The Effect of Selected Risk Factors on Perioperative Pressure Injury Development.
Patients undergoing operative and other invasive procedures are at high risk for developing pressure injuries. This study aimed to determine the incidence of perioperative pressure injuries in patients who underwent procedures lasting two hours or more in Turkey and the risk factors that affect the development of pressure injuries. Data were collected during the perioperative period. The incidence of perioperative pressure injuries was 40.4%. The results of univariate logistic regression analysis showed that intraoperative vasopressor use, skin turgor, and diastolic blood pressure less than or equal to 60 mm Hg were significantly related to the development of pressure injuries. There was no significant difference between patients who developed pressure injuries and patients who did not when comparing their preoperative Braden Scale scores. Perioperative nurses should assess each patient for pressure injury risk and perform interventions to prevent pressure injuries during each stage of the patient's perioperative course.


Clinical significance of microRNA-21 as a biomarker in each Dukes' stage of colorectal cancer.
The potential value of microRNAs (miRNAs) as prognostic biomarkers are of interest. It is known that microRNA-21 (miR-21) is implicated in the promotion, proliferation and progression of several types of human cancers. However, the prognostic significance of miR-21 in each tumor stage of colorectal cancer (CRC) remains elusive. The objective of this study was to clarify the prognostic value of miR-21 for CRC patients at each tumor stage. The expression levels of miR-21 in the tumor tissues and normal adjacent tumor tissues of 306 CRC patients were determined by TaqMan microRNA assays. In order to clarify the miRNA profile in CRC tissues, miRNA arrays were examined. In this analysis, miR-21, miR-224, miR-96, miR-31 and miR-155 showed marked upregulation, and miR-21 showed the highest level. Upon comparison of clinicopathological factors, miR-21 expression showed significant association with depth of invasion, lymphatic and venous invasion, liver metastasis and Dukes' stage. In the Kaplan-Meier survival curve analysis of all patients, overall survival (OS) and disease-free survival (DFS) rates of the patients with high miR-21 expression were significantly worse than these rates in patients with low miR-21 expression. In the Kaplan-Meier analysis of each tumor stage, the DFS of patients with high miR-21 expression was significantly worse than patients with low miR-21 levels in Dukes' stage A tumors. In Dukes' stage B and C, patients with high miR-21 expression showed a significantly worse OS and DFS than patients with low miR-21 expression. In Dukes' stage D, patients with high miR-21 expression showed a significantly worse OS than patients with low miR-21 expression. In the Cox multivariate analysis, it was shown that miR-21 expressions in CRC tissues is an independent prognostic factor in Dukes' stage B, C and D. In conclusion, miR-21 expression may be a valuable biomarker for prediction of poor prognosis in CRC patients with Dukes' stage B, C and D.


C-Arm imaging for brachytherapy source reconstruction: geometrical accuracy.
We study the accuracy of brachytherapy source reconstruction using C-Arm images. We use a phantom embedded with dummy ribbons in a regular pattern, placed at the rotation center of the C-Arm. With a commercial reconstruction jig, radiographic films are taken without the image intensifier. The average error in reconstructed seed coordinates is 0.1 cm. However, the jig is inconvenient for patient procedures. For C-Arm reconstruction without the jig, the magnifications of the image intensifier along orthogonal directions are different. We "stretch" the image to equalize the magnifications. Afterward, seed reconstruction has an average error of 0.1 cm in all directions.


Time reversal focusing in the audible range using a tunable sonic crystal.
Time reversal (TR) focusing of acoustical waves is a widely studied phenomenon that usually requires a chaotic cavity or disordered scattering medium to achieve spatial and frequency decorrelation of the acoustic field when using a single channel. On the other hand, sonic crystals were disregarded as scattering media for the TR process because of their periodic structure and previous results showing poor spatial focusing when compared to a disordered medium. In this paper, an experimental realization of a tunable sonic crystal, which can achieve single-channel TR focusing amplitudes in the audible range comparable to those obtained in a disordered scattering medium, is presented. Furthermore, the tunable nature of the system allows it to switch the time-reversed pulse on and off by changing its geometrical configuration. A robustness analysis with respect to the perturbations in the sonic crystal configurations is also presented, showing that the time-reversed pulses with high temporal and spatial contrasts are preserved only for configurations that are close to the original one.


Epigenetics, brain, behavior, and the environment.
Early experiences can modify regulatory factors affecting gene expression in such a way that, although the DNA sequence itself is not changed, the individual's physiology and behavior is substantially influenced. In some instances these epigenetic effects are exerted upon exposure, while in other instances they are transmitted across generations via incorporation into the germline. Examples of both types of epigenetic effects are presented. First, experience with siblings (littermates) organizes behaviors and their underlying neural substrates in such a way that, as adults, rats and knockout mice behave differently. Second, exposure to the fungicide vinclozolin early in pregnancy imprints the male lineage in such a manner that rats exhibit distinct behavioral profiles as well as unique patterns of gene expression in relevant brain regions. Taken together, this work demonstrates that present and past environments alike modify both social and affiliative related behaviors and their related metabolic activity in specific brain nuclei as well as influencing the abundance of specific genes altering the epigenome in the target brain areas.


piggyBac Transposon Mediated Reprogramming and Flow Cytometry Analysis of CD44 and ICAM1 Cell-Surface Marker Changes.
Generation of iPSCs is inefficient and the molecular mechanisms underlying reprogramming are not well understood. While several studies have demonstrated that reprogramming is not entirely a random process and contains predictable stepwise changes, varying degrees of cellular heterogeneity that arise in different reprogramming systems can obscure the process. Among several reprogramming systems available, delivery of polycistronic reprogramming factor expression cassettes with piggyBac transposon into mouse embryonic fibroblasts (MEFs) is one of the simplest and most robust reprogramming approaches that provide a low background of partially reprogrammed cells. Using two novel cell surface markers, ICAM1 and CD44, clear cell population changes undergoing reprogramming can be observed over a time course upon induction of the reprogramming factors. Consequently, this technique allows for easy identification of factors that enhance or delay reprogramming, and can be a useful strategy in elucidating key mechanisms for efficient generation of iPSCs.


[The physician-patient relationship in the context of the attachment theory].
This work presents the application in medical practice of relationship rules derived from the theory of attachment which was first formulated in the fifties by John Bowlby, a British psychiatrist, and further developed by the American developmental psychologist Mary Ainsworth. This theory is considered to be one of the more outstanding achievements of psychology in the 20th century. Attachment types may reveal themselves in the form of specific behavior which characterizes the relationship of the patient with medical staff. The reaction to stress is shaped by the experience of childhood during which the child develops and perpetuates its own style of emotional expression and coping with stress. The child's model of coping with stress matures along with the experience of care from adult caregivers and determines the future pattern of coping with strange situations and solving problems through open communication and "accommodation" of negative or distressing emotions during therapy.


Clinicians' practices regarding blind versus open weighing among patients with eating disorders.
Empirically supported treatments for eating disorders, such as cognitive-behavioral therapy and family-based treatment, stress the importance of weighing patients during therapy and using this information as part of treatment. However, weighing practices vary widely across eating disorders professionals, including those that purport to provide empirically supported interventions. To characterize clinicians' practices regarding the decision to share (open weighing) or withhold (blind weighing) weight information with patients, a topic that has received limited prior attention. Clinicians (N = 114; 85% female) who regularly treat individuals with an eating disorder completed an online survey to identify factors that might impact their decision to practice blind or open weighing. Approximately half of the clinicians reported generally using open weighing procedures (n = 53; 46.49%). Endorsement of cognitive-behavioral or family-based therapeutic orientation was not significantly associated with open weighing. However, clinicians who endorsed therapeutic modalities that do not specifically encourage open weighing were significantly more likely to engage in blind weighing. Clinicians working with clients with anorexia nervosa were significantly more likely to practice blind weighing, compared to clients with other eating disorder diagnoses, and cognitive or emotional impairment from malnutrition emerged as the strongest predictor of clinicians' decisions to practice blind weighing, controlling for all other variables. Development of specific training modules may be useful for improving adherence to empirically supported protocols that recommend open weighing. More importantly, however, our results highlight the need for future treatment studies to identify whether blind or open weighing is beneficial for improving patient outcomes.


SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia.
Glycogen synthase kinase-3β (GSK3β) has diverse biological roles including effects on cellular differentiation, migration, and inflammation. GSK3β phosphorylates proteins to generate phosphodegrons necessary for recognition by Skp1/Cullin-1/F-box (SCF) E3 ubiquitin ligases leading to subsequent proteasomal degradation of these substrates. However, little is known regarding how GSK3β protein stability itself is regulated and how its stability may influence inflammation. Here we show that GSK3β is degraded by the ubiquitin-proteasome pathway in murine lung epithelial cells through lysine 183 as an acceptor site for K48 polyubiquitination. We have identified FBXO17 as an F-box protein subunit that recognizes and mediates GSK3β polyubiquitination. Both endogenous and ectopically expressed FBXO17 associate with GSK3β, and its overexpression leads to decreased protein levels of GSK3β. Silencing FBXO17 gene expression increased the half-life of GSK3β in cells. Furthermore, overexpression of FBXO17 inhibits agonist-induced release of keratinocyte-derived cytokine (KC) and interleukin-6 (IL-6) production by cells. Thus, the SCFFBXO17 E3 ubiquitin ligase complex negatively regulates inflammation by targeting GSK3β in lung epithelia.


