CD20-targeted therapy: the next generation of antibodies.
Targeting the CD20 antigen on B lymphocytes with the monoclonal antibody (MoAb) rituximab has greatly improved the outcome of patients with B-cell malignancies. Despite the success of rituximab, resistance occurs in about half of the patients, resulting in non-response to treatment or early relapse with the original disease. A better understanding of the mechanism of rituximab resistance has led to the development of novel, improved anti-CD20 antibodies. This review describes the development of CD20-targeted therapy from its historical background towards the next generation of anti-CD20 MoAbs and explains new strategies to overcome resistance.


Risk factors for postthyroidectomy hypocalcemia.
Hypocalcemia is a common sequela of thyroidectomy; however, its causative factors have not been completely delineated. A prospective study of 60 patients who underwent unilateral (n = 15) or bilateral (n = 45) thyroidectomy between 1990 and 1993 was completed to determine the incidence and risk factors for hypocalcemia. Free thyroxine, thyrotropin, and alkaline phosphatase levels were obtained before operation in all patients, together with preoperative and postoperative ionized calcium, parathyroid hormone (PTH), calcitonin, and 1,25-dihydroxyvitamin D3 levels. All patients were examined for age, gender, extent of thyroidectomy, initial versus reoperative neck surgery, weight and pathologic characteristics of resected thyroid tissue, substernal thyroid extension, and parathyroid resection and autotransplantation. Hypocalcemia, defined by an ionized calcium level less than 4.5 mg/dl, occurred in 28 patients (47%), including nine (15%) symptomatic patients who required vitamin D and/or calcium for 2 to 6 weeks. In no patient did permanent hypoparathyroidism develop. With a multivariate logistic regression analysis, factors that were predictive of postoperative hypocalcemia included an elevated free thyroxine level (p = 0.003), cancer (p = 0.010), and substernal extension (p = 0.046). Postoperative decline in parathyroid hormone was not an independent risk factor for hypocalcemia, indicating that other factors besides parathyroid injury, ischemia, or removal are involved in the pathogenesis of postthyroidectomy hypocalcemia. An elevated free thyroxine level, substernal thyroid disease, and carcinoma are risk factors for postthyroidectomy hypocalcemia, and their presence should warrant routine postoperative calcium measurement. In the absence of these risk factors, routine postoperative measurement of serum calcium is unnecessary.


[Molecular genetic methods for the prognostic criteria in multiple myeloma].
Routine cytogenetic and molecular genetic analysis of plasma cell malignancies, such as multiple myeloma, became widespread only recently. As the result of these investigations, it became clear that tumor cell karyotype is fundamental from the viewpoint of therapy selection and prognosis. It is worthwhile to distinguish hyperdiploid and nonhyperdiploid myeloma, while five separate prognostic groups (TCI-5) may be identified on the basis of immunoglobulin gene translocations and cyclin expression. Deletion of the q arm of chromosome 13 or amplification of region 1q21 (and the CKS1B gene) can identify further subgroups of poor prognosis and few therapeutic options. Meanwhile, tumors harboring translocation t(11;14) respond favorably to conventional chemotherapy and exhibit exceptionally good and long-lasting response to high-dose chemotherapy. Progression of the disease may coincide with complex translocations of the c-myc gene or deletions involving the p53 tumor-suppressor gene, spreading of ras-mutations. These events represent clonal evolution at great tumor cell mass and advanced disease, therefore, are only of secondary prognostic significance.


Sexual aggression toward women: reducing the prevalence.
Date rape or acquaintance rape is far more common than rape by strangers and can lead to serious health and adjustment problems for girls and women. Research has found women and men to be similar in many of their views about sexual assault. However, studies on attribution of blame have highlighted differences in the ways in which men and women attribute blame in sexual assault. Men attribute less blame to perpetrators of sexual assault than do women, regardless of whether the perpetrator is female or male. This suggests that men identify with the power associated with the role of perpetrator. Ways of reducing the prevalence of men's sexual aggressiveness toward women are addressed.


Diffuse large B-cell lymphoma: sub-classification by massive parallel quantitative RT-PCR.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity with remarkably variable clinical outcome. Gene expression profiling (GEP) classifies DLBCL into activated B-cell like (ABC), germinal center B-cell like (GCB), and Type-III subtypes, with ABC-DLBCL characterized by a poor prognosis and constitutive NF-κB activation. A major challenge for the application of this cell of origin (COO) classification in routine clinical practice is to establish a robust clinical assay amenable to routine formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies. In this study, we investigated the possibility of COO-classification using FFPE tissue RNA samples by massive parallel quantitative reverse transcription PCR (qRT-PCR). We established a protocol for parallel qRT-PCR using FFPE RNA samples with the Fluidigm BioMark HD system, and quantified the expression of the COO classifier genes and the NF-κB targeted-genes that characterize ABC-DLBCL in 143 cases of DLBCL. We also trained and validated a series of basic machine-learning classifiers and their derived meta classifiers, and identified SimpleLogistic as the top classifier that gave excellent performance across various GEP data sets derived from fresh-frozen or FFPE tissues by different microarray platforms. Finally, we applied SimpleLogistic to our data set generated by qRT-PCR, and the ABC and GCB-DLBCL assigned showed the respective characteristics in their clinical outcome and NF-κB target gene expression. The methodology established in this study provides a robust approach for DLBCL sub-classification using routine FFPE diagnostic biopsies in a routine clinical setting.


Hematomas in multicomponent apheresis: searching for related factors.
The objective of this study was to identify donation variables that could be related to the development of hematoma during multicomponent apheresis collections (MACs). This is an observational retrospective study where 1375 donors donated 5177 MACs during a 2-year period with two different machines (Amicus Crescendo [AC], Baxter Healthcare Corp.; and Trima Accel [TA], Gambro BCT). Variable data were recorded prospectively. In the multiple logistic regression analysis, generalized estimating equations were used with an exchangeable correlation matrix to take into account the nonindependence of several measurements from the same donor. During the study period, 170 procedures failed due to hematoma (3.3%). Several variables were related to hematoma development in the adjusted model: operator experience (less than 500 procedures supervised vs. more; odds ratio [OR], 1.66; 95% confidence interval [CI], 1.19-2.31), previous apheresis donations (first time vs. more than 16 donations; OR, 2.87; 95% CI, 1.52-5.45), vein canalized (basilic vs. intermediate antebrachial or cephalic; OR, 1.42; 95% CI, 1.04-1.94), diastolic blood pressure (units divided by 10 mmHg; OR, 0.79; 95% CI, 0.66-0.94), and type of machine used (TA high return limit configuration [RLC] setting configuration vs. AC; OR, 1.94; 95% CI, 1.27-2.96; TA low RLC setting configuration vs. AC; OR, 1.24; 95% CI, 0.83-1.84). Our study suggests that hematoma in MAC is not a random event. Appropriate machine configuration in the TA could reduce the hematoma rate to a level comparable with that of the AC. Operator training and donor blood pressure are also interesting variables for study because these could be modified to reduce the hematoma rate.


[Rotaviruses].
Rotavirus, a member of the family Reoviridae, was identified as the leading etiological agent of severe gastroenteritis in infants and young children in 1973. The rotavirus genome is composed of 11 gene segments of double-stranded (ds)RNA. During the last 40 years, a large amount of basic research on rotavirus structure, genome, antigen, replication, pathogenesis, epidemiology, immune responses, and evolution has been accumulated. This article reviews the fundamental aspects of rotavirology including recent important achievements in research.


