[Salidroside regulates the phenotypic transformation of corpus cavernosum smooth muscle cells of rats through the PDGFR/STAT3 signaling pathway].
To explore the mechanism of Salidroside regulating the phenotypic transformation of cavernous smooth muscle cells (CCSMCs) in rats. Primary CCSMCs were isolated from male SD rats, cultured in hypoxic environment for 24 hours, and treated with Salidroside at 30 μg/mL. Then the expressions of HIF-1α, platelet-derived growth factor receptor (PDGFR) and phenotypic transformation-related proteins α-SMA and Collagen I were detected by Western blot. The culture system of the CCSMCs was treated with exogenous PDGF-BB at 20 ng/mL for 24 hours, and the effects of Salidroside or PDGFR inhibitor Crenolanib (100 nmol/L) were observed. The expressions of PDGFR, phosphorylated PDGFR, phenotypic transformation-related proteins α-SMA and Collagen I, STAT3, phosphorylated STAT3, STAT5 and phosphorylated STAT5 were determined by Western blot. The intervention effects of Salidroside and/or the overexpression of STAT3 were observed after stimulation of the CCSMCs by exogenous PDGF-BB, followed by detection of the expressions of phenotypic transformation-related proteins α-SMA and Collagen I, STAT3 and phosphorylated STAT3 proteins. The expression of HIF-1α in the CCSMCs was significantly upregulated after cultured in hypoxic environment for 24 hours (P < 0.05), suggesting the successful construction of the hypoxia model of CCSMCs. Meanwhile, the expressions of PDGFRα, PDGFRβ and Collagen I were remarkably increased (all P < 0.05), and that of α-SMA markedly decreased (P < 0.05) in the CCSMCs. However, the expressions of the all the proteins above were significantly inhibited by Salidroside intervention (all P < 0.05). After stimulated by exogenous PDGF-BB for 24 hours, the phosphorylation ratios of PDGFRα, PDGFRβ and STAT3 and the expression of Collagen I were significantly elevated (all P < 0.05), that of α-SMA remarkably reduced (P < 0.05), and all were inhibited by intervention with crenolanib or Salidroside (all P < 0.05). No statistically significant difference was observed in the STAT5 phosphorylation ratio between different groups (P > 0.05). Overexpression of STAT3 in the CCSMCs treated with exogenous PDGF-BB and Salidroside significantly decreased the expression of α-SMA (P < 0.05) and increased that of Collagen I (P < 0.05). Salidroside could improve the phenotypic transformation of CCSMCs in male rats through the PDGFR/STAT3 signaling pathway, which needs further exploration and verification.


Targeted Serum Metabolite Profiling Identifies Metabolic Signatures in Patients with Alzheimer's Disease, Normal Pressure Hydrocephalus and Brain Tumor.
Progression to AD is preceded by elevated levels of 2,4-dihydroxybutanoic acid (2,4-DHB), implicating hypoxia in early pathogenesis. Since hypoxia may play a role in multiple CNS disorders, we investigated serum metabolite profiles across three disorders, AD, Normal Pressure Hydrocephalus (NPH) and brain tumors (BT). Blood samples were collected from 27 NPH and 20 BT patients. The profiles of 21 metabolites were examined. Additionally, data from 37 AD patients and 46 controls from a previous study were analyzed together with the newly acquired data. No differences in 2,4-DHB were found across AD, NPH and BT samples. In the BT group, the fatty acids were increased as compared to HC and NPH groups, while the ketone body 3-hydroxybutyrate was increased as compared to AD. Glutamic acid was increased in AD as compared to the HC group. In the AD group, 3-hydroxybutyrate tended to be decreased with respect to all other groups (mean values -30% or more), but the differences were not statistically significant. Serine was increased in NPH as compared to BT. In conclusion, AD, NPH and BT have different metabolic profiles. This preliminary study may help in identifying the blood based markers that are specific to these three CNS diseases.


The Impact of Data Management on the Achievable Dose and Efficiency of Computed Tomography During the COVID-19 Era: A Facility-Based Ambispective Study.
This study primarily aimed to evaluate the effectiveness of computational data management and analytical software for establishing departmental diagnostic reference levels (DRLs) for computed tomography (CT) scanning in clinical settings, and monitor achievable doses (ADs) for CT imaging, particularly during the coronavirus disease 2019 (COVID-19) era. Secondarily, it aimed to correlate these standards with national and international benchmarks. This ambidirectional cohort study enrolled 4668 patients (6419 CT-based examinations) who visited King Fahd Hospital of the University from May 25, 2021, to November 4, 2021. Participants' demographic data were acquired from their electronic medical charts, in addition to all corresponding CT-dose determinant parameters. The study was divided into two phases (pre- and post-data management) based on the implementation of digital data management software. In both phases of the study, the size-specific dose estimate (SSDE) was the most significant confounder of dose determination compared to the dose-length product (DLP) and computed tomography dose index (CTDI) (P = 0.003). The head was the most frequently imaged body region (pre-implementation, 1051 examinations [35.1%]; post-implementation, 1071 examinations [31.3%]; P = 0.001), followed by the abdominal region (pre-implementation, 616 examinations [20.6%]; post-implementation, 256 examinations [7.48%]; P = 0.001). Based on the SSDE, DLP, and volume CTDI, the average per-section radiation exposure among organ-based scanning type was highest for the lumbar spine during the pre- and post-implementation periods. Data management software enabled the establishment of DRLs and reduction of ADs in CT examinations, which consequently improved key performance indicators, despite the ergonomic complexities of COVID-19. Institutions are encouraged to apply DRLs and ADs via automatic systems that monitor patient dose indices to evaluate aggregate results.


Targeting Key Metabolic Enzymes Involved in Lipid and Protein Biosyntheses for Breast Anticancer Therapies.
The evolution of genomic research enabled the genetic and molecular profiling of breast cancer and revealed the profound complexity and heterogeneity of this disease. Subtypes of breast cancer characterized by mutations and/or amplifications of some proto-oncogenes are associated with an increased rate of recurrence and poor prognosis. They represent a challenge in the clinic with limited arsenal to attack them. Nowadays, metabolic reprogramming is firmly established as a hallmark of cancer. An increased rate of lipid and protein syntheses in cancerous tissues, a direct consequence of alterations in key metabolic enzymes involved in these pathways, is now recognized as an important aspect of the rewired metabolism of neoplastic cells. Over the past several years, accumulating evidence has revealed that mutations or amplifications of some proto-oncogenes are primarily involved in this metabolic dysregulation. It is thus critically important to dissect the molecular mechanisms tumors use to link metabolic reprogramming with upstream altered signaling. In this article, we review the recent findings that support the importance of lipid and protein biosyntheses in breast tumorigenesis, discuss the crosstalk between growth factor signal transduction and key metabolic enzymes involved in these processes, and point out the potentials of developing new strategies and therapeutics to target these key parameters in order to help breast cancer patients by providing new therapeutic opportunities.


Cumulative Effects of Constituents from the Mushroom Calvatia nipponica on the Contractility of Penile Corpus Cavernosum Smooth Muscle.
Calvatia nipponica, a puffball mushroom (Agaricaceae), is thought to be an aphrodisiac, as this mushroom is traditionally known to improve sexual function in males. As part of the systematic study to determine the bioactive secondary metabolites from C. nipponica responsible for aphrodisiac effects, chemical analysis of methanol (MeOH) extracts of the fruiting bodies of C. nipponica resulted in the isolation of two major compounds: N,N-dimethyl-anthranilic acid (1) and (7Z,10Z)-7,10-octadecadienoic acid methyl ester (2). Compounds 1 and 2 were evaluated for cumulative dose-dependent relaxation responses to precontracted penile corpus smooth muscle (PCCSM). Results show that compounds 1 and 2 exhibited a maximum relaxation effect of 20.33 ± 2.18% and 24.63 ± 3.60%, respectively. These findings indicate that compounds 1 and 2, major components of C. nipponica, could potentially be used to treat erectile dysfunction, functioning as natural aphrodisiacs.


Managing the patient with episodic sinus tachycardia and orthostatic intolerance.
Patients with episodic sinus tachycardia and associated orthostatic intolerance present a diagnostic and management dilemma to the clinician. We define this group of disorders to include sinus node reentrant tachycardia (SNRT), inappropriate sinus tachycardia (IAST), and postural orthostatic tachycardia syndrome (POTS). After a brief review of the current understanding of the pathophysiology and epidemiology of this group of disorders, we focus on the diagnosis and management of IAST and POTS. Our approach attempts to recognize the considerable overlap in pathophysiology and clinical presentation between these two heterogeneous conditions. Thus, we focus on a mechanism-based workup and therapeutic approach. Sinus tachycardia related to identifiable causes should first be ruled out in these patients. Next, a basic cardiovascular and autonomic workup is suggested to exclude structural heart disease, identify a putative diagnosis, and guide therapy. We review both nonpharmacologic and pharmacologic therapy, with a focus on recent advances. Larger randomized control trials and further mechanistic studies will help refine management in the future.


Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study.
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase and a proposed cardiovascular risk factor, is elevated in chronic kidney disease (CKD). Pharmacological strategies that lower plasma concentration of ADMA may be expected to increase nitric oxide (NO.) bioavailability and potentially limit atherosclerosis. We hypothesized that the antioxidant alpha-tocopherol (vitamin E) reduces ADMA levels in CKD. An open-label pilot interventional study using 800 IU of vitamin E was undertaken in eight stable out-patients with non-diabetic CKD (creatinine clearance <30 ml/min/1.73 m(2)) and six healthy controls, with the objective of measuring plasma ADMA levels at baseline and after 8 weeks of treatment. Plasma ADMA, symmetric dimethylarginine (SDMA) and alpha-tocopherol concentrations were determined at study entry and exit using high-performance liquid chromatography, while plasma total F2-isoprostanes, an index of oxidative stress, were measured using a commercially available enzyme-linked immunosorbent assay kit. ADMA and SDMA concentrations were significantly higher in the plasma of patients compared with that of controls (P </= 0.001). After treatment with vitamin E, ADMA decreased by 23% in six of eight patients (P <0.001). The remaining two patients showed either an increase or no change (overall, P = 0.16). There was no significant change in plasma F2-isoprostanes with vitamin E treatment for 8 weeks. Antioxidant therapy with vitamin E has the potential to lower ADMA levels in CKD patients, implying increased NO. availability. This strategy merits further exploration in the setting of CKD prior to renal replacement.


