Distinct oxysterol requirements for positioning naïve and activated dendritic cells in the spleen.
Correct positioning of dendritic cells (DCs) is critical for efficient pathogen encounter and antigen presentation. Epstein-Barr virus-induced gene 2 (EBI2) has been identified as a chemoattractant receptor required for naïve CD4+DCIR2+ DC positioning in response to 7α,25-hydroxycholesterol (7α,25-HC). We now provide evidence that a second EBI2 ligand, 7α,27-HC, is involved in splenic DCIR2+ DC positioning and homeostasis. Cyp27a1, the enzyme uniquely required for 7α,27-HC synthesis, is expressed by stromal cells in the region of naïve DC localization. After activation, DCIR2+ DCs move into the T cell zone. We find that EBI2 is rapidly up-regulated in DCIR2+ DCs under certain activation conditions, and positioning at the B-T zone interface depends on EBI2. Under conditions of type I interferon induction, EBI2 ligand levels are elevated, causing activated DCIR2+ DCs to disperse throughout the T zone. Last, we provide evidence that oxysterol metabolism by Batf3-dependent DCs is important for EBI2-dependent positioning of activated DCIR2+ DCs. This work indicates that 7α,27-HC functions as a guidance cue in vivo and reveals a multitiered role for EBI2 in DC positioning. Deficiency in this organizing system results in defective CD4+ T cell responses.


[Evaluation of perineal comfort following delivery in primiparae].
The authors followed a population of 204 primiparous women in order to be able to tackle the causes of those frequent sexual problems that occur after delivery. Obstetric perineal lesions were found in 46 cases of left lateral episiotomies, 104 cases of midline episiotomies and 54 cases where the perineum was said to be intact. Following delivery at the Maternity Unit, those patients who had a perineal incision suffered more without any difference whether the episiotomy was a midline or a lateral one. After a mean of 78 days following delivery, at the post-partum examination, sexual troubles were found to be frequent and 41% complained of dyspareunia. These troubles were scattered in all three series. There was no difference whether the mother was breast-feeding or not in relationship to her sexuality after delivery. The authors conclude that there is no proper correlation between the way the perineum was dealth with surgically and the quality of sexual activity experienced early after delivery.


Isoflurane and Carbon Dioxide Elicit Similar Behavioral Responses in Rats.
Euthanasia in rodents is an ongoing topic of debate due to concerns regarding the aversive nature of gases with anesthetic properties such as carbon dioxide (CO2) and isoflurane. The aim of this study was to expand upon previously published work evaluating the aversiveness of CO2 by introducing an isoflurane treatment group in parallel. Aversion was tested using a forced exposure setup and an aversion-avoidance setup. In the first part of the study, 12 naïve female Sprague-Dawley rats were exposed during four consecutive days, once to each of four treatments: isoflurane, fox urine, oxygen, and CO2. In the second part of the study, 24 naïve female Sprague-Dawley rats and 12 rats from the first experiment were exposed to CO2, isoflurane, or both gases. In the forced exposure study, there were no significant differences between CO2 and isoflurane treatments except in line crosses. Overall, rats were more active in the isoflurane and CO2 treatments compared to the control groups, suggesting that isoflurane and CO2 are similarly aversive. In the aversion-avoidance study, rats previously exposed to isoflurane left the dark chamber significantly earlier compared to naïve rats during exposure to isoflurane. We also show that learned aversion to isoflurane is sustained for at least 15 days after initial exposure. Given this result, we suggest that CO2 is superior to isoflurane when euthanizing rodents with prior exposure to isoflurane. Overall, these results confirm previous studies which suggest that care should be taken when considering the serial use of isoflurane as an anesthetic.


Solid-state NMR as a probe of amyloid fibril structure.
Amyloid fibrils are intrinsically noncrystalline, insoluble, high-molecular-weight aggregates of peptides and proteins, with considerable biomedical and biophysical significance. Solid-state NMR techniques are uniquely capable of providing high-resolution, site-specific structural constraints for amyloid fibrils, at the level of specific interatomic distances and torsion angles. So far, a relatively small number of solid-state NMR studies of amyloid fibrils have been reported. These have addressed issues about the supramolecular organization of beta-sheets in the fibrils and the peptide conformation in the fibrils, and have concentrated on the beta-amyloid peptide of Alzheimer's disease. Many additional applications of solid-state NMR to amyloid fibrils from a variety of sources are anticipated in the near future, as these systems are ideally suited for the technique and are of widespread current interest.


Electrocardiogram Interpretation Using Artificial Intelligence: Diagnosis of Cardiac and Extracardiac Pathologic Conditions. How Far Has Machine Learning Reached?
Artificial intelligence (AI) is already widely used in different fields of medicine, making possible the integration of the paraclinical exams with the clinical findings in patients, for a more accurate and rapid diagnosis and treatment decision. The electrocardiogram remains one of the most important, fastest, cheapest, and noninvasive methods of diagnosis in cardiology, despite the rapid development and progression of the technology. Even if studied a long time ago, it still has a lot of less understood features that, with a better understanding, can give more clues to a correct and prompt diagnosis in a short time. The use of AI in the interpretation of the ECG improved the accuracy and the time to diagnosis in different cardiovascular diseases, and more than this, explaining the decision to make AI diagnosis improved the human understanding of the different features of the ECG that might be considered for a more accurate diagnosis. The purpose of this article is to provide an overview of the most recently published articles about the use of AI in ECG interpretation.


Associations between dietary fatty acid patterns and cognitive function in the Hispanic Community Health Study/Study of Latinos.
Our objective was to quantify the cross-sectional associations between dietary fatty acid (DFA) patterns and cognitive function among Hispanic/Latino adults. This study included data from 8,942 participants of the Hispanic Community Health Study/Study of Latinos, a population-based cohort study (weighted age 56.2 y and proportion female 55.2%). The NCI (National Cancer Institute) method was used to estimate dietary intake from two 24-hr recalls. We derived DFA patterns using principal components analysis with 26 fatty acid and total plant and animal monounsaturated fatty acid (MUFA) input variables. Global cognitive function was calculated as the average z-score of 4 neurocognitive tests. Survey linear regression models included multiple potential confounders such as age, sex, education, depressive symptoms, physical activity, energy intake, and cardiovascular disease. DFA patterns were characterized by consumption of long-chain saturated fatty acids (SFA), animal-based MUFA, and trans fatty acids (Factor 1); short to medium-chain SFA (Factor 2); very-long-chain omega-3 polyunsaturated fatty acids (PUFA) (Factor 3); very-long-chain SFA and plant-based MUFA and PUFA (Factor 4). Factor 2 was associated with greater scores for global cognitive function (β=0.037 ± 0.012) and the Digit Symbol Substitution (DSS) (β=0.56±0.17), Brief Spanish English Verbal Learning-Sum (B-SEVLT) (β=0.23 ± 0.11), and B-SEVLT-Recall (β=0.11 ± 0.05) tests (P<0.05 for all). Factors 1 (β=0.04 ± 0.01) and 4 (β=0.70 ± 0.18) were associated with the DSS test (P<0.05 for all). Consumption of short to medium-chain SFA may be associated with higher cognitive function among U.S.-residing Hispanic/Latino adults. Prospective studies are necessary to confirm these findings.


Human erythroid progenitor cells express Rhesus antigens.
The expression of Rhesus antigens on hematopoietic progenitor cells was studied using monoclonal antibodies. Because these antibodies are not capable of lysing mature red blood cells in a complement-dependent cytotoxicity assay, fluorescence-activated cell sorting was performed. Using the monoclonal anti-Rh 29 antibody B10, 68% +/- 6% of the mature erythroid progenitor cells (CFU-E) were sorted into the positive fraction, while only 2% +/- 1% of the relatively immature erythroid progenitor cells (BFU-E), and 3% +/- 1% of the granulocyte-macrophage progenitor cells (CFU-GM) were cultured from this same fraction. Thus up to a 15-fold enrichment of CFU-E could be obtained. In two experiments more than 4% of the cells in the positive fraction consisted of CFU-E; in one experiment even more than 7% did. Using fractionated cell sorting, the Rhesus antigens appeared to have a lower density on CFU-E than HLA-DR determinants. Antibodies against the Rhesus antigens can be applied to enrich erythroid-committed stem cells and to separate mature from immature erythroid progenitor cells.


Usefulness of a Low Tube Voltage: Knowledge-Based Iterative Model Reconstruction Algorithm for Computed Tomography Venography.
The objective of this study was to evaluate the use of 80-kVp scans with knowledge-based iterative model reconstruction (IMR) for computed tomography venography (CTV). This prospective study received institutional review board approval; a previous informed consent was obtained from all participants. We enrolled 30 patients with suspected deep venous thrombosis or pulmonary embolism who were to undergo 80-kVp CTV studies. The images were reconstructed with filtered back projection (FBP), hybrid iterative reconstruction (HIR), and IMR. The venous attenuation, image noise, and contrast-to-noise ratio at the iliac, femoral, and popliteal veins were compared on FBP, HIR, and IMR images. We performed qualitative image analysis (image noise, image contrast, image sharpness, streak artifacts, and overall image quality) of the 3 reconstruction methods and measured their reconstruction times. There was no significant difference in venous attenuation among the 3 reconstruction methods (P > 0.05). On IMR images, the image noise was lowest at all 3 venous locations, and the contrast-to-noise ratio was highest. Qualitative evaluation scores were also highest for IMR images. The reconstruction time for FBP, HIR, and IMR imaging was 25.4 ± 1.9 seconds, 43.3 ± 3.3 seconds, and 78.7 ± 6.0 seconds, respectively. At clinically acceptable reconstruction times, 80-kVp CTV using the IMR technique yielded better qualitative and quantitative image quality than HIR and FBP.