Regional Influence of Radiation Oncology Residency Training on Job Securement over Two Time Periods.
Purpose Recent reports have noted conflicting predictions regarding the future of the radiation oncology job market. Residents and practicing radiation oncologists (ROs) report perceptions of an increasingly saturated market. An important factor contributing to the job landscape is the potential geographic maldistribution of ROs in the United States. Given the importance of the evolving job market and appropriate supply and demand for future ROs, this study investigated whether residency training region influences employment region and whether "portability" of residency training has changed over time from 2003-2015. Methods Radiation oncology residency graduates were identified from Association of Residents in Radiation Oncology (ARRO) directories from 2003-2012. This information was cross-referenced with the American Society of Radiation Oncology directory to determine current employment location. The region of residency training and employment were categorized into four regions per the US Census Bureau: Northeast (NE), South (S), Midwest (MW), and West (W). The change in "portability" of residency training over time was determined from the results of an anonymous internet-based survey which provided information on year of graduation and location of first job. "Portability" was defined as the rate at which a trainee in one region could find employment in another region. From the survey, two cohorts were identified: early (graduated from 2003-2006) and late (graduated from 2012-2015). Results Current employment location was available for 817/1168 (70%) residents identified in the ARRO directories from 2003-2012. The percentages of residents who trained in the NE, S, MW, and W were 29%, 28%, 27%, and 15%, respectively. The percentages of residents with current employment in the NE, S, MW, and W were 20%, 34%, 22%, and 24%, respectively. Residents were more likely to remain employed in the region in which they trained (p < 0.05), with 58% having current employment in the region of their training. Residency graduation year and location of first job (in the United States) were available for 139/198 (70%) survey respondents. Portability of residency training did not significantly change from 2003-2012 with 49% of the early cohort securing their first job in the region in which they trained compared to 57% of the late cohort (p = 0.39). Conclusions This study suggests that recent residents are not moving to different geographic regions at an increased rate than previous and that residents are more likely to find employment in the region in which they trained.


Uremia induces upregulation of cerebral tissue oxidative/inflammatory cascade, down-regulation of Nrf2 pathway and disruption of blood brain barrier.
Chronic kidney disease (CKD) results in various central nervous systems (CNS) disorders including cognitive dysfunction, depression, anxiety, movement disorders, seizures and encephalopathy. Uremic retention products, oxidative stress, inflammation and impaired blood-brain barrier have been implicated as the major mediators of CKD-induced CNS disorders. However, mechanisms of CKD-induced cerebral tissue oxidative stress, inflammation and impaired blood brain barrier have not been fully elucidated and were explored. Male Sprague Dawley rats underwent sham operation or 5/6 nephrectomy and were observed for 10 weeks. Arterial pressure, body weight, and renal function were monitored. Under general anesthesia the animals' cerebral cortex was harvested. Nuclear translocations of NF-κB and Nrf2 and their key target gene products, neuronal, endothelial and inducible NO synthase (NOS) isoforms, markers of oxidative, nitrosative and myeloperoxidase reactions, fibrosis mediators and key protein constituents of capillary endothelial junctional complex were determined by Western blot analysis. The CKD rats exhibited reduced body weight, hypertension, elevated serum urea and creatinine concentrations. Compared to control group cerebral cortex of the CKD group showed activation (increased nuclear translocation) of NF-κB, elevation of pro-oxidant and pro-inflammatory molecules, diminished nuclear translocation of Nrf2 and expression of cytoprotective antioxidant molecules and depletion of the key protein constituents of endothelial junctional complex. In conclusion CKD results in the cerebral tissue activation of inflammatory and oxidative pathways, inhibition of antioxidant and cytoprotective system and erosion of cerebral capillary junctional complex, events that contribute to CNS dysfunction and impaired blood brain barrier.


Electrospun starch nanofibers: Recent advances, challenges, and strategies for potential pharmaceutical applications.
Electrospun starch nanofibers have high porosity, extremely high specific surface area, and biocompatible, biodegradable, and bioabsorbable properties. As a result, starch nanofibers have great potential in pharmaceutical applications, including drug delivery, wound dressing, and tissue engineering. Here, we summarize and review the recent developments in the synthesis of electrospun starch fibers from common starch, modified starch, and hybrids with other polymers. Moreover, the challenges and strategies for the fabrication and application of starch fibers in pharmaceutical applications are presented.


Diphenylalanine in tetrahydrofuran: a highly potent candidate for the development of novel nanomaterials.
The peptide di-L-phenylalanine (FF) has emerged as a highly potent candidate for the development of novel nanomaterials. The unprotected peptide was dissolved in 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) mixed with tetrahydrofuran (THF) and single crystals of the THF monosolvate, C18H20N2O3·C4H8O, were grown by slow evaporation in a `vial-in-closed-bottle' system. THF is a molecule that can only act as a hydrogen-bond acceptor. Thus, the hydrogen-bond patterns observed in the crystal structures at 100 and 299 K are different compared to that of crystals grown from water and methanol [Mason et al. (2014). ACS Nano. 8, 1243-1253].


Routing in Mobile Wireless Sensor Networks: A Leader-Based Approach.
This paper presents a leader-based approach to routing in Mobile Wireless Sensor Networks (MWSN). Using local information from neighbour nodes, a leader election mechanism maintains a spanning tree in order to provide the necessary adaptations for efficient routing upon the connectivity changes resulting from the mobility of sensors or sink nodes. We present two protocols following the leader election approach, which have been implemented using Castalia and OMNeT++. The protocols have been evaluated, besides other reference MWSN routing protocols, to analyse the impact of network size and node velocity on performance, which has demonstrated the validity of our approach.


Human papilloma virus and squamous cell carcinoma of the anus.
The incidence of anal cancer is increasing. In the UK, the incidence is estimated at approximately 1.5 per 100,000. Most of this increase is attributed to certain at-risk populations. Persons who are human immunodeficiency virus (HIV)-positive and men who have sex with men (MSM), Organ transplant recipients, women with a history of cervical cancer, human papilloma virus (HPV), or cervical intraepithelial neoplasia (CIN) are known to have a greater risk for anal cancer. This paper will focus on HPV as a risk factor for anal intraepithelial neoplasia (AIN) and discusses the etiology, anatomy, pathogenesis, management of squamous cell carcinoma (SCC) of the anus.


Mitochondrial Stability in Diabetic Retinopathy: Lessons Learned From Epigenetics.
Diabetic retinopathy remains the leading cause of acquired blindness in working-age adults. While the cutting-edge research in the field has identified many molecular, functional, and structural abnormalities, the exact molecular mechanism of this devastating disease remains obscure. Diabetic environment drives dysfunction of the power generator of the cell and disturbs the homeostasis of mitochondrial dynamic. Mitochondrial DNA (mtDNA) is damaged, the transcription of mtDNA-encoded genes is impaired, and the electron transport chain is compromised, fueling into a vicious cycle of free radicals. The hyperglycemic milieu also alters the epigenetic machinery, and mtDNA and other genes associated with mitochondrial homeostasis are epigenetically modified, further contributing to the mitochondrial damage. Thus, mitochondria appear to have a significant role in the development of diabetic retinopathy, and unraveling the mechanism responsible for their damage as well as the role of epigenetic modifications in mitochondrial homeostasis should identify novel therapeutic targets. This will have a major impact on inhibiting/halting diabetic retinopathy and preventing the loss of vision.


Chronic fatigue syndrome: a literature review from a physiatric perspective.
To examine the literature on chronic fatigue syndrome (CFS), especially as it relates to cognitive deficits and exercise, more than 200 articles related to CFS were selected from computer-based research as well as pertinent articles noted in the references of individual articles. All were relevant articles on CFS, although articles in a foreign language were excluded. CFS is a controversial diagnosis of exclusion, but certain subgroups do appear to exist. It may represent multiple diseases or multiple stages of the same disease. Although cognitive deficits are commonly reported, the measured impairments are relatively subtle and are in the area of complex information processing speed, or efficiency. Magnetic resonance imaging, single-photon emission computer tomography, and neuroendocrine studies present preliminary evidence suggestive of the cerebral involvement primarily in the white matter. The weakness and fatigue may be the result of alterations in the central nervous system, not in the peripheral muscles. However, it is hard to separate the documented weakness and endurance deficits from deconditioning. Autonomic symptoms such as orthostatic intolerance and a predisposition to neurally mediated syncope may be explained by cardiovascular deconditioning, a postviral idiopathic autonomic neuropathy, or both. The review points out the need for more carefully designed studies of CFS that focus on the relationship between neuropathology, psychopathology and neuropsychologic functioning. The role of exercise as a stimulus for exacerbation or in treatment needs to be further studied using clear diagnostic criteria as well as control groups that carefully match the activity level.


Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase.
Vaccinationis a critical tool in the prevention of COVID-19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently, in North America, only the BNT162b2 (Pfizer-BioNTech) mRNA vaccine is approved for individuals aged 12-17. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive PEG-asparaginase (PEG-ASNase) and 10%-30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients is critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG-ASNase allergy.


Facile Synthesis, Geometry, and 2'-Substituent-Dependent in Vivo Activity of 5'-(E)- and 5'-(Z)-Vinylphosphonate-Modified siRNA Conjugates.
(E)-Vinylphosphonate ((E)-VP), a metabolically stable phosphate mimic at the 5'-end of the antisense strand, enhances the in vivo potency of siRNA. Here we describe a straightforward synthetic approach to incorporate a nucleotide carrying a vinylphosphonate (VP) moiety at the 5'-end of oligonucleotides under standard solid-phase synthesis and deprotection conditions by utilizing pivaloyloxymethyl (POM) protected VP-nucleoside phosphoramidites. The POM protection enhances scope and scalability of 5'-VP-modified oligonucleotides and, in a broader sense, the synthesis of oligonucleotides modified with phosphonate moieties. Trivalent N-acetylgalactosamine-conjugated small interfering RNA (GalNAc-siRNA) comprising (E)-geometrical isomer of VP showed improved RISC loading with robust RNAi-mediated gene silencing in mice compared to the corresponding (Z)-isomer despite similar tissue accumulation. We also obtained structural insights into why bulkier 2'-ribosugar substitutions such as 2'-O-[2-(methylamino)-2-oxoethyl] are well tolerated only when combined with 5'-(E)-VP.