FAT1 inhibits cell migration and invasion by affecting cellular mechanical properties in esophageal squamous cell carcinoma.
FAT atypical cadherin 1 (FAT1) belongs to the cadherin superfamily and has been reported to regulate cell‑cell adhesion and other cell behaviors, suggesting its pivotal roles in human cancers. We previously identified FAT1 as one of the significant mutant genes in esophageal squamous cell carcinoma (ESCC). In the present study, the knockdown of FAT1 expression in YSE2 and Colo680N cell lines was carried out by lentivirus, and we found that knockdown of FAT1 led to acceleration of cell migration and invasion. Furthermore, we detected the cell adhesive force and cell elasticity force by atomic force microscopy (AFM) and found that the suppression of endogenous expression of FAT1 led to a decrease in the cell adhesive force and increase in the cell elasticity force compared with the control groups. In conclusion, our study demonstrated that FAT1 altered cellular mechanical properties leading to deregulation of cell migration and invasion of ESCC, which may be a novel target for ESCC therapy.


The effects of demecolcine, alone or in combination with sucrose on bovine oocyte protrusion rate, MAPK1 protein level and c-mos gene expression level.
Our study aims to clarify the effects of demecolcine, alone or in combination with sucrose on bovine oocyte protrusion rate, MAPK1 protein level and c-mos gene expression level. The effects of the demecolcine concentration, treatment duration, and synergistic effects with sucrose solution on the rate of membrane protrusions of bovine oocytes were investigated. Using real-time fluorescent quantitative PCR, western blot analysis, and immunofluorescence assays, the expression of the maternal c-mos gene, the protein level of mitogen-activated protein kinase 1 (MAPK1), and the change in the localization of spindles and nuclei during the demecolcine treatment were analyzed in bovine oocytes. Treatment of bovine oocytes with both demecolcine (0.6 μg/mL) and sucrose (0.05 M) for 1 h led to the highest rate of membrane protrusions, and synergistic effects were also observed. Real-time fluorescent quantitative PCR analysis revealed that the demecolcine treatment up-regulated the expression of the maternal c-mos gene. Western blot analysis indicated that the demecolcine treatment enhanced the protein level of MAPK1 in bovine oocytes. Immunofluorescence analysis indicated that the spindles and nuclei were localized at the place of the membrane protrusions. The present results suggest that demecolcine might contribute to the activation of the Mos/MAPK pathway and affect spindle structure. These results provide a reference for more efficient generation of enucleated bovine oocytes.


A Bayesian mixture model for metaanalysis of microarray studies.
The increased availability of microarray data has been calling for statistical methods to integrate findings across studies. A common goal of microarray analysis is to determine differentially expressed genes between two conditions, such as treatment vs control. A recent Bayesian metaanalysis model used a prior distribution for the mean log-expression ratios that was a mixture of two normal distributions. This model centered the prior distribution of differential expression at zero, and separated genes into two groups only: expressed and nonexpressed. Here, we introduce a Bayesian three-component truncated normal mixture prior model that more flexibly assigns prior distributions to the differentially expressed genes and produces three groups of genes: up and downregulated, and nonexpressed. We found in simulations of two and five studies that the three-component model outperformed the two-component model using three comparison measures. When analyzing biological data of Bacillus subtilis, we found that the three-component model discovered more genes and omitted fewer genes for the same levels of posterior probability of differential expression than the two-component model, and discovered more genes for fixed thresholds of Bayesian false discovery. We assumed that the data sets were produced from the same microarray platform and were prescaled.


Presence of proNGF-sortilin signaling complex in nigral dopamine neurons and its variation in relation to aging, lactacystin and 6-OHDA insults.
Growing evidence has shown that proNGF-p75NTR-sortilin signaling might be a crucial factor in neurodegeneration, but it remains unclear if it may function in nigral neurons under aging and disease. The purpose of this study is to examine and quantify proNGF and sortilin expression in the substantia nigra and dynamic changes of aging in lactacystin and 6-hydroxydopamine (6-OHDA) rat models of Parkinson's disease using immunofluorescence, electronic microscopy, western blot and FLIVO staining methods. The expression of proNGF and sortilin was abundantly and selectively identified in tyrosine hydroxylase (TH)-containing dopamine neurons in the substantia nigra. These proNGF/TH, sortilin/TH-positive neurons were densely distributed in the ventral tier, while they were less distributed in the dorsal tier, where calbindin-D28K-containing neurons were numerously located. A correlated decrease of proNGF, sortilin and TH was also detected during animal aging process. While increase of proNGF, sortilin and cleaved (active) caspase-3 expression was found in the lactacystin model, dynamic proNGF and sortilin changes along with dopamine neuronal loss were demonstrated in the substantia nigra of both the lactacystin and 6-OHDA models. This study has thus revealed the presence of the proNGF-sortilin signaling complex in nigral dopamine neurons and its response to aging, lactacystin and 6-OHDA insults, suggesting that it might contribute to neuronal apoptosis or neurodegeneration during pathogenesis and disease progression of Parkinson's disease; the underlying mechanism and key signaling pathways involved warrant further investigation.


Effect of metformin on ossification and inflammation of fibroblasts in ankylosing spondylitis: An in vitro study.
Ankylosing spondylitis (AS) is an autoimmune disease characterized by fibroblasts ossification. However, effective drug therapy for AS is lacking. As an antidiabetic drug, metformin has demonstrated an antiosteogenic effect on osteoblasts in vitro. And it is also a kind of specific agonists for adenosine 5'-monophosphate activated protein kinase (AMPK), which is blocked in the process of AS. Given the role in antiosteogenesis and AMPK activating, metformin was investigated of its effect on fibroblasts harvested from capsular ligament of patients with femoral neck fracture and AS. Osteogenic specific makers (Alp, Bglap, Runx2, Bmp2, and Col1) in fibroblasts administered with metformin (20 μg/mL) were detected by ALP staining, alizarin red staining, qPCR, and Western blotting after 7 and 14 days of culture. Inflammation genes (il1-β and il6) and pathway (Pi3k, Akt, and Ampk) associated markers were also evaluated. Our results showed that osteogenic specific markers were greatly downregulated and ossification was effectively inhibited in AS fibroblasts after addition of metformin. Levels of inflammation markers were also decreased by metformin. Thus, metformin exerts potent effect on suppression of ossification and inflammation in AS fibroblasts via the activation of Pi3k/Akt and AMPK pathways, which may be developed as a potential agent for treatment of AS.


European starlings use their acute vision to check on feline predators but not on conspecifics.
Head movements allow birds with laterally placed eyes to move their centers of acute vision around and align them with objects of interest. Consequently, head movements have been used as indicator of fixation behavior (where gaze is maintained). However, studies on head movement behavior have not elucidated the degree to which birds use high-acuity or low-acuity vision. We studied how European starlings (Sturnus vulgaris) used high-acuity vision in the early stages of visual exploration of a stuffed cat (common terrestrial predator), a taxidermy Cooper's hawk (common aerial predator), and a stuffed study skin of a conspecific. We found that starlings tended to use their high acuity vision when looking at predators, particularly, the cat was above chance levels. However, when they viewed a conspecific, they used high acuity vision as expected by chance. We did not observe a preference for the left or right center of acute vision. Our findings suggest that starlings exposed to a predator (particularly cats) may employ selective attention by using high-acuity vision to obtain quickly detailed information useful for a potential escape, but exposed to a social context may use divided attention by allocating similar levels high- and low-quality vision to monitor both conspecifics and the rest of the environment.