Study Effect of nAg Particle Size on the Properties and Antibacterial Characteristics of Polysulfone Membranes.
Polysulfone ultrafiltration membranes were fabricated using various sizes (20, 40, and 90-210 nm) of silver nanoparticles (nAg) blended in a dope solution. To characterize the performance and properties of the prepared membranes, scanning electron microscopy (SEM), water contact angle, protein separation, water flux, and antibacterial tests were conducted. The characterization results revealed that when nAg particles (20 nm) were blended into the base polymer PSF, the PSF/nAg blended membrane had the lowest contact angle (58.5°) and surface energy (110.7 mN/m). When experimenting with ultrafiltration using protein solutions, bare PSF and PSF/nAg-20 blended membranes gave similar values of protein rejection: 93% of bovine serum albumin (BSA) and 70% of lysozyme rejection. Furthermore, SEM studies showed that the surface pore size was reduced by adding 20 nm nAg particles in the casting solution. Most importantly, the introduction of 40 nm nAg particles reduced the growth of bacterial colonies on the membrane surface by up to 72%. These findings revealed that nAg particles are expected to be a potential modifier for the fabrication of an ultrafiltration membrane.


The role of the gut microbiota in the treatment of inflammatory bowel diseases.
The human intestinal microbiota coevolves with its host through a symbiotic relationship and exerts great influence on substantial functions including aspects of physiology, metabolism, nutrition and regulation of immune responses leading to physiological homeostasis. Over the last years, several studies have been conducted toward the assessment of the host-gut microbiota interaction, aiming to elucidate the mechanisms underlying the pathogenesis of several diseases. A defect on the microbiota-host crosstalk and the concomitant dysregulation of immune responses combined with genetic and environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). To this end, novel therapeutic options based on the gut microbiota modulation have been an area of extensive research interest. In this review we present the recent findings on the association of dysbiosis with IBD pathogenesis, we focus on the role of gut microbiota on the treatment of IBD and discuss the novel and currently available therapeutic strategies in manipulating the composition and function of gut microbiota in IBD patients. Applicable and emerging microbiota treatment modalities, such as the use of antibiotics, prebiotics, probiotics, postbiotics, synbiotics and fecal microbiota transplantation (FMT) constitute promising therapeutic options. However, the therapeutic potential of the aforementioned approaches is a topic of investigation and further studies are needed to elucidate their position in the present treatment algorithms of IBD.


Molecular Analysis of Dihydropteroate Synthase Gene Mutations in Pneumocystis jirovecii Isolates among Bulgarian Patients with Pneumocystis Pneumonia.
Pneumocystis jirovecii pneumonia (PCP) is a significant cause of morbidity and mortality in immunocompromised people. The widespread use of trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment and prophylaxis of opportunistic infections (including PCP) has led to an increased selection of TMP-SMZ-resistant microorganisms. Sulfa/sulfone resistance has been demonstrated to result from specific point mutations in the DHPS gene. This study aims to investigate the presence of DHPS gene mutations among P. jirovecii isolates from Bulgarian patients with PCP. A total of 326 patients were examined via real-time PCR targeting the P. jirovecii mitochondrial large subunit rRNA gene and further at the DHPS locus. P. jirovecii DNA was detected in 50 (15.34%) specimens. A 370 bp DHPS locus fragment was successfully amplified in 21 samples from 19 PCP-positive patients, which was then purified, sequenced, and used for phylogenetic analysis. Based on the sequencing analysis, all (n = 21) P. jirovecii isolates showed DHPS genotype 1 (the wild type, with the nucleotide sequence ACA CGG CCT at codons 55, 56, and 57, respectively). In conclusion, infections caused by P. jirovecii mutants potentially resistant to sulfonamides are still rare events in Bulgaria. DHPS genotype 1 at codons 55 and 57 is the predominant P. jirovecii strain in the country.


A Framework for Periodized Nutrition for Athletics.
Over the last decade, in support of training periodization, there has been an emergence around the concept of nutritional periodization. Within athletics (track and field), the science and art of periodization is a cornerstone concept with recent commentaries emphasizing the underappreciated complexity associated with predictable performance on demand. Nevertheless, with varying levels of evidence, sport and event specific sequencing of various training units and sessions (long [macrocycle; months], medium [mesocycle; weeks], and short [microcycle; days and within-day duration]) is a routine approach to training periodization. Indeed, implementation of strategic temporal nutrition interventions (macro, meso, and micro) can support and enhance training prescription and adaptation, as well as acute event specific performance. However, a general framework on how, why, and when nutritional periodization could be implemented has not yet been established. It is beyond the scope of this review to highlight every potential nutritional periodization application. Instead, this review will focus on a generalized framework, with specific examples of macro-, meso-, and microperiodization for the macronutrients of carbohydrates, and, by extension, fat. More specifically, the authors establish the evidence and rationale for situations of acute high carbohydrate availability, as well as the evidence for more chronic manipulation of carbohydrates coupled with training. The topic of periodized nutrition has made considerable gains over the last decade but is ripe for further scientific progress and field application.


The effects of intrathecal cyclooxygenase-1, cyclooxygenase-2, or nonselective inhibitors on pain behavior and spinal Fos-like immunoreactivity.
Prostaglandins are synthesized by cyclooxygenase (COX) and are thought to play an important role in nociceptive transmission in the spinal cord. Fos expression is an indicator of spinal neuron activation. We examined the role of intrathecal selective and nonspecific COX inhibitors on spinal C-Fos expression. To evaluate the relative contribution of COX-1 and COX-2 in nociceptive transmission in the spinal cord, we assessed the effects of the selective COX-1 inhibitor SC 560, the selective COX-2 inhibitor celecoxib, and the nonselective COX inhibitor ketorolac on formalin-evoked behavior and spinal c-Fos-like immunoreactivity (FLI). Rats received each of the drugs (30, 60, or 90 microg) intrathecally before the subcutaneous administration of formalin (5%, 50 microL) to the plantar surface of a hindpaw. The control group received vehicle intrathecally before the administration of formalin. Phase 1 flinching behavior decreased in rats given celecoxib or ketorolac 90 mug. Phase 2 flinching behavior decreased in rats given all doses of ketorolac or celecoxib 90 microg (P < 0.05). The FLI was significantly reduced in rats given celecoxib or ketorolac 90 microg for laminae I-II (P < 0.05). By contrast, for laminae V-VI, only the ketorolac 60 or 90 microg treatment group demonstrated a larger decrease in FLI (P < 0.05). The FLI expression in laminae V-VI had a significant correlation with phase 2 flinching behavior (P < 0.05). A dual inhibitor of COX-1 and COX-2 suppressed both responses of formalin-evoked behaviors and FLI expression of whole laminae in the lumbar spinal cord. FLI expression of laminae I-II alone may not be a good indicator of the ability to produce anti-hypersensitivity; however, the FLI of laminae V-VI correlates with phase 2 responses.


Effect of COMT Val108/158Met genotype on risk for polydipsia in chronic patients with schizophrenia.
Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val(108/158)Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val(108/158)Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ(2) test. A significant association between the COMT Val(108/158)Met polymorphism and polydipsia was found (genotype distribution: χ(2) = 13.0, df = 2, p = 0.001; allele frequency: χ(2) = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val(108/158)Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings.


Pearls: infectious diseases.
Neurologists have a great deal of knowledge of the classic signs of central nervous system infectious diseases. After years of taking care of patients with infectious diseases, several symptoms, signs, and cerebrospinal fluid abnormalities have been identified that are helpful time and time again in determining the etiological agent. These lessons, learned at the bedside, are reviewed in this article.


Transfer of proteins across membranes. II. Reconstitution of functional rough microsomes from heterologous components.
The data presented in this paper demonstrate that native small ribosomal subunits from reticulocytes (containing initiation factors) and large ribosomal subunits derived from free polysomes of reticulocytes by the puromycin-KCl procedures can function with stripped microsomes derived from dog pancreas rough microsomes in a protein-synthesizing system in vitro in response to added IgG light chain mRNA so as to segregate the translation product in a proteolysis-resistant space. No such segregation took place for the translation product of globin mRNA. In addition to their ability to segregate the translation product of a specific heterologous mRNA, native dog pancreas rough microsomes as well as derived stripped microsomes were able to proteolytically process the larger, primary translation product in an apparently correct manner, as evidenced by the identical mol wt of the segregated translation product and the authentic secreted light chain. Segregation as well as proteolytic processing by native and stripped microsomes occurred only during ongoing translation but not after completion of translation. Attempts to solubilize the proteolytic processing activity, presumably localized in the microsomal membrane by detergent treatment, and to achieve proteolytic processing of the completed light chain precursor protein failed. Taken together, these results establish unequivocally that the information for segregation of a translation product is encoded in the mRNA itself, not in the protein-synthesizing apparatus; this provides strong evidence in support of the signal hypothesis.


Improving end-of-life care education in home care.
A training program for home care professionals, HOPE (Home care Outreach for Palliative care Education), was designed to improve the knowledge and skills of those providing care to patients and family caregivers at home. This article presents an overview of the pilot HOPE training program and a case study to illustrate the complex end-of-life (EOL) care needs in nonhospice home care settings. HOPE was designed as five training modules based on a needs assessment survey completed by 134 home care agencies. The training modules were composed of (a) General Overview of End of Life Care; (b) Pain Management; (c) Symptom Management; (d) Communication with Patients and Families; and (e) the Death Event. The program was implemented for clinical staff (N = 52), predominantly nurses, in two home care agencies and evaluated with pre- and postcourse surveys. Pre- and postcourse evaluations demonstrated an increase in the overall rating of EOL care from a mean rating of 5.97 to 7.42 for self-assessment and from 6.59 to 7.94 for agency assessment (on a scale of 0 = not at all effective to 10 = very effective). Future palliative care education should also include evaluation of the impact of such programs on patient care. We concluded that increasing palliative care knowledge of home care professionals is necessary to improve patient care at the EOL.