[Performance of fragmenting operation for restoration of a correct rhythm while treating the isolated failure of a mitral valve].
Possibilities of application of the proposed procedure for intraoperative restoration of the sinus rhythm while the mitral valve prosthesis (MVP) were studied up. In 161 patients, suffering the isolated mitral valve failure stage IV, a surgical treatment was conducted in Department of surgical treatment of acquired heart failures. The left atrium plasty was conducted in 119 (73.9%) of them with the objective to reduce its size and eliminate the re-entry waves passability. Fragmentation in left atrium was conducted in lowradiofrequency regime of diathermy (25-35 W) in accordance to variant (cut and sew) of operations Maze - 3 and Maze - 4. On a hospital stage 3 patients died (hospital lethality 1.9%). MVP in combination with Maze operation in a lowradiofrequency regime have permitted to restore successfully a correct rhythm in 80.2% of patients on a hospital stage and to stabilize it during 1 year postoperatively.


Thermo-induced modifications and selective accumulation of glucose-conjugated magnetic nanoparticles in vivo in rats - increasing the effectiveness of magnetic-assisted therapy - pilot study.
Ferro-Magnetic nanoparticles (Fe-MNP) have gained a lot of attention in biomedical and industrial applications due to their biocompatibility, ease of surface modification and paramagnetic properties. The basic idea of our study is whether it is possible to use glucose-conjugate Fe-MNP (Glc-Fe-MNP) for targeting and more accurate focusing in order to increase the effect of high-frequency electromagnetic fields induced hyperthermia in solid tumors. Tumors demonstrate high metabolic activity for glucose in comparison with other somatic cells.Increasing of accumulation of glucose conjugated (Glc)-Fe-MNP on tumor site and precision of radio frequency electro-magnetic field (RF-EMF) energy absorption in solid tumors, precede RF-EMF induced hyperthermia. Rat model for monitoring the early development of breast cancer. Twenty female Wistar rats (MU-line-6171) were divided into two groups of 10 rats that were either treated with N-methyl-N-nitrosourea to induce breast cancer and 10 with carrageenan to induce inflammation (control). Glc-Fe-MNP can offer a solution to increase hyperthermia effect to the desired areas in the body by accumulation and increasing local concentration due to high tissue metabolic assimilation. In this condition, it is considered that the magnetization of the nanoparticles is a single-giant magnetic moment, the sum of all the individual magnetic moments and is proportional to the concentration of Glc-Fe-MNP.


Health-Related Quality of Life in Elderly Patients with Pacemakers.
Cardiac pacemaker (PM) therapy is of paramount importance. PM use increases with age, with an estimated increased use of 70% to 80% in patients over 65 years. This study evaluated the perception of the health-related quality of life (HRQoL) of elderly patients with PM, comparing them with patients without PM, by applying two quality of life questionnaires: EuroQoL 5-dimensions (EQ-5D) and 36-Item Short Form Health Survey (SF-36). This study included elderly patients divided into a group with PM and another without PM. Information on HRQoL was obtained using the EQ-5D and SF-36 questionnaires. The study involved 104 elderly patients with PM and 150 without PM. The distribution of responses to the EQ-5D was similar between groups. Statistical differences within the gender variable in the group of elderly people with PM were significant for the mobility, habitual activities, and anxiety/depression domains and for the average EQoL utility score and visual analogue scale (EQ-VAS). Elderly patients with PM presented significant differences between New York Heart Association classes 1 and 2 for the mobility domain and EQ-VAS, while those evaluated through SF-36 presented higher averages in vitality, general health status, and pain. However, a different analysis was observed in the physical aspect domain. The SF-36 demonstrated that elderly patients with PM had an HRQoL similar to or greater than those without PM. However, the results of the EQ-5D did not show significant differences regarding the implantation of PM and HRQoL between the two groups of elderly individuals in the study.


Acquired idiopathic generalized anhidrosis: A case series of two Caucasian patients.
Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder characterized by insidious or sudden onset of the inability to sweat involving >25% of body surface area in the absence of other neurologic or sweat gland abnormalities and typically affects young, healthy, Asian men. Here, we describe two Caucasian teenagers with the diagnosis. They both had variable responses to prednisone, one in the setting of an elevated ANA, suggesting an autoimmune or inflammatory pathomechanism of the disorder. It is essential the clinician recognizes this rare entity and initiates timely intervention to prevent the serious consequences of hyperpyrexia.


Cluster differentiation-36 deficiency type 1 and acute coronary syndrome without major cardiovascular risk factors: case report.
A 45-year-old man without major coronary risk factors, including hypertension, diabetes mellitus, smoking, hypercholesterolemia, hyperuricemia, or a family history of early cardiovascular disease, presented with acute coronary syndrome. Angiography showed thrombus formation in segment 7 of the left anterior descending coronary artery, and percutaneous coronary intervention was successful after implantation of a bare metal stent. Scintigraphy showed the absence of 123I-beta-methyl-iodophenyl pentadecanoic acid accumulation in the myocardium. Flow cytometric analysis of platelets and monocytes showed the absence of cluster differentiation (CD)-36 expression. These findings are consistent with a diagnosis of CD36 deficiency type 1, which might be associated with cardiovascular disease. The patient had no apparent major coronary risk factors except for insulin resistance and an abnormal lipoprotein profile. The findings suggest that in this case the CD36 deficiency type 1 was the pathogenic mechanism of acute coronary syndrome relative to insulin resistance and modification of the lipid profile.


Home delivery among antenatal care booked women in their last pregnancy and associated factors: community-based cross sectional study in Debremarkos town, North West Ethiopia, January 2016.
In Ethiopia, nearly half of the mothers who were booked for antenatal care, who supposed to have institutional delivery, gave home delivery nationally. Home delivery accounts majority while few of childbirth were attended by the skilled provider in Amhara regional state. This study aimed to determine the proportion of home delivery and associated factors among antenatal care booked women who gave childbirth in the past 1 year in Debremarkos Town, Northwest Ethiopia. A community-based Cross sectional study was conducted from January 1st- 25th 2016. Epi Info version 7 was used to determine a total sample size of 518 and simple random sampling procedure was employed. Data was collected through an interview by using pretested structured questionnaire. Data were entered into Epi Info version 7, cleaned and exported to SPSS version 21 for analysis. A p-value less than or equals to 0.05 at 95% Confidence Intervals of odds ratio were taken as significance level in the multivariable model. A total of 127 (25.3%) women gave childbirth at home. Un-attending formal education (Adjusted Odds Ratio = 7.56, 95% CI: [3.28, 17.44]), absence of health facility within 30 min distance (AOR = 3.41, 95% CI: [1.42, 8.20]), not exposed to media (AOR = 4.46, 95% CI: [2.09, 9.49]), Unplanned pregnancy (AOR = 3.47, 95% CI [1.82, 6.61]), attending ANC at health post (AOR = 5.45, 95% CI: (1.21, 24.49) and health center (AOR = 2.74, 95% CI [1.29, 5.82]), perceived privacy during ANC (AOR = 3.69[1.25, 10.91]) and less than four times ANC visit (AOR = 5.04, 95% CI (2.30, 11.04]) were significantly associated with home delivery. Home delivery in this study was found to be low. Educational level, media exposure, geographic access to a health facility, Unplanned pregnancy, an institution where ANC was booked, perceived privacy during ANC and number of ANC visit were found to be determinants of home delivery. Health institutions, health professionals, policy makers, community leaders and all concerned with the planning and implementation of maternity care in Ethiopia need to consider these associations in implementing services and providing care, for pregnant women.


Comparative analysis of RNA genomes of mouse hepatitis viruses.
The RNA genomes of various murine hepatitis virus (MHV) strains were studied by T1-oligonucleotide fingerprinting analysis with regard to their structure and sequence relationship. It was found that the MHV particles contained only positive-stranded 60S RNA which had a "cap" structure at its 5' end. No negative-stranded RNA was found. It was also shown that most of the MHV strains had diverged quite extensively in their genetic sequences. However, MHV-3, a hepatotropic strain, and A59, a nonpathogenic strain, were found to have very similar oligonucleotide fingerprinting patterns. Yet, each of them contained two to four specific oligonucleotides. The MHV-3-specific oligonucleotides were conserved in almost all of the hepatotropic MHV strains studied. In contrast, two of the A59-specific oligonucleotides were absent from the genomes of all hepatotropic strains. These findings suggest that these unique oligonucleotides might be localized at the genetic region(s) associated with viral pathogenicity or other biological properties of the virus. Comparison of viral structural proteins also suggests that MHV-3 and A59 are more closely related than other MHV strains. The significance of these findings is discussed.


Plasmonic Thermal Decomposition/Digestion of Proteins: A Rapid On-Surface Protein Digestion Technique for Mass Spectrometry Imaging.
A method based on plasmon surface resonance absorption and heating was developed to perform a rapid on-surface protein thermal decomposition and digestion suitable for imaging mass spectrometry (MS) and/or profiling. This photothermal process or plasmonic thermal decomposition/digestion (plasmonic-TDD) method incorporates a continuous wave (CW) laser excitation and gold nanoparticles (Au-NPs) to induce known thermal decomposition reactions that cleave peptides and proteins specifically at the C-terminus of aspartic acid and at the N-terminus of cysteine. These thermal decomposition reactions are induced by heating a solid protein sample to temperatures between 200 and 270 °C for a short period of time (10-50 s per 200 μm segment) and are reagentless and solventless, and thus are devoid of sample product delocalization. In the plasmonic-TDD setup the sample is coated with Au-NPs and irradiated with 532 nm laser radiation to induce thermoplasmonic heating and bring about site-specific thermal decomposition on solid peptide/protein samples. In this manner the Au-NPs act as nanoheaters that result in a highly localized thermal decomposition and digestion of the protein sample that is independent of the absorption properties of the protein, making the method universally applicable to all types of proteinaceous samples (e.g., tissues or protein arrays). Several experimental variables were optimized to maximize product yield, and they include heating time, laser intensity, size of Au-NPs, and surface coverage of Au-NPs. Using optimized parameters, proof-of-principle experiments confirmed the ability of the plasmonic-TDD method to induce both C-cleavage and D-cleavage on several peptide standards and the protein lysozyme by detecting their thermal decomposition products with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The high spatial specificity of the plasmonic-TDD method was demonstrated by using a mask to digest designated sections of the sample surface with the heating laser and MALDI-MS imaging to map the resulting products. The solventless nature of the plasmonic-TDD method enabled the nonenzymatic on-surface digestion of proteins to proceed with undetectable delocalization of the resulting products from their precursor protein location. The advantages of this novel plasmonic-TDD method include short reaction times (<30 s/200 μm), compatibility with MALDI, universal sample compatibility, high spatial specificity, and localization of the digestion products. These advantages point to potential applications of this method for on-tissue protein digestion and MS-imaging/profiling for the identification of proteins, high-fidelity MS imaging of high molecular weight (>30 kDa) proteins, and the rapid analysis of formalin-fixed paraffin-embedded (FFPE) tissue samples.


