delivery system (SMEDDS) formulation for improving the dissolution and oral absorption of atorvastatin calcium (ATV), a poorly water-soluble drug. Solubility and emulsification tests were performed to select a suitable combination of oil, surfactant, and cosurfactant. A D-optimal mixture design was used to optimize the concentration of components used in the SMEDDS formulation for achieving excellent physicochemical characteristics, such as small droplet size and high dissolution. The optimized ATV-loaded SMEDDS formulation containing 7.16% Capmul MCM (oil), 48.25% Tween 20 (surfactant), and 44.59% Tetraglycol (cosurfactant) significantly enhanced the dissolution rate of ATV in different types of medium, including simulated intestinal fluid, simulated gastric fluid, and distilled water, compared with ATV suspension. Good agreement was observed between predicted and experimental values for mean droplet size and percentage of the drug released in 15 minutes. Further, pharmacokinetic studies in rats showed that the optimized SMEDDS formulation considerably enhanced the oral absorption of ATV, with 3.4-fold and 4.3-fold increases in the area under the concentration-time curve and time taken to reach peak plasma concentration, respectively, when compared with the ATV suspension. Thus, we successfully developed an optimized ATV-loaded SMEDDS formulation by using the D-optimal mixture design, that could potentially be used for improving the oral absorption of poorly water-soluble drugs.


Change in Motherhood Status and Fertility Problem Identification: Implications for Changes in Life Satisfaction.
To determine whether the association between changes in life satisfaction and becoming a mother (or not) depends on fertility problem identification status. Evidence and symbolic interactionist theory suggest that, for women who initially perceive a fertility barrier, gaining the valued identity "mother" should be associated with increases, and continuing to face a blocked goal (i.e. not becoming a mother) should be associated with decreases in life satisfaction. This study used the nationally representative two-wave National Survey of Fertility Barriers to conduct a change-score analysis with chained multiple imputation (MICE). The focal dependent variable was change in life satisfaction. Focal independent variables were Wave 1 life satisfaction, fertility problem identification status, and birth between waves, controlling for stability and change in relationship status, talking to a doctor about how to get pregnant, religiosity, social support, importance of parenthood, importance of leisure, importance of work success, and economic hardship. Among women who perceived a fertility problem at both waves, becoming a mother was associated with increased life satisfaction and not becoming a mother was associated with decreased life satisfaction. Women who gained or lost a fertility problem perception between waves but did not have a live birth experienced a gain in life satisfaction between waves, suggesting the relevance of the duration of fertility problem perception for change in life satisfaction.


Recent insights into R gene evolution.
SUMMARY Plants are under strong evolutionary pressure to maintain surveillance against pathogens. Resistance (R) gene-dependent recognition of pathogen avirulence (Avr) determinants plays a major role in plant defence. Here we highlight recent insights into the molecular mechanisms and selective forces that drive the evolution of NB-LRR (nucleotide binding-leucine-rich repeat) resistance genes. New implications for models of R gene evolution have been raised by demonstrations that R proteins can detect cognate Avr proteins indirectly by 'guarding' virulence targets, and by evidence that R protein signalling is regulated by intramolecular interactions between different R functional domains. Comparative genomic surveys of NB-LRR diversity in different species have revealed ancient NB-LRR lineages that are unequally represented among plant taxa, consistent with a Birth and Death Model of evolution. The physical distribution of NB-LRRs in plant genomes indicates that tandem and segmental duplication are important factors in R gene proliferation. The majority of R genes reside in clusters, and the frequency of recombination between clustered genes can vary strikingly, even within a single cluster. Biotic and abiotic factors have been shown to increase the frequency of recombination in reporter transgene-based assays, suggesting that external stressors can affect genome stability. Fitness penalties have been associated with some R genes, and population studies have provided evidence for maintenance of ancient R allelic diversity by balancing selection. The available data suggest that different R genes can follow strikingly distinct evolutionary trajectories, indicating that it will be difficult to formulate universally applicable models of R gene evolution.


Evaluation of Radon Action Plans: Searching for a Systematic and Standardised Method.
Radon, a carcinogenic radioactive gas, is a leading cause of lung cancer according to the World Health Organization. European Member States are required to develop and implement National Radon Action Plans (RAPs) to address its dangerous health effects. However, assessing the effectiveness of these RAPs presents challenges for authorities. This study aims to explore the possibility of a systematic and standardised assessment method to evaluate the effectiveness of RAP strategies and its implementation. The method involved analysing the strategies of 27 EU Member States and the UK, conducting legal document analysis and group interviews with responsible authorities. Additionally, four regional workshops and one final European workshop were held. The research took place from March 2021 to May 2023. Findings indicate that evaluating RAP effectiveness is challenging due to limited existing common criteria or indicators. To address this, the study proposes guiding questions for each element required by the EU Directive, as well as additional questions related to education and training. This contribution benefits RAP owners and European regulatory authorities, supporting the development of effectiveness indicators for RAPs. By improving assessment methods, we can enhance the effectiveness of strategies in mitigating the risks associated with radon exposure.