Minimum SNR and acquisition for bias-free estimation of fractional anisotropy in diffusion tensor imaging - a comparison of two analytical techniques and field strengths.
Although it is known that low signal-to-noise ratio (SNR) can affect tensor metrics, few studies reporting disease or treatment effects on fractional anisotropy (FA) report SNR; the implicit assumption is that SNR is adequate. However, the level at which low SNR causes bias in FA may vary with tissue FA, field strength and analytical methodology. We determined the SNR thresholds at 1.5 T vs. 3 T in regions of white matter (WM) with different FA and compared FA derived using manual region-of-interest (ROI) analysis to tract-based spatial statistics (TBSS), an operator-independent whole-brain analysis tool. Using ROI analysis, SNR thresholds on our hardware-software magnetic resonance platforms were 25 at 1.5 T and 20 at 3 T in the callosal genu (CG), 40 at 1.5 and 3 T in the anterior corona radiata (ACR), and 50 at 1.5 T and 70 at 3 T in the putamen (PUT). Using TBSS, SNR thresholds were 20 at 1.5 T and 3 T in the CG, and 35 at 1.5 T and 40 at 3 T in the ACR. Below these thresholds, the mean FA increased logarithmically, and the standard deviations widened. Achieving bias-free SNR in the PUT required at least nine acquisitions at 1.5 T and six acquisitions at 3 T. In the CG and ACR, bias-free SNR was achieved with at least three acquisitions at 1.5 T and one acquisition at 3 T. Using diffusion tensor imaging (DTI) to study regions of low FA, e.g., basal ganglia, cerebral cortex, and WM in the abnormal brain, SNR should be documented. SNR thresholds below which FA is biased varied with the analytical technique, inherent tissue FA and field strength. Studies using DTI to study WM injury should document that bias-free SNR has been achieved in the region of the brain being studied as part of quality control.


Vitamin D deficiency rickets: socio-demographic and clinical risk factors in children seen at a referral hospital in Addis Ababa.
To test the association between vitamin D deficiency rickets and protein-energy malnutrition in Ethiopian children. Ethio-Swedish Children's Hospital, a tertiary health facility catering for children coming from Addis Ababa and the surrounding districts. A case-control study. One hundred and fifty seven children under three years of age who had vitamin D deficiency rickets constituted the cases. Controls were the same number of children matched with cases for sex and age within one month and were seen within a week of case recruitment. Cases and controls were similar (p < 0.5) in terms of maternal education, paternal age, paternal education and family size. Factors strongly and independently associated with rickets were underweight, nutritional status [OR = 12.7 (95% CI 4.47-11.08)], marasmus [OR = 6.3 (95% CI 2.81-19.66)], lack of exposure to sunshine [OR = 3.5 (95% CI 1.33-5.84)] and non-married maternal marital status [OR = 5.1 (95% CI 2.90-10.62)]. Protein-energy-malnutrition is strongly associated with vitamin D deficiency rickets. Intervention strategies targeting vitamin D deficiency rickets should give emphasis to children with protein energy malnutrition. Further work will be required to define the causal links between rickets and the risk factors identified in the present study.


Campsites, forest fires, and entry point distance affect earthworm abundance in the Boundary Waters Canoe Area Wilderness.
Factors controlling the spread of invasive earthworms in Minnesota's Boundary Waters Canoe Area Wilderness are poorly known. Believed to have been introduced by anglers who use them as bait, invasive earthworms can alter the physical and chemical properties of soil and modify forest plant communities. To examine factors influencing earthworm distribution and abundance, we sampled 38 islands across five lakes to assess the effects of campsites, fire and entry point distance on earthworm density, biomass and species richness. We hypothesized that all three parameters would be greater on islands with campsites, lower on burned islands and would decrease with distance from the wilderness entry point. In addition to sampling earthworms, we collected soil cores to examine soil organic matter and recorded ground and vegetation cover. Campsite presence was the single most important factor affecting sampled earthworm communities; density, biomass and species richness were all higher on islands having campsites. Fire was associated with reduced earthworm density, but had no direct effects on earthworm biomass or species richness. Fire influenced earthworm biomass primarily through its negative relationship to groundcover and through an interaction with entry point distance. Entry point distance itself affected earthworm density and biomass. For islands with campsites, earthworm biomass increased with distance from the entry point.


Surgical management practice of pelvic organ prolapse among Ethiopian gynecologists, 2021: a descriptive study.
Pelvic Organ Prolapse is the descent of one or more of the anterior vaginal wall, posterior vaginal wall, the uterus, or the apex of the vagina. Surgical intervention addresses both anatomical defect and associated symptoms. The landscape of prolapse surgery has been evolving constantly over years. Emerging evidences either support or challenge existing surgical treatment options, making urogynecology a dynamic field. In Ethiopia, the surgical management of pelvic organ prolapse has transitioned from abdominal to vaginal hysterectomy, supplemented later by McCall's culdoplasty. Disparities exist in the national uniformity of surgical approaches, linked to the establishment of Urogynecology centers in certain institutions. This study was done to assess the surgical management practice of Ethiopian gynecologists on pelvic organ prolapse. A cross-sectional study encompassing all Gynecologists in Ethiopia took place between January to June 2021. Information was gathered through online Google forms crafted in English. Subsequently, the collected data underwent verification, coding, and entry into Epi info 7 before being exported to SPSS version 22 software for descriptive statistical analysis. We reached 280 gynecologists out of the 450 practicing in the Ethiopia making 62% response rate. Anterior colporrhaphy (98.6%), vaginal hysterectomy with McCall's cul-do-plasty (51.8%), and Posterior colporrhaphy (97.5%) were the most commonly performed surgical procedures for anterior vaginal wall prolapse, apical prolapse (uterine/cervical), and posterior vaginal wall prolapse respectively. Only 3.2% and 0.7% of the gynecologists conducted abdominal and vaginal paravaginal repair for anterior vaginal wall prolapse. Sacrospinous ligament fixation and sacrocolpopexy for apical prolapse were carried out by 32.9% and 9.3% of the gynecologists respectively. Site-specific posterior repair for posterior vaginal wall prolapse was performed only by 23.9% of the gynecologists. The main reasons mentioned not to perform paravaginal repair, sacrocolpopexy, sacrospinous ligament fixation, and site-specific posterior repair were lack of skill and lack of appropriate materials. Most gynecologists in Ethiopian continue to perform vaginal hysterectomy and colporrhaphy procedures for treatment of pelvic organ prolapse due primarily to lack of skill and appropriate materials to perform the alternative procedures. Implementing short term training on alternative surgical treatment options of pelvic organ prolapse with provision of suitable materials and increasing the number of urogynecologists in the country in the long run holds the potential to enhance the standard of care of women with the condition.


A rat model of bacterial keratitis. Effect of antibiotics and corticosteroid.
A model of bacterial keratitis in rats was developed to quantify the effect of antibiotics and corticosteroid on the infective process. Corneas were inoculated with Staphylococcus aureus, Pseudomonas aeruginosa, or Streptococcus pneumoniae. The natural history of infection with these organisms was determined. Groups of animals received topical antibiotics and prednisolone acetate. The effect of treatment on the number of leukocytes and viable bacteria in the corneas was determined. Prednisolone did not influence the effect of the antibiotics; however, steroid treatment alone increased the pseudomonad count as much as 20-fold above the count in untreated eyes. In general, both the antibiotic and steroid treatments were more successful when begun eight hours after infection than when begun at 24 hours. a 1% gentamicin sulfate preparation proved effective against each of the infections, including a pneumococcal strain considered resistant on the basis of in vitro tests.


[Cytological analysis of a population of thyroid parafollicular cells].
With the aid of Sevier-Munger silver stain, parafollicular thyrocytes (C-cells) of rat males were investigated within the period of 10 minutes to 8 hours after the intraperitoneal injection of calcium gluconate solution. In the thyroid glands of both control and experimental animals four types of C-cells at different stages of their secretory cycle were described. Relative rates of these cellular types were found to be objective quantitative criteria of the functional activity of parafollicular cell population.


Solid-in-Oil Nanodispersions for Transcutaneous Immunotherapy of Japanese Cedar Pollinosis.
Japanese cedar pollinosis (JCP) is a common affliction caused by an allergic reaction to cedar pollen and is considered a disease of national importance in Japan. Antigen-specific immunotherapy (AIT) is the only available curative treatment for JCP. However, low compliance and persistence have been reported among patients subcutaneously or sublingually administered AIT comprising a conventional antigen derived from a pollen extract. To address these issues, many research studies have focused on developing a safer, simpler, and more effective AIT for JCP. Here, we review the novel antigens that have been developed for JCP AIT, discuss their different administration routes, and present the effects of anti-allergy treatment. Then, we describe a new form of AIT called transcutaneous immunotherapy (TCIT) and its solid-in-oil (S/O) nanodispersion formulation, which is a promising antigen delivery system. Finally, we discuss the applications of S/O nanodispersions for JCP TCIT. In this context, we predict that TCIT delivery by using a S/O nanodispersion loaded with novel antigens may offer an easier, safer, and more effective treatment option for JCP patients.


Analysis of urinary function using validated instruments and uroflowmetry after primary and salvage prostate cryoablation.
To evaluate changes in urinary function after cryoablation for clinically localized prostate cancer and to investigate risk factors that predict changes in urinary function after surgery. Among the patients who underwent primary or salvage cryoablation between January 2002 and May 2008, 74 patients (50 primary and 24 salvage) with both a preoperative and postoperative urinary function domain score and uroflowmetry were included in this study. The mean age was 66.8 ± 7.5 years and the mean follow-up period was 42.5 ± 20.3 months. The changes in postoperative urinary function were evaluated on the basis of several categorized groups, including surgical method, preoperative urinary symptoms, and prostate volume. Of 74 patients, 2 (2.7%) presented with mild stress incontinence after cryoablation. No patient presented with persistent urinary retention or urethral fistula. When comparing postoperative International Prostate Symptom Score (IPSS) and bother index scores with preoperative scores, it was found that on average IPSS and bother index recovered 12 and 18 months after cryoablation, respectively, and continued to improve after recovery. Only salvage cryoablation correlated with deteriorating urinary function in a logistic regression model (P = .032). However, it was noted that the patients with preoperative moderate to severe urinary symptoms and larger prostate volume showed improvement of urinary function after cryoablation. No associations were found between worsened urinary function and prostate volume, comorbidities (hypertension, obesity, and diabetes), or sexual function. Cryoablation is a minimally invasive surgery for localized prostate cancer. This study is the first to demonstrate the ability of cryoablation in terms of maintaining and potentially improving urinary function using validated instruments and uroflowmetry assessments.