Reference gene selection for clinical chimeric antigen receptor T-cell product vector copy number assays.
Reference genes are an essential part of clinical assays such as droplet digital polymerase chain reaction (ddPCR), which measure the number of copies of vector integrated into genetically engineered cells and the loss of plasmids in reprogrammed cells used in clinical cell therapies. Care should be taken to select reference genes, because it has been discovered that there may be thousands of variations in copy number from genomic segments among different individuals. In addition, within the same person in the context of cancer and other proliferative disorders, substantial parts of the genome also can differ in copy number between cells from diseased and healthy people. The purpose of this study was to identify reference genes that could be used for copy number variation analysis of transduced chimeric antigen receptor T cells and for plasmid loss analysis in induced pluripotent stem cells using ddPCR. We used The Cancer Genome Atlas (TCGA) to evaluate candidate reference genes. If TCGA found a candidate gene to have low copy number variance in cancer, ddPCR was used to measure the copy numbers of the potential reference gene in cells from healthy subjects, cancer cell lines and patients with acute lymphocytic leukemia, lymphoma, multiple myeloma and human papillomavirus-associated cancers. In addition to the rPP30 gene, which we have has been using in our copy number assays, three other candidate reference genes were evaluated using TCGA, and this analysis found that none of the four gene regions (AGO1, AP3B1, MKL2 and rPP30) were amplified or deleted in all of the cancer cell types that are currently being treated with cellular therapies by our facility. The number of copies of the genes AP3B1, AGO1, rPP30 and MKL2 measured by ddPCR was similar among cells from healthy subjects. We found that AGO1 had copy number alteration in some of the clinical samples, and the number of copies of the genes AP3B1, MKL2 and rPP30 measured by ddPCR was similar among cells from patients with the cancer cell types that are currently being treated with genetically engineered T-cell therapies by our facility. Based on our current results, the three genes, AP3B1, MKL2 and rPP30, are suitable for use as reference genes for assays measuring vector copy number in chimeric antigen receptor T cells produced from patients with acute leukemia, lymphoma, multiple myeloma and human papillomavirus-associated cancers. We will continue to evaluate AGO1 on our future samples.


Characterization of normal human CD3+ CD5- and gamma delta T cell receptor positive T lymphocytes.
The functional and phenotypic properties of normal human CD3+CD5- T cells which have a higher frequency of cytotoxic cells than CD3+CD5+ T lymphocytes have been described. Using three- and four-colour immunofluorescence flow cytometric cell sorting, the CD3+CD5- and CD3+CD5+ populations were subdivided into alpha beta or gamma delta T cell receptor positive cells. The four subsets were examined for the in vitro cytotoxic activity and were also stimulated with mitogens in limiting-dilution assays to measure the frequencies of proliferating and interleukin-2 (IL-2) producing cells. CD3+CD5- alpha beta +, CD3+CD5- gamma delta + and CD3+CD5+ gamma delta + cells had lower frequencies of proliferating and IL-2-producing cells than did CD3+CD5+ alpha beta + cells. However, the cytotoxic activity of the different phenotypes was higher in the CD3+CD5- subsets, especially when these cells were gamma delta +. Expression of gamma delta or lack of expression of CD5 appeared to be associated with the acquisition of cytolytic potentials. CD8 was expressed on 20% of fresh CD3+ gamma delta + cells. Cultured gamma delta + cells retained the expression of gamma delta, but quickly lost that of CD8 and with time modulated the expression of CD5. The expression of CD5 was found to be higher on sorted CD3+CD5+ gamma delta - than on CD3+CD5+ gamma delta + cells. These observations indicate that gamma delta is preferentially expressed on CD5-negative or weakly positive T lymphocytes and that CD3+CD5- gamma delta + cells appear to constitute a discrete small subset of mature T lymphocytes which are cytotoxic in nature. However, the exact immunological function of these cells and their place in T cell ontogeny are yet to be elucidated.


Experimental evidence of strong anomalous diffusion in living cells.
We evaluated the transport of polymeric particles internalized into living cancer cells. The mean-square displacement demonstrates superdiffusion with a scaling exponent of 1.25. Scaling exponents of a range of displacement moments are bilinear with moment order, exhibiting slopes of 0.6 and 0.8. Thus, we present experimental evidence of strong anomalous diffusion. Bilinearity indicates that particle motion is composed of subdiffusive regimes separated by active yet nonballistic flights. We discuss the results in terms of particle interactions with their microenvironment.


Program relationships of community hospitals and medical schools in CME.
In this paper, the authors report on a nationwide study that examined continuing medical education (CME) "programmatic linkages" between medical schools and community hospitals. Data were gathered to answer two major questions. To what extent are U.S. medical schools currently involved with community hospitals in providing cosponsored, accredited CME programs on an ongoing basis for hospital staffs? How do such programs differ one from the other? Data obtained indicated that a majority (70 percent) of the medical schools have CME programmatic linkages with community hospitals and that these relationships were viewed as very positive and beneficial.


Intermittent administration of parathyroid hormone ameliorated alveolar bone loss in experimental periodontitis in streptozotocin-induced diabetic rats.
Intermittent administration of parathyroid hormone (PTH) has been demonstrated to have anabolic effects on bone metabolism and is approved for use in the treatment of osteoporosis. This study evaluates the role of intermittent PTH administration on alveolar bone loss in streptozotocin (STZ)-induced diabetic rats. Fifty male Sprague Dawley rats were randomly divided into the following five groups: (1) a control group (saline placebo without ligature and STZ injection), (2) a PTH group (PTH administration without ligature and STZ injection), (3) an L group (saline placebo with ligature), (4) an L+STZ group (saline placebo with ligature and STZ injection), and (5) an L+STZ+PTH group (PTH administration with ligature and STZ injection). PTH was administered at 75μg/kg per dose four times a week for 28days. Subsequently, all rats were sacrificed, and their mandibles were extracted for micro-computed tomography (micro-CT) scanning, as well as histological and immunochemical evaluation. Micro-CT scanning demonstrated the anabolic effect of PTH on alveolar bone metabolism in STZ-induced diabetic rats (P<0.05), and histomorphometry indicated that PTH inhibited inflammation of the periodontium and increased the level of osteoblastic activity (P<0.05). Immunochemical evaluation showed that rats subjected to both ligature placement and STZ injection had the highest receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio and that PTH administration decreased this ratio. Intermittent systemic PTH administration effectively reduced alveolar bone loss and ameliorated the manifestation of experimental periodontitis in STZ-induced diabetic rats.


Quantitative structure-activity relationships among steroids. Investigations of the use of steric parameters.
The importance of steric factors in quantitative structure-activity relationships involving steroid hormones is discussed. a variety of steric parameters, such as parachlor, molecular volume, van der Waals volume, and including difference and squared steric terms, is explored in an attempt to find preferred forms for such expressions. Improved correlations for 6-substituted 16-methylene-17alpha-acetoxy-4,6-pregnadiene-3,20-dione derivatives were found in which activity is related to pi and a squared or difference steric factor. The activity of 9alpha-substituted cortisols correlates well with sigma I and a simple steric factor, provided that the 9alpha-hydroxylated compound is excluded from the series.


[Ongoing, flexible distance learning through the Internet: course on decentralized management of human resources in health care].
This paper describes the Course on Decentralized Management of Human Resources in Health Care, which is an Internet-based distance learning program to train and provide continuing education for health care professionals. The program is an initiative of the Pan American Health Organization, and it was organized in response to the growing need for self-reliant professionals who can constantly upgrade their knowledge without having to leave their place of work. The proposed model promotes an educational process that brings together theory and practice in realistic and relevant contexts and that maximizes the participation of students, both individually and in groups. The program has been evaluated in pilot studies in Brazil, Chile, and Peru. Following these assessments, the course has been adapted to facilitate its implementation and to adjust its contents to fit each country's circumstances.


A novel systemically administered Toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models.
Although topical TLR7 therapies such as imiquimod have proved successful in the treatment of dermatological malignancy, systemic delivery may be required for optimal immunotherapy of nondermatological tumors. We report that intravenous delivery of the novel small molecule TLR7 agonist, DSR-6434, leads to the induction of type 1 interferon and activation of T and B lymphocytes, NK and NKT cells. Our data demonstrate that systemic administration of DSR-6434 enhances the efficacy of ionizing radiation (IR) and leads to improved survival in mice bearing either CT26 or KHT tumors. Of the CT26 tumor-bearing mice that received combined therapy, 55% experienced complete tumor resolution. Our data reveal that these long-term surviving mice have a significantly greater frequency of tumor antigen specific CD8(+) T cells when compared to age-matched tumor-naïve cells. To evaluate therapeutic effects on spontaneous metastases, we showed that combination of DSR-6434 with local IR of the primary tumor significantly reduced metastatic burden in the lung, when compared to time-matched cohorts treated with IR alone. The data demonstrate that systemic administration of the novel TLR7 agonist DSR-6434 in combination with IR primes an antitumor CD8(+) T-cell response leading to improved survival in syngeneic models of colorectal carcinoma and fibrosarcoma. Importantly, efficacy extends to sites outside of the field of irradiation, reducing metastatic load. Clinical evaluation of systemic TLR7 therapy in combination with IR for the treatment of solid malignancy is warranted.