An interactive CD-ROM for nutrition screening and counseling.
The goal of this project was to develop an interactive CD-ROM for nutrition screening and counseling, designed to produce dietary behavior change in fat and fruit and vegetable intake. The design was based on principles of relevance to the learner, readiness for change, feedback, individualization, facilitation of skills, and goal setting. It was tested in community settings such as libraries, senior centers, and Women, Infants, and Children clinics. Nearly 80% of the respondents (n = 284), including numerous low-income persons, reported learning something new about nutrition and health or their own dietary habits. More than 50% of those recontacted 2 to 4 weeks later had put some of their dietary goals into practice. This program is useful for dietary screening, feedback, skill building, and motivation in settings in which in-person counseling by nutrition professionals is not feasible.


Pre-gravid oral contraceptive use in relation to birth weight: a prospective cohort study.
Few studies have evaluated the association between pregravid oral contraceptive (OC) use and birth weight, and findings have been conflicting. We conducted a prospective cohort study of 5921 pregnancy planners in Denmark to evaluate recency, duration, and type of OC used before conception in relation to infant birth weight. Participants completed online questionnaires and reported detailed information on contraceptive history and covariates at baseline. Participants completed bimonthly follow-up questionnaires to update their pregnancy status for up to 12 months or until conception occurred. Birth weight data were ascertained from the Danish Medical Birth Registry for 4046 live births delivered by study participants between 2008 and 2010. We used multivariable linear and log-binomial regression analyses to control for confounding. Mean birth weight was higher among women who had used OCs within 0-1 months (mean difference = 97 g, CI 26, 168) or 2-6 months (mean difference = 40 g, CI -5, 85) before conception, compared with more than 12 months before conception. Mean birth weight was lower among women who had used OCs for long durations (mean difference comparing ≥12 with <4 years of OC use = -85 g, CI -158, -11). Our findings indicate that pregravid OC use within 6 months of conception may be associated with a small increase in birth weight, but that long duration of use may have the opposite effect. Results were stronger among male infants, among 2nd and 4th generation OC users, and among users of OCs with a higher estrogen dose.


Expression of diphtheria toxin fragment A and hormone-toxin fusion proteins in toxin-resistant yeast mutants.
Mutants of the eukaryote Saccharomyces cerevisiae, previously selected for resistance to diphtheria toxin, were investigated for their suitability as hosts for the expression of tox-related proteins. The structural gene for the toxin, encoding the fragment A catalytic domain, was modified for efficient intracellular expression in eukaryotes and placed downstream of the yeast GAL1 promoter element in a plasmid. Transformed mutant yeast grown in galactose, which induces that promoter, were viable and contained active fragment A. In contrast, sensitive, wild-type cells harboring this plasmid grew normally under repressing conditions but were killed when the GAL1 promoter was induced. Additional constructions were also prepared that included sequences encoding either the lymphocyte growth factor interleukin 2 or alpha-melanocyte-stimulating hormone along with the lipid-associating domains of fragment B and the leader peptide of the Kluyveromyces lactis killer toxin. Resistant mutant strains transformed with these plasmids efficiently expressed and secreted the expected chimeric toxins.


[Corazol kindling in rats with different tolerance to hypoxia].
Research was conducted studying the peculiarities of development of pharmacological kindling in rats with different tolerance to hypoxia. Kindling was evoked by injecting subconvulsive doses of corazol (25 mg per kg) every day. Intensity of convulsions was expressed in points. Reliable distinction in intensity of convulsion between low-tolerant rats and high-tolerant rats to hypoxia was found on the 17th day of stimulation; amongst the group of low-tolerant rats the intensity of convulsions was found to be 2.46 + 0.30 points, and amongst the group of high-tolerant rats--1.20 + 0.22 points (p 0.05). On the 23rd day of injection the preparation convulsions in the group of low-tolerant rats reached up to 4.00 + 0.20 points and in the group of high-tolerant rats 2.28 + 0.45 points (p 0.01). The changes of violation of behavior were found to be different. Thus, the higher the individual resistance to hypoxia, the more is the resistance of the animal to the effect of epileptogens.


Activating and inhibitory Fcgamma receptors can differentially modulate T cell-mediated autoimmunity.
The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although FcgammaR have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (FcgammaRIII) and inhibitory (FcgammaRIIb) FcgammaR can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While FcgammaRIIb(-/-) mice showed a significant increase in EAE severity, an FcgammaRIII deficiency protected mice from disease. In addition, FcgammaRIIb(-/-) mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, FcgammaRIII(-/-) mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for FcgammaRIII(-/-) mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory FcgammaR signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression.


Femoral osteomyelitis due to Aspergillus nidulans in a patient with chronic granulomatous disease.
13 cases of osteomyelitis caused by Aspergillus nidulans have been previously reported in patients with chronic granulomatous disease (CGD). All of them have been associated with simultaneous pulmonary infection and have had an extremely poor outcome. We report an unusual case of femoral osteomyelitis due to A. nidulans in a 16-year-old male with CGD, without pulmonary involvement. Treatment with liposomal amphotericin B and granulocyte colony-stimulating factor as well as extensive surgical debridement followed by prolonged treatment with itraconazole resulted in an excellent clinical response.