Different activation of the endothelial L-arginine and cyclooxygenase pathway in the human internal mammary artery and saphenous vein.
The endothelium releases substances controlling vascular tone and platelet function. We investigated mediators of endothelium-dependent responses in human internal mammary arteries and saphenous veins. The inhibitor of nitric oxide formation, NG-monomethyl L-arginine, enhanced the sensitivity to norepinephrine (fivefold) and evoked more pronounced endothelium-dependent contractions in internal mammary arteries (19 +/- 6% of 100 mM KCl) than in saphenous veins (2 +/- 1%; p less than 0.005). In internal mammary arteries, NG-monomethyl L-arginine, but not indomethacin, markedly reduced endothelium-dependent relaxations to acetylcholine (from 95 +/- 2% to 39 +/- 7%; p less than 0.005) and prevented those to histamine (78 +/- 6% to 4 +/- 3%; p less than 0.005). In saphenous veins, endothelium-dependent relaxations to acetylcholine were weak (24 +/- 11%), while nitric oxide caused comparable relaxations (85 +/- 3%) as in internal mammary arteries (80 +/- 5%; NS). NG-Monomethyl L-arginine prevented the relaxations to acetylcholine and unmasked endothelium-dependent contractions (30 +/- 10%). Indomethacin and the thromboxane synthetase inhibitor CGS-13080 augmented relaxations of saphenous veins to acetylcholine from 24 +/- 11% to 46 +/- 9% (p less than 0.05). Histamine-evoked contractions were converted to endothelium-dependent relaxations by indomethacin and the thromboxane A2/endoperoxide receptor antagonist SQ-30741 (38 +/- 3% and 40 +/- 6%; p less than 0.05) but not CGS-13080. Thus, 1) nitric oxide mediates endothelium-dependent relaxations in human arteries and veins; 2) internal mammary arteries release more nitric oxide than do saphenous veins, and 3) in saphenous veins, the effects of nitric oxide are reduced by endothelium-derived contracting factors originating from the cyclooxygenase pathway.


Transceptors as a functional link of transporters and receptors.
Cells need to communicate with their environment in order to obtain nutrients, grow, divide and respond to signals related to adaptation in changing physiological conditions or stress. A very basic question in biology is how cells, especially of those organisms living in rapidly changing habitats, sense their environment. Apparently, this question is of particular importance to all free-living microorganisms. The critical role of receptors, transporters and channels, transmembrane proteins located in the plasma membrane of all types of cells, in signaling environmental changes is well established. A relative newcomer in environment sensing are the so called transceptors, membrane proteins that possess both solute transport and receptor-like signaling activities. Now, the transceptor concept is further enlarged to include micronutrient sensing via the iron and zinc high-affinity transporters of Saccharomyces cerevisiae. Interestingly, what seems to underline the transport and/or sensing function of receptors, transporters and transceptors is ligand-induced conformational alterations recognized by downstream intracellular effectors.


The cost of implementing inpatient bar code medication administration.
To calculate the costs associated with implementing and operating an inpatient bar-code medication administration (BCMA) system in the community hospital setting and to estimate the cost per harmful error prevented. This is a retrospective, observational study. Costs were calculated from the hospital perspective and a cost-consequence analysis was performed to estimate the cost per preventable adverse drug event averted. Costs were collected from financial records and key informant interviews at 4 not-for profit community hospitals. Costs included direct expenditures on capital, infrastructure, additional personnel, and the opportunity costs of time for existing personnel working on the project. The number of adverse drug events prevented using BCMA was estimated by multiplying the number of doses administered using BCMA by the rate of harmful errors prevented by interventions in response to system warnings. Our previous work found that BCMA identified and intercepted medication errors in 1.1% of doses administered, 9% of which potentially could have resulted in lasting harm. The cost of implementing and operating BCMA including electronic pharmacy management and drug repackaging over 5 years is $40,000 (range: $35,600 to $54,600) per BCMA-enabled bed and $2000 (range: $1800 to $2600) per harmful error prevented. BCMA can be an effective and potentially cost-saving tool for preventing the harm and costs associated with medication errors.


N439K Variant in Spike Protein Alter the Infection Efficiency and Antigenicity of SARS-CoV-2 Based on Molecular Dynamics Simulation.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), has been undergoing various mutations. The analysis of the structural and energetic effects of mutations on protein-protein interactions between the receptor binding domain (RBD) of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) or neutralizing monoclonal antibodies will be beneficial for epidemic surveillance, diagnosis, and optimization of neutralizing agents. According to the molecular dynamics simulation, a key mutation N439K in the SARS-CoV-2 RBD region created a new salt bridge with Glu329 of hACE2, which resulted in greater electrostatic complementarity, and created a weak salt bridge with Asp442 of RBD. Furthermore, the N439K-mutated RBD bound hACE2 with a higher affinity than wild-type, which may lead to more infectious. In addition, the N439K-mutated RBD was markedly resistant to the SARS-CoV-2 neutralizing antibody REGN10987, which may lead to the failure of neutralization. The results show consistent with the previous experimental conclusion and clarify the structural mechanism under affinity changes. Our methods will offer guidance on the assessment of the infection efficiency and antigenicity effect of continuing mutations in SARS-CoV-2.


Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma.
Leveraging the conserved cancer genomes across mammals has the potential to transform driver gene discovery in orphan cancers. Here, we combine cross-species genomics with validation across human-dog-mouse systems to uncover a new bone tumor suppressor gene. Comparative genomics of spontaneous human and dog osteosarcomas (OS) expose Disks Large Homolog 2 (DLG2) as a tumor suppressor candidate. DLG2 copy number loss occurs in 42% of human and 56% of canine OS. Functional validation through pertinent human and canine OS DLG2-deficient cell lines identifies a regulatory role of DLG2 in cell division, migration and tumorigenesis. Moreover, osteoblast-specific deletion of Dlg2 in a clinically relevant genetically engineered mouse model leads to acceleration of OS development, establishing DLG2 as a critical determinant of OS. This widely applicable cross-species approach serves as a platform to expedite the search of cancer drivers in rare human malignancies, offering new targets for cancer therapy.


Ipilimumab as a Cause of Severe Pan-Colitis and Colonic Perforation.
Ipilimumab is a human monoclonal antibody that functions as a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor that is used to treat malignant melanoma. Due to ipilimumab's removal of immune regulation, specifically through the inactivation of CTLA-4, it is commonly associated with inflammatory and autoimmune events. Gastrointestinal (GI) related immune-related adverse events such as diarrhea occur in 29% of patients with 7.6% of patients specifically suffering from colitis. We describe a case of colonic perforation with ipilimumab use. Our goal is to raise awareness and alert practicing gastroenterologists of this particular adverse effect. A 74-year-old male patient presented to the emergency department with complaints of hematochezia, abdominal pain and decreased appetite. The patient's past medical history included desmoplastic BRAF mutation negative melanoma with metastatic disease to the face, liver, and trigeminal nerve. He underwent his last treatment of ipilimumab three weeks prior to presentation. In total, the patient received four doses of 3 mg/kg of ipilimumab every three weeks. Since the initiation of ipilimumab, he reported diarrhea as its adverse effect, which was treated with tapering doses of prednisone one month at a time. Colonoscopy revealed mucosal ulceration and erosion in the rectum, sigmoid colon, and remaining descending colon up to the splenic flexure and cecum. After the colonoscopy, the patient became tachycardic, hypotensive and complained of sudden abdominal pain. A computed tomographic (CT) scan of the abdomen showed free intraperitoneal air. He was immediately taken to the operating room (OR) for an emergent laparotomy. In the operating room, perforations were noted at the splenic flexure and the cecum with large amounts of succus spilling from the perforations. The majority of the large bowel appeared cyanotic and dusky; consequently, a sub-total colectomy with terminal ileostomy was performed. After the procedure, the patient was started on antibiotics for severe peritonitis and admitted to the intensive care unit (ICU) with septic shock. His clinical status continued to deteriorate due to acute respiratory failure, nosocomial pneumonia, severe protein calorie malnutrition and coagulopathy from disseminated intravascular coagulation (DIC). The patient did not recover from his illness and died a few days later. It is imperative that physicians caring for patients receiving treatment with CTLA-4 inhibitors frequently monitor for and promptly treat possible immune-related adverse effects. For patients with ipilimumab-related colitis, prompt identification of symptoms and early treatment with steroids are crucial in preventing harmful or possibly fatal immune-related adverse events. Gastroenterologists should be wary of this adverse side effect in this high-risk population when performing colonoscopy and take necessary precautions.


Expression of Myosin heavy chain isoforms in rat soleus muscle spindles after 19 days of hypergravity.
The aim of this study was to determine whether a period of 19 days in hypergravity was long enough to induce changes in the expression of myosin heavy chain (MyHC) isoforms in the muscle spindles. The soleus muscle of 10 male Wistar rats (control: CONT, n=5; hypergravity: HG, n=5) was frozen, cut into serial sections, and labeled with antibodies against MyHCs: I, IIA, IIA + IIX + IIB, slow-tonic, and alpha-cardiac. Forty CONT and 45 HG spindles were analyzed. The results from HG spindles compared to CONT showed that there was no change in the cross-sectional area of intrafusal fibers. However, along the entire length of B1 fibers, the expression of both MyHC I and alpha-cardiac was increased significantly, whereas the labeling against MyHC IIA and MyHC slow-tonic was decreased. In B2 fibers, the labeling against MyHC IIA (region A), slow-tonic (region A), and fast myosins (regions A-C) was statistically decreased. In chain fibers, the labeling against both MyHC IIA and fast MyHC was reduced significantly. We conclude that hypergravity has a real impact on the MyHC content in the muscle spindles and induces some inverse changes of those observed in hypogravity for MyHCs I, alpha-cardiac, and slow-tonic.


