[A study on clinical differential diagnosis between hemangioma and vascular malformation in infant].
To explore the main points of clinical differentiation between hemangioma and vascular malformation in infant. Based on Mulliken and Waner's classification, from March, 1997 to February, 1999, 81 baby patients with hemangioma were included in this study. Thirty-eight cases, 43 cases received medical treatment of steroids. All the patients were followed up from 5 to 7 years. Thirty-eight cases of red strawberry-like lesions limited in the skin began to involute within two years old. Of the 30 patients with strawberry-like lesions and subcutaneous mass, 20 cases involuted in varying degree; 10 cases' subcutaneous mass grew gradually and didn't involute, in 4 cases biopsy was performed, 3 cases were confirmed as hemangioma accompanied with venous malformation by pathology, 1 case was hemangioma accompanied with arteriovenous malformation. Of 13 cases with light blue or normal skin and subcutaneous mass, 7 cases involuted in varying degree; 6 cases grow gradually and didn't disappear, 2 cases were confirmed as venous malformation by biopsy. Hemangioma in infant begins to involute within two years old. Vascular malformation or hemangioma with deep vascular malformation grows persistently and does not disappear. Skin temperature of lesion surface and dilative veins on the skin artery pulsation, are indexes compressibility, for differentiation between hemangioma and vascular malformation in clinical diagnosis.


Pharmacokinetics and oral bioavailability of scopolamine in normal subjects.
The pharmacokinetics and bioavailability of scopolamine were evaluated in six healthy male subjects receiving 0.4 mg of the drug by either oral or intravenous administration. Plasma and urine samples were analyzed using a radioreceptor binding assay. After iv administration, scopolamine concentrations in the plasma declined in a biexponential fashion, with a rapid distribution phase and a comparatively slow elimination phase. Mean and SE values for volume of distribution, systemic clearance, and renal clearance were 1.4 +/- 0.3 liters/kg, 65.3 +/- 5.2 liters/hr, and 4.2 +/- 1.4 liters/hr, respectively. Mean peak plasma concentrations were 2909.8 +/- 240.9 pg/ml following iv administration and 528.6 +/- 109.4 pg/ml following oral administration. Elimination half-life of the drug was 4.5 +/- 1.7 hr. Bioavailability of the oral dose was variable among subjects, ranging between 10.7 and 48.2%. The variability in absorption and poor bioavailability of oral scopolamine indicate that this route of administration may not be reliable and effective.


Infection of pigs with the Cameroon isolate (Cam/82) of African swine fever virus.
African swine fever (ASF) was produced in eight pigs by exposure to donors infected with the Cameroon/82 isolate of African swine fever virus. The primary clinical sign was pyrexia of more than 40 degrees C first observed 10 to 13 days post-exposure (dpe) in all pigs; other clinical signs were rarely observed. The most frequent post-mortem lesion was haemorrhage in the visceral lymph nodes. Other lesions included excess fluid in the abdominal cavity and petechial haemorrhages in the kidneys. Viraemia was first observed 1 to 2 days before the onset of pyrexia and maximal titres of more than 10(7.5) HAD50 per ml occurred 11 to 14 dpe. Virus excretion by the pharyngeal route was observed at 2 to 4 days before the onset of pyrexia and continued throughout the course of infection. Susceptible pigs, mixed directly with infected ones, contracted infection within 2 h; transmission time increased to 2 to 6 h when recipient pigs were separated by wire mesh from the infected pigs. The comparatively low mortality, ill-defined clinical signs and clinical recovery of many of the infected pigs show that the Cam/82 ASF virus is of relatively low virulence and thereby resembles recent European, South American and Caribbean isolates.


neo-Clerodane Diterpenoids from the Aerial Parts of Scutellaria barbata with Anti-Inflammatory Activity.
The bioactivity-guided isolation on the Scutellaria barbata extract resulted in the purification of four undescribed neo-clerodane diterpenoids, scuttenlines A-D (1-4), alone with 20 known diterpenoids (5-24). The chemical structures of them were elaborated by extensive spectroscopic means, including 1D, 2D-NMR and HR-MS. The anti-inflammatory potential ability of 1-24 was screened in lipopolysaccharide-stimulated mouse RAW 264.7 cells. Scuttenline C (IC50 =1.9 μM) and 18 (IC50 =3.7 μM) exhibited potent activity to inhibit NO production.


Corneal response to orthokeratology.
The technique of orthokeratology produces a corneal response to the mechanical pressures exerted by rigid contact lenses. This paper reports a study which investigated the topographic and pachometric corneal changes induced by orthokeratology. Six young myopic subjects (11 eyes) wore "accelerated orthokeratology" lenses (OK-74; Contex Inc., Sherman Oaks, CA) in a high Dk material (AirPerm; Dk = 88) for 28 days. Corneal and epithelial thickness were measured topographically using the Holden-Payor optical micropachometer, and corneal topography was monitored using the EyeSys system. Refractive error change reached 1.71 +/- 0.59 D reduction in myopia after 28 days. After 1 day of lens wear, statistically significant central corneal flattening was noted, which progressed to reach 0.22 +/- 0.07 mm (1.19 +/- 0.38 D) at 28 days. A trend toward central epithelial thinning was apparent, reaching statistical significance on day 28 (7.1 +/- 7.1 microm; 9.6%). Midperipheral corneal thickening was also found approximately 2.5 mm from the corneal center, which was statistically significant by day 14 (13.0 +/- 11.1 microm; 2.4%). Calculations using Munnerlyn's formula indicate that changes in corneal sagittal height based on topographical thickness changes across the flattened central 5.25-mm zone can account for the refractive changes observed. These findings suggest that the initial corneal response to orthokeratology may be explained by redistribution of corneal tissue, rather than by overall bending of the cornea.


Linear accelerator-based stereotactic radiotherapy for brain metastases, including multiple and large lesions, carries a low incidence of acute toxicities: a retrospective analysis.
Data on acute toxicities after stereotactic radiotherapy (SRT) for brain metastases, including multiple and large lesions, are lacking. We aimed to evaluate the incidence and nature of toxicities immediately after SRT using a linear accelerator. This retrospective study reviewed the medical records of 315 patients with brain metastases treated with SRT at our institution between May 2019 and February 2022. In total, 439 SRT sessions were performed for 2161 brain metastases. The outcome of interest was immediate side effects (ISEs), defined as new or worsening symptoms occurring during SRT or within 14 days after the end of SRT. Grade ≥ 2 and ≥ 3 ISEs occurred in 16 (3.6%) and 7 (1.6%) cases, respectively. Among 63 treatments for 10 or more lesions (range: 10-40), 1 (1.6%) ISE occurred. Among 22 treatments for lesions with a maximum tumor volume of > 10 cc, 2 (9.1%) ISEs occurred. Grade ≥ 3 ISEs included 1, 4, 1, and 1 cases of grade 3 nausea, grade 3 new-onset partial and generalized seizures, grade 3 obstructive hydrocephalus, and grade 5 intracranial hemorrhage, respectively. ISEs were more common in patients with a larger maximum tumor volume, primary sites other than lung and breast cancer, and pre-treatment neurological symptoms. SRT using a linear accelerator for brain metastases, including multiple and large lesions, is safe, with a low incidence of ISEs. Serious complications immediately after SRT are rare but possible; therefore, careful follow-up is necessary after treatment initiation.


Posterior Cruciate Ligament Reconstruction with Retrograde Femoral Technique, Posterior Trans-septal Portal and Full Tibial Tunnel.
Suspensory femoral graft fixation has been a popular and reliable method in anterior cruciate ligament (ACL) reconstruction. Some authors have introduced suspensory femoral fixation in posterior cruciate ligament (PCL) reconstruction using inside-out (IO) technique. The use of IO technique for femoral tunnel preparation could significantly sharpen the critical corner, which might result in graft failure. A retrograde drilling pin that recently has been popular in ACL reconstruction allows "no incision" in the outside-in (OI) technique for the creation of a femoral socket. Here we describe the suspensory femoral fixation using a retro-socket technique in single-bundle PCL reconstruction. By using this technique, it is possible to create a retrograde femoral socket for suspensory femoral fixation in an OI manner in a desirable direction and reduce angulation of the graft in the entry area of the femoral tunnel.


Association between HSPA5 Promoter Polymorphisms and a Reduced Risk of Normal Tension Glaucoma.
In normal tension glaucoma (NTG), factors other than elevated intraocular pressure (IOP) are likely to play a role in the pathogenesis of optic neuropathy. The potential similarities between Alzheimer's disease (AD) and NTG in cellular apoptosis leading to neurodegeneration have been shown in recent studies. Heat Shock Protein family A member 5 (HSPA5) promoter polymorphisms have been reported to be associated with a risk of AD. The purpose of our study was to investigate the role of HSPA5 promoter polymorphisms in NTG patients. A total of 222 patients with NTG, along with 236 normal controls were enrolled in this study. Genomic DNA was amplified through a polymerase chain reaction (PCR) and identified for the polymorphic HSPA5 (-415 and -370) by Xmn1 and BstY1 restriction digestion, respectively. PCR fragments with potential polymorphic HSPA5 (-180) were subjected to sequence-analyses by a Hex-labeled primer. Genotypes for both NTG patients and control groups were compared for statistically significant differences. Polymorphisms (-415) G/A and (-180) del/G were completely linked in our population. The genotype and allele frequency distribution at the -415 G/A and -180 del/G sites showed a significant difference between the NTG cases and controls. The genotype frequency of HSPA5 (-415) AA/(-180) GG and the allele frequency of HSPA5 (-415) A/(-180) G were significantly lower (p = 0.04 and p = 0.01, respectively) in the NTG patients when compared with those in the control group. There was no significant difference in genotype or allele frequency distribution of the HSPA5 (-370) C/T between the NTG and control groups. There was a reduced risk of NTG associated with the carriers for the HSPA5 (-415) A/(-180) G allele compared with that in the control population (p = 0.01). HSPA5 (-415) A and (-180) G allele polymorphisms may be protective factors in the development of NTG.