Neuromodulation: advances in the next five years.
Neuromodulation (deep brain stimulation; DBS) has become an established treatment for movement disorders (e.g., Parkinson's disease), and is in trials for refractory epilepsy, headache, and certain mood disorders. Two main themes will advance DBS significantly in the next five years: closed-loop DBS, that is, feedback from brain electrical activity to direct the stimulation; and computational analysis (CA)--electrophysiological modeling to enhance DBS. Closed-loop DBS is currently in clinical trials for refractory epilepsy. New imaging techniques offer preoperative modeling for DBS surgery, including nerve fiber tracts (diffusion tensor imaging), and imaging of volume of tissue activated by a specific electrode. CA techniques for DBS include mathematical models of the abnormally synchronized electrical activity which underlies epilepsy, movement disorders, and likely many mood disorders as well. By incorporating feedback loops and multiple recording and/or stimulating sites, the abnormally synchronized brain electrical activity can be desynchronized, then "unlearned" ("unkindling" in epilepsy). Characteristics of DBS utilizing CA include low frequency rather than high frequency stimulation; multiple stimulation and/or recording sites; likely 10-fold or more reduction in electrical current needs (much smaller "pulse generators"); more focused and less disruptive stimulation--fewer unwanted side effects; and potential to "cure" certain disorders by resetting abnormal firing patterns back to normal. These advantages of more sophisticated DBS techniques bring the following challenges, which may require a decade of research before reaching clinical practice because many brain disorders involve neurotransmitter abnormalities (e.g., dopamine in Parkinson's disease and certain mood disorders). Namely, how do we monitor and modulate neurotransmitters in addition to electrical activity? How do we get multiple microelectrodes into the brain in a minimally invasive manner? In the accompanying article, I address these two issues and offer some potential solutions.


Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation.
During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications. Combined with EU-RNA-seq and Hi-C analyses, we found that during prometaphase, promoters, enhancers, and insulators retain H3K4me3 and H3K4me1, while losing H3K27ac. Enhancers globally retaining mitotic H3K4me1 or locally retaining mitotic H3K27ac are associated with cell type-specific genes and their transcription factors for rapid transcriptional activation. As cells exit mitosis, promoters regain H3K27ac, which correlates with transcriptional reactivation. Insulators also gain H3K27ac and CCCTC-binding factor (CTCF) in anaphase/telophase. This increase of H3K27ac in anaphase/telophase is required for posttranscriptional activation and may play a role in the establishment of topologically associating domains (TADs). Together, our results suggest that the genome is reorganized in a sequential order, in which histone methylations occur first in prometaphase, histone acetylation, and CTCF in anaphase/telophase, transcription in cytokinesis, and long-range chromatin interactions in early G1. We thus provide insights into the histone modification landscape that allows faithful reestablishment of the transcriptional program and TADs during cell division.


GiardiaDB and TrichDB: integrated genomic resources for the eukaryotic protist pathogens Giardia lamblia and Trichomonas vaginalis.
GiardiaDB (http://GiardiaDB.org) and TrichDB (http://TrichDB.org) house the genome databases for Giardia lamblia and Trichomonas vaginalis, respectively, and represent the latest additions to the EuPathDB (http://EuPathDB.org) family of functional genomic databases. GiardiaDB and TrichDB employ the same framework as other EuPathDB sites (CryptoDB, PlasmoDB and ToxoDB), supporting fully integrated and searchable databases. Genomic-scale data available via these resources may be queried based on BLAST searches, annotation keywords and gene ID searches, GO terms, sequence motifs and other protein characteristics. Functional queries may also be formulated, based on transcript and protein expression data from a variety of platforms. Phylogenetic relationships may also be interrogated. The ability to combine the results from independent queries, and to store queries and query results for future use facilitates complex, genome-wide mining of functional genomic data.


Refined repetitive sequence searches utilizing a fast hash function and cross species information retrievals.
Searching for small tandem/disperse repetitive DNA sequences streamlines many biomedical research processes. For instance, whole genomic array analysis in yeast has revealed 22 PHO-regulated genes. The promoter regions of all but one of them contain at least one of the two core Pho4p binding sites, CACGTG and CACGTT. In humans, microsatellites play a role in a number of rare neurodegenerative diseases such as spinocerebellar ataxia type 1 (SCA1). SCA1 is a hereditary neurodegenerative disease caused by an expanded CAG repeat in the coding sequence of the gene. In bacterial pathogens, microsatellites are proposed to regulate expression of some virulence factors. For example, bacteria commonly generate intra-strain diversity through phase variation which is strongly associated with virulence determinants. A recent analysis of the complete sequences of the Helicobacter pylori strains 26695 and J99 has identified 46 putative phase-variable genes among the two genomes through their association with homopolymeric tracts and dinucleotide repeats. Life scientists are increasingly interested in studying the function of small sequences of DNA. However, current search algorithms often generate thousands of matches -- most of which are irrelevant to the researcher. We present our hash function as well as our search algorithm to locate small sequences of DNA within multiple genomes. Our system applies information retrieval algorithms to discover knowledge of cross-species conservation of repeat sequences. We discuss our incorporation of the Gene Ontology (GO) database into these algorithms. We conduct an exhaustive time analysis of our system for various repetitive sequence lengths. For instance, a search for eight bases of sequence within 3.224 GBases on 49 different chromosomes takes 1.147 seconds on average. To illustrate the relevance of the search results, we conduct a search with and without added annotation terms for the yeast Pho4p binding sites, CACGTG and CACGTT. Also, a cross-species search is presented to illustrate how potential hidden correlations in genomic data can be quickly discerned. The findings in one species are used as a catalyst to discover something new in another species. These experiments also demonstrate that our system performs well while searching multiple genomes -- without the main memory constraints present in other systems. We present a time-efficient algorithm to locate small segments of DNA and concurrently to search the annotation data accompanying the sequence. Genome-wide searches for short sequences often return hundreds of hits. Our experiments show that subsequently searching the annotation data can refine and focus the results for the user. Our algorithms are also space-efficient in terms of main memory requirements. Source code is available upon request.