Intravoxel incoherent motion diffusion-weighted MR imaging parameters predict pathological classification in thymic epithelial tumors.
We evaluated the performance of intravoxel incoherent motion (IVIM) parameters for preoperatively predicting the subtype and Masaoka stage of thymic epithelial tumors (TETs). Seventy-seven patients with pathologically confirmed TETs underwent a diffusion weighted imaging (DWI) sequence with 9 b values. Differences in the slow diffusion coefficient (D), fast perfusion coefficient (D*), and perfusion fraction (f) IVIM parameters, as well as the multi b-value fitted apparent diffusion coefficient (ADCmb), were compared among patients with low-risk (LRT) and high-risk thymomas (HRT) and thymic carcinomas (TC), and between early stage (stages I and II) and advanced stage (stages III and IV) TET patients. ADCmb, D, and D* values were higher in the LRT group than in the HRT or TC group, but did not differ between the HRT and TC groups. The mean ADCmb, D, and D* values were higher in the early stage TETs group than the advanced stage TETs group. The f values did not differ among the groups. These results suggest that IVIM DWI could be used to preoperatively predict subtype and Masaoka stage in TET patients.


Using antimicrobial host defense peptides as anti-infective and immunomodulatory agents.
Virtually all life forms express short antimicrobial cationic peptides as an important component of their innate immune defenses. They serve as endogenous antibiotics that are able to rapidly kill an unusually broad range of bacteria, fungi and viruses. Consequently, considerable efforts have been expended to exploit the therapeutic potential of these antimicrobial peptides. Within the last couple of years, it has become increasingly clear that many of these peptides, in addition to their direct antimicrobial activity, also have a wide range of functions in modulating both innate and adaptive immunity. For one class of antimicrobial peptides, such as the human defensins, their primary role may even be as immunomodulators. These properties potentially provide entirely new therapeutic approaches to anti-infective therapy.


HLA molecular typing.
HLA antigens are the major barrier to successful transplantation. Three of the seven heterodimers (HLA-A, -B, and -DR) contribute most to the immunogenicity of a mismatched organ. Although classical serology has been used in the past to phenotype donors and recipients, histocompatibility laboratories are increasingly turning to DNA-based methods to directly genotype patients and donors for the alleles of the HLA complex. Some methods are still evolving, while several others are established well enough to use in the clinical laboratory. The application to solid organ transplantation will result in greater accuracy and a better correlation between HLA matching and graft survival in the future. In fields such as bone marrow transplantation, where matching is critically important for prevention of graft-versus-host disease and engraftment, molecular HLA testing is already being mandated by the transplantation community.


The activation of pro-urokinase by plasma kallikrein and its inactivation by thrombin.
Plasma kallikrein was found to be a good activator of pro-urokinase, the inactive zymogen form of urokinase. The complete activation of pro-urokinase by plasma kallikrein was obtained in 2 h with an enzyme/substrate weight ratio of 1/30. The rate of activation of pro-urokinase by plasma kallikrein was comparable to that catalyzed by plasmin and trypsin. The rate of activation of pro-urokinase by factor XIIa was approximately one-seventh of that by plasma kallikrein. The activation of the zymogen was due to the cleavage of a single internal peptide bond, resulting in the conversion of a single chain pro-urokinase (Mr = 55,000) into two-chain urokinase (Mr = 33,000 and 22,000), and these two chains were linked by a disulfide bond(s). These results indicate an important role of plasma kallikrein for the activation of pro-urokinase in the factor XII-dependent intrinsic pathway of fibrinolysis. Thrombin also converted pro-urokinase to a two-chain form that was not activatable by plasmin, plasma kallikrein, and factor XIIa. Thrombin specifically cleaved the Arg 156-Phe 157 bond which is located 2 residues prior to the activation site of Lys 158-Ile 159.


[Distribution of respiratory arrests in preterm and term infants (author's transl)].
Incidence, distribution and periodicity of respiratory arrests larger than or equal to 2 seconds duration were studied in relation to age and sleep states by means of polygraphic recording in 61 tracing of 44 preterm and term infants free of pathologic conditions known to increase the risk of respiratory arrests. Respiratory arrests at any infant's age were found to be more frequent during active sleep. Incidence of respiratory arrests decreases with age in all sleep states. At any age the average duration of respiratory arrest is longer in quiet sleep. When restrictive definition is applied periodic breathing was found to be a rare and probably an abnormal phenomenon not in connection with any particular sleep state. Apneas of longer than 10 seconds duration were observed rather seldon, as well as cardiac slowing coinciding with respiratory arrest or apnea. Bradypnea and poor differenciation of breathing pattern according to sleep states represent a rare and presumably abnormal finding. The authors feel that the elements observed should be considered in estimating the risk of severe apnea in infants.


Evaluation of Susceptibilities to Carbapenems and Faropenem Against Cephalosporin-Resistant Neisseria gonorrhoeae Clinical Isolates with penA Mosaic Alleles.
Neisseria gonorrhoeae is a principal pathogen for sexually transmitted infections, especially for male urethritis. Currently, the prevalence of multidrug resistance is increasing. Carbapenems are broad-spectrum antimicrobials that are widely used in the clinical setting, especially for multidrug-resistant Gram-negative bacteria. However, susceptibility to carbapenems has not been well evaluated for cephalosporin-resistant N. gonorrhoeae isolates. In this study, we determined the susceptibility to a series of carbapenems (meropenem, imipenem, doripenem, and biapenem) and faropenem against cephalosporin-resistant (resistant to cefixime, but susceptible to ceftriaxone) and cephalosporin-susceptible N. gonorrhoeae clinical isolates. The gene mutations associated with β-lactam resistance were evaluated. All cephalosporin-resistant N. gonorrhoeae isolates possessed mosaic mutation alleles in penA (NG-STAR penA-10.001, 27.001, or 108.001). They exhibited a low minimum inhibitory concentration (MIC) (≤0.125 mg/L) for meropenem and markedly high MICs (0.5-2 mg/L) for other carbapenems and faropenem. The strongest association was observed between the mosaic alleles in penA and decreased susceptibility to carbapenems and faropenem compared with mutations in mtrR, porB, and ponA. These results suggest that meropenem may serve as an alternative therapeutic agent for cephalosporin-resistant N. gonorrhoeae with a mosaic allele in penA, whereas other carbapenems and faropenem may be ineffective.


Community level exposure to chemicals and oxidative stress in adult population.
Little information is available on the role of environmental chemical exposure in oxidative stress. This study was designed to investigate whether exposure to environmental chemicals, such as polycyclic aromatic hydrocarbons, volatile organic compounds, bisphenol A or phthalates, induces oxidative stress in urban adult populations. A total of 960 adults dwelling in urban areas were evaluated between April and December 2005. To assess environmental chemical exposure, we measured urinary levels of 1-hydroxypyrene, 2-naphthol, hippuric acid, methyl hippuric acid, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, and mono-butyl phthalate and bisphenol A. Urinary malondialdehyde and 8-hydroxydeoxyguanosine were also measured to evaluate oxidative stress. Significant dose-responsive relationship was found between urinary concentrations of the chemical exposure biomarkers and oxidative stress levels in simple regression analyses (P<0.05). Regression coefficients of these exposure biomarkers except bisphenol A remained significantly in the multiple regression models after controlling for age, sex, weight, smoking, and exercise for at least one of the two oxidative stress biomarkers (P<0.05). The oxidative stress biomarkers significantly affected the indicators of insulin resistance, particularly glucose level. This study indicates that environmental chemical exposure is associated with oxidative stress in urban adult populations and suggests that exposure to certain environmental chemicals might contribute to insulin resistance.