Patient-specific Deformation Modelling via Elastography: Application to Image-guided Prostate Interventions.
Image-guided prostate interventions often require the registration of preoperative magnetic resonance (MR) images to real-time transrectal ultrasound (TRUS) images to provide high-quality guidance. One of the main challenges for registering MR images to TRUS images is how to estimate the TRUS-probe-induced prostate deformation that occurs during TRUS imaging. The combined statistical and biomechanical modeling approach shows promise for the adequate estimation of prostate deformation. However, the right setting of the biomechanical parameters is very crucial for realistic deformation modeling. We propose a patient-specific deformation model equipped with personalized biomechanical parameters obtained from shear wave elastography to reliably predict the prostate deformation during image-guided interventions. Using data acquired from a prostate phantom and twelve patients with suspected prostate cancer, we compared the prostate deformation model with and without patient-specific biomechanical parameters in terms of deformation estimation accuracy. The results show that the patient-specific deformation model possesses favorable model ability, and outperforms the model without patient-specific biomechanical parameters. The employment of the patient-specific biomechanical parameters obtained from elastography for deformation modeling shows promise for providing more precise deformation estimation in applications that use computer-assisted image-guided intervention systems.


Patterning collagen/poloxamine-methacrylate hydrogels for tissue-engineering-inspired microfluidic and laser lithography applications.
The ability to pattern semi-synthetic collagen/poloxamine-methacrylate hydrogels into straight-channel flow circuits and sub-millimeter-sized rectangular blocks for tissue-engineering applications was evaluated. Endothelial cells, grown on the surface of flat collagen/poloxamine-methacrylate hydrogels, proliferated, expressed ICAM-1 (but not VCAM-1) and began to detach after 6 days. Seeding endothelial cells onto the lumen surface of straight collagen/poloxamine-methacrylate flow channels increased ICAM-1 and VCAM-1 expression, and exposure to laminar shear stress (0.3-10 dyn/cm(2)) was unable to attenuate activation on the relatively few cells that were able to withstand flow associated ablation. The enrichment of poloxamine-methacrylate at the lumen surface during fabrication likely caused the decrease in cell attachment and increased activation. To micropattern more complex structures, confocal microscopy UV laser lithography was used to selectively cross-link a HepG2-containing pre-polymer solution of collagen/poloxamine-methacrylate. Turbidity (caused by suspended cells and the incomplete miscibility of collagen and poloxamine-methacrylate) scattered the UV laser energy and necessitated the optimization of exposure times with respect to cross-linking extent and cell viability. Free radical diffusion beyond the bounds of the initial photopattern reduced the resolution of the structures and created a weakly cross-linked periphery around the original pattern. Over time, HepG2 cells migrated towards the less cross-linked periphery and proliferated, creating a non-uniform distribution of cells.


Association of physical activity and cardiorespiratory function or BMI and body composition in preterm-born individuals: a systematic review.
To evaluate the association of physical activity (PA) and forced expiratory volume in one second (FEV1), peak oxygen consumption (pVO2), body mass index (BMI) and body composition in preterm-born individuals. Cochrane Library, EMBASE, MEDLINE, AMED, ERIC, Web of Science and PsycInfo were searched with no restriction on language and date of publication from inception to January 2018. Data were extracted comparing preterm-born individuals with different frequencies of PA and the outcome of interest. One randomized controlled, two longitudinal and thirteen cross-sectional studies comprising 1922 preterm-born individuals aged 5-25 were included. Assessment varied from a PA program to accelerometer data, interviews and self-report questionnaires. In preterm-born children, more PA was associated with better cardiorespiratory function in those groups with impaired lung function or with lower BMI in those groups with increased risk factors, but no association was found in unimpaired children. In preterm-born adults, more PA was associated with higher pVO2 and lower BMI. Only tentative conclusions can be drawn, especially regarding differences of the association of PA between preterm- and term-born populations. Further studies are needed to analyse the association of PA in preterm-born individuals with reduced cardiorespiratory function.


Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer.
Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivoConclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987-2001. ©2018 AACR.


A pilot investigation to subjectively measure treatment effect and side-effect profile of non-ablative skin remodeling using a 532 nm, 2 ms pulse-duration laser.
Carbon dioxide laser skin resurfacing has become a standard treatment for wrinkles and sun-damaged skin. This ablative treatment, however, is associated with undesirable complications and long recovery times. A growing body of evidence suggests that dermal inflammation and subsequent collagen formation can be stimulated without removal of the epidermis, raising the possibility of effective non-ablative skin remodeling for mild to moderately photodamaged skin. This preliminary study was performed to evaluate the safety and subject satisfaction of non-ablative skin remodeling using a 532 nm, 2 ms pulse-duration, frequency-doubled Nd:YAG laser. Subjects with mild-to-deep lip wrinkles and mild-moderate acne scarring were treated one half of their lip (wrinkles) or cheek (acne scarring), leaving the other side as an untreated control. Subjects were treated at 3-6 week intervals for an average of three treatments. Subjective assessment of improvement was estimated by subject self-evaluation of the percentage improvement over baseline, and a blinded observer attempted to identify the treated side on physical examination. Subjective assessment revealed an average improvement of 51.4% and 53.6% for upper lip wrinkles and facial acne scarring, respectively. Side effects were limited to transient erythema that resolved over 0.25-2 hours following treatment. These results demonstrate that non-ablative treatment with the 532 nm, 2 ms pulse-duration Nd:YAG laser results in subjective improvement of rhytides and acne scarring, with a high safety profile.


Parents' Primary Professional Sources of Parenting Advice Moderate Predictors of Parental Attitudes toward Corporal Punishment.
Despite the risk it poses to children's mental and physical health, approval and use of corporal punishment (CP) remains high in the United States. Informed by the Theory of Planned Behavior, we examined potential predictors of attitudes supportive of CP while assessing the moderating effects of parents' (N=500) chosen primary professional source of advice regarding child discipline: pediatricians (47.8%), religious leaders (20.8%), mental health professionals (MHPs) (n=18.4%), or other identified professionals (13.0%). We conducted a random-digit-dial telephone survey among parents ages 18 and over within New Orleans, LA. The main outcome measure was derived from the Attitudes Toward Spanking scale (ATS). The main "predictors" were: perceived injunctive norms (i.e., perceived approval of CP by professionals; and by family and friends), perceived descriptive norms of family and friends regarding CP, and expected outcomes of CP use. We used multivariate OLS models to regress ATS scores on the predictor variables for each subset of parents based on their chosen professional source of advice. Perceived approval of CP by professionals was the strongest predictor of parental attitudes supportive of CP, except for those seeking advice from MHPs. Perceived injunctive and descriptive norms of family and friends were important, but only for those seeking advice from pediatricians or religious leaders. Positive expected outcomes of CP mattered, but only for those seeking advice from religious leaders or MHPs. In conclusion, the strength and relevance of variables predicting attitudes toward CP varied according to the professional from which the parent was most likely to seek advice.


New insights into the molecular mechanisms of action of bisphosphonates.
Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system.


Chronic, Multi-Site Recordings Supported by Two Low-Cost, Stationary Probe Designs Optimized to Capture Either Single Unit or Local Field Potential Activity in Behaving Rats.
Rodent models of cognitive behavior have greatly contributed to our understanding of human neuropsychiatric disorders. However, to elucidate the neurobiological underpinnings of such disorders or impairments, animal models are more useful when paired with methods for measuring brain function in awake, behaving animals. Standard tools used for systems-neuroscience level investigations are not optimized for large-scale and high-throughput behavioral battery testing due to various factors including cost, time, poor longevity, and selective targeting limited to measuring only a few brain regions at a time. Here we describe two different "user-friendly" methods for building extracellular electrophysiological probes that can be used to measure either single units or local field potentials in rats performing cognitive tasks. Both probe designs leverage several readily available, yet affordable, commercial products to facilitate ease of production and offer maximum flexibility in terms of brain-target locations that can be scalable (32-64 channels) based on experimental needs. Our approach allows neural activity to be recorded simultaneously with behavior and compared between micro (single unit) and more macro (local field potentials) levels of brain activity in order to gain a better understanding of how local brain regions and their connected networks support cognitive functions in rats. We believe our novel probe designs make collecting electrophysiology data easier and will begin to fill the gap in knowledge between basic and clinical research.


The Long-Term Effects of Non-Pharmacological Interventions on Diabetes and Chronic Complication Outcomes in Patients With Hyperglycemia: A Systematic Review and Meta-Analysis.
This study aimed at examining the long-term effects of non-pharmacological interventions on reducing the diabetes incidence among patients with prediabetes and chronic complications events among patients with hyperglycemia (pre-diabetes and diabetes) by performing a systematic review and meta-analysis of randomized controlled trials (RCTs). PubMed, MEDLINE, EMBASE, the Cochrane Library, and the Web of Science Core Collection were searched for studies published between January 1990 and November 2021, looking for RCTs to evaluate the effects of non-pharmacological interventions on preventing the incidence of diabetes and chronic complications in comparison with medical therapy, placebo, or usual diabetes care. Two independent reviews extracted relevant data and quality assessment. Any discrepancies were resolved by a third reviewer. In total, 20 articles involved 16 RCTs (follow-up ranged from 2 to 30 years) were included. Pooled analysis of intervention studies demonstrated clearly that non-pharmacological interventions have a significant effect on reducing the diabetes events in patients with prediabetes (RR 0.62; 95% CI 0.54, 0.71). Pooled analysis of extended follow-up studies showed that non-pharmacological interventions could effectively reduce the diabetes incidence in patients with prediabetes (RR 0.78; 95% CI 0.63, 0.96). Meta-regression and subgroup analysis indicates that the diabetes incidence of the long-term group (duration > 3 years) was clearly reduced by 0.05% compared with the relatively short-term group (duration ≤ 3 years). The incidence of microvascular complications in patients with hyperglycemia was effectively lowered by non-pharmacological interventions (RR 0.60; 95% CI 0.43, 0.83). Non-pharmacological interventions have a long-term effect on reducing the diabetes incidence among prediabetic patients and effectively preventing microvascular complications on hyperglycemia. https://www.crd.york.ac.uk/prospero/.