SELECT-GLYCOCIN: a recombinant microbial system for expression and high-throughput screening of glycocins.
Glycosylated bacteriocins (glycocins) are potential clean label food preservatives and new alternatives to antibiotics. Further development requires the availability of a method for laboratory evolution of glycocins, wherein the challenges to overcome include ensuring glycosylation in a heterologous host, avoiding potential toxicity of active glycocins to the host, and provisioning of a one-pot screening assay for active mutants. Employing EntS, a sequential O/S- di-glycosyltransferase from Enterococcus faecalis TX0104, a proof of the concept microbial system and high throughput screening assay (SELECT-GLYCOCIN) is developed for generation of O/S- linked glycopeptide libraries and screening of glycocins for desired activity/property. The method enabled enzyme-dependent in vivo glycosylation in the heterologous host and rapid screening of mutants of enterocin 96 (Ent96)- a glycocin active against food-borne pathogen L. monocytogenes. Using SELECT-GLYCOCIN, a library of random (1.5 X 10^3) and rational (17) mutants of Ent96 was generated. The mutants were screened for bioactivity to identify a total of 376 random and 14 rational mutants as bioactive. Downstream detailed analysis of 16 random and 14 rational mutants led to the identification of sequence- and or glyco-variants namely, G16E-H24Q, C13T, and Ent96-K4_K5insYYGNGV (PedioEnt96) as improved antimicrobials. To summaries, SELECT-GLYCOCIN provides a system and a generic method for discovery and screening of glycocins that can further be adapted to any known/unknown glycocins and can be employed in food preservatives' and drug discovery programs.


Role of systemic inflammatory factors in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with peptide receptor radionuclide therapy (PRRT): From biology to theragnosis.
Systemic inflammatory factors have been validated as indicators of ongoing systemic inflammation that could be predictive markers of poor prognosis for oncological outcomes. However, the prognostic impact of systemic inflammation markers is unknown in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with peptide receptor radionuclide therapy (PRRT). We conducted an observational, retrospective, multicentric study of 40 patients with GEP or unknown origin NETs treated with PRRT between 2016 and 2020. The systemic inflammatory markers were calculated as follows: neutrophil to lymphocyte ratio (NLR)=neutrophil count/lymphocyte count, monocyte to lymphocyte ratio (MLR)=monocyte count/lymphocyte count, platelet to lymphocyte ratio (PLR)=platelet count/lymphocyte count, albumin to lymphocyte ratio (ALR)=albumin levels/lymphocyte count and derived Neutrophil to Lymphocyte ratio (dNLR)=neutrophil count/(leucocytes count - neutrophils count). Baseline analysis and after the second dose were used for the calculation of different ratios. The median age was 63 years (range 41-85), 55% were male. The baseline cut-off values for NLR were 2.61, for MLR 0.31, for PLR 110.14, for ALR 2.39 and for dNLR 1.71. The cut-off values after the 2° dose were, for NLR 2.3, for MLR 0.3, for PLR 131.61, ALR 4.16, and dNLR 1.48. Median progression-free survival (PFS) was 21.7 months (95% CI 10.7-32.8 months) and overall survival (OS) was 32.1 months (95% CI 19.6-44.7 months), PFS was shorter in patients with elevated NLR (p=0.001), ALR (0.03), and dNLR (p=0.001) in baseline analysis. DCR was 81% and ORR 18%. In GEP or unknown origin NETs treated with PRRT, we have identified the predictive and prognostic impact of baseline systemic inflammatory factors.


Effect of superior cervical ganglionectomy on insulin release by murine pancreas slices.
The effect of superior cervical ganglionectomy (SCGx) on basal and glucose-stimulated insulin release in vitro was examined in pancreas slices of BALB/c mice subjected to surgery 14-96 h earlier. Fourteen or 20 h after SCGx a significant increase of insulin response to 11 mM glucose was detectable, while 96 h after SCGx a depression in response was found. Perifused pancreas slices obtained from mice subjected to SCGx 7 days earlier showed a decreased in vitro insulin response to glucose during both phases of insulin secretion. In sham-operated mice, injection of the beta-adrenoceptor blocker propranolol or of the cholinergic muscarinic antagonist atropine decreased basal and glucose-stimulated insulin release, while the alpha-adrenoceptor blocker phenoxybenzamine did not affect it significantly. In mice subjected to SCGx 14 h earlier, propranolol treatment decreased basal insulin release and impaired the release elicited by glucose to values similar to those found in controls, phenoxybenzamine injection increased the basal and amplified the enhanced glucose-stimulated insulin release, and atropine injection, although unable to affect basal insulin release, impaired partially the amplification of response detectable after surgery. Our results support the existence of significant effects of SCG neurons on insulin release in mice.


Daily energy expenditure and the cost of activity in a free-living mammal.
Antelope ground squirrels (Ammospermophilus leucurus, 80-100 g) began surface activity 1.0-1.5 h after sunrise and ended it 0.5-1.25 h before sunset throughout the year near Barstow, California. Daily energy expenditure (DEE) of free-living animals measured with doubly labeled water (H3H18O) decreased from 1,340 kJ kg-1 d-1 in April to 970 in October. Resting metabolic rates (RMR) of freshly-captured, fed, ground squirrels varied through the year (22.1 J g-1 h-1 in August, 19.1 in January) but most of the change in DEE could be explained by differences in thermoregulatory costs between seasons. The ground squirrels had lower rates of resting metabolism at night (15.3J g-1 H-1) than during the day.The cost of activity (calculated by subtracting 24 h resting costs from total DEE during August and October, periods when thermoregulatory costs were negligible) was ∼ 550 kJ kg-1 d-1 in August and October. Thus, activity accounted for about 50% of the total DEE. The mean rate of energy expenditure during the activity period, calculated as activity cost (kJ d-1) divided by activity time (h d-1), then plus RMR, was about 3xRMR. This multiplication factor may be useful as an estimator of foraging costs or in estimating DEE from time budgets.


Growth and differentiation signals as determinants of cancer cell proliferation.
The development and the maintenance of a tissue involves the sequential differentiation of precursor cells along multiple intermediate stages of maturity. At these stages the cells can proliferate or differentiate depending upon the growth or differentiation signals they receive. Terminally mature cells lose their ability to proliferate. Alterations can occur at the level of the cell or the whole organism that lead to the sustained proliferation of incompletely mature cells. This process constitutes an oncogenic event, and the cellular and molecular changes that lead to its occurrence are surveyed in this review.


Evaluating the online platform of a blended-learning pharmacist continuing education degree program.
Distance-based continuing education opportunities are increasingly embraced by health professionals worldwide. To evaluate the online component of a blended-learning degree program for pharmacists, we conducted a structured self-assessment and peer review using an instrument systematically devised according to Moore's principles of transactional distance. The web-based platform for 14 courses was reviewed by both local and external faculty, followed by shared reflection of individual and aggregate results. Findings indicated a number of course elements for modification to enhance the structure, dialog, and autonomy of the student learning experience. Our process was an important exercise in quality assurance and is worthwhile for other health disciplines developing and delivering distance-based content to pursue.


Variation in supportive care practices in hematopoietic cell transplantation.
Hematopoietic cell transplantation is an elective procedure that results in prolonged immune suppression and high treatment-related morbidity and mortality. Transplant centers and physicians use a variety of prophylaxis and monitoring strategies to prevent or minimize complications. Little is known about the variability in these practices. We conducted an international Internet-based survey of 526 physicians to describe the spectrum of supportive care practices employed. Consistency in pretransplant cardiac (96%) and pulmonary (95%) screening, informed consent documentation (93%), and use of antifungal prophylaxis (92%) was observed. Greater heterogeneity was seen in use of myelogenous growth factors, empiric antibiotic therapy, protective isolation procedures, posttransplant monitoring, and environmental and social restrictions. Although some practice differences were associated with physician characteristics and transplant type, most practice variation remained unexplained. These results suggest a need for well-designed observational and interventional studies to provide data about which supportive care practices improve outcomes. For practices proved to be beneficial, publication of guidelines and incorporation of monitoring into quality improvement initiatives may help standardize practices.


Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies.
Surgery is the only curative treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but the prediction of residual disease/recurrence is limited in the absence of optimal biomarkers. We examined whether a blood-based multianalyte neuroendocrine gene transcript assay (NETest) would define tumor cytoreduction and therapeutic efficacy. The NETest is a polymerase chain reaction-based analysis of 51 genes. Disease activity is scaled 0-100%; minimal <14%, low 14-47%, and high >47%. A total of 35 GEP-NETs in 2 groups were evaluated. I: after surgery (R0, n = 15; residual, n = 12); II: nonsurgery (n = 8: embolization with gel-foam alone [bland: n = 3]), transarterial chemoembolization (n = 2), and radiofrequency embolization (n = 3). Measurement (quantitative real-time-polymerase chain reaction) and chromogranin A (CgA; enzyme-linked immunosorbent assay) were undertaken preoperatively and 1 month after treatment. NETest score was increased in 35 (100%) preoperatively; 14 (40%) had increased CgA (χ(2) = 30, P < 2 × 10(-8)). Resection reduced NETest from 80 ± 5% to 29% ± 5, (P < .0001). CgA decrease was insignificant (14.3 ± 1.6 U/L to 12.2 ± 1.7 U/L). NETest decreases correlated with diminished tumor volume (R(2) = 0.29, P = .03). Cytoreduction significantly reduced NETest from 82 ± 3% to 41% ± 6, P < .0001). CgA was not decreased (21.4 ± 5.5 U/L to 18.4 ± 10.1 U/L). Four (36%) of 11 R0s with increased NETest at 1 month developed positive imaging (sensitivity 100%, specificity 20%). One hundred percent (ablated group) were transcript- and image-positive. Blood NET transcripts delineate surgical resection/cytoreduction and facilitate identification of residual disease.


Pharmaceutical costs of assisted reproduction in Spain.
Assisted reproduction is one of the health services currently being considered for possible limitation or exclusion from the public health services portfolio in Spain. One of the main reasons claimed for this is the impact on the budget for pharmaceutical expenditure. The objective of this study was to assess the significance of the pharmaceutical costs of assisted reproduction in Spain. This study focused on medical practice in Spain, and is based on the opinions of experts in assisted reproduction and the results provided by professional societies' publications. The reference year is 2012 and the setting was secondary care. We have included all existing pharmaceutical modalities for assisted reproduction, as well as the most common drug for each modality. We have considered the pharmaceutical cost per cycle for artificial insemination, in vitro fertilisation with or without intracytoplasmic sperm injection (IVF_ICSI), and cryotransfer and donated fresh oocytes reception. In Spain, artificial insemination has a pharmaceutical cost per cycle of between €69.36 and €873.79. This amounts to an average cycle cost of €364.87 for partner's sperm and €327.10 for donor sperm. The pharmaceutical cost of IVF_ICSI ranges between €278.16 and €1,902.66, giving an average cost per cycle of €1,139.65. In the case of cryotransfer and donated fresh oocytes reception, the pharmaceutical cost per cycle is between €22.61 and €58.73, yielding an average cost of €40.67. The budgetary impact of pharmaceutical expenditure for assisted reproduction in Spain for the year 2012 was estimated at €98.7 million. In Spain, the total pharmaceutical cost of assisted reproduction is substantial. According to our results, we can say that about 29% of the total pharmaceutical expenditure for assisted reproduction techniques is funded by the National Health System and the rest represents 2.4% of the total annual out-of-pocket family expenditure on drugs.