Non-Vitamin K Antagonist Oral Anticoagulants: The Clinician's New Challenge.
Millions of US patients are prescribed oral anticoagulants. Traditionally, oral anticoagulation was achieved with vitamin K antagonists (VKAs). In recent years, non-VKA oral anticoagulants (NOACs) have emerged that provide an effective and convenient alternative to VKAs. These agents possess very different pharmacologic properties from what the medical community has grown accustom to with the VKAs. Thus, a new knowledge base is required for NOACs. One particular challenge with the NOACs is the lack of specific reversal agent, resulting in difficulties correcting the coagulopathy induced by these drugs when needed. A review of the current literature is presented to assist clinicians in gaining knowledge of the NOACs to care for patients.


The influence of housing on sexual and reproductive health status and service utilization among Filipina migrant domestic workers in Macao (SAR), China: A population survey.
Sexual and reproductive health (SRH) and service utilization among female migrant domestic workers are under-studied. No studies to date have investigated the unique health vulnerabilities that affect female foreign domestic workers. The objective of this study was to investigate how stay-in and stay-out living conditions in domestic work may differentially affect SRH status, service utilization, and sexual risk behavior among female migrant domestic workers in Macao (SAR), China. Data were analyzed from a cross-sectional survey conducted between November 2016 and August 2017 among 1368 female Filipina migrant domestic workers living and working in Macao. Participants were recruited through respondent-driven sampling. Bivariable and multivariable logistic regression analyses were used to assess relationships between living context and outcomes of interest. Domestic workers' living context (i.e. stay-in versus stay-out) was significantly related to sexual risk behavior patterns and SRH status and service utilization. Compared to stay-out workers, stay-in workers had reduced odds of sexual risk behaviors but were also more likely to report that their sexual partners were likely to have concurrent sexual partners. In addition, stay-in workers had significantly decreased odds of having visited an OBGYN in Macao in the past year. This research is the first to evaluate the impact of stay-in and stay-out conditions within a foreign domestic worker population. This study further provides novel evidence of contextual factors (e.g. financial, employment, living conditions) that contribute to inequalities in SRH status and service utilization among Filipina migrant domestic workers. Results indicate that living context is significantly correlated with sexual risk behaviors, SRH status, and service utilization among domestic workers in Macao, highlighting the need to more effectively tailor specific interventions to meet female domestic workers' needs.


The use of oral sedatives in dental care.
Oral administration of tranquilizing and anxiety-suppressing drugs has long been the commonest method of achieving light sedation. The benzodiazepines are the drugs of first choice. Benzodiazepines given orally may be indicated to avoid 'treatment stress', alleviate mild anxiety before dental treatment, and facilitate sleep on the night before the treatment. Furthermore, they could be used for the dental treatment of medically poor risk patients, particularly those with cardiovascular disease. The drug can be given either in a fractionated dose or a single dose. The recommended doses for diazepam vary from 0.1-0.8 mg/kg body weight, depending on age, with higher doses in children and lower doses in elderly patients. Few side effects are reported.


Cavity equations for a positive- or negative-refraction-index material with electric and magnetic nonlinearities.
We study evolution equations for electric and magnetic field amplitudes in a ring cavity with plane mirrors. The cavity is filled with a positive or negative-refraction-index material with third-order effective electric and magnetic nonlinearities. Two coupled nonlinear equations for the electric and magnetic amplitudes are obtained. We prove that the description can be reduced to one Lugiato-Lefever equation with generalized coefficients. A stability analysis of the homogeneous solution, complemented with numerical integration, shows that any combination of the parameters should correspond to one of three characteristic behaviors.


Genetic variation within species and haplotypes of the Wiseana (Lepidoptera: Hepialidae) complex and development of non-sequenced based identification tools to aid field studies.
Porina is the common name used to describe moths and caterpillars of the seven endemic species and three haplotypes of Wiseana in New Zealand. Several species have adapted to eating introduced pasture plants; however, a paucity of defining morphological characteristics has meant that porina are grouped as indistinguishable species within a complex. This study aimed to develop non-sequencing identification methods for porina species. We sequenced 1718 bp of the mitochondrial cytochrome oxidase genes for all Wiseana species and haplotypes using 75 specimens collected from 42 sites throughout New Zealand. Two identification methods were developed; the high-resolution melt method uses 106 bp of the cytochrome oxidase I gene, and the restriction fragment polymorphism method uses a larger 700 bp region from the same gene. Validation was performed on a further 275 specimens. Melt curve profiles varied more with population heterogeneity than digest results. In both methods, W. mimica and W. jocosa were inseparable. W. fuliginea grouped with W. mimica and W. jocosa in the restriction method, but the melt curve profile differed. Until now, ecological studies of porina at the species level have been implausible. Our non-sequencing based methods allow rapid identification of moths and caterpillars to species and haplotype level, paving the way for ecological studies of pasture pest species and the development of species-specific mitigation strategies. © 2017 Society of Chemical Industry.


Lignans from the aerial parts of Saururus chinensis: isolation, structural characterization, and their effects on platelet aggregation.
Five new diaryldimethylbutane lignans, saurulignans A-E (1-5), four new tetrahydrofuran lignans, saurufurins A-D (6-9), and one arylnaphthalene lignan, saurunarin (10), were isolated from Saururus chinensis, along with 18 known compounds. Lignan 5 showed significant inhibition of ADP-induced aggregation with an IC50 value of 9.8 μM and AA-induced aggregation with an IC50 value of 14.0 μM. Compound 19 showed significant activity to inhibit PAF-induced aggregation with an IC50 value of 9.1 μM. In addition, five isolated compounds could induce platelet aggregation. These results suggest that secondary metabolites in S. chinensis have bidirectional regulation on blood clotting and anticlotting effects.


Kind and estimated stocking amount of antidotes for initial treatment for acute poisoning at emergency medical centers in Korea.
Antidotes for toxicological emergencies can be life-saving. However, there is no nationwide estimation of the antidotes stocking amount in Korea. This study tried to estimate the quantities of stocking antidotes at emergency department (ED). An expert panel of clinical toxicologists made a list of 18 emergency antidotes. The quantity was estimated by comparing the antidote utilization frequency in a multicenter epidemiological study and the nation-wide EDs' data of National Emergency Department Information System (NEDIS). In an epidemiological study of 11 nationwide EDs from January 2009 to December 2010, only 92 (1.9%) patients had been administered emergency antidotes except activated charcoal among 4,870 cases of acute adult poisoning patients. Comparing with NEDIS data, about 1,400,000 patients visited the 124 EDs nationwide due to acute poisoning and about 103,348 adult doses of the 18 emergency antidotes may be required considering poisoning severity score. Of these, 13,224 (1.9%) adult doses of emergency antidotes (575 of atropine, 144 of calcium gluconate or other calcium salts, 2,587 of flumazenil, 3,450 of N-acetylcysteine, 5,893 of pralidoxime, 287 of hydroxocobalamin, 144 of sodium nitrite, and 144 of sodium thiosulfate) would be needed for maintaining the present level of initial treatment with emergency antidotes at EDs in Korea.


Traumatic persistent trigeminal artery--cavernous sinus fistula treated by transcatheter arterial embolization. A case report.
We describe a rare case of traumatic persistent trigeminal artery (PTA) - cavernous sinus fistula. Cerebral angiography showed direct communication between the right PTA and the cavernous sinus which was treated by transcathether arterial embolization. Although previous reports have indicated the use of more coils to treat this condition, we successfully treated the patient with only two coils placed near the orifice of the fistula after sufficient anatomical evaluation.


Surface properties determine bioadhesive outcomes: methods and results.
This investigation developed experimental evidence for the influence of different surface energy states on tissue incorporation of biomedical materials. Implants of two smooth metals, each with three different surface energy states, were placed in the subdermal fascial plane of the backs of New Zealand White rabbits and were allowed healing times of 10 and 20 days. The implant surfaces were thoroughly characterized by physical-chemical criteria prior to surgical placement and again following removal from the tissue capsules generated by the host animals. Quantitative histopathologic analysis, using standard morphometric criteria, of the adjacent tissues revealed up to a threefold increase of fibroblastic-fibrocytic cells against the initially scrupulously cleaned, high-surface-energy materials. The cells were flattened and active, producing tenacious bonds through a thin pre-adsorbed protein-dominated "conditioning" film, that could be broken only by cohesive failure in the tissue itself. In contrast, the lower-surface-energy materials typical of standard dental implants were "walled off" by a cell-poor, nonadhesive capsule with a fibrous interface separated from a thicker "conditioning" film by a lipid-rich mucus zone. The advantages of proper surface treatment to favor the desired degree of biological adhesion are apparent.


3-Hydroxyisobutyryl-CoA hydrolase involved in isoleucine catabolism regulates triacylglycerol accumulation in Phaeodactylum tricornutum.
Since methylmalonyl-CoA epimerase appears to be absent in the majority of photosynthetic organisms, including diatoms, (S)-methylmalonyl-CoA, the intermediate of isoleucine (Ile) catabolism, cannot be metabolized to (R)-methylmalonyl-CoA then to succinyl-CoA. In this study, propionyl-CoA carboxylase (PCC) RNAi silenced strains and 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) overexpression strains were constructed to elucidate the Ile degradation pathway and its influence on lipid accumulation in Phaeodactylum tricornutum based on growth, neutral lipid content and metabolite profile analysis. Knockdown of PCC disturbed the metabolism of Ile through propionyl-CoA to methylmalonyl-CoA, as illustrated by much higher Ile content at day 6. However, Ile decreased to comparable levels to the wild-type at day 10. PCC silencing redirected propionyl-CoA to acetyl-CoA via a modified β-oxidation pathway, and transcript levels for some branched-chain amino acid (BCAA) degradation-related genes, especially HIBCH, significantly upregulated in the PCC mutant, which enhanced the BCAA degradations and thus resulted in higher triacylglycerol (TAG) content. Overexpression of HIBCH accelerates Ile degradation and results in a lowered Ile content in the overexpression strains, thus enhancing carbon skeletons to the tricarboxylic acid cycle and giving rise to increasing TAG accumulation. Our study provides a good strategy to obtain high-lipid-yield transgenic diatoms by modifying the propionyl-CoA metabolism.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'.