Implementation of a Standardized Protocol for Telehealth Provider in Triage to Improve Efficiency and ED Throughput: A Quality Improvement Project.
There has been a significant rise in the number of emergency department (ED) visits over the past 15 years despite the number of ED providers and treatment spaces remaining fixed (M. P. Lin et al., 2018). A hospital's need to quickly initiate care upon patient arrival is of paramount importance to combat these ED overcrowding trends. A teleprovider in triage (TPIT) program without a standardized operating protocol leads to significant provider practice variations and limits effectiveness of a TPIT program. The intention of this health care project was to reduce ED time metrics and reduce the number of patients who left before evaluation by implementing a standardized TPIT protocol. This standardization allowed for a more predictable experience for the patient and ED staff. This quality improvement project involved developing and implementing a standardized TPIT protocol to improve TPIT efficiency and throughput. Patient ED visit metrics were collected during the pre- and postimplementation periods to evaluate for any improvement in throughput due to the TPIT protocol. The TPIT advanced practice providers (APPs) showed significant improvement in knowledge following the TPIT protocol education with an increase in provider comfort (p < 0.05). Time spent by the TPIT provider on each patient encounter was reduced by 23%, demonstrating increased provider efficiency. Improvements in discharge lengths of stay (LOS) (p = 0.68) and room to discharge LOS (p < 0.05) were noted following the implementation of the TPIT protocol. The implementation of the TPIT protocol provided improvements in APP knowledge and understanding of the process while increasing provider efficiency. Improvements were identified in specific ED patient metrics demonstrating the significance of the TPIT protocol on patient care.


Highly Selective Vertically Aligned Nanopores in Sustainably Derived Polymer Membranes by Molecular Templating.
We describe a combination of molecular templating and directed self-assembly to realize highly selective vertically aligned nanopores in polymer membranes using sustainably derived materials. The approach exploits a structure-directing molecule to template the assembly of plant-derived fatty acids into highly ordered columnar mesophases. Directed self-assembly using physical confinement and magnetic fields provides vertical alignment of the columnar nanostructures in large area (several cm2) thin films. Chemically cross-linking the mesophase with added conventional vinyl comonomers and removing the molecular template results in a mechanically robust polymer film with vertically aligned 1.2-1.5 nm diameter nanopores with a large specific surface area of ∼670 m2/g. The nanoporous polymer films display exceptional size and charge selectivity as demonstrated by adsorption experiments using model penetrant molecules. These materials have significant potential to function as high-performance nanofiltration membranes and as nanoporous thin films for high-density lithographic pattern transfer. The scalability of the fabrication process suggests that practical applications can be reasonably anticipated.


High gradient magnetic separation of yeast.
High gradient magnetic separation (HGMS) is used to separate nonmagnetic microorganisms from solution by a technique known as seeding. Fine magnetic particles are adhered to the cells' surfaces, making them magnetic and amenable to magnetic separation. Attachment of the sub-micron, acicular gamma-Fe(2)O(3) seed to the yeast surface occurs irrespective of the solution pH and surface charge and is essentially irreversible. A model is developed to predict the separation of yeast in a high gradient magnetic separator. The effective capture radius is assumed to be proportional to the derived magnetic parameter gamma for the case where the dominant competing force to magnetic attraction is the magnetic floc's inertia. Using this parameter, yeast separation in an HGMS unit is predicted. The measured separation of Saccharomyces cerevisiae at differing magnetic seed concentrations and two flow rates supports the above model.


Fear learning increases the number of polyribosomes associated with excitatory and inhibitory synapses in the barrel cortex.
Associative fear learning, resulting from whisker stimulation paired with application of a mild electric shock to the tail in a classical conditioning paradigm, changes the motor behavior of mice and modifies the cortical functional representation of sensory receptors involved in the conditioning. It also induces the formation of new inhibitory synapses on double-synapse spines of the cognate barrel hollows. We studied density and distribution of polyribosomes, the putative structural markers of enhanced synaptic activation, following conditioning. By analyzing serial sections of the barrel cortex by electron microscopy and stereology, we found that the density of polyribosomes was significantly increased in dendrites of the barrel activated during conditioning. The results revealed fear learning-induced increase in the density of polyribosomes associated with both excitatory and inhibitory synapses located on dendritic spines (in both single- and double-synapse spines) and only with the inhibitory synapses located on dendritic shafts. This effect was accompanied by a significant increase in the postsynaptic density area of the excitatory synapses on single-synapse spines and of the inhibitory synapses on double-synapse spines containing polyribosomes. The present results show that associative fear learning not only induces inhibitory synaptogenesis, as demonstrated in the previous studies, but also stimulates local protein synthesis and produces modifications of the synapses that indicate their potentiation.


Mammalian leukocytes contain all the genetic information necessary for the development of a new individual.
We have used leukocytes and oocytes from commercially slaughtered animals to clone a progeny tested Brown Swiss bull. Mononuclear cells were separated from the heparinized blood of the donor male on a Histopaque gradient and cryopreserved. The nuclei of thawed leukocytes were directly microinjected into enucleated Holstein Friesian oocytes that were subsequently activated. Development to morula was 23% and to blastocysts was 17%. Some of the cloned compacting morulae were subjected to a second round of nucleus transfer by fusion of individual blastomeres to enucleated oocytes. Development of these second generation embryos to the blastocyst stage was 19%. Following embryo transfer of 50 blastocysts to 50 recipient heifers (31 from first generation and 19 from second generation), 28 pregnancies were established as evidenced by fetal heartbeat at 35 days. A high proportion of the pregnancies established were lost by day 45. One fetus from a second generation embryo developed to term. The phenotype (Brown Swiss) and DNA analysis (11 microsatellites on 11 different chromosomes) of the resultant normal healthy calf confirmed its identity to the donor sire. The ability to clone animals from hematopoietic cells that can be easily collected and cryopreserved from any donor irrespective of species, age, or sex has important implications for the preservation of genetic resources from a wide variety of animals in the animal breeding and artificial insemination industries and for human medicine.


A new A-scan ultrasonoscope.
A new A-mode biometry system for determining axial length measurements of the eye has been developed that incorporates a soft-membrane transducer. The soft transducer decreases the risk of indenting the cornea with the probe resulting in inaccurate measurements. A microprocessor evaluates echo patterns and determines whether or not axial alignment has been obtained, eliminating possible user error. The new A-scan requires minimal user skill and can be used successfully by both physician and technician.


Symptomatic unilateral pleural effusion as a presentation of ovarian hyperstimulation syndrome.
Isolated acute unilateral pleural effusion has twice been reported as the only symptom of ovarian hyperstimulation syndrome (Kingsland et al, 1989; Jewelewicz and Vande Wiele, 1975). The pathogenesis of this disorder is not fully understood and the presence of an isolated pleural effusion lends support to the role of systemic factors rather than purely the transudation of fluid from grossly enlarged ovaries in the progression of this disease. This article describes a second case of an isolated pleural effusion following in-vitro fertilization and embryo transfer.


SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation.
A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.


A web-based anger management program for parent-female adolescents' conflicts: a cluster randomized controlled trial.
Objective This cluster randomized control trial was performed to evaluate the effectiveness of a web-based anger management program for mother-female adolescents' conflicts. Methods Eight out of 23 high-schools in District Two of Shiraz, Iran were chosen using random cluster sampling and randomly assigned to an intervention and a control group (each group consisted of four schools). The conflict tactics scale was filled out by all eligible third grade high school students in both groups and 140 students who had the scores higher than 30 were randomly selected; 70 adolescents in the intervention group participated in an 8 week intervention, while 70 adolescents in the control group did not undergo any intervention. Data collection was performed at the end of the intervention and 1 month later. Results The results of the t-test revealed no statistically significant differences between the study groups regarding the total conflict tactics scores (p = 0.935) or any of the three subscales before the intervention (p > 0.05). However, a significant difference was observed between the two groups in this regard immediately and 1 month after the intervention (p < 0.05). The results of repeated measure analysis of variance (ANOVA) demonstrated a significant difference between the intervention and control groups regarding the conflict scores and its subscales during the three study periods and groups (F = 79.43, p < 0.001). Conclusion This study highlighted the importance of applying a web-based anger management program in decreasing mother-female adolescents' conflicts. Similar studies are recommended to be conducted on the issue.


Emerging Pyrethroid Resistance among Anopheles arabiensis in Kenya.
Vector control programs, particularly in the form of insecticide-treated bed nets (ITNs), are essential for achieving malaria elimination goals. Recent reports of increasing knockdown resistance (kdr) mutation frequencies for Anopheles arabiensis in Western Kenya heightens the concern on the future effectiveness of ITNs in Kenya. We examined resistance in An. arabiensis populations across Kenya through kdr mutations and World Health Organization-recommended bioassays. We detected two kdr alleles, L1014F and L1014S. Kdr mutations were found in five of the 11 study sites, with mutation frequencies ranging from 3% to 63%. In two Western Kenya populations, the kdr L1014F allele frequency was as high as 10%. The L1014S frequency was highest at Chulaimbo at 55%. Notably, the kdr L1014F mutation was found to be associated with pyrethroid resistance at Port Victoria, but kdr mutations were not significantly associated with resistance at Chulaimbo, which had the highest kdr mutation frequency among all sites. This study demonstrated the emerging pyrethroid resistance in An. arabiensis and that pyrethroid resistance may be related to kdr mutations. Resistance monitoring and management are urgently needed for this species in Kenya where resistance is emerging and its abundance is becoming predominant. Kdr mutations may serve as a biomarker for pyrethroid resistance in An. arabiensis.


Radiofrequency catheter ablation for paroxysmal supraventricular tachycardia: a report of 135 procedures.
Paroxysmal Supraventricular Tachycardia (PSVT) is a common condition which until recently has been treated with anti-arrhythmic drugs or surgery. Radiofrequency (RF) catheter ablation is a new mode of treatment which provides a cure of this condition. To present our early experience of RF catheter ablation for PSVT. One hundred and thirty-five procedures were performed in 117 patients. The diagnostic study and therapeutic catheter ablation were performed as a combined electrophysiological procedure in 74 patients (63%). In 58 patients (50%), PSVT was due to Atrio-ventricular junctional (nodal) re-entrant tachycardia (AVJRT). Twenty-five of the 58 patients underwent a fast pathway ablation while 33 had ablation of their slow pathway. The mean number of radiofrequency pulses delivered was ten for a mean duration of 25 seconds. Radiofrequency ablation of accessory pathways was attempted in 58 patients; pathways were left-sided in 29 patients, postero-septal in 21, midseptal in five, Mahaim connection in two, antero-septal in one and right free wall in one patient. One patient with incessant automatic atrial tachycardia also underwent a successful RF ablation. Using RF ablation cure of PSVT was achieved in 90% of patients. Cure of AVJRT was achieved in 95% (55/58) of patients using either fast or slow pathway ablation. Only one patient required permanent pacemaker implantation for Mobitz type I AV block following fast pathway ablation. The overall success rate for ablation of accessory pathways was 85%. There is an operator learning curve for this procedure suggested by the fact that the success rate for accessory pathway ablation at first attempt was 63% in the first 29 patients and 93% in the remaining 29. There was no significant morbidity or mortality during or after the procedure. In a mean follow-up of nine months in the patients with successful ablation only two patients with AVJRT had a recurrence of documented PSVT. Both these patients had successful repeat RF ablation. Catheter ablation using radiofrequency energy is an effective and safe therapeutic option for patients with symptomatic PSVT.


Fetal surgery for sacrococcygeal teratoma.
A great deal has been learned regarding the natural history and pathophysiology of fetal SCT. The logic behind fetal intervention for SCT and hydrops appears to be correct, and open and minimal access techniques of fetal intervention have been shown to be feasible. The development of fetal intervention for SCT has mirrored those developed for other diseases such as congenital diaphragmatic hernia. In a recent presentation, Harrison, the original pioneer in fetal surgery, outlined trends in fetal intervention. The first trend is that of moving from open, invasive techniques to minimally invasive techniques. In the case of SCT surgeons are moving from open resection to RFA and possibly to fetoscopic resection. The second trend outlined by Harrison is a movement away from total in utero repair of a defect that recapitulates postnatal treatment and toward manipulation of fetal pathophysiology to reverse life-threatening events. In SCT surgeons employ RFA to ablate causative blood vessels to reverse fetal hydrops with the knowledge that these fetuses will require postnatal resection of the tumor. In contrast to resection, RFA requires less time and significantly less maternal morbidity than open resection. Further study is required to determine the role of minimal access techniques in SCT. Future directions for treatment of fetal SCT with hydrops might include fetoscopic resection or high-intensity ultrasound ablation.


Food intake and high density lipoprotein cholesterol levels changes during ramadan fasting in healthy young subjects.
During the holy month of Ramadan, it is obligatory for all adult healthy Muslims to abstain from food, drink and smoking each day from dawn to sunset. The aims of our study were to evaluate the effects of Ramadan fasting on plasma lipids, lipoproteins and the change of food consumption in healthy subjects. Thirty young healthy and normal weighted adults (9 males and 21 females) were evaluated during three periods: 3 weeks before Ramadan (T0); the 4th week of Ramadan (T1) and 3 weeks after the end of Ramadan (T2). Main Clinical and biological parameters investigated were: body weight, blood glucose, plasma triglycerides (TG), plasma total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and. low density lipoprotein cholesterol (LDL-c) Body weight, and blood glucose were unchanged. There was a significant increase of the mean daily caloric intake, the lipids intake particularly mono-unsaturated and poly-unsaturated fatty acids (p < 0.001) and cholesterol intake (p < 0.001) during Ramadan with a decrease of the meal frequency. There was also a significant increase of plasma total cholesterol and HDL-cholesterol. The most striking finding was a significant increase in the HDL-Cholesterol during Ramadan +20% (p < 0.02). This increase was lost after Ramadan. Fasting Ramadan affects beneficially serum lipoprotein metabolism in young adult healthy subjects with an increase of HDL-cholesterol.