Effect of the erbium:yttrium-aluminum-garnet laser or diamond bur cavity preparation on the marginal microleakage of class V cavities restored with different adhesives and composite systems.
The aim of this in vitro study was to compare the microleakage of Er:YAG laser and diamond bur on different bonding systems in class V restorations. Class V cavities were prepared with Er:YAG laser or diamond bur on 80 intact human molars. Teeth were randomly distributed into ten groups and cavities were restored with CeramX duo (DENTSPLY) or Filtek Silorane (3M/ESPE) using different bonding materials (One Coat 7.0 (Coltène), XP Bond (DENTSPLY), Clearfil Protect Bond (Kuraray), AdperSE (3M/ESPE), and Silorane System Adhesive (3M/ESPE). All specimens were subjected to thermocycling and load cycling. After being immersed in silver nitrate dye, the specimens were sectioned. Microleakage was evaluated by stereomicroscope and SEM. Data were statistically analyzed by one-way ANOVA, Kruskal-Wallis, and Mann-Whitney tests. Statistically differences were found between groups (p > 0.05) and cavities prepared with the Er:YAG laser showed higher microleakage than diamond bur. The microleakage of different bonding systems was influenced by the choice of diamond bur or Er:YAG laser for class V composite cavity preparation.


Characteristics and outcome of 27 elbow periprosthetic joint infections: results from a 14-year cohort study of 358 elbow prostheses.
Elbow arthroplasty is increasingly performed in patients with rheumatic and post-traumatic arthritis. Data on elbow periprosthetic joint infection (PJI) are limited. We investigated the characteristics and outcome of elbow PJI in a 14-year cohort of total elbow arthroplasties in a single centre. Elbow prosthesis, which were implanted between 1994 and 2007 at Schulthess Clinic in Zurich, were retrospectively screened for infection. PJI was defined as periprosthetic purulence, the presence of sinus tract or microbial growth. A Kaplan-Meier survival method and Cox proportional hazard analysis were performed. Of 358 elbow prostheses, PJI was identified in 27 (7.5%). The median patient age (range) was 61 (39-82) years; 63% were females. Seventeen patients (63%) had a rheumatic disorder and ten (37%) had osteoarthritis. Debridement and implant retention was performed in 78%, followed by exchange or removal of the prosthesis (15%) or no surgery (7%).The relapse-free survival (95% CI) was 79% (63-95%) after 1 year and 65% (45-85%) after 2 years. The outcome after 2 years was significantly better when patients were treated according to the algorithm compared to patients who were not (100% vs. 33%, p <0.05). In 21 patients treated with debridement and retention, the cure rate was also higher when the algorithm was followed (100% vs. 11%, p <0.05). The findings of the present study suggest that the treatment algorithm developed for hip and knee PJI can be applied to elbow PJI. With proper patient selection and antimicrobial therapy, debridement and retention of the elbow prosthesis is associated with good treatment outcome.


Burden of Renal Cysts Imaging: A Survey of Patients among the Greater Plains Collaborative.
Renal cysts are a frequent incidental finding on cross-sectional radiographic imaging. While most cysts are indolent, individuals with such cysts are frequently monitored for interval growth and potential malignant transformation, which is ultimately rare. In this study, we aimed to assess patients' values and preferences (believes and attitudes) about renal cysts. We deployed a cross-sectional survey to a random sample of patients with a diagnosis of renal cysts who were identified by billing code and self-identification. We collected data about demographics, insurance status, family history and overall health, and characteristics of patients with renal cysts. We performed a binary regression analysis (adjusted for age, gender, family history of cancer and kidney disease, and treatment plan for renal cysts) to determine anxiety predictors in patients with renal cysts. We included 301 respondents in whom billing code and self-identification corresponded; of these, 138 had renal cysts and 163 did not. In an adjusted regression analysis, there was a suggestion that a clear management plan (OR = 0.49, 95% CI [0.22-1.11]) (p value 0.08) may be associated with less anxiety and a family history of renal disease may be associated with more anxiety (OR = 1.94 [0.76-4.94]) (p value 0.17). Family history of cancer also did not significantly predict anxiety (OR = 0.54 [0.24-1.19]) (p value 0.13). All these results were not statistically significant and had wide confidence intervals of the effect estimates make the results imprecise. Findings of this pilot study suggest a clear management plan for the renal cyst(s) management may be associated with a lower level of anxiety, thereby by emphasizing the importance of good communication, patient engagement and evidence-based guidance. More definitive, adequately powered studies are needed to evaluate this finding further. In addition, further studies exploring differences in imaging practices, patient symptomatology and patient engagement by different provider types would be insightful. Ultimately, tools to improve shared decision-making are needed to provide more patient-centered care.