Extent of lesions in idiopathic sudden hearing loss with vertigo: study using click and galvanic vestibular evoked myogenic potentials.
To clarify the extent of the vestibular lesions in idiopathic sudden hearing loss with vertigo using vestibular evoked myogenic potentials (VEMPs) in response to click (click-VEMP) and galvanic (galvanic-VEMP) stimulation, as well as caloric tests. Retrospective study. University hospital. We enrolled 22 patients with idiopathic sudden hearing loss with vertigo in this study. All patients underwent audiometry and click-VEMP and caloric tests. Eight patients underwent a galvanic-VEMP test. Among the 22 patients, 17 (77%) showed an absence of click-VEMPs on the affected side. In response to caloric testing, 10 patients (45%) showed a decreased response on the affected side. All 8 patients who underwent galvanic-VEMP testing showed normal responses. Most patients with decreased caloric responses (9 [90%] of 10 patients) showed an absence of click-VEMPs, whereas 9 (53%) of the 17 patients who showed abnormal click-VEMPs showed decreased caloric responses. Initial hearing level and hearing outcome significantly correlated with abnormalities on the vestibular test results. The lesion site of vestibular disorders in idiopathic sudden hearing loss with vertigo appeared to be within the labyrinth on the basis of galvanic-VEMP findings. Results of the click-VEMP and caloric tests suggested that the saccule could be involved more frequently than the semicircular canals. The combined use of click-VEMP and caloric tests is useful for evaluating vestibular functions in idiopathic sudden hearing loss with vertigo because the extent of vestibular abnormalities correlated well with hearing outcome.


Role of PTH1R Signaling in Prx1+ Mesenchymal Progenitors during Eruption.
Tooth eruption is a complex process requiring precise interaction between teeth and adjacent tissues. Molecular analysis demonstrates that bone remodeling plays an essential role during eruption, suggesting that a parathyroid hormone 1 receptor (PTH1R) gene mutation is associated with disturbances in bone remodeling and results in primary failure of eruption (PFE). Recent research reveals the function of PTH1R signaling in mesenchymal progenitors, whereas the function of PTH1R in mesenchymal stem cells during tooth eruption remains incompletely understood. We investigated the specific role of PTH1R in Prx1+ progenitor expression during eruption. We found that Prx1+-progenitors occur in mesenchymal stem cells residing in alveolar bone marrow surrounding incisors, at the base of molars and in the dental follicle and pulp of incisors. Mice with conditional deletion of PTH1R using the Prx1 promoter exhibited arrested mandibular incisor eruption and delayed molar eruption. Micro-computed tomography, histomorphometry, and molecular analyses revealed that mutant mice had significantly reduced alveolar bone formation concomitant with downregulated gene expression of key regulators of osteogenesis in PTH1R-deficient cells. Moreover, culturing orofacial bone-marrow-derived mesenchymal stem cells (OMSCs) from Prx1Cre;PTH1Rfl/fl mice or from transfecting Cre recombinase adenovirus in OMSCs from PTH1Rfl/fl mice suggested that lack of Pth1r expression inhibited osteogenic differentiation in vitro. However, bone resorption was not affected by PTH1R ablation, indicating the observed reduced alveolar bone volume was mainly due to impaired bone formation. Furthermore, we found irregular periodontal ligaments and reduced Periostin expression in mutant incisors, implying loss of PTH1R results in aberrant differentiation of periodontal ligament cells. Collectively, these data suggest that PTH1R signaling in Prx1+ progenitors plays a critical role in alveolar bone formation and periodontal ligament development during eruption. These findings have implications for our understanding of the physiologic and pathologic function of PTH1R signaling in tooth eruption and the progression of PFE.


Characterization of social determinants of health of a liver transplant referral population.
Disparities exist in referral and access to the liver transplant (LT) waitlist, and social determinants of health (SDOH) are increasingly recognized as important factors driving health inequities, including in LT. The SDOH of potential transplant candidates is therefore important to characterize when designing targeted interventions to promote equity in access to LT. Yet, it is uncertain how a transplant center should approach this issue, characterize SDOH, identify disparities, and use these data to inform interventions. We performed a retrospective study of referrals for first-time, single-organ LT to our center from 2016 to 2020. Addresses were geoprocessed and mapped to the corresponding county, census tract, and census block group to assess their geospatial distribution, identify potential disparities in referrals, and characterize their communities across multiple domains of SDOH to identify potential barriers to evaluation and selection. We identified variability in referral patterns and areas with disproportionately low referrals, including counties in the highest quartile of liver disease mortality (9%) and neighborhoods in the highest quintile of socioeconomic deprivation (17%) and quartile of poverty (21%). Black individuals were also under-represented compared with expected state demographics (12% vs. 18%). Among the referral population, several potential barriers to evaluation and selection for LT were identified, including poverty, educational attainment, access to healthy food, and access to technology. This approach to the characterization of a transplant center's referral population by geographic location and associated SDOH demonstrates a model for identifying disparities in a referral population and potential barriers to evaluation that can be used to inform targeted interventions for disparities in LT access.


Structure of (KIAGKIA)3 aggregates in phospholipid bilayers by solid-state NMR.
The interchain (13)C-(19)F dipolar coupling measured in a rotational-echo double-resonance (REDOR) experiment performed on mixtures of differently labeled KIAGKIA-KIAGKIA-KIAGKIA (K3) peptides (one specifically (13)C labeled, and the other specifically (19)F labeled) in multilamellar vesicles of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (1:1) shows that K3 forms close-packed clusters, primarily dimers, in bilayers at a lipid/peptide molar ratio (L/P) of 20. Dipolar coupling to additional peptides is weaker than that within the dimers, consistent with aggregates of monomers and dimers. Analysis of the sideband dephasing rates indicates a preferred orientation between the peptide chains of the dimers. The combination of the distance and orientation information from REDOR is consistent with a parallel (N-N) dimer structure in which two K3 helices intersect at a cross-angle of approximately 20 degrees. Static (19)F NMR experiments performed on K3 in oriented lipid bilayers show that between L/P = 200 and L/P = 20, K3 chains change their absolute orientation with respect to the membrane normal. This result suggests that the K3 dimers detected by REDOR at L/P = 20 are not on the surface of the bilayer but are in a membrane pore.


Macrophage Polarization: Implications on Metabolic Diseases and the Role of Exercise.
Macrophages are cells of the innate immune response that trigger inflammation resolution. The phenotype of "classically activated macrophages" (M1) has anti-tumoricidal and anti-bactericidal activities. On the other hand, "alternatively activated macrophages" (M2) are involved in tissue remodeling and immunomodulatory functions. The change in the polarization of macrophages varies according to the diversity of cytokines present in the microenvironment or by the stimuli of an antigen. It involves such factors as interferon-regulatory factors, peroxisome proliferator-activated receptors (PPARs), hypoxia-inducible factors (HIFs), and signal transducers and activators of transcription (STATs). Switching the phenotype of macrophages can help attenuate the development of an inflammatory disease. Exercise can promote alterations in the number of innate immune cells and stimulates phagocytic function. Chronic exercise seems to inhibit macrophage infiltration into adipose tissue by attenuating the expression of F4/80 mRNA. Furthermore, exercise may also increase the expression of M2 markers and reduce TNF-α and TLR4 mRNA expression, which activates the inflammatory pathway of NF-κB. Chronic exercise reduces β2-adrenergic receptors in monocytes and macrophages by modulating TLR4 signaling as well as suppressing IL-12 production, a stimulator of interferon Y. In this review, we discuss macrophage polarization in metabolic diseases and how exercise can modulate macrophage plasticity.


Associations between seven-year C-reactive protein trajectory or pack-years smoked with choroidal or retinal thicknesses in young adults.
Inflammation and cigarette smoking predispose to macular diseases, and choroidal and retinal thinning. We explored the choroidal and retinal thicknesses in young adults against their 7-year C-reactive protein (CRP) level trajectory and pack-years smoked. Participants from the Raine study, a longitudinal cohort study, had serum CRP levels analysed at the 14-, 17-, and 20-year follow-ups. Group-based trajectory modelling was used to classify participants according to their 7-year CRP levels. At the 20-year follow-up (at 18-22 years old), participants completed questionnaires on their smoking history, and underwent optical coherence tomography imaging to obtain their choroidal and retinal thicknesses at the macula. Three CRP trajectories were identified: consistently low CRP levels (78% of sample), increasing (11%), or consistently high (11%). 340 and 1035 participants were included in the choroidal and retinal thickness analyses, respectively. Compared to those in the "Low" trajectory group, participants in the "Increasing" and "High" groups had 14-21 μm thinner choroids at most macular regions. Every additional pack-year smoked was linked with a 0.06-0.10 μm thinner retina at the inner and outer macular rings, suggesting a dose-dependent relationship between smoking and thinner retinas. These associations may suggest that an increased risk of future visual impairment or eye disease associated with these risk factors may be present since young adulthood.