Corneal ultrastructural changes in Fabry's disease.
A case of Fabry's disease is reported. The findings of the corneal alterations with the light microscope as well as with the electron microscope are described. The diffuse corneal haziness seems to be due to small intracellular osmiophilic inclusions of the epithelium. There seems also to be a relation between the giant inclusions in the corneal epithelium, not yet described, and the clinical presence of punctiform grey opacities. The pathogenesis of the whorl-like opacities remains unsolved.


Pulling and analyzing silk fibers from aqueous solution using a robotic device.
Spiders, silkworms, and many other animals can spin silk with exceptional properties. However, artificially spun fibers often fall short of their natural counterparts partly due sub-optimal production methods. A variety of methods, such as wet-, dry-, and biomimetic spinning have been used. The methods are based on extrusion, whereas natural spinning also involves pulling. Another shortcoming is that there is a lack feedback control during extension. Here we demonstrate a robotic fiber pulling device that enables controlled pulling of silk fibers and in situ measurement of extensional forces during the pulling and tensile testing of the pulled fibers. The pulling device was used to study two types of silk-one recombinant spider silk (a structural variant of ADF3) and one regenerated silk fibroin. Also, dextran-a branched polysaccharide-was used as a reference material for the procedure due to its straightforward preparation and storage. No post-treatments were applied. The pulled regenerated silk fibroin fibers achieved high tensile strength in comparison to similar extrusion-based methods. The mechanical properties of the recombinant spider silk fibers seemed to be affected by the liquid-liquid phase separation of the silk proteins.


Cascade PSI-BLAST web server: a remote homology search tool for relating protein domains.
Owing to high evolutionary divergence, it is not always possible to identify distantly related protein domains by sequence search techniques. Intermediate sequences possess sequence features of more than one protein and facilitate detection of remotely related proteins. We have demonstrated recently the employment of Cascade PSI-BLAST where we perform PSI-BLAST for many 'generations', initiating searches from new homologues as well. Such a rigorous propagation through generations of PSI-BLAST employs effectively the role of intermediates in detecting distant similarities between proteins. This approach has been tested on a large number of folds and its performance in detecting superfamily level relationships is approximately 35% better than simple PSI-BLAST searches. We present a web server for this search method that permits users to perform Cascade PSI-BLAST searches against the Pfam, SCOP and SwissProt databases. The URL for this server is http://crick.mbu.iisc.ernet.in/~CASCADE/CascadeBlast.html.


Neurite formation and membrane changes of mouse neurobalstoma cells induced by valinomycin.
A clonal cell line of mouse neuroblastoma cells was found to undergo morphological differentiation in the presence of a K+ ionophore, valinomycin, in the assay medium. This effect was blocked by increasing the concentration of KCl of the medium, suggesting that the changes in resting membrane potential and ion fluxes may be involved in the mechanism of the formation of neurites. No enhancement of the neurite formation was observed in salines containing high concentrations of KCl in the absence of valinomycin. Depolarizing agents including veratridine, gramicidin and ouabain did not stimulate the outgrowth of neurites. Neither electrophoretic mobility of the cells nor molecular anisotropy of fluorescence probes in the membranes was modified by the treatment of valinomycin. Instead, it modified the slow binding phase in kinetics of the interaction of 1-anilinonaphthalene-8-sulfonate (ANS) with the cells, which is related to the penetration process of the probe into membranes. Valinomycin also enhanced the fluorescence intensity of ANS by increasing the binding sites in neuroblastoma cells.


Cytogenetics of bone marrow fibroblastic cells in idiopathic chronic myelofibrosis.
To determine the nature of the fibroblastic proliferation in myelofibrosis, we studied the cytogenetic composition of a pure population of in-vitro bone marrow fibroblastic cells (FC) from a patient with idiopathic chronic myelofibrosis who had trisomy 8 in her unstimulated peripheral blood cells. This cytogenetic abnormality was absent in all the FC studied supporting the premise that in the myeloproliferative disorders the myelofibrosis represents a secondary or non-neoplastic reaction to the clonal proliferation of haematopoietic stem cells.


Kinetic effects of TiO2 fine particles and nanoparticles aggregates on the nanomechanical properties of human neutrophils assessed by force spectroscopy.
Increasing applications of titanium dioxide (TiO2) fine particles (FPs) and nanoparticles (NPs) require coupled knowledge improvement concerning their biokinetic effects. Neutrophils are quickly recruited to titanium implantation areas. Neutrophils mechanical properties display a crucial role on cell physiology and immune responsive functions. Then, micro and nanomechanical characterization assessed by force spectroscopy (FS) technique has been largely applied in this field. Scanning electron microscopy (SEM) images highlighted neutrophils morphological changes along TiO2 FPs and NPs aggregates exposure time (1, 5, and 30 min) compared to controls. FS approaches showed an increasing on attraction forces to TiO2 FPs and NPs treated neutrophils. This group depicted stronger stiffness features than controls just at 1 min of exposure. Treated neutrophils showed a tendency to increase adhesive properties after 1 and 5 min of exposure. These cells maintained comparatively higher elasticity behavior for a longer time possibly due to intense phagocytosis and cell stiffness opposing to the tip indentation. Neutrophils activation caused by FPs and NPs uptake could be related to increasing dissipated energy results. Mechanical modifications resulted from TiO2 FPs and NPs aggregates interaction with neutrophils showed increasing stiffness and also cell morphology alteration. Cells treatment by this metal FPs and NPs caused an increase in attractive forces. This event was mainly observed on the initial exposure times probably regarding to the interaction of neutrophils membrane and phagocytosis. Similar results were found to adhesion forces and dissipated energy outcomes. Treated cells presented comparatively higher elasticity behavior for a longer time. SEM images clearly suggested cell morphology alteration along time course probably related to activation, cytoskeleton rearrangement and phagocytosis. This scenario with increase in stiffness strongly suggests a direct relationship over neutrophil rolling, arrest, and transmigration. Scrutinizing these interactions represents an essential step to clarify the mechanisms involved on treatments containing micro and nanomaterials and their fates on the organisms.


Novel anticancer agent, SQAP, binds to focal adhesion kinase and modulates its activity.
SQAP is a novel and promising anticancer agent that was obtained by structural modifications from a natural compound. SQAP inhibits angiogenesis in vivo resulting in increased hypoxia and reduced tumor volume. In this study, the mechanism by which SQAP modifies the tumor microenvironment was revealed through the application of a T7 phage display screening. This approach identified five SQAP-binding proteins including sterol carrier protein 2, multifunctional enzyme type 2, proteasomal ubiquitin receptor, UV excision repair protein and focal adhesion kinase (FAK). All the interactions were confirmed by surface plasmon resonance analysis. Since FAK plays an important role in cell turnover and angiogenesis, the influence of SQAP on FAK was the principal goal of this study. SQAP decreased FAK phosphorylation and cell migration in human umbilical vein endothelial cells and A549 cancer cells. These findings suggest that inhibition of FAK phosphorylation works as the mechanism for the anti-angiogenesis activity of SQAP.


[Some aroylhydrazones of halobenzaldehydes and halogen-substituted 2,5-diaryl-1,3,4-oxadiazoles].
The preparation of a series of aroylhydrazones of halogenobenzaldehydes (I) - (XI) is described together with that of the corresponding reduction products (XII) - (XXV) and of 2,5-diaryl-1,3,4-oxadiazoles with halogen substitution (XXVI) - (XLIII). The results of pharmacological and microbiological examination of the compounds is reported.


Reanalysis of single-cell data reveals macrophage subsets associated with the immunotherapy response and prognosis of patients with endometrial cancer.
Endometrial cancer (EC) is an aggressive gynecological malignancy with an increased incidence rate. The immune landscape crucially affects immunotherapy efficacy and prognosis in EC patients. Here, we characterized the distinct tumor microenvironment signatures of EC tumors by analyzing single-cell RNA sequencing data from Gene Expression Omnibus and bulk RNA sequencing data from The Cancer Genome Atlas, which were compared with normal endometrium. Three macrophage subsets were identified, and two of them showed tissue-specific distribution. One of the macrophage subsets was dominant in macrophages derived from EC and exhibited characteristic behaviors such as promoting tumor growth and metastasis. One of the other macrophage subsets was mainly found in normal endometrium and served functions related to antigen presentation. We also identified a macrophage subset that was found in both EC and normal endometrial tissue. However, the pathway and cellular cross-talk of this subset were completely different based on the respective origin, suggesting a tumor-related differentiation mechanism of macrophages. Additionally, the tumor-enriched macrophage subset was found to predict immunotherapy responses in EC. Notably, we selected six genes from macrophage subset markers that could predict the survival of EC patients, SCL8A1, TXN, ANXA5, CST3, CD74 and NANS, and constructed a prognostic signature. To verify the signature, we identified immunohistochemistry for the tumor samples of 83 EC patients based on the selected genes and further followed up with the survival of the patients. Our results provide strong evidence that the signature can effectively predict the prognosis of EC patients.


Sleep duration and all-cause mortality: a critical review of measurement and associations.
Variation in sleep duration has been linked with mortality risk. The purpose of this review is to provide an updated evaluation of the literature on sleep duration and mortality, including a critical examination of sleep duration measurement and an examination of correlates of self-reported sleep duration. We conducted a systematic search of studies reporting associations between sleep duration and all-cause mortality and extracted the sleep duration measure and the measure(s) of association. We identified 42 prospective studies of sleep duration and mortality drawing on 35 distinct study populations worldwide. Unlike previous reviews, we find that the published literature does not support a consistent finding of an association between self-reported sleep duration and mortality. Most studies have employed survey measures of sleep duration, which are not highly correlated with estimates based on physiologic measures. Despite a large body of literature, it is premature to conclude, as previous reviews have, that a robust, U-shaped association between sleep duration and mortality risk exists across populations. Careful attention must be paid to measurement, response bias, confounding, and reverse causation in the interpretation of associations between sleep duration and mortality.