Familial hemophagocytic lymphohistiocytosis.
The cytologic features of familial hemophagocytic lymphohistiocytosis in two infant siblings were reviewed and compared to the histopathologic features in the same cases. The cytologic features of familial hemophagocytic lymphohistiocytosis in imprint smears from the spleen, lymph nodes, and liver were distinct, with proliferation of benign histiocytes engulfing erythrocytes and platelets. Hemophagocytic activity was more readily identifiable in imprint smears than in paraffin-embedded histologic sections. The differential diagnosis of histiocytic proliferative syndromes is also discussed.


Assessing potency of high- and low-preference reinforcers with respect to response rate and response patterns.
Previous research has suggested that the availability of high-preference stimuli may override the reinforcing efficacy of concurrently available low-preference stimuli under relatively low schedule requirements (e.g., fixed-ratio 1 schedule). It is unknown if similar effects would be obtained under higher schedule requirements. Thus, the current study compared high-preference and low-preference reinforcers under progressively increasing schedule requirements. Results for 3 of the 4 participants indicated that high-preference stimuli maintained responding under higher schedule requirements relative to low-preference stimuli. For 1 participant, high-preference and low-preference stimuli were demonstrated to be equally effective reinforcers under increasing schedule requirements. Implications with respect to rate of performance and response patterns are discussed.


Erectile dysfunction after PlasmaKinetic vaporization of the prostate: incidence and risk factors.
To determine the incidence of erectile dysfunction (ED) after PlasmaKinetic vaporization of the prostate (PKVP) using objective and subjective parameters and risk factors. A total of 153 men completed a questionnaire detailing perceived sexual dysfunction and underwent nocturnal penile-tumescence testing using the RigiScan for three consecutive nights 3 or 4 days preoperatively and 3 months postoperatively. The International Index of Erectile Function (IIEF)-5 scores were obtained preoperatively and postoperatively. Full details of each operation were recorded, including grams of tissue resected, operative time, any short-term complications, especially emphasizing capsular perforation, and concomitant diseases such as diabetes and hypertension. The association of risk factors with the development of ED after PKVP was assessed. Complete data were available for 103 men (67.3%). Their mean age was 62.1 years (range 48-83 years). Postoperatively, 11 patients (10.6%) were found to have ED. Patients who developed ED postoperatively had a lower IIEF-5 score and penile-tumescence parameters preoperatively (for all parameters, P < 0.0001). As risk factors, diabetes, capsular perforation, and an IIEF-5 score <21 were found to be significant. The incidence of ED after PKVP measured objectively was 10.6%. In the absence of the risk factors, PKVP is a safe therapeutic strategy with regard to sexual function.


Rate of health insurance reimbursement and adherence to anti-hypertensive treatment among Japanese patients.
Although several studies have reported the effects of free medical care on compliance in patients with hypertension, no study has reported the effects of an economic incentive, such as subsidized medical costs, on compliance with medication protocol, in patients with hypertension. The unique characteristics of the Japanese health insurance system provide for a 10% decrease in the subsidy for medication immediately on retirement (approximately 60 years of age) for insured patients, and a 100% subsidy for insured patients who are 70 years of age or older. We examined the association between level of health insurance coverage and follow-up rate of medical treatment among Japanese patients with hypertension. The subjects, from throughout Japan, were patients with hypertension (n=1236). The study was conducted in 1991. The odds of completing a 1-year treatment in relation to the rate of health insurance reimbursement were calculated using multiple logistic regression analysis. We found the following. (1) Compared with the base group, the odds of completing a 1-year treatment increased to 2.62 or 2.51 in the group whose reimbursement rate was 100%. (2) Compared with the base group, the odds of completing a 1-year treatment was no larger than 1 in the group whose reimbursement rate had been 100% for more than 6 years ('76-'). (3) Compared with the base level, the odds of completing a 1-year treatment increased to 1-1.81 in the group whose liability decreased to 80%. Although the results imply that even a small economic incentive might be effective in securing a patient's compliance with anti-hypertensive medical treatment, the effect appear limited in both duration and magnitude.


Retrospective analysis of onychomycosis prescribing patterns using the medicare part D prescribers database 2016-2020.
Onychomycosis, defined as a fungal nail infection, affects 5.5% of the global population. Our objectives were to analyse prescription trends of onychomycosis medications using the Medicare Part D Prescribers database from 2016 to 2020, stratified by physician specialty. There was a 4% annual increase in the total cost of onychomycosis medications, with a notable decrease of 12.8% in 2020 during the COVID-19 pandemic. Physicians demonstrated a strong consideration for price when selecting treatments, with the least expensive medications (ciclopirox and terbinafine) accounting for nearly 99% of all prescriptions. In contrast, the more costly medications (efinaconazole and tavaborole) were rarely prescribed. In addition, physicians often opted for the less costly generic versions of ciclopirox and itraconazole, prescribing them 99% and 91% of the time, respectively. Notably, physician assistants and nurse practitioners had higher overall increases in prescription rates, at 15%, compared to 1%-6% for other specialties. There are no recent United States onychomycosis guidelines, and our study emphasizes cost considerations when prescribing onychomycosis treatments.


Age-related differences in the motor unit action potential size in relation to recruitment threshold.
Motor unit action potential size (MUAPsize ) versus recruitment threshold (RT) relationship analysis provides a non-invasive measure of motor unit (MU) hypertrophy; however, this method's ability to identify MU atrophy is unknown. This investigation sought to determine if MUAPsize versus RT relationship slope (APslope ) comparison could identify evidence of MU atrophy in older individuals. Surface electromyography signals were recorded from the first dorsal interosseous (FDI) of fourteen young (YG, age = 22·29 ± 2·79 years) and ten older (OG, 61·0 ± 2·0 years) subjects during a 50% maximal voluntary contraction (MVC) isometric trapezoidal muscle action. The signals were decomposed to yield a MUAPsize and RT for each MU. For each subject, the MUs recruited between 10% and 50% MVC were linearly regressed as a function of RT to calculate an individual APslope . FDI cross-sectional area (CSA) and echo intensity (EI) were quantified via ultrasonography. The mean APslope was lower for OG (0·033 ± 0·010 mV %MVC-1 ) than YG (0·056 ± 0·019 mV %MVC-1 ). OG and YG possessed similar CSAs (OG: 2·09 ± 0·31 cm2 ; YG: 2·08 ± 0·41 cm2 ); however, OG (53·25 ± 7·56 AU) had greater EI than YG (43·87 ± 7·59 AU). The lower OG mean APslope was due to smaller MUAPsizes of higher-threshold MUs, likely due to atrophy of muscle fibres that comprise those MUs. In support, similar CSA with greater EI indicated increased adipose and fibrous tissue and reduced contractile tissue in OG. Thus, MUAPsize versus RT relationship may provide a non-invasive measure of MU atrophy.


A new succinylcholine-based assay of plasma cholinesterase.
We describe a new method for measuring the in vitro rate of hydrolysis of the muscle relaxant succinylcholine. This substrate is hydrolyzed by plasma cholinesterase (EC 220.127.116.11). The resulting choline is determined by measuring the hydrogen peroxide formed on its oxidation by choline oxidase (EC 184.108.40.206). This is done by use of phenol and aminoantipyrine coupled to peroxidase, and yields an intense chromophore, Amax 500 nm. The assay requires 0.1 mL of plasma, and is precise and specific. The CV was 2.7% within run, 7.3% between run. For the usual (U variant) enzyme the Km is 53 mumol/L. Enzyme activity is removed by anticholinesterase antiserum, and is inhibited by dibucaine with a Ki of 2 mumol/L. Ten samples can be assayed in duplicate in an hour. This method is suited to routine use in any laboratory that has a simple spectrophotometer. The mean activity in 11 individuals with the cholinesterase phenotype UU was 105 U/L, for seven UA heterozygotes 61 U/L, and for three AA homozygotes 4 U/L. To the extent allowed by extrapolation from in vitro to in vivo results, this method should increase diagnostic accuracy and may directly predict duration of succinylcholine-induced apnea.


Supporting Community Partners in Reducing HIV-Related Health Disparities: Technical Assistance Across a Spectrum of Intensity.
The HIV epidemic remains a public health threat in the U.S., and the dissemination and implementation of evidence-based prevention and care programs are critical to addressing significant HIV health disparities. The provision of technical assistance (TA) to program providers and evaluators is key for uptake of these programs. The University of California San Francisco Prevention Research Center (UCSF PRC) model for TA delivery uses topics and strategies adapted to address HIV health disparities for a global audience. This model specifically matches TA requests to a TA provider who has expertise in that area upon receiving a request through various communication channels. Areas of expertise include research methods, community engagement strategies, interventions, and Implementation Sciences. Our evaluation of diverse TA services indicates that on-demand TA is effective for light-touch requests and well-suited for moderate to intensive requests. The model is a promising, broad-reaching, and responsive alternative for providing TA to a multitude of HIV workforce recipients.


Influence of age on carotid body size and arterial chemoreceptor reflex effects in spontaneously hypertensive (SHR) and normotensive rats.
In normotensive Wistar rats of a random-bred strain and in spontaneously hypertensive rats (SHR) of the Okamoto-Aoki-strain, the mean systemic arterial blood pressure, the pO2, pCO2, pH-values and the base excess of the arterial blood were measured during ventilating normal air as well as hypoxic (12.6% O2 in N2) and hyperoxic (100% O2) gas mixtures. The animals were anaesthetized and breathed spontaneously; they aged 5-6, 15-20, 30-40, and 50-70 weeks. The volume of their carotid bodies was determined morphometrically. When compared with the age-matched normotensive controls at an age of 5-6 weeks the SHR already exhibited slightly but significantly elevated blood pressures but had equal carotid body size and arterial carbon dioxide tension. In contrast, hypertensive animals in the established phase of hypertension (older than 15 weeks) showed greater carotid bodies and a highly significant respiratory alkalosis when compared with the corresponding age-group of the normotensive rats. The reactions of the mean systemic arterial blood pressure and the arterial pCO2 provoked by hypoxia and hyperoxia proved to be age-dependent in both the normotensive and hypertensive animals but this influence of age was different in the two strains of rats. The data support the concept that alterations of arterial chemoreceptor structures and reflex effects found in the established phase of hypertension are the result of this disease. Furthermore they indicate that, when interpreting arterial chemoreceptor reflex effects in hypertensive humans and animals, the stage of hypertension must be taken into account.