Fitness declines towards range limits and local adaptation to climate affect dispersal evolution during climate-induced range shifts.
Dispersal ability will largely determine whether species track their climatic niches during climate change, a process especially important for populations at contracting (low-latitude/low-elevation) range limits that otherwise risk extinction. We investigate whether dispersal evolution at contracting range limits is facilitated by two processes that potentially enable edge populations to experience and adjust to the effects of climate deterioration before they cause extinction: (i) climate-induced fitness declines towards range limits and (ii) local adaptation to a shifting climate gradient. We simulate a species distributed continuously along a temperature gradient using a spatially explicit, individual-based model. We compare range-wide dispersal evolution during climate stability vs. directional climate change, with uniform fitness vs. fitness that declines towards range limits (RLs), and for a single climate genotype vs. multiple genotypes locally adapted to temperature. During climate stability, dispersal decreased towards RLs when fitness was uniform, but increased when fitness declined towards RLs, due to highly dispersive genotypes maintaining sink populations at RLs, increased kin selection in smaller populations, and an emergent fitness asymmetry that favoured dispersal in low-quality habitat. However, this initial dispersal advantage at low-fitness RLs did not facilitate climate tracking, as it was outweighed by an increased probability of extinction. Locally adapted genotypes benefited from staying close to their climate optima; this selected against dispersal under stable climates but for increased dispersal throughout shifting ranges, compared to cases without local adaptation. Dispersal increased at expanding RLs in most scenarios, but only increased at the range centre and contracting RLs given local adaptation to climate.


Provision of micronutrient powder in response to the Cyclone Sidr emergency in Bangladesh: cross-sectional assessment at the end of the intervention.
Micronutrient powder has been endorsed as an effective means to improve the micronutrient status of emergency-affected populations. To document the experience and findings of a cross-sectional assessment of the micronutrient powder program implemented as part of the emergency response to Cyclone Sidr. Micronutrient powder was distributed to 100,714 children under 5 years of age and 59,439 pregnant or lactating women severely affected by Cyclone Sidr in Bangladesh. A cross-sectional assessment, including hemoglobin and anthropometric measurements, was conducted after the completion of the micronutrient powder program among children under 5 years of age, lactating mothers, and postmenarcheal adolescent girls in the intervention area. Comparison groups for each, drawn from the control area, which had not received micronutrient powder, were assessed at the same time. The prevalence of anemia among children under 5 years of age was approximately 80% in both areas. Among children in the intervention area, those who consumed at least 75% of the micronutrient powder sachets had a lower prevalence of stunting than those who consumed less than 75% of the sachets (40% vs. 52%, p < .05). Among lactating mothers in the intervention area, the prevalence rates of thinness and anemia were lower among those who consumed at least 75% of the sachets than among those who consumed less than 75% of the sachets (thinness, 31% vs. 46%, p < .05; anemia, 50% vs. 61%, p = .07). For adolescent girls in the intervention and control areas, none of whom had received micronutrient powder, the prevalence rates of anemia were 52% and 45%, respectively (p = .05). Micronutrient powder may reduce anemia among lactating mothers, when the compliance rate is high. Anemia prevalence prior to micronutrient powder distribution had not been investigated and could have been higher among children and lactating mothers in the intervention than in the control area, resulting in the negation of the potential positive impact of micronutrient powder on anemia.


Surgery for nonarteritic anterior ischemic optic neuropathy.
Nonarteritic ischemic optic neuropathy is characterized by sudden and painless loss of vision in one eye, accompanied by pallid swelling of the optic disc. Although various medical interventions, such as corticosteroids and phenytoin sodium, have been used to treat nonarteritic ischemic optic neuropathy, no therapy has been proven effective. The objective of this review is to assess the safety and efficacy of surgical treatment compared with other treatment or usual care in people with nonarteritic ischemic optic neuropathy. We searched the Cochrane Controlled Trials Register - Central and MEDLINE. The most recent searches were performed in December 1997. We included randomized trials comparing surgery to no surgery in people with nonarteritic ischemic optic neuropathy. We obtained full copies of all potentially relevant articles. Only one article described a randomized trial of surgery and it was eligible for inclusion. No formal assessment of quality was done. One reviewer extracted data. No synthesis was required, as there was only one trial. The one trial identified randomized 258 patients. The only published report with outcomes data for that trial presents preliminary results from 244 patients who had achieved six months of follow-up at the time of the report. Participants assigned to surgery did no better than participants assigned to careful follow-up regarding improved visual acuity of three or more lines of vision at six months: 32.6% of the surgery group improved compared with 42.7% of the careful follow-up group. The adjusted odds ratio (OR), adjusted for baseline visual acuity and diabetes, comparing the two groups for three or more lines improvement was 0.74 (95% confidence interval (CI) 0.39 to 1. 38) (surgery group improvement was worse than careful follow-up). In addition, participants receiving surgery had a significantly greater risk of losing three or more lines of vision at six months: 23.9% in the surgery group worsened compared with 12.4% in the careful follow-up group. The six-month adjusted OR comparing the two groups for loss of three or more lines of vision was 1.96 (95% CI 0.87 to 4.41). Spontaneous improvement of three or more lines of vision was observed in 42.7% of participants in the careful follow-up group. Results from the Ischemic Optic Neuropathy Decompression Trial indicate that optic nerve decompression surgery for nonarteritic ischemic optic neuropathy is not effective.