Careers clinic helps turn around trust's staff retention troubles.
Two nurse-led projects at a leading trust are having a positive effect on its staff retention and vacancy rates.


[Phospholipid fatty acid composition of microorganisms in pine forest soils of Central Siberia].
The phospholipid fatty acid (PLFA) composition of microorganisms in podzolic soils of pine forests of Central Siberia was studied. The living microbial biomass gradually decreased in the studied mineral soil layer from 0 to 1 m. Despite a twofold drop in biomass in the lower layers, its level remained sufficiently high (12-14 nmol FA/g soil). The coefficient of similarity of fatty acid composition of soils of forested and open sites was 0.85. The fatty acid richness decreased and distinctions in fatty acid profiles increased with depth of the mineral soil layer.


[Hydrophobic quality and the level of surface proteins in the cell wall of cultures of Streptococcus pyogenes isolated from clinically healthy children from an organized collective].
The Str. pyogenes cultures isolated from clinically healthy children were found to have different hydrophobic properties and quantities of surface cell wall proteins, and to exhibit pronounced variability in these signs in time. Most studied cultures lacked a correlation between their hydrophobic properties and the quantity of surface proteins of the cell wall.


Sensitivity to interaural correlation of single neurons in the inferior colliculus of guinea pigs.
Sensitivity to changes in the interaural correlation of 50-ms bursts of narrowband or broadband noise was measured in single neurons in the inferior colliculus of urethane-anaesthetized guinea pigs. Rate vs. interaural correlation functions (rICFs) were measured using two methods. These methods compensated in different ways for the inherent variance in interaural correlation between tokens with the same expected correlation. The shape of all rICFs could be best described by power functions allowing them to be summarized by two parameters. Most rICFs were best fit by a power below 2, indicating that they were only slightly nonlinear. However, there were a few fitted functions that had a power of 3-6, indicating marked curvature. Modeling results indicate that the nonlinearity of the majority of rICFs was explicable in terms of the monaural transduction stages; however, some of the rICFs with power greater than 2 require either multiple inputs to the coincidence detector or additional nonlinearities to be included in the model. Discrimination thresholds were estimated at reference correlations of -1, 0, and +1 using receiver operating characteristic (ROC) analysis of the spike-count distribution at each correlation. Thresholds spanned the full possible range, from a minimum of 0.1 to the maximum possible of 2. Thresholds were generally highest with a reference correlation of -1, intermediate with a reference of 0, and lowest with a reference correlation of +1. Thresholds were lowest for the most steeply sloped rICFs, but thresholds were not strongly correlated to the spike rate variance. The lowest thresholds occurred using narrowband noise that was compensated for internal delays, but they were still about three times larger than human psychophysical thresholds measured using similar stimuli. The data suggest that, unlike pure tone interaural time difference, discrimination of a population measure is required to account for behavioral interaural correlation discrimination performance.


A new Monte Carlo simulation tool for designing an archaeological landscape sampling strategy.
This article describes in detail how the Dig It, Design It (DIDI) simulation tool operates to design a subsurface landscape sampling strategy and predict its likely effectiveness. The purpose of the DIDI model is to help archaeologists develop statistically sound subsurface sampling programs that maximise the number of sites found while minimising the number of sampling units used. It has been unusual for archaeological test-pitting programs to be theoretically tested or statistically justified by simulation prior to implementation. Previous research by Kintigh (1988) and Krakker et al. (1983) established the statistical principles underlying the subsurface sampling of a rectangular survey area, and Kintigh pioneered the use of Monte Carlo simulations to test the effectiveness of these sampling strategies. DIDI provides an updated version of this simulation approach that has three key benefits over the original version:1.It allows the user to model a larger range of possible archaeological conditions by providing an additional density distribution function (see below), and making the clustering parameter available with all distribution functions;2.DIDI gives the user the option of filling the previously unavoidable gaps around the edges of the survey area with additional, suitably placed test-units, thereby increasing the detection rate of a sampling strategy; and3.It is free to download and use and is compatible with modern operating systems.


Musculoskeletal ultrasound imaging and clinical reasoning in the management of a patient with cervicogenic headache: a case report.
Background: Clinical decision-making within the physical therapy treatment process typically follows the hypothetical-deductive method. The accuracy and reliability of clinical tests affect this reasoning process. Musculoskeletal ultrasound imaging (MSK US) is an emerging valid and reliable diagnostic tool in physical therapy. MSK US allows for dynamic visualization of tissues in real time with devices that are often portable.Case Description: The patient was a 55-year-old female, who presented by direct access. She had been suffering from cervicogenic headaches since the age of 18. It was hypothesized that this patient presented with a right rotation positional default of atlas and facet hypomobility at C5-6.Outcomes: After six visits (over 7 weeks) of manual therapy interventions, the patient reported that her headaches and neck pain were no longer present. Her physical therapy goals had been met and she was discharged with the instruction to continue working on her posture correction and self-management.Discussion: This case report describes the use of MSK US imaging as part of the clinical decision-making process when treating a patient with cervicogenic headaches. This case illustrates the successful management using manual therapy to restore position, mobility, decrease muscle tone, and normalize upright posture. Complementary research is necessary to further validate MSK US imaging as the preferred method to objectivize joint mobility and guide decision-making. Additionally, the cause-effect relationship between the treatment and positive outcomes in this case report has to be further validated.


An economic evaluation of two PCR-based respiratory panel assays for patients admitted to hospital with community-acquired pneumonia (CAP) in the UK, France and Spain.
On admission to hospital, patients with community-acquired pneumonia (CAP), undergo extensive diagnostic testing. Two high-throughput laboratory-based PCR panels which return a result in 5.5 hours (h) have been developed to test for pathogens commonly associated with upper (Respiratory 1 Panel) and lower (Respiratory 3 Panel) respiratory tract infections (GeneFirst, Oxford). These could replace multiple diagnostic tests currently used. An online survey, completed by senior clinicians in the UK, France and Spain, was used to collect data on the diagnostic testing of immunocompetent and immunocompromised adults admitted to hospital with CAP, including the cost of diagnostics. Data were used to inform a cost-comparison model. For each country, the average cost of diagnostic testing per patient was calculated separately for immunocompetent and immunocompromised patients. The model compared three testing strategies with standard of care (SoC). In the Panel 1 strategy, the Respiratory 1 Panel was used for patients that would otherwise have tests which could be replaced by Respiratory 1 Panel, equivalent strategies for Respiratory 3 Panel and for both panels combined were assessed. In total, 48 surveys were completed (UK = 17; France = 15; Spain = 16). Compared with SoC, the Panel 1 + 3 strategy was most favourable, resulting in cost savings for immunocompetent and immunocompromised patients respectively, of €22.09 (£18.50) and €26.12 (£21.88) in the UK, €99.60 and €108.77 in France and €27.07 and €51.87 in Spain. In all three countries, the use of these respiratory panels could reduce the average cost of diagnostics used for patients admitted to hospital with CAP.


Synthesis and mesogenic properties of glycosyl diacylglycerols.
We synthesised glycosyl diacylglycerols bearing unsaturated or chiral methyl branched fatty acid chains. The thermotropism was measured with polarising microscopy and additionally the lyotropism with the contact preparation method. The synthesised compounds displayed thermotropic S(A) (lamellar), cubic and columnar phases and investigation of the lyotropic phase behaviour led to the observation of inverted bicontinuous cubic V(II) phases, lamellar L(alpha) phases and normal bicontinuous cubic V(I) phases. The phases are discussed with respect to the chemical structures that have been varied systematically to derive structure--property relationships.


Viability, maturation and embryo development in vitro of immature porcine and ovine oocytes vitrified in different devices.
This study was designed to evaluate the effects of vitrification on immature porcine and ovine oocytes, collected at a slaughterhouse, by performing vitrification in devices with different volumes. Viability was evaluated both before and after vitrification and maturation. Immediately after warming, the percentage of viable pig oocytes was 81% regardless the type of device, while in the control (after oocyte selection) was 95%. The viability of matured pig oocytes after warming, vitrified in beveled edge open straws (BES) was 6%, in small-open-pulled-straw (SOPS) was 17% and in cryotop was 4%, while the viability of the control group was 86%. The viability and maturation results were similar with all devices. Embryo development (ED) was observed in fresh porcine oocytes with 15% 2-8 cell embryos, 7% morulae and 3% blastocysts, and non-embryo cleavage was observed in warmed oocytes. The viability of sheep oocytes immediately after warming averaged 90% in all devices, while that of the control (after oocyte selection) averaged 95%. The viability of warmed oocytes after maturation was: BES 21%, SOPS 30%, cryotop 21% and control group 86%; while maturation values were 11, 21, 34 and 70%, respectively. After vitrification, the highest ED was achieved with ovine oocytes vitrified in SOPS, with 17% morulae development and it was the only device in which blastocysts developed. A direct relationship was observed between viability and actin filament integrity in both species.


Radiolabeling and quality control of therapeutic radiopharmaceuticals: optimization, clinical implementation and comparison of radio-TLC/HPLC analysis, demonstrated by [177Lu]Lu-PSMA.
Radiopharmaceuticals are considered as regular medicinal products and therefore the same regulations as for non-radioactive medicinal products apply. However, specific aspects should be considered due to the radiochemical properties. Radiopharmaceutical dedicated monographs are developed in the European Pharmacopoeia to address this. Currently, different quality control methods for non-registered radiopharmaceuticals are utilized, often focusing on radio-TLC only, which has its limitations. When the radiochemical yield (RCY) is measured by radio-TLC analysis, degradation products caused by radiolysis are frequently not detected. In contrast, HPLC analysis defines the radiochemical purity (RCP), allowing for detection of peak formation related to radiolysis. During the introduction and optimization phase of therapeutic radiopharmaceuticals, significant percentages of impurities, like radiolysed construct formation, may have consequential impact on patient treatment. Since more hospitals and institutes are offering radiopharmaceutical therapies, such as [177Lu]Lu-PSMA with an in-house production, the demand for adequate quality control is increasing. Here we show the optimization and implementation of a therapeutic radiopharmaceutical, including the comparison of ITLC and HPLC quality control. Downscaled conditions (74 MBq/μg) were in concordance to clinical conditions (18 GBq/250 µg, 5 mL syringe/100 mL flacon); all results were consistent with an > 98% RCY (radio-TLC) and stability of > 95% RCP (HPLC). Radio-TLC did not identify radiolysis peaks, while clear identification was performed by HPLC analysis. Decreasing the RCP with 50%, reduced the cell-binding capacity with 27%. This research underlines the importance of the radiolabeling and optimization including clinical implementation and clarifies the need for cross-validation of the RCY and RCP for quality control measurements. Only HPLC analysis is suitable for identification of radiolysis. Here we have proven that radiolysed [177Lu]Lu-PSMA has less binding affinity and thus likely will influence treatment efficacy. HPLC analysis is therefore essential to include in at least the validation phase of radiopharmaceutical implementation to ensure clinical treatment quality.