Influence of insoluble excipients on film coating systems.
Insoluble excipients are added to polymeric film coating solutions and dispersions to improve the physical appearance of dosage forms, enhance the stability of photolytic drugs, and aid in processing. These insoluble additives, however, may significantly affect the physical, mechanical, adhesive, and drug-release properties of the films. In this review, the theories of the interactions between polymer and insoluble excipient are addressed. This article also discusses the influence of the concentration, particle size, morphology, and surface chemistry of insoluble excipients on the various polymer properties.


Sealed with a Kiz: How Plk1 ensures spindle pole integrity.
The kinase Plk1 plays multiple roles in regulating mitotic progression, including stabilization of spindle poles, but its substrates are largely unknown. A new study by Yamamoto and coworkers has identified a centrosomal protein, Kizuna (Kiz), as a mitotic substrate of Plk1 (Oshimori et al., 2006). Phosphorylation of Kiz ensures the integrity of spindle poles in the face of severe pulling forces exerted by the chromosome-attached spindle microtubules.


PINOID AGC kinases are necessary for phytochrome-mediated enhancement of hypocotyl phototropism in Arabidopsis.
Several members of the AGCVIII kinase subfamily, which includes PINOID (PID), PID2, and WAVY ROOT GROWTH (WAG) proteins, have previously been shown to phosphorylate PIN-FORMED (PIN) auxin transporters and control the auxin flow in plants. PID has been proposed as a key component of the phototropin signaling pathway that induces phototropic responses, although the responses were not significantly impaired in the pid single and pid wag1 wag2 triple mutants. This raises questions about the functional roles of the PID family in phototropic responses. Here, we investigated hypocotyl phototropism in the pid pid2 wag1 wag2 quadruple mutant in detail to clarify the roles of the PID family in Arabidopsis (Arabidopsis thaliana). The pid quadruple mutants exhibited moderate responses in continuous light-induced phototropism with a decrease in growth rates of hypocotyls and normal responses in pulse-induced phototropism. However, they showed serious defects in enhancements of pulse-induced phototropic curvatures and lateral fluorescent auxin transport by red light pretreatment. Red light pretreatment significantly reduced the expression level of PID, and the constitutive expression of PID prevented pulse-induced phototropism, irrespective of red light pretreatment. This suggests that the PID family plays a significant role in phytochrome-mediated phototropic enhancement but not the phototropin signaling pathway. Red light treatment enhanced the intracellular accumulation of PIN proteins in response to the vesicle-trafficking inhibitor brefeldin A in addition to increasing their expression levels. Taken together, these results suggest that red light preirradiation enhances phototropic curvatures by up-regulation of PIN proteins, which are not being phosphorylated by the PID family.


High resolution soft x-ray spectroscopy of low Z K-shell emission from laser-produced plasmas.
A large radius, R=44.3 m, high resolution grating spectrometer (HRGS) with 2400 lines/mm variable line spacing has been designed for laser-produced plasma experiments conducted at the Lawrence Livermore National Laboratory Jupiter Laser Facility. The instrument has been run with a low-noise, charge-coupled device detector to record high signal-to-noise spectra in the 10-50 A wavelength range. The instrument can be run with a 10-20 microm wide slit to achieve the best spectral resolving power, approaching 1000 and similar to crystal spectrometers at 12-20 A, or in slitless operation with a small symmetrical emission source. We describe preliminary spectra emitted from various H-like and He-like low Z ion plasmas heated by 100-500 ps (full width at half maximum), 527 nm wavelength laser pulses. This instrument can be developed as a useful spectroscopy platform relevant to laboratory-based astrophysics as well as high energy density plasma studies.


A combined flexi-rule/hydrogoniometer for measurement of lumbar spine and its sagittal movement.
A portable device is described which can record contours of the spine when standing normally and in extreme postures of flexion and extension. It can also give a numerical record of the range of lumbar movement and of the angles to the vertical in which the sacrum and upper spine are held in relation to the lordotic curve. It is felt that the device may be useful for clinical reports, ongoing assessments of therapy, and for epidemiological studies. Its use as a predictor of those at risk to develop low-back pain or for prognosis in established cases remains to be tested. The device has been used in a back-pain clinic and in an epidemiological survey, where it has been found to be assay and quick to use. Further adaptations may be found to be desirable; these would not detract from the usefulness of the device in that successive readings would still be comparable.


Modern Spirometry Supports Anesthetic Management in Small Animal Clinical Practice: A Case Series.
Modern spirometry, like no other monitoring technique, allows insight into breath-to-breath respiratory mechanics. Spirometers continuously measure volume, airway pressure, and flow while calculating and continuously displaying respiratory system compliance and resistance in the form of loops. The aim of this case series is to show how observation of spirometric loops, similar to electrocardiogram or CO2 curve monitoring, can improve safety of anesthetic management in small animals. Spirometric monitoring cases described in this case series are based on use of the anaesthesia monitor Capnomac Ultima with a side stream spirometry sensor. The cases illustrate how recognition and understanding of spirometric loops allows for easy diagnosis of iatrogenic pneumothorax, incorrect ventilator settings, leaks in the system, kinked or partially obstructed endotracheal tube, and spontaneous breathing interfering with intermittent positive-pressure ventilation. The case series demonstrates the potential of spirometry to improve the quality and safety of anesthetic management, and, hence, its use can be recommended during intermittent positive-pressure ventilation and procedures in which interference with ventilation can be expected.


Enhancement of a pyroelectric body energy harvesting scheme employing pulsed electric fields.
This research utilizes waste heat energy as a sustainable energy source to enhance pyroelectric power output by combining pyroelectric nanogenerators with an external pulsed electric field. When the surface temperature of the pyroelectric body varies, applying different pulses of the external electric field results in maximum power accumulation. A novel power-generating experimental setup was developed to measure and compute pyroelectric power generation. A standard Fuji ceramic C-9 sample was used to generate pyroelectric energy in a 20 °C temperature range from 120 to 140 °C. The continuous temperature variation frequency was 0.05 Hz, and the pulsed electric field was applied when the temperature rose. Pulses of the electric field with widths of 10, 50, 100, and 200 ms were applied to the sample under different pulse amplitudes, and the amplitude of each pulse was 250, 500, 1000, or 1500 V/mm. The maximum power generated through the application of an external pulsed electric field under the above-mentioned conditions was evaluated. This system had the highest power density of 0.204 mJ cm-2 °C-1 kV-1. In addition, for the lowest input power, the maximum power generation condition was a 10 ms pulse width and an amplitude of 250 V mm-1 in the applied electric field. This state might power smart sensor modules, IoT devices, automobiles, and other waste heat energy applications. Nano-pulse electric field applications may reduce input power to its lowest level, dependent on net-producing power. Therefore, new researchers can use net-generation power efficiency to create a large-scale power source using multiple pyroelectric arrays.


Self-Assembled Chiral Nanostructures as Scaffolds for Asymmetric Reactions.
The asymmetric reaction is one of the most important reactions in organic synthesis. While a large number of efficient molecular catalysts have been developed and applied, recently, supramolecular and nanostructured catalysts have been attracting interest. In this Minireview, we focus on self-assembled chiral nanostructures and review their possibility and feasibility as enantioselective catalysts. The design concept and the requirement of the chiral scaffold as the catalysts are discussed. Based on the chirality and catalytic performance of the building molecules and the supramolecular nanostructures, the nanocatalyst is divided into chiral nanostructure driven (CND) and chiral nanostructure enhanced (CNE) enantioselective catalysts. Then, several typical self-assembled chiral nanostructures such as nanocages, nanotubes, nanorods, micelles and vesicles are selected as the chiral scaffold and their catalytic behaviors for the asymmetric reactions were demonstrated. Finally, the future developments of the field are also discussed.


Analysis of intracellular human immunodeficiency virus (HIV)-1 drug resistance mutations in multi-failed HIV-1-infected patients treated with a salvage regimen: 72-week follow-up.
The human immunodeficiency virus (HIV) mutational archive of proviral DNA was monitored during a 72-week follow-up in 20 multidrug-experienced HIV-1-infected patients treated with a darunavir/ritonavir-based salvage therapy. At the beginning of the study, all patients harboured a number of intracellular drug resistance-associated mutations (RAMs) in peripheral blood mononuclear cells. In some patients, a significant fluctuation in the number of RAMs was observed during the observation period. However, all patients, notwithstanding the presence or the fluctuation of intracellular RAMs, showed a persistently undetectable viraemia. The data suggest that the archived resistant viral variants change during suppressive therapy, but that the variants are unable to re-emerge and to affect virological response.


Noninfectious pulmonary complications of haematopoietic stem cell transplantation.
Haematopoietic stem cell transplantation (HSCT) is an established treatment for a variety of malignant and nonmalignant conditions. Pulmonary complications, both infectious and noninfectious, are a major cause of morbidity and mortality in patients who undergo HSCT. Recent advances in prophylaxis and treatment of infectious complications has increased the significance of noninfectious pulmonary conditions. Acute lung injury associated with idiopathic pneumonia syndrome remains a major acute complication with high morbidity and mortality. On the other hand, bronchiolitis obliterans syndrome is the most challenging chronic pulmonary complication facing clinicians who are taking care of allogeneic HSCT recipients. Other noninfectious pulmonary complications following HSCT are less frequent. This review provides a clinical update of the incidence, risk factors, pathogenesis, clinical characteristics and management of the main noninfectious pulmonary complications following HSCT.