Influenza 2009 pandemic: Cellular immunemediated surveillance modulated by TH17 & Tregs.
Influenza A virus is a serious public health threat. Most recently the 2009/H1N1 pandemic virus had an inherent ability to evade the host's immune surveillance through genetic drift, shift, and genomic reassortment. Immune characterization of 2009/H1N1 utilized monoclonal antibodies, neutralizing sera, and proteomics. Increased age may have provided some degree of immunity, but vaccines against seasonal influenza viruses seldom yield cross-reactive immunity, exemplified by 2009/H1N1. Nonetheless, about 33% of individuals, over the age of 60, had cross-reactive neutralizing antibodies against 2009/H1N1, whereas only 6-9% young adults had these antibodies. Children characteristically had no detectable immunity against 2009/H1N1. Taken together, these observations suggest some degree of immune transference with at least certain strains of virus that have afflicted the human population in past decades. Because internal influenza proteins may exhibit less antigenic variation, it is possible that prior exposure to diverse strains of influenza virus provide some immunity to novel strains, including the recent pandemic strain (swine-avian A/H1N1). Current trends in immunological studies - specifically the modulation of cellular immune surveillance provided by TH17 and Tregs - also support the need for additional proteomic research for characterizing novel translational evidence-based treatment interventions based on cytokine function to help defeat the virus. Timely and critical research must characterize the impact of genetics and epigenetics of oral and systemic host immune surveillance responses to influenza A virus. The continued development and application of proteomics and gene expression across viral strains and human tissues increases our ability to combat the spread of influenza epidemics and pandemics.


In vivo endoscopic optical coherence tomography by use of a rotational microelectromechanical system probe.
A novel endoscopic optical coherence tomography probe was designed and constructed with a 1.9-mm microelectromechanical system (MEMS) motor. The new MEMS endoscopic probe design eliminates the need to couple the rotational energy from the proximal to the distal end of the probe. Furthermore, the endoscopic probe's sheath and fiber have the advantages of having a much smaller diameter and being more flexible than traditional endoscopes since no reinforcement is needed to couple the rotational torque. At the distal end, a prism mounted on a micromotor deflects the light rays to create a transverse circular-scanning pathway. Because our MEMS scanner does not require the coupling of a rotational single-mode fiber, a high scanning speed is possible while eliminating unstable optical signals caused by nonuniform coupling.


Precious memories: a randomized controlled trial on the effects of an autobiographical memory intervention delivered by trained volunteers in residential care homes.
This study assesses the effects of an autobiographical memory intervention on the prevention and reduction of depressive symptoms in older persons in residential care. Trained volunteers delivered the intervention. A randomized controlled trial was carried out with depressive symptoms as the primary outcome. The experimental condition received the intervention Precious Memories one-on-one, whereas the control condition had individual unstructured contacts with a volunteer. Participants were 86 older persons living in residential care. There were three measurements: pre-intervention, post-intervention (2 months after the first measurement), and follow-up (8 months after the first measurement). Besides depressive symptoms, the retrieval of specific positive memories was measured as a process variable. Anxiety, loneliness, well-being, and mastery were assessed as secondary outcomes. Depressive symptoms improved equally in the intervention and the control condition at post-measurement. Participants with clinically relevant depressive symptoms also maintained the effects at follow-up in both conditions. The retrieval of specific positive memories improved more in the autobiographical memory intervention, although this was not maintained at follow-up. Anxiety and loneliness improved equally well in both conditions, but no effects were found for well-being or mastery. It is concluded that volunteers can deliver the intervention and contribute to the mental health of this highly vulnerable group of older adults.


Human achaete-scute homologue 1 (HASH-1) is downregulated in differentiating neuroblastoma cells.
The mammalian achaete-scute homologue, MASH-1, is crucial for early development of the sympathetic nervous system and is transiently expressed in sympathetic neuroblasts during embryogenesis. Here we report that the human homologue (HASH-1) was expressed in all analyzed cell lines (6/6) derived from the sympathetic nervous system tumor neuroblastoma. The majority of small-cell lung carcinoma (4/5) cell lines tested expressed HASH-1, while other nonneuronal/non-neuroendocrine cell lines were negative. Induced differentiation of neuroblastoma cells resulted in HASH-1 downregulation. This occurred concomitant with induction of neurite outgrowth and expression of the neuronal marker genes GAP-43 and neuropeptide Y. Constitutive expression of exogenous HASH-1 did not alter the capacity of the neuroblastoma cells to differentiate in response to differentiation-inducing agents. It is concluded that moderate HASH-1 expression does not compromise the capacity of these cells to differentiate.


Genotoxicity of aspartame.
In the present study, the genotoxic effects of the low-calorie sweetener aspartame (ASP), which is a dipeptide derivative, was investigated using chromosome aberration (CA) test, sister chromatid exchange (SCE) test, micronucleus test in human lymphocytes and also Ames/Salmonella/ microsome test. ASP induced CAs at all concentrations (500, 1000 and 2000 microg/ml) and treatment periods (24 and 48 h) dose-dependently, while it did not induce SCEs. On the other hand, ASP decreased the replication index (RI) only at the highest concentration for 48 h treatment period. However, ASP decreased the mitotic index (MI) at all concentrations and treatment periods dose-dependently. In addition, ASP induced micronuclei at the highest concentrations only. This induction was also dose-dependent for 48 hours treatment period. ASP was not mutagenic for Salmonella typhimurium TA98 and TA100 strains in the absence and presence of S9 mix.


Giant leiomyoma of the stomach.
A giant smooth muscle tumour of the stomach was excised in a 58-year-old man. Although small leiomyomas are not rare, the giant gastric leiomyoma is not common, and may present diagnostic and operative difficulties. It is an essentially benign tumour, unlike the "bizarre" leiomyoma or leiomyoblastoma.


Thyroid hormone transport in and out of cells.
Thyroid hormone (TH) is essential for the proper development of numerous tissues, notably the brain. TH acts mostly intracellularly, which requires transport by TH transporters across the plasma membrane. Although several transporter families have been identified, only monocarboxylate transporter (MCT)8, MCT10 and organic anion-transporting polypeptide (OATP)1C1 demonstrate a high degree of specificity towards TH. Recently, the biological importance of MCT8 has been elucidated. Mutations in MCT8 are associated with elevated serum T(3) levels and severe psychomotor retardation, indicating a pivotal role for MCT8 in brain development. MCT8 knockout mice lack neurological damage, but mimic TH abnormalities of MCT8 patients. The exact pathophysiological mechanisms in MCT8 patients remain to be elucidated fully. Future research will probably identify novel TH transporters and disorders based on TH transporter defects.


A Review of Nonanesthetic Uses of Ketamine.
Ketamine, a nonselective NMDA receptor antagonist, is used widely in medicine as an anesthetic agent. However, ketamine's mechanisms of action lead to widespread physiological effects, some of which are now coming to the forefront of research for the treatment of diverse medical disorders. This paper aims at reviewing recent data on key nonanesthetic uses of ketamine in the current literature. MEDLINE, CINAHL, and Google Scholar databases were queried to find articles related to ketamine in the treatment of depression, pain syndromes including acute pain, chronic pain, and headache, neurologic applications including neuroprotection and seizures, and alcohol and substance use disorders. It can be concluded that ketamine has a potential role in the treatment of all of these conditions. However, research in this area is still in its early stages, and larger studies are required to evaluate ketamine's efficacy for nonanesthetic purposes in the general population.


Circulating membrane vesicles in leukemic blood.
Ultramicroscopic membrane vesicles were found in the plasma of 17 patients with certain types of leukemia (acute promyelocytic leukemia, acute monocytic leukemia, acute myelomonocytic leukemia, and chronic myelogenous leukemia) and in guinea pigs with the L2C leukemia. Labeled vesicles were cleared from normal guinea pig plasma according to a two exponential function with a half-life for the second exponent of greater than 11 h. By immunofluorescence, vesicles shared antigens with the L2C leukemic cells. Attempts to elucidate the cellular origin of the circulating vesicles in human leukemias were less definitive. However, vesicles did not react with the platelet membrane antigen GP IIb/IIIa nor did the presence of circulating vesicles or vesicle-associated procoagulant activity correlate with the platelet count. In three patients studied serially, circulating vesicles paralleled disease activity. Vesicles were not detected in 16 other patients with leukemias including acute myelogenous leukemia and most lymphoid leukemias. Similarly, vesicles were not present in 29 normal plasmas or in 10 plasmas from patients with solid tumors or nonmalignant hematological disorders. In contrast to vesicles of similar appearance shed by a variety of solid and ascites tumor cells in vitro and in vivo, the vesicles circulating in leukemia patients and guinea pigs expressed variable and generally weak procoagulant activity and no tissue factor activity. Thus, although many of the patients with circulating vesicles expressed abnormal coagulation, we were not able to establish a close pathogenetic relationship between the procoagulant activity of circulating vesicles and clinical coagulopathies.


Exploring the potential of optical remote sensing for oil spill detection in shallow coastal waters--a case study in the Arabian Gulf.
Remote sensing provides an effective tool for timely oil pollution response. In this paper, the spectral signature in the optical and infrared domains of oil slicks observed in shallow coastal waters of the Arabian Gulf was investigated with MODIS, MERIS, and Landsat data. Images of the Floating Algae Index (FAI) and estimates of sea currents from hydrodynamic models supported the multi-sensor oil tracking technique. Scenes with and without sunglint were studied as the spectral signature of oil slicks in the optical domain depends upon the viewing geometry and the solar angle in addition to the type of oil and its thickness. Depending on the combination of those factors, oil slicks may exhibit dark or bright contrasts with respect to oil-free waters. Three oil spills events were thoroughly analyzed, namely, those detected on May 26 2000 by Landsat 7 ETM + and MODIS/Terra, on October 21 2007 by MERIS and MODIS, and on August 17 2013 by Landsat 8 and MODIS/Aqua. The oil slick with bright contrast observed by Landsat 7 ETM + on May 26 2000 showed lower temperature than oil-free areas. The spectral Rayleigh-corrected reflectance (R(rc)) signature of oil-covered areas indicated higher variability due to differences in oil fractions while the R(rc) spectra of the oil-free area were persistent. Combined with RGB composites, FAI images showed potentials in differentiating oil slicks from algal blooms. Ocean circulation and wind data were used to track oil slicks and forecast their potential landfall. The developed oil spill maps were in agreement with official records. The synergistic use of satellite observations and hydrodynamic modeling is recommended for establishing an early warning and decision support system for oil pollution response.