Zwitterionic near-infrared fluorophore for targeted photothermal cancer therapy.
Precise photothermal cancer therapy still relies on the development of multifunctional theranostic agents to integrate tumor-specific targeting, imaging, and therapy. In this study, we identified the zwitterionic near-infrared (NIR) fluorophore ZW800-Cl, an analog of the well-known ZW800-1, and found that it preferentially accumulated in tumors in various xenograft models. We have demonstrated that the optical and physicochemical properties of ZW800-Cl are similar to those of ZW800-1, but it has a unique tumor targetability. Since ZW800-Cl showed binding selectivity to cancer cells in vitro, it could be specifically targeted to xenograft models of multiple tumor types, including MCF-7, NCI-H460, and HT-29. The in vivo results of photothermal cancer therapy indicated that the xenograft tumors could be effectively ablated by the combination of ZW800-Cl and an 808 nm laser irradiation. In this regard, our finding may provide a new approach for developing multifunctional cancer theranostic agents, setting them apart from conventional nanoparticles based on inorganic and polymeric materials. Therefore, ZW800-Cl may hold promise as a multifunctional theranostic agent for tumor-targeted imaging and effective photothermal cancer therapy.


A randomized clinical trial evaluating plasma rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis.
This multicenter, double-blind clinical trial evaluated and compared the efficacy and safety of PRGF-Endoret (BTI Biotechnology Institute, Vitoria-Gasteiz, Spain), an autologous biological therapy for regenerative purposes, versus hyaluronic acid (HA) as a short-term treatment for knee pain from osteoarthritis. We randomly assigned 176 patients with symptomatic knee osteoarthritis to receive infiltrations with PRGF-Endoret or with HA (3 injections on a weekly basis). The primary outcome measure was a 50% decrease in knee pain from baseline to week 24. As secondary outcomes, we also assessed pain, stiffness, and physical function using the Western Ontario and McMaster Universities Osteoarthritis Index; the rate of response using the criteria of the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI); and safety. The mean age of the patients was 59.8 years, and 52% were women. Compared with the rate of response to HA, the rate of response to PRGF-Endoret was 14.1 percentage points higher (95% confidence interval, 0.5 to 27.6; P = .044). Regarding the secondary outcome measures, the rate of response to PRGF-Endoret was higher in all cases, although no significant differences were reached. Adverse events were mild and evenly distributed between the groups. Plasma rich in growth factors showed superior short-term results when compared with HA in a randomized controlled trial, with a comparable safety profile, in alleviating symptoms of mild to moderate osteoarthritis of the knee. Level I, randomized controlled multicenter trial.


The crystal structure of the RNA/DNA hybrid r(GAAGAGAAGC). d(GCTTCTCTTC) shows significant differences to that found in solution.
The crystal structure of the RNA/DNA hybrid r(GAAGAGAAGC). d(GCTTCTCTTC) has been solved and refined at 2.5 A resolution. The refinement procedure converged at R = 0.181 for all reflections in the range 20.0-2.5 A. In the crystal, the RNA/DNA hybrid duplex has an A' conformation with all but one of the nucleotide sugar moieties adopting a C3'- endo (N) conformation. Both strands in the double helix adopt a global conformation close to the A-form and the width of the minor groove is typical of that found in the crystal structures of other A-form duplexes. However, differences are observed between the RNA and DNA strands that make up the hybrid at the local level. In the central portion of the duplex, the RNA strand has backbone alpha, beta and gamma torsion angles that alternate between the normal gauche -/ trans / gauche + conformation and an unusual trans / trans / trans conformation. Coupled with this so-called 'alpha/gamma flipping' of the backbone torsion angles, the distance between adjacent phosphorous atoms on the RNA strand systematically varies. Neither of these phenomena are observed on the DNA strand. The structure of the RNA/DNA hybrid presented here differs significantly from that found in solution for this and other sequences. Possible reasons for these differences and their implications for the current model of RNase H activity are discussed.


Dissection of the hippocampus proper and the associated structures in preserved horse brains.
The limbic system is a complicated region of the brain to teach in an undergraduate neuroanatomy course. The students often struggled with the complexity and interconnection of the structures of this system to other cortical regions. The following is a description of two dissections that used preserved horse brains to help students visualize the major components of this system and also comprehend the topographic organization of some of these structures to other regions or structures of the brain.


Telomerase deficiency affects the formation of chromosomal translocations by homologous recombination in Saccharomyces cerevisiae.
Telomerase is a ribonucleoprotein complex required for the replication and protection of telomeric DNA in eukaryotes. Cells lacking telomerase undergo a progressive loss of telomeric DNA that results in loss of viability and a concomitant increase in genome instability. We have used budding yeast to investigate the relationship between telomerase deficiency and the generation of chromosomal translocations, a common characteristic of cancer cells. Telomerase deficiency increased the rate of formation of spontaneous translocations by homologous recombination involving telomere proximal sequences during crisis. However, telomerase deficiency also decreased the frequency of translocation formation following multiple HO-endonuclease catalyzed DNA double-strand breaks at telomere proximal or distal sequences before, during and after crisis. This decrease correlated with a sequestration of the central homologous recombination factor, Rad52, to telomeres determined by chromatin immuno-precipitation. This suggests that telomerase deficiency results in the sequestration of Rad52 to telomeres, limiting the capacity of the cell to repair double-strand breaks throughout the genome. Increased spontaneous translocation formation in telomerase-deficient yeast cells undergoing crisis is consistent with the increased incidence of cancer in elderly humans, as the majority of our cells lack telomerase. Decreased translocation formation by recombinational repair of double-strand breaks in telomerase-deficient yeast suggests that the reemergence of telomerase expression observed in many human tumors may further stimulate genome rearrangement. Thus, telomerase may exert a substantial effect on global genome stability, which may bear significantly on the appearance and progression of cancer in humans.