PuReD-MCL: a graph-based PubMed document clustering methodology.
Biomedical literature is the principal repository of biomedical knowledge, with PubMed being the most complete database collecting, organizing and analyzing such textual knowledge. There are numerous efforts that attempt to exploit this information by using text mining and machine learning techniques. We developed a novel approach, called PuReD-MCL (Pubmed Related Documents-MCL), which is based on the graph clustering algorithm MCL and relevant resources from PubMed. PuReD-MCL avoids using natural language processing (NLP) techniques directly; instead, it takes advantage of existing resources, available from PubMed. PuReD-MCL then clusters documents efficiently using the MCL graph clustering algorithm, which is based on graph flow simulation. This process allows users to analyse the results by highlighting important clues, and finally to visualize the clusters and all relevant information using an interactive graph layout algorithm, for instance BioLayout Express 3D. The methodology was applied to two different datasets, previously used for the validation of the document clustering tool TextQuest. The first dataset involves the organisms Escherichia coli and yeast, whereas the second is related to Drosophila development. PuReD-MCL successfully reproduces the annotated results obtained from TextQuest, while at the same time provides additional insights into the clusters and the corresponding documents. Source code in perl and R are available from http://tartara.csd.auth.gr/~theodos/


Pharmacological overview of hederagenin and its derivatives.
Hederagenin is a pentacyclic triterpenoid isolated from plants and widely distributed in a variety of medicinal plants. By integrating and analyzing external related literature reports, the latest research progress on the pharmacological effects and structural modification of hederagenin was reviewed. Hederagenin has a wide range of pharmacological activities, including antitumor, anti-inflammatory, antidepressant, anti-neurodegenerative, antihyperlipidemic, antidiabetic, anti-leishmaniasis, and antiviral activities. Among them, it shows high potential in the field of anti-tumor treatment. This paper also reviews the structural modifications of hederagenin, including carboxyl group modifications and two hydroxyl group modifications. Future research on hederagenin will focus on prolonging its half-life, improving its bioavailability and structural modification to enhance its pharmacological activity, accelerating the preclinical research stage of hederagenin for it to enter the clinical research stage as soon as possible.


RhoA and RhoC are involved in stromal cell-derived factor-1-induced cell migration by regulating F-actin redistribution and assembly.
Stromal cell-derived factor-1 (SDF-1) signaling is important to the maintenance and progression of T-cell acute lymphoblastic leukemia by inducing chemotaxis migration. To identify the mechanism of SDF-1 signaling in the migration of T-ALL, Jurkat acute lymphoblastic leukemia cells were used. Results showed that SDF-1 induces Jurkat cell migration by F-actin redistribution and assembly, which is dependent on Rho activity. SDF-1 induced RhoA and RhoC activation, as well as reactive oxygen species (ROS) production, which was inhibited by Rho inhibitor. The Rho-dependent ROS production led to subsequent cytoskeleton redistribution and assembly in the process of migration. Additionally, RhoA and RhoC were involved in SDF-1-induced Jurkat cell migration. Taken together, we found a SDF-1/CXCR4-RhoA and RhoC-ROS-cytoskeleton pathway that regulates Jurkat cell migration in response to SDF-1. This work will contribute to a clearer insight into the migration mechanism of acute lymphoblastic leukemia.


Late-Stage Aryl C-H Bond Cyclopropenylation with Cyclopropenium Cations.
Herein, we disclose the first regio-, site- and chemoselective late-stage (hetero)aryl C-H bond cyclopropenylation with cyclopropenium cations (CPCs). The process is fast, operationally simple and shows an excellent functional group tolerance in densely-functionalized drug molecules, natural products, agrochemicals and fluorescent dyes. Moreover, we discovered that the installation of the cyclopropene ring in drug molecules could not only be used to shield against metabolic instability but also as a synthetic tool to reach medicinally-relevant sp3 -rich scaffolds exploiting the highly-strained nature of the cyclopropene ring with known transformations.


Titania Nanotubes/Hydroxyapatite Nanocomposites Produced with the Use of the Atomic Layer Deposition Technique: Estimation of Bioactivity and Nanomechanical Properties.
Titanium dioxide nanotubes/hydroxyapatite nanocomposites were produced on a titanium alloy (Ti6Al4V/TNT/HA) and studied as a biocompatible coating for an implant surface modification. As a novel approach for this type of nanocomposite fabrication, the atomic layer deposition (ALD) method with an extremely low number of cycles was used to enrich titania nanotubes (TNT) with a very thin hydroxyapatite coating. X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used for determination of the structure and the surface morphology of the fabricated nanocoatings. The biointegration activity of the layers was estimated based on fibroblasts' proliferation on the TNT/HA surface. The antibacterial activity was determined by analyzing the ability of the layers to inhibit bacterial colonization and biofilm formation. Mechanical properties of the Ti6Al4V/TNT/HA samples were estimated by measuring the hardness, Young's module, and susceptibility to scratching. The results revealed that the nanoporous titanium alloy coatings enriched with a very thin hydroxyapatite layer may be a promising way to achieve the desired balance between biofunctional and biomechanical properties of modern implants.


Energy and field size dependence of a silicon diode designed for small-field dosimetry.
To investigate the energy dependence/spectral sensitivity of silicon diodes designed for small-field dosimetry and obtain response factors (RFs) for arbitrary photon spectra using Monte Carlo (MC) simulations. The EGSnrc user-code DOSRZnrc was used to calculate the dose deposition in water and in the active volume of a stereotactic diode field detector (SFD). Then, the RFs of the SFD were calculated for several circular field sizes and energies at 5 cm depth in water. Several low-energy photon spectra (mean energy 55 to 200 keV), as well as Co-60 radiation (mean energy 1.25 MeV) and a 6 MV Elekta Synergy beam (mean energy 2.9 MeV), in 10 × 10 cm2 field size were used to validate the MC calculations, using a simple beam model. The RFs of the SFD detector for a 6 MV Elekta Synergy linac photon beam in different field sizes were calculated. These were also measured with EBT3 Gafchromic film and the SFD detector. For the reference field size, differences between measured and calculated RFs were less than 5% at mean energies below 1 MeV and less than 1% at energies above 1 MeV. The calculated RFs for a 6 MV Elekta Synergy linac photon beam as a function of different field sizes showed a good agreement between the measurements and previously reported results. This agreement was within 2% for all considered field sizes. While at high photon energies, the change of response of the SFD is marginal, whereas it is extreme at low energies. Therefore, it is desirable to benchmark response calculations also in the low-energy domain. Our results, with a simple beam model and geometry, indicate that a validation of the simulations by experimental results is achievable. The present work provides a comprehensive table that can be used to calculate SFD detector response factors depending on both, field size and photon energy.


Association of oligodendroglioma-like cell proliferation and angiomatous vasculature--coincidence or pathogenetically related lesions?
We report a case of an oligodendroglioma associated with a cavernous angioma. The patient, a 20-year-old man with an 8-year history of epileptic seizures, presented an acute onset of headache, nausea, and vomiting. Computerized tomographic scan and angiogram revealed multiple vascular malformations in both hemispheres including a cystic hemorraghic lesion with a perifocal edema attributing to a mass effect. Repeated puncture of the cyst failed to give improvement of elevated intracranial pressure. At surgery, the cyst and the underlying lesion were excised and found to be oligodendrocyte-rich tissue with malformed vascular tissue. Final histological examination revealed an oligodendroglioma associated with a cavernous angioma. As concurrence of oligodendroglioma and vascular malformation is rare, this case raises a broad range of differential diagnoses such as reactive oligodendroglial gliosis due to a vascular malformation, unusual vascularity of an oligodendroglioma as well as other kinds of cerebral tumors or malformations. The diagnostic difficulties as well as the pathogenetic and pathological significance of the concurrence of an oligodendroglioma and cavernous angioma are discussed.


Chemotherapeutic agents for controlling plaque and gingivitis.
There has been a vigorous search for many years for chemical agents that could supplement or even supplant patient-dependent mechanical plaque control and thus reduce or prevent oral disease. 5 categories of agents or approaches have been considered: (1) broad spectrum antiseptics, (2) antibiotics aimed at specific bacteria, (3) single or combinations of enzymes that could modify plaque structure or activity, (4) non-enzymatic dispersing or modifying agents and (5) agents that could affect bacterial attachment. The success of these approaches can be evaluated clinically by the use of standard scoring methods for measuring plaque and gingivitis and their safety established by soft tissue and microbiologic examination. Antiseptic agents have received the bulk of the attention over the years. At present, only 2 antiseptics, the bis-biguanide, chlorhexidine gluconate (Peridex) and a combination of phenol related essential oils (Listerine), have developed sufficient supporting data in 6-month (or longer) studies to gain the approval of the Council On Dental Therapeutics of the American Dental Association. On the basis of short-term studies, cetylpyridinium chloride, zinc and copper salts, sanguinarine and octenidine warrant continued study as does stannous fluoride at an appropriate concentration. On the basis of current research, a new generation of more specific antibacterial agents that interfere with attachment to pellicle can be developed. It is hard to predict, however, that they will affect gingivitis, at least until there is more information on what specific organisms should be targeted.


Inhibition of estrogen synthetase (aromatase) by 4-cyclohexylaniline.
4- Cyclohexylaniline , a structurally simple analog of the drug aminoglutethimide [d,l-3-(4-aminophenyl)3-ethyl-2, 6- piperidinedione ], was found to be an effective inhibitor of the aromatization of testosterone and androstenedione. With human placental microsomes, 4- cyclohexylaniline was a more potent aromatase inhibitor than d-aminoglutethimide. For androstenedione and testosterone aromatization, competitive inhibition by 4- cyclohexylaniline was observed; a Ki value of 0.14 microM was found with both substrates. A Ki value for d-aminoglutethimide inhibition of androstenedione aromatization of 0.3 microM was obtained. Kinetic analysis of the simultaneous inhibition by 4- cyclohexylaniline and d-aminoglutethimide suggests that both compounds bind to the same site on the enzyme. 4- Cyclohexylaniline and d-aminoglutethimide were also tested for inhibition of androstenedione aromatization in human and rat ovarian microsomes. With the human aromatase, both inhibitors exhibited approximately the same effectiveness; with rat aromatase, however, d-aminoglutethimide was more potent. 4- Cyclohexylaniline and d-aminoglutethimide were also assayed for their inhibition of cytochrome P-450-catalyzed cholesterol side-chain cleavage. When the enzyme from human placenta was used, 4- cyclohexylaniline was 24-fold less effective than d-aminoglutethimide, and when the purified bovine adrenal enzyme was used, it was 16-fold less effective. Thus, 4- cyclohexylaniline exhibits inhibitory specificity toward aromatase. Difference spectral measurements using crude placental microsomes and cholate extracts of these microsomes show that binding of 4- cyclohexylaniline produces a type II spectral change; this is indicative of coordination of the arylamine to the heme-iron of the aromatase cytochrome P-450. Consistent with this spectral finding was the fact that blockade of the amino group of both 4- cyclohexylaniline and d-aminoglutethimide by acetylation resulted in essentially complete loss of inhibitory activity toward aromatase. These findings establish that the arylamine moieties of both 4- cyclohexylaniline and d-aminoglutethimide are essential for their inhibitory actions. The potent aromatase inhibition by 4- cyclohexylaniline indicates that neither the complex glutarimide ring nor the chiral 3-ethyl substituent of d-aminoglutethimide is required for high affinity binding of this class of inhibitor to aromatase P-450.