[Not Available].
The article tries to clarify the relation between history of medicine and medical ethics. Therefore it distinguishes between the double meaning of the German word "Geschichte", which means both: "development of events" and "story". For the first option no systematic relation between history and ethics can be reconstructed. In the second sense historical knowledge can be a readable and worth reading text for the ethical debate. Therefore the methodological professionality of the historian is required.


Fenton-enhanced gamma-radiolysis of cyanuric acid.
Degradation of cyanuric acid (OOOT), a stable end product of oxidative decomposition of atrazine, is investigated in a combined field of gamma radiolysis and fenton reaction. The reaction of hydroxyl radical (OH) at pH 6 was carried out by irradiating N(2)O saturated aqueous solutions containing OOOT (1 x 10(-3) mol dm(-3)), and this resulted only a marginal degradation (20%). However, when the same reaction was carried out in the presence of varying concentrations of ferrous sulfate ((5-10)x10(-5) mol dm(-3)), the decay of OOOT has been enhanced to more than 80%. This decay followed a first order kinetics. Nearly similar effects were observed with another triazine derivative, 2,4-dioxohexahydro-1,3,5-triazine (DHT). Two major reaction mechanisms are proposed for the enhanced decay of OOOT. The formation of unstable hydroxyl radical adducts from the reaction of .OH which is the result of gamma radiolysis and the Fenton reaction (resulting from the reaction of the added Fe(II) and of the H(2)O(2) from the radiolysis of water), is proposed as the first mechanism. The second mechanism, which is likely the major contributor to degradation, is proposed as the reaction of a nucleophilic adduct, Fe(II)OOH, which could directly react with the electron deficient triazine ring. It is highlighted that such degradation reactions must be explored for the complete degradation of the byproducts of the oxidative decomposition of atrazine.


Head-and-face anthropometric survey of U.S. respirator users.
Sizing data generated by the military for use in fitting respirators have been the normative basis for commercial respirator sizing. Anthropometric data developed for males and females of military age in the 1950s and 1960s are still in use today and form the only comprehensive body of information available on this subject. The twofold objective of this study was to: (1) develop an anthropometric database detailing the face size distributions of respirator users using both traditional measurement methods and three-dimensional scanning systems; and (2) use the database to establish fit test panels to be incorporated into the National Institute for Occupational Safety and Health's respirator certification and international standards. A stratified sampling plan was used with three age strata, two gender strata, and four race/ethnic group strata. The plan called for an equal sample size of 166 in each cell. Subjects were obtained at 41 sites from 8 states. In addition to height and weight, 18 facial dimensions and neck circumferences were measured using traditional methods. A total of 3997 subjects were measured using traditional methods, and 1013 of them were also scanned using a 3-D head scanner. As this was a volunteer sample, subjects did not appear in the specific proportions needed for the sampling plan. The resulting data were weighted to correspond to the U.S. population. This article presents the summary statistics for the traditional measurement data only. Multivariate analyses of the data from this study and military data revealed that using historical, military data would be inadequate for describing the anthropometric variability of the current U.S. work force.


Solid Pseudopapillary Tumor of the Pancreas in a Patient With Sarcoidosis: A Rare Combination.
Sarcoidosis is a chronic granulomatous disease that is characterized by the formation of non-caseating granulomas, predominantly involving the lung and lymph nodes. Over the years, sarcoidosis has been associated with a high risk of malignancy. Solid pseudopapillary tumor of the pancreas is an uncommon pancreatic tumor with a 15% malignant potential. Ours is an interesting case of a 34-year-old patient who was found to have a pancreatic mass and incidental mediastinal lymphadenopathy on imaging, initially raising concern for metastatic pancreatic cancer. However, she was later diagnosed to have an isolated solid pseudopapillary tumor of the pancreas in association with concurrent sarcoidosis.


Xenon Tetrafluoride: Heat of Formation.
Calorimetric measurements of the heat of reaction of xenon tetrafluoride with aqueous iodide solution give -60 kilocalories per mole for the standard heat of formation, or an average thermochemical bond energy of about 31 kilocalories.


Possible role of light in the maintenance of EIN3/EIL1 stability in Arabidopsis seedlings.
To examine the mechanism of EIN3-mediated gene expression by ethylene, the expression patterns of ethylene-inducible genes by ethylene were monitored in Col-0 and ethylene signaling mutants. In Col-0, the inducibility of ACC oxidase by ethylene in light-grown seedlings was much higher than in dark-grown seedlings. While the expression of ACC oxidase was highly increased by ethylene not only in Col-0 but in ein3-1 under light treatment, this pattern was completely abrogated in etiolated ein3-1 seedlings, suggesting the expression of EIN3-mediated ACC oxidase genes could be affected by light. To check if the level of EIN3 and EIL1 was regulated by light, cell-free degradation assays were performed. This resulted in the rapid degradation of these proteins within 1h after adding dark-grown cell extracts and this degradation was retarded by light-grown extracts. Here, we propose that light may act as a negative regulator in the destabilization of EIN3/EIL1.


Development of the energy flow in light-harvesting dendrimers.
Modeling the multistep flow of energy in light-harvesting dendrimers presents a considerable challenge. Recent studies have introduced an operator approach based on a matrix representation of the connectivity between constituent chromophores. Following a review of the theory, detailed applications are now shown to exhibit the time development of the core excitation following pulsed laser irradiation and the steady-state behavior that can be expected under conditions of constant illumination. It is also shown how energy capture by whole dendrimers can be analytically related to chromophore pair-transfer properties and, in particular, the spectroscopic gradient toward the core. Indicative calculations also illustrate the consequences of tertiary folding. In each respect, the model affords opportunities to derive new, physically meaningful information on the photophysical and structural features of dendrimeric systems.


Thermal performance of the electron transport system Complex III in seven Alabama fishes.
Management of fish populations for conservation in thermally variable systems requires an understanding of the fish's underlying physiology and responses to thermal stress. Physiological research at the organismal level provides information on the overall effects of stressors such as extreme temperature fluctuations. While experiments with whole organisms provide information as to the overall effects of temperature fluctuations, biochemical assays of thermal stress provide direct results of exposure that are both sensitive and specific. Electron transport system (ETS; Complex III) assays quantify a rate-limiting step of respiratory enzymes. Parameters that can be estimated via this approach include optimum thermal temperature (Topt ) and optimal breadth of thermal performance (Tbreadth ), which can both be related to organismal-level temperature thresholds. We exposed enzymes of seven fish species (native fish chosen to represent a typical community in Alabama streams) to temperatures in the range 11-44°C. The resultant enzymatic thermal performance curves showed that Topt , the lower temperature for enzyme optimal thermal performance (Tlow ), the upper temperature for enzyme optimal thermal performance (Tup ), and Tbreadth differed among species. Relationships between enzymatic activity and temperature for all fish followed a pattern of steadily increasing enzyme activity to Topt before gradually decreasing with increasing temperature. A comparison of our enzyme optimum and upper-temperature limit results versus published critical thermal maxima values supports that ETS Complex III assays may be useful for assessing organismal-level thermal tolerance.