Development of synchrotron radiation storage rings.
Many third-generation light sources have been commissioned over the past ten years, and the soundness of the principal design concepts has been well recognized through experiences at these facilities. Also, technological developments concerning third-generation light sources have been remarkable. With the emittance and current of the beams far exceeding the previous levels, stability requirements of the beams have become much more stringent. In this report the present status of light sources, operational and projected, is summarized, and developments and future prospects of synchrotron radiation storage rings in view of accelerator physics and technology are reviewed.


Development, Reproduction, Survival, and Demographic Patterns of Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) on Different Commercial Tomato Cultivars.
The increase in the production of tomato, Solanum lycopersicon Mill. (Solanaceae), has favored the proliferation of pests, especially Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae). In this study, the development, reproduction, survival, and demographic parameters of T. absoluta reared on six commercial tomato cultivars (Cherry, Cordilheira, Giuliana, Nemoneta, Paron, and Santa Clara) were evaluated. Tuta absoluta completed its development in all tomato cultivars. Development from newly hatched caterpillar to newly emerged adult varied between 24.8 and 28.2 days. Female fecundity ranged from 126.3 to 166.9 eggs, with fertility from 54.2 to 84.1%. Mortality during egg-adult development varied between 21.4 and 46.4% for insects reared on cultivars Cherry and Giuliana, respectively. The cultivars Cordilheira, Giuliana, and Santa Clara are promising options to tomato producers in order to decrease the attack and proliferation of T. absoluta. However, the development and population growth of T. absoluta is faster on the tomato cultivar Cherry.


[A Case Report : Metastatic Carcinoma of the Collecting Ducts of Bellini in a Hemodialysis Patient Treated with Temsirolimus].
Carcinoma of the collecting ductsof Bellini isa rare histological subtype of renal cell carcinoma and mostly has unfavorable prognosis. Radical nephrectomy is generally chosen for the 1st line treatment but therapeutic approaches for the metastasis/recurrence have not been established. We report a case of carcinoma of collecting ducts of Bellini in a patient receiving hemodialysis treated with temsirolimus. A 62- year-old man receiving hemodialysis was admitted to our hospital with drug-resistant anemia and high-grade cyclic fever. Computed tomography revealed the right renal tumor and multiple metastatic lung tumors. Open radical nephrectomy wasperformed. Pathological findingswere compatible with carcinoma of the collecting ducts of Bellini. He was given weekly temsirolimus treatment. The disease progressed modestly but kept the stable disease (SD) status for six months. He died of the cancer 11 months after the initial diagnosis.


Temporal Patterns of Vertigo and Migraine in Vestibular Migraine.
Vestibular migraine (VM) is a multidisciplinary disease under exploration. Multiple temporal patterns of vertigo and migraine make it difficult to diagnose VM, and their effect on the clinical features of VM is still unclear. Here we investigated the clinical features of VM under three temporal patterns. 172 VM patients were enrolled in this study and divided into three groups: 86 patients in group A had an earlier onset of migraine than vertigo, 35 patients in group B had an earlier onset of vertigo than migraine, and 51 patients in group C had concurrent vertigo and migraine. No significant difference was found among three groups regarding types, intensity and accompanying symptoms of the vestibular attack. Patients in group C presented higher frequency and longer duration of vertigo than group A and B, while patients in group A presented lower frequency and shorter duration of headaches than group B and C. Additionally, the frequency, duration, intensity and accompanying symptoms of headache in group A decreased significantly after the onset of vertigo, especially in women around menopause. We hypothesized that vestibular stimulation could inhibit the trigeminal pain pathway, while painful trigeminal stimulation could excite the vestibular system. Our findings may contribute to the clinical identification of VM and further clarification of its pathogenesis.


Medication management model as experiential education tool for students of pharmacy.
A visiting nurse association (VNA) and a college of Pharmacy sought cost-effective models by which consultant pharmacy services could be offered at a rural branch office to improve medication management for high-risk patients. Through a collaborative relationship with the Albany College of Pharmacy, the Eddy VNA used the structure and support of the Partners In Care Foundation (The Model) Medication Management Model to simultaneously provide patient services and train Doctor of Pharmacy candidates. The Model brings the pharmacist into the homecare team to provide pharmaceutical care and can provide the framework by which pharmacist preceptors and interns can effectively provide services to high-risk patients identified through the agency's CQI process. Results from program implementation with 100 Medicaid waiver patients indicate positive staff response and an overall 43% acceptance rate with prescribers and suggest that this is a cost-effective medication management service with implications for adaptation by other HHAs.


Identification of polymorphisms by genomic denaturing gradient gel electrophoresis: application to the proximal region of human chromosome 21.
Genomic Denaturing Gradient Gel Electrophoresis (gDGGE) provides an alternative to the standard method of restriction fragment length polymorphism (RFLP) analysis for identifying polymorphic sequence variation in genomic DNA. For gDGGE, genomic DNA is cleaved by restriction enzymes, separated in a polyacrylamide gel containing a gradient of DNA denaturants, and then transferred by electroblotting to nylon membranes. Unlike other applications of DGGE, gDGGE is not limited by the size of the probe and does not require probe sequence information. gDGGE can be used in conjunction with any unique DNA probe. Here we use gDGGE with probes from the proximal region of the long arm of human chromosome 21 to identify polymorphic DNA sequence variation in this segment of the chromosome. Our screening panel consisted of DNA from nine individuals, which was cleaved with five restriction enzymes and submitted to electrophoresis in two denaturing gradient conditions. We detected at least one potential polymorphism for nine of eleven probes that were tested. Two polymorphisms, one at D21S4 and one at D21S90, were characterized in detail. Our study demonstrates that gDGGE is a fast and efficient method for identifying polymorphisms that are useful for genetic linkage analysis.


Social dominance orientation moderates the effectiveness of mindset messages.
In this work, we examine whether differences in social dominance orientation (SDO) moderate the effectiveness of mindsets of intelligence messages. We suggest that SDO is a foundational ideological belief system, on which individuals vary, that maintains the desire to endorse fixed beliefs about the nature of human intelligence. Thus, attempts to change individuals' mindsets should be met with resistance from those who strongly endorse the social dominance ideology - individuals high on SDO. In contrast, individuals low on SDO are less likely to use mindsets of intelligence to justify an ideological belief system, and thus, mindset manipulations should be effective for them. We test these predictions across three experimental studies (NStudy1 = 271, NStudy2 = 207, NStudy3 = 313). Across the studies, we find that individuals who are high, relative to low, on SDO have more fixed beliefs about the nature of intelligence and show smaller effects of manipulations of mindsets. However, when comparing to a control condition, there was no evidence that high-SDO participants resisted the growth message that contradicts their ideology more than the fixed one that supports it; additionally, low-SDO participants showed heightened responsiveness to a fixed message. We discuss implications for theoretical advances in our understanding of mindsets.


Identification of a protein factor binding to the 5'-flanking region of a tRNA gene and being involved in modulation of tRNA gene transcription in vivo in Saccharomyces cerevisiae.
Control mechanisms of tRNA gene transcription were studied in vivo in Saccharomyces cerevisiae. In order to be able to monitor in vivo transcription products of an individual tRNA gene, a 'tester gene' was used which is readily transcribed in vivo in yeast but does not cross-hybridize with any cellular yeast tRNA. A series of insertion mutants were constructed, modifying thereby the immediate and further distant 5'-flanking region of the 'tester tRNA gene'. Small linker molecules of different length and different sequence were inserted at positions -3 and -56 on the non-coding strand. Resulting tRNA gene variants were transformed into yeast cells and in vivo synthesized products were monitored by primer extension analysis. From the experimental data we suggest that a few essential nucleotides within the flanking region are able to determine the in vivo transcription activity of the 'tester tRNA gene'. Our results are rationalized on a biochemical level by protein binding assays: At least one protein binds to the 5'-flanking region of the 'tester tRNA gene' and different protein complexes are sequestered on active or less active tRNA gene variants.


A case of IgG4-related hepatic inflammatory pseudotumor replaced by an abscess after steroid treatment.
Hepatic inflammatory pseudotumor (IPT) is a rare disease which often mimics a malignant tumor and is therefore often misdiagnosed and surgically resected. Recently, a concept of IgG4-related diseases (IgG4-RD) has been proposed that is becoming widely recognized and includes IgG4-related hepatic IPT. Corticosteroids are widely accepted as the standard treatment. A 72-year-old Japanese man, who had been followed for ten years after surgery and chemotherapy for treatment of hilar and lower bile duct cancers, developed intermittent fever and abdominal pain and visited this hospital. Blood examinations revealed an inflammatory reaction, worsened glucose intolerance, and an increased level of serum IgG4 (137 mg/dL). Computed tomography (CT) revealed a 5 cm-sized mass in hepatic segment 7. Because of his cancer history, not only was a benign mass suspected, but there was also the possibility of a recurrent biliary malignancy. Liver biopsy was performed and the histology met the criteria for IgG4-related IPT. Corticosteroid therapy was initiated and his symptoms quickly resolved. However, two months later, a repeat CT demonstrated that the hepatic mass had been replaced by an abscess. The abscess was initially refractory, despite tapering corticosteroid treatment, controlling diabetes by intensive insulin therapy, administration of antibiotics, and percutaneous abscess drainage. Finally, after six months, the condition resolved. The diagnosis of hepatic IPT is sometimes difficult. To differentiate it from a malignant tumor, histological examination is necessary. Although corticosteroids are recognized as the standard therapy, unexpected and critical complications can develop in cases of IgG4-related hepatic IPT.