Podocyte biology in diabetic nephropathy.
Glomerular visceral epithelial cells, namely podocytes, are highly specialized cells and give rise to primary processes, secondary processes, and finally foot processes. The foot processes of neighboring podocytes interdigitate, leaving between them filtration slits. These are bridged by an extracellular substance, known as the slit diaphragm, which plays a major role in establishing size-selective barrier to protein loss. Furthermore, podocytes are known to synthesize matrix molecules to the glomerular basement membrane (GBM), including type IV collagen, laminin, entactin, and agrin. Because diabetic nephropathy is clinically characterized by proteinuria and pathologically by glomerular hypertrophy and GBM thickening with foot process effacement, podocytes have been the focus in the field of research on diabetic nephropathy. As a result, many investigations have demonstrated that the diabetic milieu per se, hemodynamic changes, and local growth factors such as transforming growth factor-beta and angiotensin II, which are considered mediators in the pathogenesis of diabetic nephropathy, induce directly and/or indirectly hypertrophy, apoptosis, and structural changes, and increase type IV collagen synthesis in podocytes. This review explores some of the structural and functional changes of podocytes under diabetic conditions and their role in the development and progression of diabetic nephropathy.


Release of oxygen free radicals by macrophages and neutrophils in patients with rheumatic fever.
The generation of oxygen free radicals (OFR) by peripheral blood monocytes and neutrophils of patients with rheumatic fever (RF) and rheumatic heart disease (RHD) has been studied using the luminol-enhanced chemiluminescence technique. The mechanism of OFR generation was studied by measuring NADPH oxidase enzyme activity. The effect of substrate was studied by measuring the hexose monophosphate (HMP) shunt enzymes: glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Three groups of patients [i) recurrent rheumatic activity, (ii) chronic RHD, (iii) acute pharyngitis) and normal controls were studied at day 0 and followed-up serially at 15, 90 and 180 days. The release of OFR, was significantly higher (P less than 0.001) in patients with recurrent rheumatic activity than in those with acute pharyngitis or chronic RHD, throughout the study period. A significant decline (P less than 0.001) in OFR release was observed from day 0 to day 180 in these patients, whereas no such change was observed in the chronic RHD group. This study raises the possibility that these phagocytic cells, which infiltrate the myocardium, may through generation of OFR, have a role in the pathogenesis of cardiac damage seen in patients with RHD.


Conventional high-resolution CT versus contiguous multidetector CT in the detection of bronchiolitis obliterans syndrome in lung transplant recipients.
To compare the detection rate of pulmonary abnormalities between conventional high-resolution computed tomography (HRCT) and high-resolution multidetector computed tomography (MDCT) in lung transplant recipients and to correlate a composite computed tomography (CT) score with bronchiolitis obliterans syndrome (BOS) stage. Twenty-four lung transplant recipients (12 single/12 double lung transplants, 13 males/11 females, mean age: 53 y, range: 28 to 71) underwent contiguous 16-slice high-resolution MDCT of the lungs at maximal inspiration and maximal expiration. Eight reformatted image sets were reconstructed: (i) contiguous 1-mm slice MDCT image set in the transverse, sagittal, and coronal image planes at maximal inspiration; (ii) contiguous 1-mm slice MDCT image set in the transverse, sagittal, and coronal image planes at maximal expiration; (iii) conventional HRCT image set of 1-mm slices every 10 mm at maximal inspiration; and (iv) conventional expiratory HRCT of 1-mm slices at 3 selected levels at maximal expiration. Individual pulmonary abnormalities were added to give a composite CT score. Individual abnormalities and the composite CT score were correlated with BOS stage, as based on functional testing of airflow obstruction, for each of the 8 image sets. Transverse, sagittal, and coronal MDCT correlated significantly with BOS stage (R=0.46, 0.49, 0.52, respectively), whereas conventional HRCT did not. Multiple regression analysis demonstrated that transverse MDCT was the only independent predictor of BOS stage (R=0.33, P<0.01). Interobserver agreement for composite CT scores for HRCT, transverse, sagittal, and coronal MDCT were R2=0.89, 0.87, 0.83 and 0.80, respectively. Interobserver agreement for individual abnormalities was better with MDCT than with conventional HRCT. In lung transplant recipients, high-resolution MDCT detects significantly more pulmonary abnormalities and has better interobserver agreement than conventional HRCT and is an independent predictor of BOS stage.