[Role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in hypoxic pulmonary arterial hypertension].
Pulmonary arterial hypertension (PAH) is a rare disease with a complex aetiology characterized by elevated pulmonary artery resistance, which leads to progressive right ventricular failure and ultimately death. The aberrant metabolism of arachidonic acid in the pulmonary vasculature plays a central role in the pathogenesis of PAH. The levels of 15-lipoxygenase (15-LO) and 15-hydroxyeicosatetraenoic acid (15-HETE) are elevated in the pulmonary arterial endothelial cells (PAECs), pulmonary smooth muscle cells (PASMCs) and fibroblasts of PAH patients. Under hypoxia condition, 15-LO/15-HETE induces pulmonary artery contraction, promotes the proliferation of PAECs and PASMCs, inhibits apoptosis of PASMCs, promotes fibrosis of pulmonary vessels, and then leads to the occurrence of PAH. Here, we review the research progress on the relationship between 15-LO/15-HETE and hypoxic PAH, in order to clarify the significance of 15-LO/15-HETE in hypoxic PAH.


Genetic variation in bone growth patterns defines adult mouse bone fragility.
Femoral morphology and composition were determined for three inbred mouse strains between ages E18.5 and 1 year. Genotype-specific variation in postnatal, pubertal, and postpubertal growth patterns and mineral accrual explained differences in adult bone trait combinations and thus bone fragility. Fracture risk is strongly regulated by genetic factors. However, this regulation is generally considered complex and polygenic. Therefore, the development of effective genetic-based diagnostic and treatment tools hinges on understanding how multiple genes and multiple cell types interact to create mechanically functional structures. The goal of this study was to connect variability in whole bone mechanical function, including measures of fragility, to variability in the biological processes underlying skeletal development. We accomplished this by testing for variation in bone morphology and composition among three inbred mouse strains from E18.5 to 1 year of age. Mid-diaphyseal cross-sectional areas, diameters, moments of inertia, and ash content were determined for three strains of mice with widely differing adult whole bone femoral mechanical properties (A/J, C57BL/6J, and C3H/HeJ) at E18.5 and postnatal days 1, 7, 14, 28, 56, 112, 182, and 365 (n = 5-15 mice/strain/age). Significant differences in the magnitude and rate of change in morphological and compositional bone traits were observed among the three strains at each phase of growth, including prenatal, postnatal, pubertal, and adult ages. These genotype-specific variations in growth patterns mathematically determined how variation in adult bone trait combinations and mechanical properties arose. Furthermore, six bone traits were identified that characterize phenotypic variability in femoral growth. These include (1) bone size and shape at postnatal day 1, (2) periosteal and (3) endosteal expansion during early growth, (4) periosteal expansion and (5) endosteal contraction in later growth, and (6) ash content. These results show that genetic variability in adult bone traits arises from variation in biological processes at each phase of growth. Inbred mice achieve different combinations of adult bone traits through genotype-specific regulation of bone surface activity, growth patterns, and whole bone mineral accrual throughout femoral development. This study provides a systematic approach, which can be applied to the human skeleton, to uncover genetic control mechanisms influencing bone fragility.


T-cell activation. VI. Inhibitory and stimulatory effects of anti-major histocompatibility complex class I antibodies in allogeneic mixed lymphocyte culture.
Murine T splenocytes stimulated in primary allogeneic mixed lymphocyte culture (MLC) were incubated with soluble anti-major histocompatibility complex (MHC) class I monoclonal antibodies. These antibodies induced inhibition in the cytotoxicity of the responding population and this inhibition was not dependent on the domain on class I molecules recognized by the antibodies. Cross-reactivity of the antibodies between the responder and stimulating cell population caused a marked reduction in the inhibitory effect compared to systems where no such cross-reactivity was present. Saturating levels of the antibodies caused a reduction in generation of T-cell cytotoxicity, whereas low concentrations stimulated the same response. These results demonstrate that the MHC class I molecules of T cells are of significant importance in antigen-induced signal transduction.


Endoscopic Endonasal Repair and Reconstruction of Traumatic Anterior Skull Base Defects.
Eighty percent of cerebrospinal fluid leaks (CSF) occur following trauma and complicate 12 to 13% percent of all basilar skull fractures (Prosser, Vender, and Solares, 2011). An endoscopic endonasal approach (EEA) is often the preferred method of repair with greater than 90% success rates (Prosser, Vender, and Solares, 2011). We report a case of a 37-year-old man who presented to our regional level 1 trauma centre with multiple facial injuries. Initial cross-sectional imaging revealed multiple, continuous anterior skull base fractures with associated pneumocephalus. Though initially managed conservatively, the patient represented five days later with unilateral left-sided rhinorrhoea. An endoscopic endonasal repair with a multilayer fat, tensor fascia lata, free mucosal graft, and vascularised local flap reconstruction was undertaken. This case highlights the importance of maintaining a high level of suspicion for delayed CSF leak in traumatic base of skull injury. The EEA enables meticulous dissection and thorough inspection of the skull base, facilitating multilayered repair and reconstruction of defects.


[Metal 3D printing in dentistry].
The article describes the use of 3D printing in dentistry, the principle of operation of 3D printers for metals, a review of comparative data on the quality and accuracy of the final product of 3D metal printing is carried out. Possibilities and prospects of using 3D metal printing in dentistry are indicated.


PKC isozymes in chronic cardiac disease: possible therapeutic targets?
Cardiovascular disease is the leading cause of death in the United States. Therefore, identifying therapeutic targets is a major focus of current research. Protein kinase C (PKC), a family of serine/threonine kinases, has been identified as playing a role in many of the pathologies of heart disease. However, the lack of specific PKC regulators and the ubiquitous expression and normal physiological functions of the 11 PKC isozymes has made drug development a challenge. Here we discuss the validity of therapeutically targeting PKC, an intracellular signaling enzyme. We describe PKC structure, function, and distribution in the healthy and diseased heart, as well as the development of rationally designed isozyme-selective regulators of PKC functions. The review focuses on the roles of specific PKC isozymes in atherosclerosis, fibrosis, and cardiac hypertrophy, and examines principles of pharmacology as they pertain to regulators of signaling cascades associated with these diseases.


Unplanned emergency surgery in relation to length of wait lists at registration.
To compare the cumulative incidence of emergency surgery between two groups of patients classified according to the length of wait lists at the time of their registration for coronary artery bypass grafting (CABG) and to test for significant differences in the risk of emergency surgery resulting from registration on a longer wait list. A prospective study of all adult British Columbia residents who registered to undergo isolated CABG. We compared the time-dependent cumulative incidence for undergoing planned surgery through unplanned emergency admission before or during a certain wait-list week between two categories of wait-list size. The list size was a simple count of patients with higher or equal urgency to undergo CABG who were on a wait list at the time of registration of a new patient. Wait lists with one month or less of clearance time were observed in all urgent patients and were more prevalent in semi-urgent than non-urgent patients (79.1% vs 44.7%, respectively). The patients registered on a list with a clearance time of more than one month had a rate of unplanned emergency admission similar to those on a list with a clearance time of one month or less, OR = 1.07 (95% CI, 0.78-1.47) after adjustment for age, sex, comorbidity, calendar period, urgency and week on the list. During fifty-two weeks of the wait-list follow-up, an equal proportion of patients underwent unplanned emergency surgery after registration on lists in both clearance-time categories, OR = 1.03 (95% CI, 0.78-1.37) after adjustment. The number of patients who underwent CABG without having been registered on a wait list in the same hospital exerted no independent effect. The length of a wait list at registration had no effect on the probability that a semi-urgent or non-urgent patient would undergo CABG through unplanned emergency admission before or during a certain wait-list week.