Outside case review of surgical pathology for referred patients: the impact on patient care.
Original surgical pathology materials from external sources are reviewed by our pathologists for referred patients before their clinical evaluation and treatment. To identify the rate of major disagreements with diagnoses from external institutions and to characterize the nature and impact of discordant diagnoses on patient care. We identified and reviewed all surgical pathology cases, except for medical liver, medical renal, and cardiac pathology cases, for the period between January 1, 2005, and December 31, 2010, to determine the overall frequency of major disagreements, defined as any change in diagnosis having a substantial impact on patient management. Our review of 71 811 cases initially examined between 2005 and 2010 identified 457 major disagreements (0.6%). The most frequent areas of disagreement were gastrointestinal (80 cases; 17.5%), lymph node (73; 16.0%), bone/soft tissue (47; 10.3%), and genitourinary (43; 9.4%). For a subset of 166 cases reviewed between July 1, 2009, and December 31, 2010, follow-up data were available for 140 (84.3%). Treatment was affected by a changed diagnosis in 126 cases (90.0%), and prognosis was affected in 129 cases (92.1%). For 86 (51.8%) of the 166 cases, additional tissue was obtained. Revised diagnoses concurred with follow-up tissue diagnosis in 84.9% (73 cases), whereas they differed from follow-up tissue diagnosis in 15.1% (13 cases). Our findings demonstrate the value of outside case review of pathology materials for referred patients, and suggest that it decreases the likelihood of diagnostic errors and provides better protection for patients.


Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group.
Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.


Integration of a task strengthening strategy for hypertension management into HIV care in Nigeria: a cluster randomized controlled trial study protocol.
In regions with weak healthcare systems, critical shortages of the healthcare workforce, and increasing prevalence of dual disease burdens, there is an urgent need for the implementation of proven effective interventions and strategies to address these challenges. Our mixed-methods hybrid type II effectiveness-implementation study is designed to fill this evidence-to-practice gap. This study protocol describes a cluster randomized controlled trial which evaluates the effectiveness of an implementation strategy, practice facilitation (PF), on the integration, adoption, and sustainability of a task-strengthening strategy for hypertension control (TASSH) intervention within primary healthcare centers (PHCs) in Lagos State, Nigeria. Guided by the Consolidated Framework for Implementation Research (CFIR) and the Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM), this study tests the impact of a proven effective implementation strategy to integrate hypertension management into the HIV care cascade, across 30 PHCs. The study will be conducted in three phases: (1) a pre-implementation phase that will use CFIR to develop a tailored PF intervention for integrating TASSH into HIV clinics; (2) an implementation phase that will use RE-AIM to compare the clinical effectiveness of PF vs. a self-directed condition (receipt of information on TASSH without PF) on BP reduction; and (3) a post-implementation phase that will use RE-AIM to evaluate the effect of PF vs. self-directed condition on adoption and sustainability of TASSH. The PF intervention components comprise (a) an advisory board to provide leadership support for implementing TASSH in PHCs; (b) training of the HIV nurses on TASSH protocol; and (c) training of practice facilitators, who will serve as coaches, provide support, and performance feedback to the HIV nurses. This study is one of few, if any trials, to evaluate the impact of an implementation strategy for integrating hypertension management into HIV care, on clinical and implementation outcomes. Findings from this study will advance implementation science research on the effectiveness of tailoring an implementation strategy for the integration of an evidence-based, system-level hypertension control intervention into HIV care and treatment. ClinicalTrials.gov ( NCT04704336 ). Registered on 11 January 2021.


Functionally active t1-t1 interfaces revealed by the accessibility of intracellular thiolate groups in kv4 channels.
Gating of voltage-dependent K(+) channels involves movements of membrane-spanning regions that control the opening of the pore. Much less is known, however, about the contributions of large intracellular channel domains to the conformational changes that underlie gating. Here, we investigated the functional role of intracellular regions in Kv4 channels by probing relevant cysteines with thiol-specific reagents. We find that reagent application to the intracellular side of inside-out patches results in time-dependent irreversible inhibition of Kv4.1 and Kv4.3 currents. In the absence or presence of Kv4-specific auxiliary subunits, mutational and electrophysiological analyses showed that none of the 14 intracellular cysteines is essential for channel gating. C110, C131, and C132 in the intersubunit interface of the tetramerization domain (T1) are targets responsible for the irreversible inhibition by a methanethiosulfonate derivative (MTSET). This result is surprising because structural studies of Kv4-T1 crystals predicted protection of the targeted thiolate groups by constitutive high-affinity Zn(2+) coordination. Also, added Zn(2+) or a potent Zn(2+) chelator (TPEN) does not significantly modulate the accessibility of MTSET to C110, C131, or C132; and furthermore, when the three critical cysteines remained as possible targets, the MTSET modification rate of the activated state is approximately 200-fold faster than that of the resting state. Biochemical experiments confirmed the chemical modification of the intact alpha-subunit and the purified tetrameric T1 domain by MTS reagents. These results conclusively demonstrate that the T1--T1 interface of Kv4 channels is functionally active and dynamic, and that critical reactive thiolate groups in this interface may not be protected by Zn(2+) binding.


Differential word expression analyses highlight plague dynamics during the second pandemic.
Research on the second plague pandemic that swept over Europe from the fourteenth to nineteenth centuries mainly relies on the exegesis of contemporary texts and is prone to interpretive bias. By leveraging certain bioinformatic tools routinely used in biology, we developed a quantitative lexicography of 32 texts describing two major plague outbreaks, using contemporary plague-unrelated texts as negative controls. Nested, network and category analyses of a 207-word pan-lexicome, comprising overrepresented terms in plague-related texts, indicated that 'buboes' and 'carbuncles' are words that were significantly associated with the plague and signalled an ectoparasite-borne plague. Moreover, plague-related words were associated with the terms 'merchandise', 'movable', 'tatters', 'bed' and 'clothes'. Analysing ancient texts using the method reported in this paper can certify plague-related historical records and indicate the particularities of each plague outbreak, which can inform on the potential sources for the causative Yersinia pestis.


Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection.
Inbred mouse strains exhibit differences in susceptibility to influenza A infections. However, the molecular mechanisms underlying these differences are unknown. Therefore, we infected a highly susceptible mouse strain (DBA/2J) and a resistant strain (C57BL/6J) with influenza A H1N1 (PR8) and performed genome-wide expression analysis. We found genes expressed in lung epithelium that were specifically down-regulated in DBA/2J mice, whereas a cluster of genes on chromosome 3 was only down-regulated in C57BL/6J. In both mouse strains, chemokines, cytokines and interferon-response genes were up-regulated, indicating that the main innate immune defense pathways were activated. However, many immune response genes were up-regulated in DBA/2J much stronger than in C57BL/6J, and several immune response genes were exclusively regulated in DBA/2J. Thus, susceptible DBA/2J mice showed a hyper-inflammatory response. This response is similar to infections with highly pathogenic influenza virus and may serve as a paradigm for a hyper-inflammatory host response to influenza A virus.


Bulk-driven acoustic streaming at resonance in closed microcavities.
Bulk-driven acoustic (Eckart) streaming is the steady flow resulting from the time-averaged acoustic energy flux density in the bulk of a viscous fluid. In simple cases, like the one-dimensional single standing-wave resonance, this energy flux is negligible, and therefore the bulk-driven streaming is often ignored relative to the boundary-driven (Rayleigh) streaming in the analysis of resonating acoustofluidic devices with length scales comparable to the acoustic wavelength. However, in closed acoustic microcavities with viscous dissipation, two overlapping resonances may be excited at the same frequency as a double mode. In contrast to single modes, the double modes can support a steady rotating acoustic energy flux density and thus a corresponding rotating bulk-driven acoustic streaming. We derive analytical solutions for the double modes in a rectangular-box-shaped cavity including the viscous boundary layers, and use them to map out possible rotating patterns of bulk-driven acoustic streaming. Remarkably, the rotating bulk-driven streaming may be excited by a nonrotating actuation, and we determine the optimal geometry that maximizes this excitation. In the optimal geometry, we finally simulate a horizontal 2×2, 4×4, and 6×6 streaming-roll pattern in a shallow square cavity. We find that the high-frequency 6×6 streaming-roll pattern is dominated by the bulk-driven streaming as opposed to the low-frequency 2×2 streaming pattern, which is dominated by the boundary-driven streaming.


Long-term stimulation with alternating electric fields modulates the differentiation and mineralization of human pre-osteoblasts.
Biophysical stimulation by electric fields can promote bone formation in bone defects of critical size. Even though, long-term effects of alternating electric fields on the differentiation of osteoblasts are not fully understood. Human pre-osteoblasts were stimulated over 31 days to gain more information about these cellular processes. An alternating electric field with 0.7 Vrms and 20 Hz at two distances was applied and viability, mineralization, gene expression, and protein release of differentiation factors were analyzed. The viability was enhanced during the first days of stimulation. A higher electric field resulted in upregulation of typical osteogenic markers like osteoprotegerin, osteopontin, and interleukin-6, but no significant changes in mineralization. Upregulation of the osteogenic markers could be detected with a lower electric field after the first days of stimulation. As a significant increase in the mineralized matrix was identified, an enhanced osteogenesis due to low alternating electric fields can be assumed.


An empirical meta-analysis of the life sciences linked open data on the web.
While the biomedical community has published several "open data" sources in the last decade, most researchers still endure severe logistical and technical challenges to discover, query, and integrate heterogeneous data and knowledge from multiple sources. To tackle these challenges, the community has experimented with Semantic Web and linked data technologies to create the Life Sciences Linked Open Data (LSLOD) cloud. In this paper, we extract schemas from more than 80 biomedical linked open data sources into an LSLOD schema graph and conduct an empirical meta-analysis to evaluate the extent of semantic heterogeneity across the LSLOD cloud. We observe that several LSLOD sources exist as stand-alone data sources that are not inter-linked with other sources, use unpublished schemas with minimal reuse or mappings, and have elements that are not useful for data integration from a biomedical perspective. We envision that the LSLOD schema graph and the findings from this research will aid researchers who wish to query and integrate data and knowledge from multiple biomedical sources simultaneously on the Web.