Reduction in bacterial contamination of toothbrushes using the Violight ultraviolet light activated toothbrush sanitizer.
This two armed, self-controlled, investigator blinded, clinical study tested the efficacy of an ultraviolet (UV) light toothbrush holder (Violight) to decrease toothbrush bacterial contamination. 25 subjects were randomly assigned to control or experimental groups and received two toothbrushes for home use on either even or odd days. The control group rinsed both toothbrushes after use in cold tap water with no mechanical manipulation. The experimental group rinsed one toothbrush in cold running water while storing the other toothbrush in the Violight toothbrush holder after use. The toothbrushes were returned after 2 weeks use in sealed plastic bags and were analyzed for the number of colony forming units (CFU) of S. mutans, S. salivarius, lactobacilli, E. coli, and other coliforms, and total bacterial counts by culture. An additional analysis of the total bacterial profile was performed using denaturing gradient gel electrophoresis (DGGE). The Violight toothbrush holder reduced total CFU by an average of 86% (ANCOVA, P = 0.037). In addition, a tendency was noted for a reduction in total bacterial population as detected by DGGE.


Non-coding RNA derived from the region adjacent to the human HO-1 E2 enhancer selectively regulates HO-1 gene induction by modulating Pol II binding.
Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation. However, it remains unclear whether eRNAs are involved in the regulation of human heme oxygenase-1 gene (HO-1) induction. Here, we report that multiple nuclear-enriched eRNAs are transcribed from the regions adjacent to two human HO-1 enhancers (i.e. the distal E2 and proximal E1 enhancers), and some of these eRNAs are induced by the oxidative stress-causing reagent diethyl maleate (DEM). We demonstrated that the expression of one forward direction (5' to 3') eRNA transcribed from the human HO-1 E2 enhancer region (named human HO-1enhancer RNA E2-3; hereafter called eRNA E2-3) was induced by DEM in an NRF2-dependent manner in HeLa cells. Conversely, knockdown of BACH1, a repressor of HO-1 transcription, further increased DEM-inducible eRNA E2-3 transcription as well as HO-1 expression. In addition, we showed that knockdown of eRNA E2-3 selectively down-regulated DEM-induced HO-1 expression. Furthermore, eRNA E2-3 knockdown attenuated DEM-induced Pol II binding to the promoter and E2 enhancer regions of HO-1 without affecting NRF2 recruitment to the E2 enhancer. These findings indicate that eRNAE2-3 is functional and is required for HO-1 induction.


Laparoscopic living-donor nephrectomy.
In order to increase the number of renal donors, laparoscopic live-donor nephrectomy (LLDN) was first performed 8 years ago. Today, LLDN is a routine procedure in many centres worldwide. We reviewed the literature with regard to extend the use of this method, the feasibility and safety for donor, graft and recipient. Laparoscopic and open-donor nephrectomy are compared, and the impact of LLDN on donors' willingness is evaluated. Literature search (PubMed, DIMDI, Medline) for the period from 1995 to 2003. More than 200 centres worldwide perform LLDN. It is a feasible and safe surgical procedure. For the donor, LLDN has numerous advantages, while graft and recipient outcome are the same as with the open approach. The learning curve on the way to performing this operation safely is long, and surgeons planning to integrate LLDN into their programme must be trained thoroughly. There are some indications that with LLDN the number of donors willing to donate a kidney can be increased. LLDN is widely used and will spread further. It is of the utmost importance to undergo thorough laparoscopic training in general urology prior to performing this procedure.


SplicingCompass: differential splicing detection using RNA-seq data.
Alternative splicing is central for cellular processes and substantially increases transcriptome and proteome diversity. Aberrant splicing events often have pathological consequences and are associated with various diseases and cancer types. The emergence of next-generation RNA sequencing (RNA-seq) provides an exciting new technology to analyse alternative splicing on a large scale. However, algorithms that enable the analysis of alternative splicing from short-read sequencing are not fully established yet and there are still no standard solutions available for a variety of data analysis tasks. We present a new method and software to predict genes that are differentially spliced between two different conditions using RNA-seq data. Our method uses geometric angles between the high dimensional vectors of exon read counts. With this, differential splicing can be detected even if the splicing events are composed of higher complexity and involve previously unknown splicing patterns. We applied our approach to two case studies including neuroblastoma tumour data with favourable and unfavourable clinical courses. We show the validity of our predictions as well as the applicability of our method in the context of patient clustering. We verified our predictions by several methods including simulated experiments and complementary in silico analyses. We found a significant number of exons with specific regulatory splicing factor motifs for predicted genes and a substantial number of publications linking those genes to alternative splicing. Furthermore, we could successfully exploit splicing information to cluster tissues and patients. Finally, we found additional evidence of splicing diversity for many predicted genes in normalized read coverage plots and in reads that span exon-exon junctions. SplicingCompass is licensed under the GNU GPL and freely available as a package in the statistical language R at http://www.ichip.de/software/SplicingCompass.html


Repeat endovascular repair for multiple intimal tears after endovascular stent grafting of Stanford type B aortic dissection.
A 59-year-old man with hypertension was found to have a Stanford type B aortic dissection with a false lumen extending to the abdominal aorta. We placed a stent graft to the thoracic aorta covering the proximal entry and planned a second endovascular repair to cover the entries in the abdominal aorta. Five years later, computed tomography angiography revealed an extensive dissection to the right common iliac artery with multiple intimal tears. We placed stent grafts in the distal end of the primary stent graft and an abdominal stent graft to the aortic bifurcation to cover the entry tears. However, 3 months later it developed into a newly formed intimal tear in the right renal artery, leading to retrograde reperfusion into the false lumen. The patient was successfully treated with a third time endovascular repair and recovered smoothly during follow-up.


Safety of anti-TNF therapy in inflammatory bowel disease during pregnancy.
The highest incidence of inflammatory bowel disease (IBD) is seen between the second and fourth decades of life, which is the most fertile age for women. Increased disease activity has been shown to effect female fertility and pregnancy outcomes, stressing the need for drugs that can safely induce and maintain clinical remission without harming either the mother or fetus. Anti-TNF-α agents have been shown to be effective in both inducing and maintaining remission among IBD patients. This review highlights the results of previous studies conducted on pregnant women who were exposed to anti-TNF-α agents during the course of their pregnancy. The drugs reviewed include infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP) and golimumab (GMB). Of > 200 articles reviewed, 105 were included in the manuscript based on relevance. The keywords used were anti-TNF, infliximab, adalimumab, certolizumab, golimumab, biologics, pregnancy and inflammatory bowel disease. Anti-TNF agents have been studied extensively during pregnancy from the early case reports to the more recent prospective Pregnancy in IBD and Neonatal Outcomes study. A comprehensive review of the literature has shown that biologics can be safely used during pregnancy. In view of this safety data, it is recommended to maintain therapy during pregnancy.


Estradiol promotes cells invasion by activating β-catenin signaling pathway in endometriosis.
Endometriosis is an estrogen-dependent disease that involves the adhesion, invasion, and angiogenesis of endometrial tissues outside of the uterine cavity. We hypothesized that a link exists between estrogen and beta-catenin (β-catenin) signaling in the pathogenesis of endometriosis. Human endometrial stromal cells (HESCs) were separated from eutopic endometrial tissues that were obtained from patients with endometriosis. β-catenin expression and cells invasiveness ability were up-regulated by 17β-estradiol (E2) in an estrogen receptor (ESR)-dependent manner, whereas β-catenin siRNA abrogated this phenomenon. Moreover, co-immunoprecipitation and dual immunofluorescence studies confirmed ESR1, β-catenin, and lymphoid enhancer factor 1/T cell factor 3 co-localization in the nucleus in HESCs after E2 treatment. To determine the role of β-catenin signaling in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium from endometriosis patients into ovariectomized severe combined immunodeficiency mice. The implantation of the endometrium was suppressed by β-catenin siRNA. Collectively, studies regarding β-catenin signaling are critical for improving our understanding of the pathogenesis of estrogen-induced endometriosis, which can translate into the development of treatments and therapeutic strategies for endometriosis.


Molecular and Epidemiological Characterization of Infant Botulism in Beijing, China.
Laboratory-based pathogen isolation, identification, and toxicity determination were performed on samples from a suspected case of infant botulism. Mice injected with cultures generated from the enema sample and ingested Powered infant formula (PIF) presented typical signs of botulism. Antitoxins to polyvalent botulinum neurotoxins (BoNTs) and monovalent BoNT type B antitoxin had protective effects. Clostridium botulinum isolated from the enema and residual PIF samples were positive for type B toxin. Pulsed-field gel electrophoresis (PFGE) revealed that the two strains of C. botulinum isolated from the two samples produced indistinguishable pulsotypes. These findings confirmed this case of type B infant botulism associated with the ingestion of PIF contaminated by type B C. botulinum spores.


A case of mediastinal mesenchymal tumor resembling hemopericardium.
Mediastinal neoplasms are rare in the elderly, and clinical suspicion is the first and most important step of differential diagnosis. Mediastinal tumors can be misdiagnosed because their symptoms or signs can overlap with cardiovascular diseases, which have a higher prevalence among the older population. The diagnostic process should be managed with multimodality imaging and clinical judgement. Here, the case of a 74-year-old male patient, who presented with shortness of breath, is examined. A chest X-ray revealed an increased cardiothoracic ratio, and he was diagnosed with hemopericardium following an emergent chest computed tomography. In the echocardiography, it was suspected that a hyperechogenic area adjacent to the heart might be due to a mass, and further examinations confirmed a mediastinal neoplasm. A surgical biopsy was performed, and it was determined to be a mesenchymal tumor. To conclude, clinicians should keep in mind the possibility of paracardiac neoplasm in the elderly, as well as in other age groups, when encountering mediastinal widening so that the patient can be protected from unnecessary interventions such as pericardiocentesis.