Development and validation of a cumulative exposure shoulder risk assessment tool based on fatigue failure theory.
To present a new risk assessment tool for shoulder intensive occupational tasks based on fatigue failure theory. The tool estimates cumulative damage (CD) based on shoulder moments and loading cycles using an S-N curve derived from in vitro tendon fatigue failure tests. If multiple shoulder tasks are performed, the CD for each is summed. In the validation, 293 workers were evaluated for five separate shoulder outcomes. Logistic regression was used to assess the log CD against five shoulder outcomes adjusted for covariates including age, sex, body mass index (BMI), and plant site. Both crude and adjusted logistic regression results demonstrated strong dose-response associations between the log CD measure and all five shoulder outcomes (continuous ORs ranged from 2.12 to 5.20). The CD measure of The Shoulder Tool demonstrated dose-response relationships with multiple health outcomes. This provides further support that MSDs may be the result of a fatigue failure process. This study presents a new, easy-to-use risk assessment tool for occupational tasks involving stressful shoulder exertions. The tool is based on fatigue failure theory. The tool was tested against an existing epidemiology study and demonstrated strong relationships to multiple shoulder outcomes. MSD: musculoskeletal disorder; NORA: national occupational research agenda; RULA: rapid upper limb assessment; REBA: rapid entire body assessment; S-N: stress-number of cycles; EDL: extensor digitorum longus; DPC: damage per cycle; CD: cumulative damage; UTS: ultimate tensile strength; FTOV: first time office visit; 3DSSPP: 3-dimensional static strength prediction program; AS: visual analogue scale; BMI: body mass index; CI: confidence interval; Nm: newton-metre; LiFFT: lifting fatigue failure tool; DUET: distal upper extremity tool; OMNI-RES: OMNI resistance exercise scale.


Duck Plague Virus Promotes DEF Cell Apoptosis by Activating Caspases, Increasing Intracellular ROS Levels and Inducing Cell Cycle S-Phase Arrest.
Duck plague virus (DPV) can induce apoptosis in duck embryo fibroblasts (DEFs) and in infected ducks, but the molecular mechanism of DPV-induced apoptosis remains unknown. We first used qRT-PCR and a Caspase-Glo assay to determine whether the caspase protein family plays an important role in DPV-induced apoptosis. Then, we used an intracellular ROS detection kit and the mitochondrial probe JC-1 to respectively detect ROS levels and mitochondrial membrane potential (MMP). Finally, flow cytometry was used to detect apoptosis and cell cycle progression. In this study, the mRNA levels and enzymatic activities of caspase-3, caspase-7, caspase-8, and caspase-9 were significantly increased during DPV-induced apoptosis. The caspase inhibitors Z-DEVD-FMK, Z-LEHD-FMK, and Q-VD-OphA could inhibit DPV-induced apoptosis and promote viral replication. Subsequently, a significant decrease in MMP and an increase in the intracellular ROS levels were observed. Further study showed that pretreating infected cells with NAC (a ROS scavenger) decreased the intracellular ROS levels, increased the MMP, inhibited apoptosis, and promoted viral replication. Finally, we showed that DPV infection can cause cell cycle S-phase arrest. This study shows that DPV causes cell cycle S-phase arrest and leads to apoptosis through caspase activation and increased intracellular ROS levels. These findings may be useful for gaining an understanding of the pathogenesis of DPV and the apoptotic pathways induced by α-herpesviruses.


Nonequivalent binding sites in cystathionase. Nanosecond and steady fluorescence studies.
The analogs P-pyridoxyl-L-alanine and P-pyridoxyl-L-homoserine bind to the apoprotein of the enzyme cystathionase and inhibit the reactivation of enzymatic activity after addition of pyridoxyl-5-P. The binding of the inhibitors was monitored by measuring the fluorescence emitted by the P-pyridoxyl moiety at 395 nm (excitation 325 nm). The fluorometric titration results indicate the presence of nonequivalent binding sites in the apoprotein. A model based on two classes of independent binding sites fits the fluorometric data reasonably well. The presence of nonequivalent fluorescent sites in reduced cystathionase was also detected by nanosecond spectroscopy. In contrast to the model compound P-pyridoxyl-epsilon-lysine (tau equals 2.6 ns), the P-pyridoxyl residues of cystathionase display multiexponential fluorescence decay. Two fluorescence lifetimes (tau2 equals 4.1 ns and tau2 equals 15 ns) fit the deconvoluted decay results obtained by pulse fluorimetry. It is proposed that the P-pyridoxyl chromophores of reduced cystathionase have different environments.


Purification of Keratan Sulfate-endogalactosidase and its action on keratan sulfates of different origin.
A glycosidase which attacks corneal keratan sulfate was purified from extracts of Pseudomonas sp. IFO-13309. When corneal keratan sulfate was degraded by the purified enzyme, Sephadex G-50 chromatography indicated the presence of a number of oligosaccharides differing in size and sulfate content. The characterization of two major fractions of the oligosaccharides indicated that the point of enzyme attack is limited to the endo-beta-D-galactoside bonds in which nonsulfated D-galactose residues participate. The enzyme, unlike ordinary exo-beta-D-galactosidases, did not catalyze the hydrolysis of phenyl beta-D-galactoside. Moreover, beta-D-galactosyl-(1 leads to 3)-2-acetamido-2-deoxy-beta-D-glucosyl-(1 leads to 3)-beta-D-galactosyl-(1 leads to 4)-D-glucose ("lacto-N-tetraose") was completely refractory to the action of this enzyme, suggesting that a structure of the type, X-(1 leads to 3)-beta-D-galactosyl-(1 leads to 4)-Y, is not the only specificity-determining factor, i.e. neighboring sugars, X and Y, or even larger portions of substrate molecule must have an important effect. Compared with corneal keratan sulfate, keratan sulfates from human nucleus pulposus and shark cartilage were attacked at lower rates with a resultant production of oligosaccharides of relatively large size. The result is in agreement with the view that considerable variations exist in the structure of keratan sulfates of different origin, and further suggests that the enzyme may serve as a useful reagent in studying these variations.


THE TENSILE BEHAVIORS OF THE ILIOTIBIAL BAND - A CADAVERIC INVESTIGATION.
Clinical stretching is frequently recommended for iliotibial band syndrome management. Current literature lacks conclusive findings regarding isolated human iliotibial band tissue elongation and stiffness behaviors. Applying clinical-grade stretching force results to iliotibial band tissue behavior is thus challenging. This study's objectives were to determine isolated iliotibial band tissue tensile behaviors during tension-to-failure testing and to relate the results to previously reported iliotibial band stretch findings. Descriptive in vitro laboratory study. Ten isolated un-embalmed iliotibial band specimens were exposed to tension-to-failure testing using a 10kN material testing system. Peak load, load at yield point, and ultimate failure load were measured in Newtons. Corresponding absolute (mm) and relative (%) tissue deformation was recorded. Load-deformation curves were established to calculate iliotibial band stiffness (N/mm). A mean peak load of 872.8 ± 285.9N and resulting 9.0 ± 3.9% tissue deformation from initial length was recorded. An 805.5 ± 249.7N mean load at yield point and resulting 7.0 ± 1.9% tissue deformation was observed. A 727.6 ± 258.4N mean load was recorded directly prior to ultimate tissue failure. Mean tissue deformation at ultimate failure was 11.3 ± 4.2%. Mean iliotibial band system stiffness was 27.2 ± 4.5N/mm. The iliotibial band can withstand substantial tensile forces. Clinical stretching forces likely fall within the load-deformation curve elastic region and may not result in permanent iliotibial band tissue deformation. Sustained elongation resulting from stretching the ITB may require substantial patient compliance. Future studies should investigate potential underlying factors related to positive symptom relief from iliotibial band stretching that include immunological responses, fluid accumulation, altered proprioception, and pain perception. 3.


The effect of the virus-serum incubation period upon vaccinia virus serum neutralization titers.
Rabbit and human vaccinia virus immune sera were titrated by the plaque reduction serum neutralization (SN) method. Titers determined following a 2-h, 37 degree C virus-serum incubation period were not significantly different from those determined following an 18-h incubation period (2-h, 37 degree C incubation followed by a 16-h, 4 degree C period). However, control virus plaque counts decreased significantly after the longer incubation period. Numerous factors affecting SN titer estimation are reviewed. Standardization of SN test conditions may be useful in comparative potency evaluation of vaccinia-vectored recombinant DNA viral vaccines.


A study on the interactions of doctors with medical representatives of pharmaceutical companies in a Tertiary Care Teaching Hospital of South India.
The promotional activities by medical representatives (MRs) of the pharmaceutical companies can impact the prescribing pattern of doctors. Hence, the interaction between doctors and the pharmaceutical industry is coming under increasing scrutiny. The primary objective was to assess the attitude of the doctors toward the interaction with the MRs of the pharmaceutical company. The secondary objective was to assess the awareness of the doctors about regulations governing their interaction with the pharmaceutical company. This was a cross-sectional study. This study was carried out using a pretested questionnaire containing 10 questions between June and September 2014. The doctors working in the Dhanalakshmi Srinivasan Medical College and Hospital, Perambalur (Tamil Nadu) during the study period was included. A total of 100 pretested questionnaires were distributed, and 81 doctors responded (response rate 81%). 37% doctors responded that they interacted with MR once a week whereas 25.9% told that they interact with MRs twice a month. About 69.1% doctors think that MR exaggerate the benefits of medicines and downplays the risks and contraindications of medicine(P = 0.000). 61.7% doctors think that MR has an impact on their prescribing (P = 0.000). 63% doctors stated that they had received promotional tools such as stationery items, drug sample, textbooks or journal reprints from MR in last 12 months (P = 0.0012). Unfortunately, 70.4% doctors have not read the guidelines about interacting with the pharmaceutical industry or its representative (P = 0.000). Rather than forbidding any connection between doctors and industry, it is better to establish ethical guidelines. The Medical Council of India code is a step in the right direction, but the majority of doctors in this study have not read the guidelines about interacting with the pharmaceutical industry or its representative.