In Silico and In Vitro studies of taiwan chingguan yihau (NRICM101) on TNF-α/IL-1β-induced human lung cells.
COVID-19 pandemic has been a global outbreak of coronavirus (SARS-CoV-2 virus) since 2019. Taiwan Chingguan Yihau (NRICM101) is the first traditional Chinese medicine (TCM) classic herbal formula and is widely used for COVID-19 patients in Taiwan and more than 50 nations. This study is to investigate in silico target fishing for the components of NRICM101 and to explore whether NRICM101 inhibits cytokines-induced normal human lung cell injury in vitro. Our results showed that network prediction of NRICM101 by a high throughput target screening platform showed that NRICM101 has multiple functions that may affect cytokine regulation to prevent human lung cell injury. In addition, NRICM101 revealed protective effects against TNF-α/IL-1β-induced normal human lung HEL 299 cell injury through JNK and p38MAPK kinase signaling. Next-generation sequencing (NGS) analysis of NRICM101 on TNF-α/IL-1β-injured HEL 299 cells indicated that inflammatory pathway, cell movement of macrophages, cellular infiltration by macrophages, and Th1/Th2 immuno-regulation pathways were included. Thus, NRICM101 is a therapeutic agent, and it can improve COVID-19 syndrome to confer beneficial effects through multiple targeting and multiple mechanisms.


Spray-dried microparticles containing polymeric micelles encapsulating hematoporphyrin.
The purpose of this study was to examine the properties of a new pulmonary delivery platform of microparticles containing micelles in which a therapeutic photosensitizing drug, hematoporphyrin (Hp), was encapsulated. Different poloxamers were used to form micellar Hp, and one of these, Pluronic L122-Hp, was subsequently incorporated into lactose microparticles by spray-drying. Spectral and morphological analyses were performed on both micellar Hp, and lactose microparticles containing micellar Hp (lactose-micellar Hp) before and after dissolution of the microparticles in water. Photodynamic activity of the various Hp samples were evaluated in human lung epithelial carcinoma A549 cells using a light-emitting diode (LED) device at a wavelength of 630 +/- 5 nm. No significant difference was observed between micellar Hp and lactose-micellar Hp regarding the generation of singlet oxygen. The mean particle size of the microparticles was 2.3 +/- 0.7 microm which is within the size range for potential lung delivery. The cellular uptake of micellar Hp and lactose-micellar Hp measured on A549 cells was at least twofold higher than those obtained with the Hp at equivalent concentrations. Micellar Hp exhibited higher cytotoxicity than Hp due to reduced formation of Hp aggregates and increased cellar uptake. The spectral properties as well as the photodynamic activity of the micellar Hp was retained when formulated into microparticles by spray-drying. Microparticles containing micelles have the potential for delivering micelle-encapsulated hydrophobic drugs in targeted therapy of pulmonary diseases.


Reversible stapling of unprotected peptides via chemoselective methionine bis-alkylation/dealkylation.
We have developed a general peptide macrocyclization strategy that involves a facile and chemoselective methionine bis-alkylation/dealkylation process. This method provides a straightforward and easy approach to generate cyclic peptides with tolerances of all amino acids (including Cys), variable loop sizes, and different linkers. The Met bis-alkylation we apply in this strategy yields two additional on-tether positive charges that could assist in the cellular uptake of the peptides. Notably, the bis-alkylated peptide could be reduced to release the original peptide both in vitro and within cellular environments. This strategy provides an intriguing and facile traceless post-peptide-synthesis modification with enhanced cellular uptakes. Peptides constructed with this method could be utilized to zero in on various protein targets or to achieve other goals, such as drug delivery.


Chiral thin films of metal oxide.
In this paper, we describe for the first time the synthesis of new chiral nanosized metal oxide surfaces based on chiral self-assembled monolayers (SAMs) coated with metal oxide (TiO2) nanolayers. In this new type of nanosize chiral surface, the metal oxide nanolayers enable the protection of the chiral self-assembled monolayers while preserving their enantioselective nature. The chiral nature of the SAM/TiO2 films was characterized by variety of unique techniques, such as second-harmonic generation circular dichroism (SHG-CD), quartz crystal microbalance, and chiral adsorption measurements with circular dichroism spectroscopy. The chiral resolution abilities of the SAMs coated with metal oxide (TiO2) nanolayers were investigated in the crystallization of a racemic mixture of threonine and glutamic acid. Our proposed methodology for the preparation of nanoscale chiral surfaces described in this article could open up opportunities in other fields of chemistry, such as chiral catalysis.


The systems medicine of cannabinoids in pediatrics: the case for more pediatric studies.
The legal and illicit use of cannabinoid-containing products is accelerating worldwide and is accompanied by increasing abuse problems. Due to legal issues, the USA will be entering a period of rapidly expanding recreational use of cannabinoids without the benefit of needed basic or clinical research. Most clinical cannabinoid research is focused on adults. However, the pediatric population is particularly vulnerable since the central nervous system is still undergoing developmental changes and is potentially susceptible to cannabinoid-induced alterations. This review focuses on the systems medicine of cannabinoids with emphasis on the need for future studies to include pediatric populations and mother-infant dyads. Systems medicine integrates omics-derived data with traditional clinical medicine with the long-term goal of optimizing individualized patient care and providing proactive medical advice. Omics refers to large-scale data sets primarily derived from genomics, epigenomics, proteomics, and metabolomics.


Interleukin-6 and interleukin-15 are selectively regulated by lipopolysaccharide and interferon-gamma in primary pig adipocytes.
3T3-L1 adipocytes express the lipopolysaccharide (LPS) receptor and respond to direct stimulation with the antigen by increasing the expression of inflammatory mediators. Activation of this receptor by its ligand in the macrophage causes the activation and translocation of nuclear factor-kappaB (NF-kappaB) to the nucleus where it regulates the expression of proinflammatory cytokines and other target genes. We investigated whether LPS could stimulate NF-kappaB translocation in primary pig adipocytes and regulate the expression and secretion of TNF-alpha and IL-6. LPS clearly induced the nuclear translocation of NF-kappaB and also upregulated (P < 0.05) the mRNA expression and secretion of IL-6 into the culture medium. An induction of TNF-alpha expression by LPS was not detected, but with extended incubation (8 h), there was a modest increase (P < 0.09) in the media concentration of this cytokine. Inhibition of either ERK1/2, PKC, or the inhibitory G protein (Gi) with U-0126, bisindolylmaleimide HCl, and pertussis toxin, respectively, blocked (P < 0.05) the increase in IL-6 expression caused by LPS. Because LPS administration in vivo increases circulating concentrations of IFN-gamma, and because this cytokine also regulates multiple immune modulators in the adipocyte, we also determined whether IFN-gamma regulates cytokine expression in primary adipocytes. Although the expression of IL-6 and TNF-alpha was unresponsive to IFN-gamma, the expression of IL-15 was markedly upregulated (P < 0.01). Furthermore, the induction of IL-15 expression by IFN-gamma was blocked by inhibition of PKC. These data indicate that NF-kappaB is responsive to LPS in the adipocyte and also identify key mediators of LPS-induced IL-6 expression. In addition, we provide novel evidence that IFN-gamma targets the adipocyte to induce IL-15 expression, thus indicating a possible role for the adipocyte in the regulation of T-cell function and muscle metabolism during the innate immune response.


Small bowel rejection in isolated small bowel transplantation and in multivisceral transplantation: a comparative study in a large animal model.
The proposition that a combined graft including the liver protects other organ allografts from the same donor is well known. However, it is not evident in the clinical results. The present experiments were undertaken to compare acute small bowel rejection in isolated small bowel transplantation with multivisceral transplantation. Using 36 outbred, male Large-White pigs, isolated small bowel transplantation (SBTX: n = 9) and abdominal multivisceral transplantation (MVTX: n = 9) were performed without immunosuppression. The survival rate and blood serum samples were monitored postoperatively. In order to compare acute small bowel rejection, sequential biopsy specimens from Thiry-Vella loops were also monitored daily beginning on me 3rd day after transplantation. The specimens were scored from 0 to 3 according to the severity of the rejection. The survival rate was not significantly different. However, significant differences were noted in the cause of the death and in the pathologic changes of the small bowel. In contrast to SBTX, the small bowel rejection of MVTX was significantly delayed and less severe. The rejection score of MVTX was significantly better than SBTX from 5 postoperative days (POD) to 1 lPOD (P < 0.05). The present study demonstrated mat acute small bowel rejection of MVTX graft including the liver was delayed and less severe than that of SBTX in an outbred large animal model.


A Systemic Review on the Regulatory Roles of miR-34a in Gastrointestinal Cancer.
MicroRNAs (miRNAs) are a class of endogenous non-coding single-stranded small-molecule RNAs that regulate gene expression by repressing target messenger RNA (mRNA) translation or degrading mRNA. miR-34a is one of the most important miRNAs participating in various physiological and pathological processes. miR-34a is abnormally expressed in a variety of tumors. The roles of miR-34a in gastrointestinal cancer (GIC) draw lots of attention. Numerous studies have demonstrated that dysregulated miR-34a is closely related to the proliferation, differentiation, migration, and invasion of tumor cells, as well as the diagnosis, prognosis, treatment, and chemo-resistance of tumors. Thus, we systematically reviewed the abnormal expression and regulatory roles of miR-34a in GICs including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC). It may provide a profile of versatile roles of miR-34a in GICs.