[From physics to biology: the intrinsic dynamics of the cosmos].
The History of Universe is described in an extremely summarized manner through the use of graphics, from Big bang until today. This is done according to the most recent standard models of Cosmology and Physics of elementary particles; in other words, according to those fields in Physics of a presupposed universal reference. The History of Life is immersed in this universal physical context, in a frame where our knowledge from Geology and Biology can be only terrestrial. The underlying ideas we try to arise are: 1) the transition from a relatively elementary structure to a posterior and a relatively more complex one requires some very special "environmental" conditions; and 2) the new structure can not be described only through its materic constituents, because in cosmic dynamicity new structures and new relationships (of intrinsic respectivity) arise, together with new laws (of extrinsic respectivity). Consequently and as an objective, physical knowledge (for example, elementary particles or atoms) alone in no way can explain biological reality (for example, cell or man).


[Digital semiological anesthesia in horses: technique and elements of interpretation].
Digital semiological anesthesia in horses: Technique and elements of interpretation. Semiological anesthesia of the pes is used during examinations for lameness in horses. Recent research data on the distal digital, distal interphalangeal articular, and podotrochlear intrathecal nerve blocks indicate that they are less than specific when considered in isolation. They should be used in combination to localize pain in the pes. A positive response to anesthesia of the distal interphalangeal articulation could also indicate that the source of the pain was in the podotrochlear apparatus or the dorsal part of the sole. Podotrochlear anesthesia also anesthetizes the dorsal part of the sole and, later, the distal interphalangeal joint. Distal digital anesthesia affects a large palmar area of the hoof and extends dorsally. Overall, basic research provides little support for the practical uses of semiological blocks.


Duration of residence and psychotropic drug use in recently settled refugees in Sweden--a register-based study.
Recently settled refugee populations have consistently been reported to have high rates of mental health problems, particularly Post-traumatic stress disorder, depression, and anxiety disorders. The aim of this study was to investigate psychotropic drug use among young adult refugees according to duration of residence during the first 10 years in Sweden. Cross-sectional register study of a national cohort of 43 403 refugees and their families (23-35 years old) from Iraq, Iran, Eritrea, Ethiopia, Somalia and Afghanistan and a comparison population of 1.1 million Swedish-born residents. Logistic regression was used to assess the association between duration of residence in Sweden and the dispensing of at least one psychotropic medication during 2009 in four categories (any drug, neuroleptics, antidepressants and anxiolytics/hypnotics), adjusting for age, gender and domicile. Rates of dispensed psychotropic drugs among recently settled refugees were low, compared to the Swedish-born, with an increase with duration of residence. For refugee men and women from Iraq/Iran who had resided for 0-3 years the adjusted ORs compared to Swedish natives, were 0.83 (95% CI 0.77-0.90) and 0.48 (0.44-0.53) respectively; for men and women from the Horn of Africa the ORs were 0.50 (0.42-0.61) and 0.36 (0.30-0.41) respectively. After 7-10 years of residence, the ORs in these refugee groups approached the Swedish comparison population. Refugees from Afghanistan presented ORs similar to the Swedish-born, with no consistent trend by duration of residence. Women from the Horn of Africa and Iraq/Iran consumed less psychotropic drugs compared with men from these regions of origin, relative to the Swedish-born (p < 0.01). The ORs for dispensed neuroleptics were similar between the different refugee study groups, while the ORs for dispensed antidepressants differed fourfold between the group with the lowest (Horn of Africa) and the highest (Afghanistan). The rates of dispensed psychotropic drugs in the newly settled refugee populations in this study were low, with an increase with longer duration of residence. This pattern suggests barriers to access mental health care. Interventions that can lower these barriers are needed to enable newly settled refugees to access mental health care on equal terms with the native population.


FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice.
We studied the role of FGF-2 on regulation of neurogenesis and cell loss in the granule cell layer (GCL) of the hippocampal dentate gyrus after experimental traumatic brain injury (TBI). In both FGF-2(-/-) and FGF-2(+/+) mice subjected to controlled cortical impact, the number of dividing cells labeled with BrdU, injected on posttrauma days 6 through 8, increased at 9 days after TBI, and the number of BrdU-positive cells colabeled with neuron-specific nuclear antigen significantly increased at 35 days. However, in injured FGF-2-/- mice, BrdU-positive cells and BrdU-positive neurons (days 9, 35) were fewer compared with FGF-2(+/+) mice. There was also a decrease in the volume of the GCL and the number of GCL neurons after TBI in both FGF-2(-/-) and FGF-2(+/+) mice, but the decrease in both was greater in FGF-2-/- mice at 35 days. Overexpression of FGF-2 by intracerebral injection of herpes simplex virus-1 amplicon vectors encoding this factor increased numbers of dividing cells (day 9) and BrdU-positive neurons (day 35) significantly in C57BL/6 mice. Furthermore, the decrease in GCL volume was also attenuated. These results suggest that FGF-2 upregulates neurogenesis and protects neurons against degeneration in the adult hippocampus after TBI, and that FGF-2 supplementation via gene transfer can reduce GCL degeneration after TBI.


Nutritional status in patients with rheumatoid arthritis.
A nutritional assessment of 50 patients with rheumatoid arthritis (RA) showed evidence of malnutrition in 13 (26%), while all 50 control subjects had normal nutritional status. Of the anthropometric measurements the body-mass index and triceps skinfold thickness values in men and women were significantly reduced in RA patients compared with controls. Upper arm muscle circumference was significantly less in male but not female rheumatoid patients. In addition all six biochemical determinants of nutrition assayed-serum albumin, transferrin, retinol-binding protein, thyroxine-binding prealbumin, zinc, and folic acid-were significantly lower in the RA group of patients. Malnourished patients had more active disease than the remaining RA patients, with significantly higher ESR, C-reactive protein, and alpha 1 antichymotrypsin measurements. Significant inverse correlations were found between some biochemical measurements of nutrition and indices of disease activity. Our results suggest that in RA the severity of disease adversely affects the nutritional status.


[Analgesic Effect of Deqi Induced by Needling at Sanyinjiao (SP 6) Acupoint on Primary Dysmenorrheal Patients with Cold Damp Stagnation Syndrome].
To observe the analgesic effect of deqi induced by needling at Sanyinjiao (SP 6) on primary dysmenorrheal (PD) patients with cold damp stagnation syndrome (CDSS). A total of 64 PD patients with CDSS experiencing abdominal pain (≥40 mm in visual analogue scale ,VAS) were randomly assigned into deqi-expectation(DE) group(n=15) and no-deqi-expectation(NDE) group(n=49). On the first day of abdominal pain attack, bilateral SP 6 were punctured respectively with thicker needles with deeper insertion for deqi-expectation patients and thin filiform needles with shallow insertion for no-deqi-expectation patients. The needles were removed after 30 minutes, a deqi scale was used to evaluate the deqi condition. According to the results, patients in the DE group were further divided into deqi DE group and no-deqi DE group, patients in the NDE group were also divided into deqi NDE group and no-deqi NDE group. The VAS was used to evaluate the patients' abdominal pain severity before treatment and 0, 10, 20, 30 min after acupuncture needle withdrawal. The rate of deqi in the DE group was higher than that in the NDE group(P<0.05). The VAS scores of abdominal pain in the four groups were decreased at all time-points after needle withdrawal compared with those before treatment (P<0.01), while the VAS score in the deqi DE group were lower than in the no-deqi NDE group 30 min after needle withdrawal (P<0.05). The intervention method of thick needle, deep insertion and some manipulation is easier in inducing deqi than that of thin needle, shallow insertion and no manipulation. The analgesic effect of deqi is better than that of no-deqi for PD patients with CDSS.


Development of enzymes of glycerol metabolism in human fetal liver.
The activities of three key enzymes of glycerol metabolism were measured in liver samples from 37 human fetuses ranging in gestational age from 18 weeks to term, from neonates (1-3 days) and from infants to 2 years. Glycerol kinase specific activity was constant throughout the period of fetal development examined, and was comparable to that measured in neonates and infants. However, the subcellular distribution of the activity changed markedly, being predominantly particulate in fetal samples and cytoplasmic in postnatal samples. The particulate activity had an elevated Km for glycerol. Cytoplasmic glycerol-3-phosphate dehydrogenase activity was very low in the fetal period, and then rose to adult levels during infancy. There were no kinetic differences between the fetal and postnatal activities. Mitochondrial glycerol-3-phosphate dehydrogenase activity rose somewhat after birth to near adult levels. The data indicate that glycerol can be metabolized by human fetal, neonatal and infant liver.


Current developments in human molecular cytogenetic techniques.
In the last decade a variety of fluorescence in situ hybridization (FISH) assays have been developed. In this paper we present an overview on the currently available methods in molecular cytogenetics, highlighting their advantages and limitations, as well as their applications. Even though one has to be impressed by the total number of new techniques introduced in molecular cytogenetics, one has to be aware of the fact that it is not the brilliance of a technique that is important but the scientific question that can be addressed by it. In this review special emphasis has given in describing possible strategies for the characterization of marker and derivative chromosomes in tumor- and clinical cytogenetics.


How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication?
FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1st and 2nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).


Spatial evolutionary games with weak selection.
Recently, a rigorous mathematical theory has been developed for spatial games with weak selection, i.e., when the payoff differences between strategies are small. The key to the analysis is that when space and time are suitably rescaled, the spatial model converges to the solution of a partial differential equation (PDE). This approach can be used to analyze all [Formula: see text] games, but there are a number of [Formula: see text] games for which the behavior of the limiting PDE is not known. In this paper, we give rules for determining the behavior of a large class of [Formula: see text] games and check their validity using simulation. In words, the effect of space is equivalent to making changes in the payoff matrix, and once this is done, the behavior of the spatial game can be predicted from the behavior of the replicator equation for the modified game. We say predicted here because in some cases the behavior of the spatial game is different from that of the replicator equation for the modified game. For example, if a rock-paper-scissors game has a replicator equation that spirals out to the boundary, space stabilizes the system and produces an equilibrium.