Adapting a home telemonitoring intervention for underserved Hispanic/Latino patients with type 2 diabetes: an acceptability and feasibility study.
Home telemonitoring is a promising approach to optimizing outcomes for patients with Type 2 Diabetes; however, this care strategy has not been adapted for use with understudied and underserved Hispanic/Latinos (H/L) patients with Type 2 Diabetes. A formative, Community-Based Participatory Research approach was used to adapt a home telemonitoring intervention to facilitate acceptability and feasibility for vulnerable H/L patients. Utilizing the ADAPT-ITT framework, key stakeholders were engaged over an 8-month iterative process using a combination of strategies, including focus groups and structured interviews. Nine Community Advisory Board, Patient Advisory, and Provider Panel Committee focus group discussions were conducted, in English and Spanish, to garner stakeholder input before intervention implementation. Focus groups and structured interviews were also conducted with 12 patients enrolled in a 1-month pilot study, to obtain feedback from patients in the home to further adapt the intervention. Focus groups and structured interviews were approximately 2 hours and 30 min, respectively. All focus groups and structured interviews were audio-recorded and professionally transcribed. Structural coding was used to mark responses to topical questions in the moderator and interview guides. Two major themes emerged from qualitative analyses of Community Advisory Board/subcommittee focus group data. The first major theme involved intervention components to maximize acceptance/usability. Subthemes included tablet screens (e.g., privacy/identity concerns; enlarging font sizes; lighter tablet to facilitate portability); cultural incongruence (e.g., language translation/literacy, foods, actors "who look like me"); nursing staff (e.g., ensuring accessibility; appointment flexibility); and, educational videos (e.g., the importance of information repetition). A second major theme involved suggested changes to the randomized control trial study structure to maximize participation, including a major restructuring of the consenting process and changes designed to optimize recruitment strategies. Themes from pilot participant focus group/structured interviews were similar to those of the Community Advisory Board such as the need to address and simplify a burdensome consenting process, the importance of assuring privacy, and an accessible, culturally congruent nurse. These findings identify important adaptation recommendations from the stakeholder and potential user perspective that should be considered when implementing home telemonitoring for underserved patients with Type 2 Diabetes. NCT03960424; ClinicalTrials.gov (US National Institutes of Health). Registered 23 May 2019. Registered prior to data collection. https://www.clinicaltrials.gov/ct2/show/NCT03960424?term=NCT03960424&draw=2&rank=1.


Neutralizing monoclonal antibodies to bovine viral diarrhoea virus bind to the 56K to 58K glycoprotein.
A panel of murine monoclonal antibodies (MAbs) against the two major glycoproteins of bovine viral diarrhoea virus (BDV) was produced and assayed by serum neutralization, radioimmunoprecipitation (RIP) and immunoblotting. Based on their viral polypeptide specificity and on their ability to neutralize viral infectivity, the MAbs in the panel were divided into three classes: Class 1 MAbs reacted with the 56K to 58K glycoprotein and neutralized the virus, class 2 MAbs recognized the 56K to 58K glycoprotein but were not neutralizing, and class 3 MAbs reacted with the 48K glycoprotein and did not neutralize the virus. These results identify the 56K to 58K protein as one of the envelope glycoproteins of BDV. Evidence was obtained indicating that it is responsible for the induction of neutralizing antibodies. No large uncleaved precursors of the 56K to 58K protein could be identified unequivocally by RIP of infected cell extracts, suggesting that this polypeptide is proteolytically processed cotranslationally. A subset of MAbs that reacted with BDV isolates of the noncytopathic biotypes yielded similar results, indicating that these findings are applicable to both biotypes of BDV.


Spread of carcinoma of the base of the tongue as detected by computer tomography.
21 patients with histologically proven carcinoma involving the base of the tongue were studied with computer tomography utilizing a high dose of intravenous infusion of contrast material. Computer tomography demonstrated not only excellent visualization of the primary carcinoma at the base of the tongue, but also its traditional means of spread to contiguous soft tissues of the pharyngeal walls and lymph node metastasis. Computer tomography also demonstrated the unusual spread to the retropharyngeal lymph nodes and nasopharynx. Computer tomography with high-dose intravenous contrast is the best radiographic modality for the evaluation of carcinoma of the base of the tongue.


Developing an interdisciplinary, community-based education program for health professions students: the Rochester experience.
To successfully meet the nation's changing health needs, future health professionals must learn skills in applied health promotion and disease prevention. To achieve these goals, the Center for Rochester's Health (the Center), a collaboration of the Monroe County Department of Public Health and the University of Rochester School of Medicine and Dentistry and School of Nursing, all located in Rochester, New York, developed an innovative education program that gives interdisciplinary teams of students opportunities to partner with community agencies engaged in research-oriented health improvement initiatives. The Center started this course in 1998, under the auspices of a national initiative supported by the Health Resources and Services Administration and the Institute for Healthcare Improvement. The authors discuss the challenges related to the implementation and institutionalization of this interdisciplinary population-based education program. They describe their experiences over a seven-year period, from 1998 to 2005, including the various factors that enabled them to make necessary changes in the program activities and the ways in which the Center was able to bring departments together to consider new course directions for engaging students in the community health improvement process. They discuss the different stages of program development, including the early years of program planning and later curriculum changes that involved the development of an online population health curriculum. The authors conclude that by understanding changes in the education goals of various health professions schools and by adapting education programs to meet the needs of students from these schools, program planners will have more opportunities to sustain community-based education programs.


Iron overload in sickle cell disease.
In sickle cell disease transfusions improve blood flow by reducing the proportion of red cells capable of forming sickle hemoglobin polymer. This limits hemolysis and the endothelial damage that result from high proportions of sickle polymer-containing red cells. Additionally, transfusions are used to increase blood oxygen carrying capacity in sickle cell patients with severe chronic anemia or with severe anemic episodes. Transfusion is well-defined as prophylaxis (stroke) and as therapy (acute chest syndrome and stroke) for major complications of sickle cell disease and has been instituted, based on less conclusive data, for a range of additional complications, such as priapism, vaso-occlusive crises, leg ulcers, pulmonary hypertension, and during complicated pregnancies. The major and unavoidable complication of transfusions in sickle cell disease is iron overload. This paper provides an overview of normal iron metabolism, iron overload in transfused patients with sickle cell disease, patterns of end organ damage, diagnosis, treatment, and prevention of iron overload.