First-line molecular therapies in the treatment of metastatic colorectal cancer - a literature-based review of phases II and III trials.
Metastatic colorectal cancer (mCRC) is one of the most common cancers and the second leading cause of cancer worldwide. With the improvement of systemic and operative therapies, median overall survival (mOS) reached 30 months or longer. Here, we will review the use of the anti-vascular endothelial growth factor (VEGF) and anti-epidermal growth factor receptor (EGFR) antibodies in combination with doublet and triplet chemotherapy in patients with borderline and primary unresectable mCRC. Phases II and III trials were included in investigating chemotherapy in the first-line in combination with an anti-VEGF(R) or anti-EGFR in a cohort of patients with mCRC. The VEGF-antibody bevacizumab has improved progression-free survival (PFS) in several phase III trials in combination with a chemotherapy doublet. More recently, a higher efficacy has been demonstrated in combination with an intensified chemotherapy including 5-fluoropyrimidine (5-FU), oxaliplatin, and irinotecan within the phase III TRIBE study. Similarly, high resectability rates have been shown in the phase II Olivia trial for patients with liver-limited disease with an intensified chemotherapeutic regime. However, this increase in efficacy was accompanied by an increase in toxicity as well. The efficacy of the EGFR-antibodies cetuximab and panitumumab has been shown in several phase III trials, but their use is restricted to patients whose tumors are RAS wildtype (WT). The phase II trials, CELIM and PLANET, demonstrated a favorable long-term survival for patients with initially non-resectable colorectal liver metastases who respond to conversion therapy with EGFR-antibodies and undergo secondary resection. The CLGB and FIRE-3 trials delivered an inconsistent finding whether anti-VEGF or -EGFR treatment is the better option in the first-line setting. However, there is increasing evidence from post hoc analyses of prospective clinical trials that patients with left-sided tumors benefit from EGFR-directed combination therapy in terms of prolongation of OS and PFS compared with limited, if any, benefit for those with right-sided tumors. Both anti-VEGF- and anti-EGFR-directed therapies represent efficient treatment options for patients with mCRC in the first line. For patients with RAS WT, left-sided tumor anti-EGFR-based treatment is recommended. Intensified regimens can be offered initially to unresectable patients in order to achieve resectability at a price of higher toxicity.


Sensitivity and specificity of magnetic resonance enterography in the clinical management of fistulizing Crohn's disease.
High diagnostic accuracy is reported for magnetic resonance enterography (MRE) in Crohn's disease (CD), but few studies have evaluated its role in abdominal fistulae. The primary aim of this study was to assess the reliability of MRE in the identification of internal fistulae in CD. One hundred and eighty-six patients with moderate CD (CD Activity Index : 250-400) were prospectively selected from the inflammatory bowel disease clinic of Parma University Hospital. Eligible patients had already undergone nutritional screening, pancolonoscopy, and computed tomography enterography (CTE) in the month before enrollment. MRE was performed according to the study protocol. Additional fluoroscopic contrast-enhanced studies or surgical evaluation were used for discordance between CTE and MRE results. A consensus committee resolved equivocal findings. Surgical findings and/or fluoroscopic contrast-enhanced studies together with the clinical data were considered the composite "reference standard" to which the results of MRE were compared. MRE identified 22 internal fistulae in 21 patients (11%), of whom 4 (19%) also had perianal fistulae and found 7 abscesses (33%). Forty-one (22%) additional patients with perianal fistulae were identified. Thirteen patients (57%) with internal fistulae required enteral nutrition support. No statistically significant differences were found between MRE and CTE in fistula detection. There was also no significant difference between MRE and the composite diagnosis in those who underwent surgery (n = 8) and/or contrast-enhanced studies (n = 7). CTE and MRE accurately detect internal fistulae in CD. MRE is preferable because it avoids radiation. Reliable identification of internal fistulae by MRE should permit earlier and improved treatment.


Ion and ion channel involvement in alpha-melanocyte-stimulating hormone secretion from superfused slices of rat hypothalamus.
Release of alpha-melanocyte-stimulating hormone (alpha-MSH) from 250 micron frontal slices of rat hypothalamus superfused at 37 degrees C with oxygenated artificial cerebrospinal fluid (ACSF) was quantified in freeze-dried samples of ACSF by radioimmunoassay. Significant reproducible increases in alpha-MSH release were caused by 40-70 mM K+ in ACSF, maximum release being caused by 50 mM K+. Fifty mM K+-stimulated alpha-MSH release was abolished in the absence of Ca2+ from ACSF and by the presence of 10(-6) M tetrodotoxin. Tetrapentylammonium ions, 10(-4) M and 10(-3) M, stimulated dose-dependent increases in alpha-MSH release. The data support a putative neurotransmitter/neuromodulator role for alpha-MSH in the CNS.


Antigen perception by T lymphocytes. Influence of the major histocompatibility complex.
There is considerable evidence that T cell activation to soluble antigens occurs only if this is processed by macrophages and displayed appropriately on the plasma membrane in association with products of the genes of the major histocompatibility complex. The genes responsible differ according to the antigens involved. For cytotoxicity, targets and killer T cells must share K or D region gene products. For delayed type hypersensitivity to fowl gammaglobulin in mice, I-A identity is necessary; for dinitrofluorobenzene, identity at either the I, K or D region is sufficient. Experiments using three different approaches do not support the notion that these genetic constraints are due to the necessity for the T cell and stimulator cell to match an identical gene product or "cell interaction molecule." Rather they favour the hypothesis that activated T cells recognize antigen and products of genes of the major histocompatibility complex. The implications of the results are discussed in terms of the mode of action of immune responsiveness (Ir) genes and of the possible parallel evolution of T cell receptors for antigen and gene products of the major histocompatibility complex.


[Epidemiology of hepatitis C virus infection in ColombiaEpidemiologia da infecção pelo vírus da hepatite C na Colômbia].
To describe the epidemiology of hepatitis C virus (HCV) infection in Colombia. Critical review of epidemiological studies of HCV infection in Colombia. The PubMed, SciELO, and ScienceDirect databases were searched for original articles and reviews on the subject published from 1989 to 2020. Reports from the National Institute of Health and the High Cost Account of the Ministry of Health and Social Protection were also reviewed. Data on seroprevalence of HCV antibodies in blood donors range from 1.5% to 0.32%, corresponding to reports at the beginning and end of the study period, respectively. In the population with risk factors, a high prevalence of HCV infection is observed, although with variations over time. With respect to HCV genotypes in Colombia, genotypes 1, 2, 3, and 4 (subtypes 1a, 1b, 2a, and 3a) have been identified. In the observation period, a decrease was seen in seroprevalence of HCV infection in blood donors and hemodialysis patients in Colombia, demonstrating the impact of safe blood policies and biosafety measures. Studies in people who inject illicit drugs indicate a high prevalence of infection, with regional differences within the country. HCV genotype 1, subtype 1b, is the most frequent in the different studies carried out in Colombia, and the most recent report of the High Cost Account of the Ministry of Health and Social Protection indicates that genotype 4 is the second most frequent genotype in the country.


Educating Primary Care Providers and Associate Care Providers About Hepatitis C Screening of Baby Boomers: a Multi-practice Study.
Chronic hepatitis C virus (HCV) increases the risk for hepatocellular carcinoma. Despite higher prevalence of HCV in persons born 1945-1965 (baby boomer), screening has not been widely adopted. Both primary care providers (PCPs) and associate care providers (ACPs) need to be educated about the rationale and methods to screen for HCV. In five Federally Qualified Health Centers serving low-income Hispanic communities, PCPs and ACPs attended a 50-min training lecture about HCV epidemiology, screening methods, and evaluation. Using a 12-item questionnaire, knowledge and attitudes were compared for PCPs and ACPs at baseline (pre-test) and following training (post-test). A higher proportion of PCPs correctly answered 3 of 6 knowledge questions on both pre-test and post-test but ACPs' showed more improvement in knowledge (all P < 0.05). ACPs had more favorable attitudes about linking patients to care on pre- and post-tests than PCPs, and ACPs' attitudes improved on all 6 items versus 4 for PCPs. Both PCPs and ACPs improved knowledge and attitudes after training about HCV screening but ACPs had more favorable attitudes than PCPs. Engaging the entire primary care practice team in learning about HCV screening promotes knowledge and attitudes necessary for successful implementation.


Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts.
Free radicals have been implicated in the pathogenesis of reperfusion injury, but it is unclear how they exert their deleterious effects on cellular metabolism. Several lines of indirect evidence suggest that free radicals elevate intracellular Ca2+ concentration ([Ca2+]i) and inhibit glycolysis as part of their mechanism of injury. We tested these ideas directly in hearts subjected to hydroxyl radicals produced by the Fenton and Haber-Weiss reactions. Nuclear magnetic resonance spectra were obtained from Langendorff-perfused rabbit hearts before, during, and after 4 min of perfusion with H2O2 (0.75 mM) and Fe(3+)-chelate (0.1 mM). Isovolumic left ventricular pressure exhibited progressive functional deterioration and contracture after exposure to H2O2 + Fe3+. Phosphorus nuclear magnetic resonance (NMR) spectra revealed partial ATP depletion and sugar phosphate accumulation indicative of glycolytic inhibition. To measure [Ca2+]i, fluorine NMR spectra were acquired in a separate group of hearts loaded with the Ca2+ indicator 5F-BAPTA [5,5'-difluoro derivative of 1,2-bis-(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid]. Mean time-averaged [Ca2+]i increased from 347 +/- 14 nM in control to 1,026 +/- 295 nM 4 min after free radical generation (means +/- SEM, n = 7), and remained elevated thereafter. We conclude that free radicals induce clear-cut, specific derangements of cellular metabolism in the form of glycolytic inhibition and calcium overload. The observed increase in [Ca2+]i suggests that the deleterious effects of free radicals are at least partially mediated by secondary changes in cellular calcium homeostasis.


Cardiomyopathy complicated by left ventricular aneurysms in children.
Ventricular aneurysms in children are unusual. Three patients with cardiomyopathy associated with angiographically proved left ventricular aneurysms in this age group are reported. Two of them were girls. The ages were 20 months, 7 years, and 14 years. Heart failure was present in all patients. There was radiological evidence of cardiomegaly in all three, and the electrocardiogram showed signs of necrosis in two of them. Selective left ventricular angiography disclosed generalized hypokinesis in all patients. One child had an aneurysm of the diaphragmatic wall. In another the aneurysm was localized in the muscular ventricular septum, causing severe subpulmonary stenosis by encroaching in the right ventricular outflow tract during systole. The third patient had an aneurysm of the left ventricular free wall partly encircling the left ventricle. The coronary arteries appeared normal in all cases. The clinical features of the underlying disease were not altered by the presence of the aneurysm except in the patient with the septal aneurysm and subpulmonary stenosis. In this patient the aneurysm was successfully resected.


Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in Swine.
The local environment of delivered mesenchymal stem cells (MSCs) may affect their ultimate phenotype. MR fluoroscopy has the potential to guide intramyocardial MSC injection to desirable targets, such as the border between infarcted and normal tissue. We tested the ability to (1) identify infarcts, (2) navigate injection catheters to preselected targets, (3) inject safely even into fresh infarcts, and (4) confirm injection success immediately. A 1.5-T MRI scanner was customized for interventional use, with rapid imaging, independent color highlighting of catheter channels, multiple-slice 3D rendering, catheter-only viewing mode, and infarct-enhanced imaging. MRI receiver coils were incorporated into guiding catheters and injection needles. These devices were tested for heating and used for targeted MSC delivery. In infarcted pigs, myocardium was targeted by MR fluoroscopy. Infarct-enhanced imaging included both saturation preparation MRI after intravenous gadolinium and wall motion. Porcine MSCs were MRI-labeled with iron-fluorescent particles. Catheter navigation and multiple cell injections were performed entirely with MR fluoroscopy at 8 frames/s with 1.7x3.3x8-mm voxels. Infarct-enhanced MR fluoroscopy permitted excellent delineation of infarct borders. All injections were safely and successfully delivered to their preselected targets, including infarct borders. Iron-fluorescent particle-labeled MSCs were readily visible on delivery in vivo and post mortem. Precise targeted delivery of potentially regenerative cellular treatments to recent myocardial infarction borders is feasible with an MR catheter delivery system. MR fluoroscopy permits visualization of catheter navigation, myocardial function, infarct borders, and labeled cells after injection.


Temozolomide downregulates P-glycoprotein expression in glioblastoma stem cells by interfering with the Wnt3a/glycogen synthase-3 kinase/β-catenin pathway.
Glioblastoma multiforme stem cells display a highly chemoresistant phenotype, whose molecular basis is poorly known. We aim to clarify this issue and to investigate the effects of temozolomide on chemoresistant stem cells. A panel of human glioblastoma cultures, grown as stem cells (neurospheres) and adherent cells, was used. Neurospheres had a multidrug resistant phenotype compared with adherent cells. Such chemoresistance was overcome by apparently noncytotoxic doses of temozolomide, which chemosensitized glioblastoma cells to doxorubicin, vinblastine, and etoposide. This effect was selective for P-glycoprotein (Pgp) substrates and for stem cells, leading to an investigation of whether there was a correlation between the expression of Pgp and the activity of typical stemness pathways. We found that Wnt3a and ABCB1, which encodes for Pgp, were both highly expressed in glioblastoma stem cells and reduced by temozolomide. Temozolomide-treated cells had increased methylation of the cytosine-phosphate-guanine islands in the Wnt3a gene promoter, decreased expression of Wnt3a, disrupted glycogen synthase-3 kinase/β-catenin axis, reduced transcriptional activation of ABCB1, and a lower amount and activity of Pgp. Wnt3a overexpression was sufficient to transform adherent cells into neurospheres and to simultaneously increase proliferation and ABCB1 expression. On the contrary, glioblastoma stem cells silenced for Wnt3a lost the ability to form neurospheres and reduced at the same time the proliferation rate and ABCB1 levels. Our work suggests that Wnt3a is an autocrine mediator of stemness, proliferation, and chemoresistance in human glioblastoma and that temozolomide may chemosensitize the stem cell population by downregulating Wnt3a signaling.


Piano hammers and their force compression characteristics: does a power law make sense?
We have studied the force characteristics of a collection of piano hammers, through studies of the acceleration of the hammer head, the force due to the compression of the hammer felt, Fh, and the associated bending of the hammer shank which occurs when a hammer strikes a rigid object. By integration of the acceleration one can estimate the compression of the felt, and thus obtain a force-compression Fh(z) relationship; our results for this function are compared with previous experiments and theoretical models. Close examination of our findings suggests that bending of the hammer shank, and also the time required for the force to be transmitted from the outer edge of the hammer to its core, play significant roles in the hammer dynamics. The data are used to estimate the quantitative impact of these effects on the derived Fh(z) relation. The implications for physical modeling of a piano tone are briefly discussed.


Stents are associated with increased risk of respiratory infections in patients undergoing airway interventions for malignant airways disease.
Long-term complications of therapeutic bronchoscopy include infections and airway restenosis due to tumor. No studies have compared the incidence rates of infection in patients with stents with those without stents. We hypothesized that patients with stents would have a higher incidence of lower respiratory tract infections than would patients without stents. We conducted a retrospective cohort study, covering the period September 2009 to August 2011, of patients who had therapeutic bronchoscopy for malignant airways disease. Outcomes recorded were lower respiratory tract infection and airway restenosis by tumor. Seventy-two patients had therapeutic bronchoscopy for malignant airways disease. Twenty-four of these patients had one or more stents placed. Twenty-three of the 72 patients (32%) developed lower respiratory tract infections. Stents were associated with an increased risk of infection (hazard ratio [HR], 3.76; 95% CI, 1.57-8.99; P = .003). The incidence rate of lower respiratory tract infection was 0.0057 infections per person-day in patients with stents vs 0.0011 infections per person-day in patients without stents. The incidence rate difference, 0.0046 infections per person-day, was significant (95% CI, 0.0012-0.0081; P = .0002). Restenosis due to tumor overgrowth was associated with more severe obstruction at baseline (obstruction ≥ 50% vs < 50% preprocedure; HR, 13.71; 95% CI, 1.75-107.55; P = .013). Therapeutic bronchoscopy with stent placement is associated with a higher risk of infection than is therapeutic bronchoscopy alone. If ablative techniques reopen the airway and there is a good chance that the tumor may respond to chemotherapy and/or radiation, a strategy of initially holding off on stenting may be warranted.


The small G protein Arl8 contributes to lysosomal function and long-range axonal transport in Drosophila.
The small GTPase Arl8 has emerged as a major regulatory GTPase on lysosomes. Studies in mammalian cells have shown that it regulates both fusion with late endosomes and also lysosomal motility. In its active GTP-bound state, it recruits to lysosomes the HOPS (homotypic fusion and protein sorting) endosomal tethering complex and also proteins that link lysosomes to microtubule motors such as the kinesin adaptor PLEKHM2. To gain further insights into Arl8 biology, we examined the single Drosophila ortholog. Drosophila Arl8 is essential for viability, and mitotic clones of mutant cells are able to continue to divide but show perturbation of the late endocytic pathway. Progeny-lacking Arl8 die as late larvae with movement-paralysis characteristic of defects in neuronal function. This phenotype was rescued by expression of Arl8 in motor neurons. Examination of these neurons in the mutant larvae revealed smaller synapses and axons with elevated levels of carriers containing synaptic components. Affinity chromatography revealed binding of Drosophila Arl8 to the HOPS complex, and to the Drosophila ortholog of RILP, a protein that, in mammals, recruits dynein to late endosomes, with dynein being known to be required for neuronal transport. Thus Drosophila Arl8 controls late endocytic function and transport via at least two distinct effectors.This article has an associated First Person interview with the first author of the paper.


Identification of a new class of lipid droplet-associated proteins in plants.
Lipid droplets in plants (also known as oil bodies, lipid bodies, or oleosomes) are well characterized in seeds, and oleosins, the major proteins associated with their surface, were shown to be important for stabilizing lipid droplets during seed desiccation and rehydration. However, lipid droplets occur in essentially all plant cell types, many of which may not require oleosin-mediated stabilization. The proteins associated with the surface of nonseed lipid droplets, which are likely to influence the formation, stability, and turnover of this compartment, remain to be elucidated. Here, we have combined lipidomic, proteomic, and transcriptomic studies of avocado (Persea americana) mesocarp to identify two new lipid droplet-associated proteins, which we named LDAP1 and LDAP2. These proteins are highly similar to each other and also to the small rubber particle proteins that accumulate in rubber-producing plants. An Arabidopsis (Arabidopsis thaliana) homolog to LDAP1 and LDAP2, At3g05500, was localized to the surface of lipid droplets after transient expression in tobacco (Nicotiana tabacum) cells that were induced to accumulate triacylglycerols. We propose that small rubber particle protein-like proteins are involved in the general process of binding and perhaps the stabilization of lipid-rich particles in the cytosol of plant cells and that the avocado and Arabidopsis protein members reveal a new aspect of the cellular machinery that is involved in the packaging of triacylglycerols in plant tissues.


The incidence of dementia in Canada. The Canadian Study of Health and Aging Working Group.
To estimate the incidence of dementia, including AD, among Canadians aged 65 and over. A 5-year cohort study of 10,263 seniors was undertaken, including community and institutional samples. The baseline study in 1991 identified 1,132 prevalent cases of dementia through screening and clinical examination. The remaining 9,131 cases formed the incidence study sample and were rescreened and selectively reexamined in 1996. Incident cases were diagnosed using established criteria. Incidence was estimated based on the 1991 population, and included data on those who died between the first and second phases of the study. Of the nondemented cohort who remained alive in 1996, 5,432 people in the community (88.3%) and 210 (91.3%) in the institutional sample participated in the incidence study. Nine hundred sixty incident cases were identified; the overall age-standardized incidence rates were 21.8 (women) and 19.1 (men) per 1,000 nondemented persons per year. This translates into 60,150 new cases of dementia per year in Canada. The logarithm of the rates rises linearly with age, but suggests a slight slowing of growth in incidence in the oldest age groups. Our incidence estimates lie toward the upper end of the range of incidence estimates found in other studies. Nonetheless, we calculate that several factors may have biased our estimates downward, suggesting that the incidence of dementia may be higher than many studies have reported.


The effects of local cooling on canine spinal cord blood flow.
The internal spinal cord blood flow was measured in dogs at the site of local cooling using hydrogen polarography. Blood flow decreased to 50% of the normothermic values during cooling of the cord to a central temperature of 16 degrees Celsius. Upon cessation of cooling internal blood flow rapidly returned to normal values. Implications of this finding for the treatment of spinal cord injury are discussed.