Bone scaffolds loaded with siRNA-Semaphorin4d for the treatment of osteoporosis related bone defects.
Osteoporosis is a prominent disorder affecting over 200 million people worldwide. Recently, semaphorins have been implicated in the cell-cell communication between osteoclasts and osteoblasts and have been associated with the progression of osteoporosis. Previously, we demonstrated that knockdown of semaphorin4d (Sema4d) using siRNA delivered with a bone-targeting system prevented bone loss in an osteoporotic animal model. Here, we used this bone-specific technology containing siRNA-Sema4d and fabricated a PLLA scaffold capable of enhancing bone repair following fracture. We investigated the ability of the implant to release siRNA-Sema4d into the surrounding tissues over time and to influence new bone formation in a 3 mm femur osteoporotic defect model in ovariectomized rats. Delivery of the bone-targeting system released from PLLA scaffolds began 2 hours post-implantation, peaked at 1 day, and was sustained over a 21 day period. μCT analysis demonstrated a significantly higher bone volume/total volume bone mineral density and number of osteoblasts in the rats that were transplanted with scaffolds loaded with siRNA-Sema4d. These results confirm the specific role of Sema4d in bone remodeling and demonstrate that significant increases in the speed and quality of new bone formation occur when siRNA-Sema4d is delivered via a PLLA scaffold.


Determination of tyrosinase-cyanidin-3-O-glucoside and (-/+)-catechin binding modes reveal mechanistic differences in tyrosinase inhibition.
Tyrosinase, exquisitely catalyzes the phenolic compounds into brown or black pigment, inhibition is used as a treatment for dermatological or neurodegenerative disorders. Natural products, such as cyanidin-3-O-glucoside and (-/+)-catechin, are considered safe and non-toxic food additives in tyrosinase inhibition but their ambiguous inhibitory mechanism against tyrosinase is still elusive. Thus, we presented the mechanistic insights into tyrosinase with cyanidin-3-O-glucoside and (-/+)-catechin using computational simulations and in vitro assessment. Initial molecular docking results predicted ideal docked poses (- 9.346 to - 5.795 kcal/mol) for tyrosinase with selected flavonoids. Furthermore, 100 ns molecular dynamics simulations and post-simulation analysis of docked poses established their stability and oxidation of flavonoids as substrate by tyrosinase. Particularly, metal chelation via catechol group linked with the free 3-OH group on the unconjugated dihydropyran heterocycle chain was elucidated to contribute to tyrosinase inhibition by (-/+)-catechin against cyanidin-3-O-glucoside. Also, predicted binding free energy using molecular mechanics/generalized Born surface area for each docked pose was consistent with in vitro enzyme inhibition for both mushroom and murine tyrosinases. Conclusively, (-/+)-catechin was observed for substantial tyrosinase inhibition and advocated for further investigation for drug development against tyrosinase-associated diseases.


Fibromyalgia syndrome and cognitive dysfunction in elderly: a case series.
Fibromyalgia syndrome (FMS) is an extremely rare complication of neurocognitive disorders (NCDs). We experienced seven such cases, and we discuss their clinical manifestation and pathomechanisms. Seven patients with FMS as a complication of NCD were enrolled. We used the patients' medical records to identify clinical manifestations and obtain experimental data, such as pain questionnaire scores, cognitive tests, genetics and radiological imaging of the brain. The seven patients were clinically diagnosed with frontotemporal NCD (n = 3) or Alzheimer's disease (n = 4). No patient presented with any organic disorder that would explain their chronic pain. Through their courses, they experienced refractory widespread pain continuously despite analgesics. Brain magnetic resonance imaging revealed moderate or severe atrophic changes in the temporal lobes and hippocampus. Three-dimensional stereotactic surface projection (3D-SSP) analysis of brain single photon emission computed tomography (SPECT), indicated severe hypoperfusion on the right side of the medial temporal lobe, both sides of the anterior corpus callosum, anterior cingulate gyrus, and primary sensory area. Genetic analysis uncovered no pathogenic mutations. Neurodegenerative disorders are rarely complicated by FMS, which is associated with relatively severe pain. Central sensitization may be a possible risk factor of widespread pain in elderly patients with NCD.


Increased Prevalence and Associated Costs of Psychiatric Comorbidities in Patients Undergoing Sports Medicine Operative Procedures.
To evaluate the prevalence of preoperatively diagnosed psychiatric comorbidities and the impact of these comorbidities on the healthcare costs of ten common orthopaedic sports medicine procedures. Patients undergoing 10 common sports medicine procedures from 2007 to 2017q1 were identified using the Humana claims database. These procedures included anterior cruciate ligament reconstruction; posterior cruciate ligament reconstruction; medial collateral ligament repair/reconstruction; Achilles repair/reconstruction; Rotator cuff repair; meniscectomy/meniscus repair; hip arthroscopy; arthroscopic shoulder labral repair; patellofemoral instability procedures; and shoulder instability repair. Patients were stratified by preoperative diagnoses of depression, anxiety, bipolar disorder, or schizophrenia. Cohorts included patients with ≥1 psychiatric comorbidity (psychiatric) versus those without psychiatric comorbidities (no psychiatric). Differences in costs across groups were compared using Mann-Whitney U tests, with significance defined as P < .05. Linear regression analysis was used to assess rates of procedures per year from 2006 to 2016. In total, 226,402 patients (57.7% male) from 2007 to 2017q1 were assessed. The prevalence of ≥1 psychiatric comorbidity within the entire database was 10.31% (reference) versus 21.21% in those patients undergoing the 10 investigated procedures. Patients with psychiatric comorbidity most frequently underwent rotator cuff repair (28%), hip labral repair (26.3%) and meniscectomy/meniscus repair (25.0%%) had ≥1 psychiatric comorbidity. Compared with the no psychiatric cohort, diagnosis of ≥1 psychiatric comorbidity was associated with increased health care costs for all 10 sports medicine procedures ($9678.81 vs $6436.20, P < .0001). The prevalence of preoperatively diagnosed psychiatric comorbidities among patients undergoing orthopaedic sports medicine procedures is high. The presence of psychiatric comorbidities preoperatively was associated with increased postoperative costs following all investigated orthopaedic sports medicine procedures. Level III; retrospective comparative study.


Perspectives on Priapism Education in Emergency Medicine.
Priapism is a urologic emergency managed by both emergency medicine (EM) providers and urologists. Attitudes regarding its management and understanding of education of non-urology trainees in this area are poorly defined. The aim of this study was to describe attitudes toward priapism management among multiple stakeholders and define the current state of priapism education among EM residency programs. Surveys were developed and distributed online to EM residency leadership, EM residents, and urology providers. Each solicited attitudes and preferences regarding independent priapism management by EM providers. EM residents were further queried about their educational and clinical experiences in priapism management, and EM residency leadership were surveyed about their educational curricula. Responses among all 3 groups were compared using Fisher's exact tests. Quantitative and descriptive responses were solicited regarding EM providers' management of acute ischemic priapism and current priapism curricula for EM residents. 91 EM residency program directors and assistant program directors (31.6% of programs), 227 EM residents (14.7% of programs), and 94 urologists (6.3% of survey recipients) responded. All geographic regions and all years of EM training were represented. Over 90% of all surveyed groups felt that EM providers should independently manage priapism in practice. 17% of senior EM residents felt "not at all" confident in managing priapism; and 25.5% had never primarily managed this entity in training. 81% of programs had a formalized priapism curriculum, of which 19% included treatment simulation. However, 36% of residents felt that current curricula were insufficient. Widespread approval from both EM providers and urologists support EM-based management for uncomplicated cases of acute ischemic priapism. Current educational curricula for EM trainees may not be sufficient to prepare them to manage this entity in practice. This is the first study to examine provider attitudes toward EM-based management of priapism and assess the current state of education in this area with input from all key stakeholders. This survey was limited in its scope and the response rate was lower than desired. Urologists support independent priapism management by EM providers, but an educational gap remains for EM trainees who do not feel adequately trained to manage this independently in practice. Dai JC, Franzen DS, Lendvay TS, et al. Perspectives on Priapism Education in Emergency Medicine. J Sex Med 2020;17:159-162.


Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Lactams: Enantioselective Construction of All-Carbon Quaternary Stereocenters in Saturated Nitrogen-Containing Heterocycles.
Stereogenic nitrogen-containing heterocycles are ubiquitous in natural products and pharmaceutical compounds, but methods for their enantioselective construction have remained elusive. We report a general method for the asymmetric conjugate addition of arylboronic acids to β-alkyl/aryl α,β-unsaturated lactams that affords chiral β,β-disubstituted lactams. The transformation is operationally simple and air- and moisture-tolerant and uses a commercially available (S)-t-Bu-PyOx ligand. The method is high-yielding (up to 95% yield) and enantioselective (up to 97% ee) for a wide range of arylboronic acids and α,β-unsaturated lactams, including those with different ring sizes.


Cortico-striatal functional connectivity and cerebral small vessel disease: Contribution to mild Parkinsonian signs.
Mild Parkinsonian signs (MPS) are common in older adults. We hypothesized that MPS are associated with lower functional connectivity (FC) in dopamine-dependent cortico-striatal networks, and these associations vary with white matter hyperintensity (WMH), a risk factor for MPS. We examined resting-state functional MRI in 266 participants (mean age 83; 57% female; 41% African American) with data on MPS (Unified Parkinson's Disease Rating Scale), demographics, cognition, muscle-skeletal, and cardiometabolic health. FC between cortex and striatum was examined separately for sensorimotor, executive, and limbic functional subregions. Logistic regression tested the association of FC in each network with MPS, adjusted for covariates. Interactions of FC by WMH were tested; and analyses were repeated stratified by WMH above/below the median. Compared to those without MPS, those with MPS had lower cortico-striatal FC in the left executive network (adjusted odds ratio [95% confidence interval], p-value: 0.188 [0.043, 0.824], .027). The interaction with WMH was p = .064; left executive FC was inversely associated with MPS for high WMH (0.077 [0.010, 0.599], .014) but not low WMH participants (1.245 [0.128, 12.132], .850). MPS appear related to lower executive network FC, robust to adjustment for other risk factors, and stronger for those with higher burden of WMH. Future longitudinal studies should examine the interplay between cerebral small vessel disease and connectivity influencing MPS.


Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018.
Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward. All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time. Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.


Development of anticancer agents targeting the Hedgehog signaling.
Hedgehog signaling is an evolutionarily conserved pathway which is essential in embryonic and postnatal development as well as adult organ homeostasis. Abnormal regulation of Hedgehog signaling is implicated in many diseases including cancer. Consequently, substantial efforts have made in the past to develop potential therapeutic agents that specifically target the Hedgehog signaling for cancer treatment. Here, we review the therapeutic agents for inhibition of the Hedgehog signaling and their clinical advances in cancer treatment.


The Toxoplasma gondii bradyzoite antigens BAG1 and MAG1 induce early humoral and cell-mediated immune responses upon human infection.
Infection of humans by Toxoplasma gondii leads to an acute systemic phase, in which tachyzoites disseminate throughout the body, followed by a chronic phase characterized by the presence of tissue cysts, containing bradyzoites, in brain, heart and skeletal muscles. This work focused on studying the antigenic regions of bradyzoite-specific proteins involved in human B- and T-cell responses. To this aim, we constructed a phage-display library of DNA fragments derived from the bradyzoite-specific genes BAG1, MAG1, SAG2D, SAG4, BSR4, LDH2, ENO1 and p-ATPase. Challenge of the bradyzoite library with sera of infected individuals led to the identification of antigenic regions within BAG1 and MAG1 gene products. Analysis of the humoral and lymphoproliferative responses to recombinant antigens demonstrated that the BAG1 fragment induced T-cell proliferation in 34% of T. gondii-exposed individuals, while 50% of them had specific IgG. In the same subjects, the MAG1 fragment was recognized by T cells from 17% of the exposed donors and by antibodies from 73% of them. A detailed analysis of the antibody response against BAG1 and MAG1 antigen fragments demonstrated that the immune response against bradyzoites occurs early after infection in humans. Finally, we provide evidence that the T-cell response against BAG1 is associated with the production of interferon-gamma, suggesting that bradyzoite antigens should be considered in the design of potential vaccines in humans.


Inhibition of Staphylococcus aureus by the commensal bacteria of human milk.
To study the bacterial diversity in expressed human milk with a focus on detecting bacteria with an antimicrobial activity against Staphylococcus aureus, known as a causative agent of maternal breast infections and neonatal infections. Random isolates (n = 509) were collected from breast milk samples (n = 40) of healthy lactating women, genotypically identified, and tested for antimicrobial activity against Staph. aureus. Commensal staphylococci (64%) and oral streptococci (30%), with Staph. epidermidis, Strep. salivarius, and Strep. mitis as the most frequent isolates, were the predominant bacterial species in breast milk. One-fifth of Staph. epidermidis and half of Strep. salivarius isolates suppressed growth of Staph. aureus. Enterococci (Ent. faecalis), isolated from 7.5% of samples, and lactic acid bacteria (LAB) (Lactobacillus rhamnosus, Lact. crispatus, Lactococcus lactis, Leuconoctoc mesenteroides), isolated from 12.5% of samples, were also effective against Staph. aureus. One L. lactis isolate was shown to produce nisin, a bacteriocin used in food industry to prevent bacterial pathogens and spoilage. Expressed breast milk contains commensal bacteria, which inhibit Staph. aureus. The strains inhibitory against the pathogen Staph. aureus have potential use as bacteriotherapeutic agents in preventing neonatal and maternal breast infections caused by this bacterium.


The protection of ischemic lung with verapamil and hydralazine.
The optimum method for lung preservation in preparation for transplantation remains unresolved. In this study, we evaluated the effectiveness of two pharmacologic agents for prolonging the preservation time of the ischemic lung. We compared hydralazine, a vasodilator, and verapamil, which is both a vasodilator and a calcium channel blocker, in regard to their effectiveness in promoting functional recovery of the ischemic dog lung in a new experimental model. The model consists of exposing the left lung of each dog to normothermic ischemia after clamping the pulmonary artery, vein, and bronchus. After ischemic periods of 1 to 5 hours, pulmonary circulation was reestablished. The functional integrity of the left lung was then evaluated by ligating the right bronchus, so that the dog was completely dependent on the previously ischemic lung. The left lung of eight dogs was perfused with 200 ml of Collins-Sachs solution alone in group A, with Collins-Sachs solution containing 20 mg of hydralazine in group B (n = 8), and with Collins-Sachs solution containing 5 mg of verapamil in group C (n = 8). The mean ischemic time was 2.3 hours in group A, 3.0 hours in group B, and 3.1 hours in group C. One dog in group A survived after 1 hour of ischemia, two dogs in group B survived after 1 and 3 hours of ischemia, and six dogs in group C survived 2 to 4 hours of ischemia. Oxygen tension in room air after bronchial ligation was 39.9 +/- 10.2 mm Hg in group A, 59.4 +/- 35.3 in group B, and 76.1 +/- 32.9 in group C. Statistical significance existed between groups A and C (p less than 0.05). Pulmonary vascular resistance after bronchial ligation was 428.9 +/- 158.8 dynes.sec.cm-5 in group A, 219.9 +/- 51.9 in group B, and 208.3 +/- 84.5 in group C. Thus tissue damage caused by ischemia was significantly less with verapamil than with the vasodilating drug hydralazine.


Assessment of standing passenger traumatic brain injury caused by ground impact in subway collisions.
Human head is the most vulnerable region in subway collisions. To design a safer subway, the head impact biomechanical response should be studied first. This paper aims to investigate the standing passenger head-ground impact dynamic response and traumatic brain injury (TBI) in subway collisions. A standing passenger-subway interior dynamic model was numerically developed by using our previous validated finite element (FE)-multibody (MB) coupled human body model, which was integrated by the Total Human Model for Safety (THUMS) head-neck FE model and the extracted remaining body segments pedestrian MB model of TNO. A parametric study considering the handrail type, standing angle, and friction coefficient between the shoes and ground was performed. Results show that the passenger dynamic response could be divided into two categories according to whether the passenger hit handrails. Passenger TBIs severity could be efficiently alleviated by the passenger body (excluding the head) hitting the handrail first before head-ground impact. The probabilities of DAI in the cerebellum and brain stem were low. A statistical analysis of TBIs demonstrated that the risks of TBIs were sensitive to the handrail type in subway collisions, but did not to the standing angle and friction coefficient. This study provides practical help for improving the interior crashworthiness performance of subways.


Identification of impurities in acarbose by using an integrated liquid chromatography-nuclear magnetic resonance and liquid chromatography-mass spectrometry approach.
The usefulness of applying an integrated LC-NMR and LC-MS approach to acarbose bulk drug impurity profiling is demonstrated. LC-MS and LC-NMR methodologies were employed for the online separation and structural elucidation of a final drug product. Combining data provided by the stop-flow LC-NMR and LC-MS experiments made it possible to identify the main components present in the acarbose sample. Spectral analysis revealed that A and B were known impurities while C was an unknown compound. LC-MS and LC-NMR analyses revealed that C was a pentasaccharide differing from the acarbose in number and nature of sugar subunits in the molecule. It was subsequently isolated and its structure was confirmed by the offline 1- and 2-D NMR experiments, and atom assignment was made.


"No allogeneic blood transfusion" protocol for the surgical correction of craniosynostoses. II. Clinical application.
The authors describe the results obtained in 13 consecutive cases of craniosynostosis operated on according to a protocol devised at avoiding allogeneic blood transfusion. The protocol is based on pre- and postoperative treatment with erythropoietin, preoperative autologous blood donation, preoperative normovolemic hemodilution and intraoperative blood salvage. Nine subjects were affected by simple forms of craniosynostosis, whereas the remaining 4 presented with oxycephaly or craniofacial syndromes. Five of the 13 children were under 7 months and a further 3, under 10 months of age at the time of the surgical operation. Seven children weighed less than 10 kg. Allogeneic blood transfusion was avoided in 11 of the 13 children considered. Two failures - defined as the necessity to reinfuse the patient with an allogeneic blood transfusion - were recorded, 1 of them resulting from an unexpected hemorrhage during surgery. The results obtained indicate that this protocol designed to avoid allogeneic blood transfusion can be safely applied in the great majority of children with craniosynostosis, even when the surgical correction is carried out early in life.


Radiation dermatitis.
Even in this era of modern radiotherapy, injuries associated with the medical and industrial use of radiation devices will continue to pose a difficult problem for the reconstructive surgeon. It must be borne in mind that the single most serious hazard to surgery in irradiated tissue is the lodgement of bacteria in tissue rendered avascular by the radiation and the secondary necrosis from the infection itself. The basic principles of wound management must be augmented by thorough knowledge of the use of well-vascularized muscle and musculocutaneous flap to provide adequate, blood-rich, soft-tissue coverage.


Midwives' intrapartum monitoring process and management resulting in emergency referrals in Tanzania: a qualitative study.
In the United Republic of Tanzania, the maternal mortality ratio, and neonatal mortality rate have remained high for the last 10 years. It is well documented that many complications of pregnancy are avoidable by providing skilled midwifery care during and immediately after childbirth. However, there have been delays in providing timely and necessary obstetric interventions, most likely due to lack of proper monitoring during labor. Yet, there has been little research concerning how midwives monitor the process of childbirth. Therefore, this study aimed to describe how midwives monitored and managed the process of childbirth to achieve early consulting and timely referral to obstetricians. The design was qualitative and descriptive, using data from comprehensive semi-structured interviews of midwives. The interviews were conducted at one hospital and one health center in Dar es Salaam, Tanzania's largest city. Eleven participants were purposively recruited and interviewed about their experiences managing complicated intrapartum cases. After the interviews, data were analyzed using content analysis. Derived from the data were three activity phases: initial encounter, monitoring, and acting. During these phases, midwives noticed danger signs, identified problems, revised and confirmed initial problem identification, and organized for medical intervention or referral. The timing of taking action was different for each midwife and depended on the nature of the prolonged and obstructed labor case. For the majority of midwives, the processing of assessments and judgments was brief and without reflection, and only a few midwives took time to continue to monitor the labor after the initial identification of problems and before taking actions. To make a final judgment that the labor was becoming prolonged or obstructed, midwives should consider taking time to review and synthesize all their findings.


FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling.
We report that the Forkhead family of transcription factors, FKHRL1, FKHR and AFX are novel components of neurotrophin receptor signaling. NGF rapidly induced the phosphorylation of FKHRL1 in PC12 cells. This effect is mediated by high-affinity TrkA receptor as nerve growth factor (NGF) induced the phosphorylation of FKHRL1 only in TrkA expressing cells and not p75-expressing cells. Additional experiments with various kinase inhibitors, the transient expression of constitutively active and dominant-negative Akt, and in vitro kinase assay revealed that phosphatidylinositol-3 (PtdIns3)/Akt kinase mediated the actions of NGF. Similar data were obtained for brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) in primary cortical cultured neurons. These findings demonstrate for the first time that the phosphorylation of the Forkhead family of transcription factors can be modulated by neurotrophins via Trk receptors and PtdIns3K/Akt kinase (but not MAP or S6p70 kinases) in neuronal and non-neuronal cells. Moreover, survival assays with the PtdIns3 kinase inhibitor LY294002, active and dominant-negative forms of Akt indicate that the phosphorylation of FKHRL1 plays a role in neurotrophins-mediated cell survival.


Simultaneous defecography and peritoneography in defecation disorders.
A number of physiologic and radiologic investigations are used in investigating defecation disorders. Defecography is one important part of these investigations. However, a correct diagnosis of an enterocele is sometimes difficult despite use of contrast media in the rectum, vagina, and small bowel. This study was undertaken to ascertain if it was technically possible to perform simultaneous defecography and peritoneography in an effort to improve the diagnostic possibilities in patients with defecation disorders. Twelve patients with defecation disorders and an unexplained widening of the rectovaginal space at defecography were investigated. Contrast medium was introduced intraperitoneally, after which conventional defecography was performed. All investigations were carried out without complications and demonstrated the peritoneal outline in all patients. Simultaneous defecography and peritoneography differentiated between an enterocele and a pathologically deep pouch of Douglas--a peritoneocele. Three types of peritoneocele were visualized: vaginal peritoneocele, septal peritoneocele, and rectal peritoneocele with or without enterocele. Combinations of the three types were also found. Eight of the 12 patients had rectal intussusception or rectal prolapse. All of these eight patients had a rectal peritoneocele. Simultaneous defecography and peritoneography can be performed without technical difficulties or complications. Peritoneal outlines and pouches can, therefore, be studied directly during the act of defecation. An unexplained widening of the rectovaginal space at defecography can be clarified as a peritoneocele, with or without an enterocele. Peritoneocele can be of three different types: rectal, septal, or vaginal.


Allergen carriage by atmospheric aerosol. II. Ragweed-pollen determinants in submicronic atmospheric fractions.
Outdoor air was drawn by a vacuum system through a 0.8 micron molecular membrane filter and a back-up, refrigerated condensor from 8 A.M. to 5 P.M. daily during the 1982 ragweed-pollen season. Sample sets from each day were collected and stored separately. Condensate was collected in a freezing jacket, thawed, refiltered through a 0.45 micron filter, and lyophilized. Reconstituted condensates evoked wheal-and-flare skin reactions in a ragweed-sensitive individual and produced significant inhibition in an IgG-ELISA system by use of ragweed-pollen protein or ragweed antigen E conjugated to polystyrene microtiter plates, pooled serum of patients on ragweed immunotherapy, and alkaline phosphatase-labeled anti-human IgG. Earlier, in 1983 in this JOURNAL, we reported the presence of airborne ragweed-pollen antigen in aerosol fractions below 5 micron. The present data demonstrate similar in filtrates well below the micronic range. Furthermore, these antigenic properties are substantially associated with atmospheric water vapor-either naturally or as a readily-induced result of the collection procedure. These results suggest that naturally occurring mists, although free of native particulates, may yet carry allergens of clinical significance.


The effects of lithium chloride and cathodal/anodal transcranial direct current stimulation on conditional fear memory changes and the level of p-mTOR/mTOR in PFC of male NMRI mice.
Lithium chloride clinically used to treat mental diseases but it has some side effects like cognitive impairment, memory deficit. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is able to change neural activity and gene transcription in the brain. The aim of the study is to provide a conceptual theoretical framework based on behavioral and molecular effects of tDCS on memory changes induced by lithium in male mice. we applied Anodal-tDCS and Cathodal-tDCS over the left PFC for 3 consecutive days tDCS for 20 min with 2 mA after injection of different doses of lithium/saline.Trained in fear condition and finally the day after that tested their memory persistency factors (freezing-latency) and other behavior such as grooming and rearing percentage time in the fear conditioning. P-mTOR/mTOR was analyzed using western blotting. The results obtained from the preliminary analysis of behavioral fear memory showed that lithium had destructive effect in higher doses and decreased freezing percentage time. However, both cathodal and anodal tDCS significantly improved memory and increased P-mTOR/mTOR level in the PFC. The results of this study indicate that cathodal and anodal tDCS upon the left prefrontal increased memory and reduced lithium side effects on memory consolidation and altered expression of plasticity-associated genes in the prefrontal cortex.


Shigella species epidemiology and antimicrobial susceptibility: the implications of emerging azithromycin resistance for guiding treatment, guidelines and breakpoints.
To examine antimicrobial susceptibility patterns and predictors of resistance among Shigella isolates in New South Wales (NSW), Australia during 2013-14 with emphasis on azithromycin. Cross-sectional analysis of all shigellosis cases (160) notified to public health authorities in NSW, Australia was performed. Among 160 Shigella isolates tested, 139 (86.9%) were susceptible to azithromycin, 104 (65.0%) to ciprofloxacin and 38 (23.7%) to co-trimoxazole. Ciprofloxacin resistance was 1.9 times more common in infections acquired in Australia compared with those acquired overseas, while azithromycin resistance was 8.5 times more common in males. We recommend ongoing reconsideration of guidelines for the treatment of shigellosis based on emerging resistance patterns. First-line therapy may need to be reconsidered based on local resistance rates due to common resistance to co-trimoxazole and ciprofloxacin. We recommend culture and susceptibility testing for suspected and proven shigellosis. Azithromycin susceptibility breakpoints for Shigella species may need to be species specific.


High-status lobbyists are most likely to overrate their success.
Overconfidence helps individuals reach higher status within social groups by making them seem more competent regardless of objective ability, so this bias may be especially prevalent among status-oriented members of elite communities. Based on this premise, we explore whether lobbyists in the USA misperceive their success. Using models that (1) control for legislative outcome when predicting self-assessed policy success and (2) compare self-assessed policy success on specific proposals against the average success reported by all lobbyists working on the same side of an issue, we identify systematic tendencies to overrate achievements. Lobbyists with higher incomes, who reside in Washington, DC, USA, have congressional experience and who engage in a broader range of activities are more likely to overrate their success. Public interest group lobbyists tend to underestimate success. We conclude that political elites are subject to the same biases as others when evaluating their performance, and these biases may be largely status-driven.


Zosteriform connective tissue nevus in a pediatric patient.
We report an 8-year-old girl affected by hypochromic, asymptomatic, acquired lesions with a paving-stone aspect on the right lumbosacral area and proximal right leg. The results of serum and urine biochemical screening were normal, as was the bone survey A biopsy was performed. The clinical and histologic aspects led to the diagnosis of connective tissue nevus with zosteriform distribution.


Coxsackie B4 viral infection, anti-islet immunity and immunogenetics in insulin-dependent diabetes mellitus.
The interrelationship between Coxsackie B4 (CB4) virus antibodies, islet-cell antibodies and HLA B8 was studied in 67 patients with juvenile-onset diabetes mellitus (JOD). In 41 JOD patients (61%) CB4 antibodies (greater than 1:4) were found. A high prevalence (69%) of significant CB4 antibody titers (greater than 1:64) was observed in patients with age at onset between 11 and 20 years compared with those with age at onset below or over that age-range (27% and 33%, respectively). Islet-cell antibodies (ICA) could be detected only in 11 JOD patients, which is probably due to the relatively long mean duration of disease. However, 8 of them presented with significant CB4 antibody production. Although no correlation between CB4 antibodies and the JOD-associated HLA-antigens (B8, Bw15, Cw3 and B7) could be detected in the entire group of JOD patients, a close association between ICA persistence and HLA B8 was found. Furthermore, in the ICA-positive, moderate or high CB4 antibody titers were prevalent. Thus, the present data point to a possible interrelationship between CB4 virus antibodies, persistent ICA production and HLA B8 in a minor proportion of JOD patients. However, it seems premature to assume direct implication of these factors in the pathogenesis of JOD.


Thoracoabdominal asynchrony in a virtual preterm infant: computational modeling and analysis.
Thoracoabdominal asynchrony (TAA), the asynchronous volume changes between the rib cage and abdomen during breathing, is associated with respiratory distress, progressive lung volume loss, and chronic lung disease in the newborn infant. Preterm infants are prone to TAA risk factors such as weak intercostal muscles, surfactant deficiency, and a flaccid chest wall. The causes of TAA in this fragile population are not fully understood and, to date, the assessment of TAA has not included a mechanistic modeling framework to explore the role these risk factors play in breathing dynamics and how TAA can be resolved. We present a dynamic compartmental model of pulmonary mechanics that simulates TAA in the preterm infant under various adverse clinical conditions, including high chest wall compliance, applied inspiratory resistive loads, bronchopulmonary dysplasia, anesthesia-induced intercostal muscle deactivation, weakened costal diaphragm, impaired lung compliance, and upper airway obstruction. Sensitivity analyses performed to screen and rank model parameter influence on model TAA and respiratory volume outputs show that risk factors are additive so that maximal TAA occurs in a virtual preterm infant with multiple adverse conditions, and addressing risk factors individually causes incremental changes in TAA. An abruptly obstructed upper airway caused immediate nearly paradoxical breathing and tidal volume reduction despite greater effort. In most simulations, increased TAA occurred together with decreased tidal volume. Simulated indices of TAA are consistent with published experimental studies and clinically observed pathophysiology, motivating further investigation into the use of computational modeling for assessing and managing TAA.NEW & NOTEWORTHY A novel model of thoracoabdominal asynchrony incorporates literature-derived mechanics and simulates the impact of risk factors on a virtual preterm infant. Sensitivity analyses were performed to determine the influence of model parameters on TAA and respiratory volume. Predicted phase angles are consistent with prior experimental and clinical results, and influential parameters are associated with clinical scenarios that significantly alter phase angle, motivating further investigation into the use of computational modeling for assessing and managing thoracoabdominal asynchrony.