Acetaldehyde dehydrogenase (Ahd-2)-associated DNA polymorphisms in mouse strains with variable ethanol preferences.
The genotype-dependent response of mice to ethanol has been well documented. Cytosolic acetaldehyde dehydrogenase (ALDH-2) increases in some strains while decreasing in others with ethanol treatment. Further work suggests that the mRNA for ALDH-2 (Ahd-2 mRNA) levels are altered following ethanol feeding in a strain-dependent fashion. This report identifies differences in Ahd-2 at the genomic DNA level among different strains of mice. Restriction fragment length polymorphisms (RFLPs) associated with the Ahd-2 locus were found for the restriction enzymes EcoRI, HindIII, Pst I and Rsa I. The mouse strains included in this study could be categorized into two groups based on their overall Ahd-2 associated DNA banding patterns. Strains C57BL/6J, C57BL/6J*, C57BL/10J and BALB/c form group 1 while strains C3H/HeJ, C3H/HeSnJ, 129/ReJ, Csb, SW and DBA/2J form group 2. With the exception of BALB/c, group 1 represents alcohol preferring strains while group 2 are alcohol avoiding strains. Additional work will be required to determine the physiological significance (if any) of these RFLPs and their possible relationship to ethanol preference and avoidance.


Nocturnal enuresis.
The answer to nocturnal enuresis is nocturnal self-awakening. Enuresis alarms teach this skill and, therefore, have the highest cure rate and the lowest relapse rate of any intervention. An alarm costs the same as a 2-week supply of desmopressin. Alarms can be used anytime from age 5 onward if the child elects to use one. If an alarm alone is not successful, combining it with medication increases the cure rate. The ability to teach a family how to use an enuresis alarm is an important part of pediatric office practice.


Altered reactivity of central amygdala to GABAAR antagonist in the BACHD rat model of Huntington disease.
In Huntington's disease (HD), dysfunctional affective processes emerge as key symptoms of disturbances. In human HD and transgenic rat models of the disease, the amygdala was previously shown to have a reduced volume and to carry a high load of mutant huntingtin (mHTT) aggregates. In search of the pathophysiology of affective dysregulation in HD, we hypothesized a specific role of the central amygdala (CeA), known to be particularly involved in emotional regulation. Using transgenic BACHD rats carrying full-length human mHTT, we compared behavioral consequences of pharmacological modulation of CeA function by infusing GABAA receptor (GABAAR) antagonist picrotoxin into ∼4.5 month old BACHD and WT rats before confronting them to potentially threatening situations. Our results show that disinhibition of the CeA induced differential behaviors in WT and BACHD rats in our tasks: it increased social contacts and responses to the threatening warning signal in an avoidance task in BACHD rats but not in WT animals. At the cellular level, analyzes of amygdala alteration/dysfunction showed (1) an age-dependent increase in number and size of mHTT aggregates specifically in the CeA of BACHD rats; (2) no alteration of GABA and GABAAR expression level, but (3) an increased neuronal reactivity (Arc labelling) to a threatening stimulus in the medial part of this nucleus in 4.5 months old BACHD rats. These results suggest a basal pathological hyper-reactivity in the CeA (in particular its medial part) in the transgenic animals. Such amygdala dysfunction could account, at least in part, for affective symptoms in HD patients.


Erosional exhumation of carbonate rock facilitates dispersal-mediated allopatric speciation in freshwater fishes.
A fundamental goal of evolutionary biology is to understand the mechanisms that generate and maintain biodiversity. Discovery and delimitation of species represent essential prerequisites for such investigations. We investigate a freshwater fish species complex comprising Etheostoma bellator and the endangered E. chermocki, which is endemic to the Black Warrior River system in Alabama, USA, a global hotspot of temperate freshwater biodiversity. Phylogenomic analyses delimit five geographically disjunct species masquerading as E. bellator. Three of these new species exhibit microendemic distributions comparable to that of E. chermocki raising the possibility that they also require protection. The species of the complex are found in streams flowing over carbonate rock and they are separated by waterways flowing over siliciclastic rock, a geographic pattern dictated by the underlying stratigraphy and structural geology. Over time, rivers have eroded downward through layers of siliciclastic rocks in the basin, gradually exposing underlying carbonate rock, the substrate of suitable habitat today. Our results suggest that episodic dispersal to patches of suitable habitat set the stage for allopatric speciation in the species complex. Our study suggests that the presence of heterogeneous rock can facilitate dispersal-mediated allopatric speciation in freshwater organisms in the absence of external tectonic or climatic perturbations.


Reduction of high-risk polypharmacy drug combinations in patients in a managed care setting.
To enhance physician and patient awareness of polypharmacy; to decrease the risks, drug costs, and waste resulting from polypharmacy; and to make the business case for reducing misuse, overuse, and underuse of drugs by reducing polypharmacy. Longitudinal, time series cohort. Outpatient, managed care, integrated delivery system. A total of 195,971 patients who received health care from the Henry Ford Medical Group and had health insurance coverage from the Health Alliance Plan. Two identical interventions separated by 1 year were conducted in patients at high risk of harm from polypharmacy based on five categories of high-risk drug combinations (referred to as polypharmacy events). Six months of pharmacy claims data were reviewed before and after each intervention to identify these patients. The intervention program consisted of clinical pharmacists performing drug therapy reviews, educating physicians and patients about drug safety and polypharmacy, and working with physicians and patients to correct polypharmacy problems. Prescription cost/member/month, number of prescriptions/member/month, and rates of polypharmacy events/1000 members were measured before and after each of the two interventions. After the first intervention, the overall rate of polypharmacy events decreased from 29.01 to 9.43/1000 patients (67.5% reduction). The number of prescriptions/member/month decreased from 4.6 to 2.2 (52.2% reduction), prescription cost/member/month decreased from $222 to $113 (49.1% reduction), and overall institution drug cost was reduced by $4.8 million. Six months after the second intervention, the overall rate of polypharmacy events was reduced from 27.99 to 17.07/1000 (39% reduction), the number of prescriptions/member/month decreased from 4.5 to 4.0 (11.1% reduction), and prescription cost/member/month decreased from $264 to $239 (9.5% reduction). Overall institution drug costs were reduced by $1.3 million. Sustained effects were seen for all measures of polypharmacy (p=0.001). These interventions reduced drug costs and numbers of prescriptions in a managed care cohort of patients at high risk for adverse drug events due to polypharmacy. By providing clinical information, decision support, patient self-management support, and care delivery redesign some of the problems resulting from polypharmacy can be solved.


Accreditation of diagnostic imaging services in developing countries.
In recent decades, medical imaging has experienced a technological revolution. After conducting several surveys to assess the quality and safety of diagnostic imaging services in Latin America and the Caribbean, the Pan American Health Organization (PAHO) developed a basic accreditation program that can be implemented by the ministry of health of any developing country. Patterned after the American College of Radiology's accreditation program, the PAHO program relies on a national accreditation committee to establish and maintain accreditation standards. The process involves a peer review evaluation of: (1) imaging and processing equipment, (2) physician and technologist staff qualifications, (3) quality control and quality assurance programs, and (4) image quality and, where applicable, radiation dose. Public and private conventional radiography/fluoroscopy, mammography, and ultrasound services may request accreditation. The radiography/fluoroscopy accreditation program has three modules from which to choose: chest radiography, general radiography, and fluoroscopy. The national accreditation committee verifies compliance with the standards. On behalf of the ministry of health, the accreditation committee also issues a three-year accreditation certificate. As needed, the accreditation committee consults with foreign technical and clinical experts.


Release of somatomedin-like activity by cultured WI-38 human fibroblasts.
Confluent cultures of normal diploid WI-38 human embryonic lung fibroblasts released somatomedin (SM)-like activity into their incubation medium during culture in serum-free medium. This postculture medium (conditioned medium) stimulated cell division in these same cultured WI-38 fibroblasts and 35SO4 uptake by hypophysectomized rat cartilage in vitro. The conditioned medium also contained immunoreactive SM (IRSM) activity which yielded parallel dose-response curves to human serum in a RIA for SM. The IRSM activity measured in conditioned medium was not the artifactual result of effects of possible SM-binding proteins or proteolytic enzymes in conditioned medium. These studies suggest that cultured WI-38 fibroblasts produce and release SM-like activity which has SM-like biological activity and is immunoreactive with a basic SM purified from human plasma Cohn fraction and having similarity with SM-C and insulin-like growth factor-I. Human GH appears to stimulate production and release of IRSM activity by these cells.


Depression--An emerging indication for botulinum toxin treatment.
The treatment of glabellar frown lines with botulinum toxin injection is one of the most prevalent procedures in esthetic medicine. It is possible that the popularity of this intervention is not only owing to its cosmetic effect but also to modulatory effects on mood and affectivity. Recently, a series of studies including three randomized controlled trials have consistently shown that such effects can be used in the treatment of depression. Predominantly female patients suffering from partly chronic and treatment resistant unipolar depression experienced a quick, strong and sustained improvement in depressive symptoms after a single glabellar treatment with botulinum toxin A as a sole or adjunctive therapy. If these findings are further corroborated in additional studies, the ever-growing spectrum of applications for botulinum toxin may spread into the field of psychiatry, showing that the superficial paralysis of facial muscles may, probably via proprioceptive feedback mechanisms, have profound effects on the emotional brain.


A neonatal case of congenital coronary artery fistula.
Coronary artery fistulae (CAF) are rare forms of congenital heart disease with an incidence of one in 50 000 live births. The authors present the case of an asymptomatic neonate with a precordial murmur. Pre and postductal saturations, blood pressure and ECG were normal. Echocardiography revealed a large right coronary artery fistula to the right ventricle (4.5 mm). At 11 months, transcatheter occlusion of the fistula with a vascular plug was performed. A year on, the child was thriving, ECG and echocardiogram remained normal. CAF complications and symptoms (including aneurysm, myocardial ischaemia, angina, heart failure and dyspnoea) are commoner in older patients, so traditionally we intervene early. With increasing case reports of spontaneous closure of even large and symptomatic fistulae, management of especially asymptomatic children is unclear. Long-term complications of intervention also remain largely unknown. As such more information is required on the conditions natural history to better manage patients and counsel parents.