New pseudomonad utilizing methanol for growth.
A bacterium capable of rapid growth on methanol as sole carbon source was isolated and classified as a new pseudomonad. Its doubling time was about 100 min at 32 to 37 C, and it grew well at methanol concentrations up to 2%. The organism was sensitive to phosphate, but reasonable cell densities could be obtained by using pH control. Cell yields of about 31%, based on methanol consumed, were obtained. The amino acid pattern of the protein indicated that the bacterium holds promise as a source of single-cell protein.


Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney.
In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared-mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets.


Association of maternal smoking with child cotinine levels.
Our aim was to understand the strength of association between parental smoking and child environmental tobacco smoke (ETS) exposure in order to inform the development of future tobacco control policies. ETS was measured using child cotinine levels below the active smoking threshold. Participants were drawn from the Avon Longitudinal Study of Parents and Children and included 3,128 participants at age 7 years and 1,868 participants at age 15 years. The primary outcome was cotinine levels of nonsmoking children, to investigate the relationship between maternal smoking and child cotinine levels. The secondary outcome was cotinine levels of all individuals to investigate the relationship between child smoking and child cotinine levels. Maternal and child smoking behavior was assessed by self-report questionnaire. We adjusted for several sociodemographic variables. We found an association between maternal smoking and child cotinine at age 7 years (mean cotinine = 1.16ng/ml serum, ratio of geometric means = 3.94, 95% CI = 2.86-5.42) and at age 15 years (mean cotinine = 0.94ng/ml serum, ratio of geometric means = 5.26, 95% CI = 3.06-9.03), after adjustment for potential confounders. The magnitude of this association for children whose mothers were heavy smokers was comparable with the quantity of half the levels of cotinine observed among children who were irregular (i.e., nonweekly) active smokers, and it was greater than five times higher than that seen in nonsmoking children whose mothers didn't smoke. This provides further evidence for the importance of public health interventions to reduce smoking exposure in the home.


Correlation between essential fatty acids and parameters of bone formation and degradation.
There are two types of essential fatty acids (EFAs), the n-6 derived from linoleic acid (LA) and the n-3, derived from alpha-linolenic acid (ALA). Most of the functions of the EFAs require the conversion of LA and ALA to their metabolites including, gammalinolenic (GLA), dihomogammalinolenic (DGLA), arachidonic (AA) (n-6) and eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (n-3). Supplementing specific GLA:EPA ratios has effects on bone formation and degradation. A study was designed to investigate the effect of various dietary ratios of n-6:n-3 on calcium homeostasis. Female Sprague Dawley rats were ovariectomised (OVX) at age =11 weeks, and were supplemented from age 12 weeks for six weeks with different ratios (9:1; 3:1; 1:3; 1:9) of GLA:EPA. Bone parameters and red blood cell (RBC) fatty acid profiles were measured at age=18 weeks. RBC GLA and DGLA increased in groups 9:1 and 3:1(p<0.05). EPA and DGLA increased in 1:3 and 1:9 while AA decreased (p<0.05). Correlations were calculated between bone calcium, deoxypyridinoline (Dpyd) and specific fatty acids. DGLA was positively correlated with femur calcium and negatively with Dpyd excretion while DHA and EPA were correlated with femur calcium.


Targeted radiotherapy with submyeloablative doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma.
Treatment of refractory neuroblastoma remains a significant clinical problem. Targeted radiotherapy with 131I-MIBG has demonstrated antitumor activity in heavily pretreated neuroblastoma patients with recurrent disease. Response rates may be correlated with total radionuclide dose per kilogram body weight delivered, but higher dose levels are associated with protracted grade 4 hematologic toxicity. The optimal method for using single-agent 131I-MIBG for patients with relapsed high-risk neuroblastoma has not been defined. This study was designed to retrospectively determine the clinical response to 131I-MIBG therapy at submyeloablative doses in patients with refractory neuroblastoma and to describe the toxicities. A retrospective chart review of 20 patients with neuroblastoma treated with 131I-MIBG at the Children's Hospital of Philadelphia from 1988 to 2000 was performed. Demographic data, 131I-MIBG dose delivered, toxicities, and clinical responses were reviewed. A median dose of 9.5 mCi/kg of 131I-MIBG was delivered in 32 courses to 20 patients. Three patients were treated in first complete response, and the remaining 17 patients for residual and/or progressive disease. The objective response rate to the first therapy was 31%, and the remaining patients achieved disease stabilization. In addition, 9 of 11 patients with pain at study entry had significant improvement. Disease response was not correlated with 131I-MIBG dose delivered. No unanticipated toxicities were observed. Submyeloablative-dose 131I-MIBG is an effective and relatively nontoxic method for neuroblastoma disease palliation. Most patients show subjective improvement in pain and/or performance status. Increased availability and experience with 131I-MIBG therapy would benefit a large number of children with end-stage neuroblastoma and no realistic hope for cure.


Hatching failure and accumulation of organic pollutants through the terrestrial food web of a declining songbird in Western Europe.
Population growth in passerine birds is largely driven by fecundity. If fecundity is affected, for instance by hatching failure, populations may decline. We noted high hatching failure of up to 27% per year in relict populations of the Northern wheatear (Oenanthe oenanthe) in The Netherlands, a strongly declining, migratory passerine in Europe. This hatching failure itself can cause population decline, irrespective of other adverse factors. Additionally, we investigated the cause of hatching failure. Unhatched eggs showed egg yolk infections or embryonic malformations, part of which is associated with the actions of dioxin-like compounds (DLCs). Indeed, DLCs appear to bioaccumulate in the local foodweb, where the soil contained only background concentrations, similar to those found at many other locations. DLC concentrations in Dutch eggs were six-fold higher than those in a reference population in Sweden, where egg failure was only 6%. However, Northern wheatears appear to be only moderately sensitive to the actions of DLCs, because of their specific Ah-receptor type which may moderate the receptor mediated effects of DLCs. This indicates that the concentrations of DLCs, although elevated, may not have caused the embryo malformations or the low hatching rates. We discuss whether other toxins may be important or imbalances in the nutrition and if inbreeding may play a larger role than expected.


Perioperative beta-blockers for preventing surgery-related mortality and morbidity: a systematic review and meta-analysis.
Perioperative beta-blockers are suggested to reduce cardiovascular mortality, myocardial-ischemia/infarction, and supraventricular arrhythmias after surgery. We reviewed the evidence regarding the effectiveness of perioperative beta-blockers for improving patient outcomes after cardiac and noncardiac surgery. Eleven large databases were searched from the time of their inception until October 2005. Various online-resources were consulted for the identification of unpublished trials and conference abstracts. We included randomized, controlled trials comparing perioperative beta-blockers with either placebo or the standard-of-care. Of the 3680 retrieved titles, 69 met inclusion criteria for analysis. Odds ratios (OR) assuming random effects were computed in the absence of significant clinical heterogeneity. Beta-blockers reduced the frequency of ventricular tachyarrhythmias [OR (cardiac surgery): 0.28, 95% CI 0.13-0.57; OR (noncardiac surgery): 0.56, 95% CI 0.21-1.45], atrial fibrillation/flutter [OR (cardiac surgery): 0.37, 95% CI 0.28-0.48], other supraventricular arrhythmias [OR (cardiac surgery): 0.25, 95% CI 0.18-0.35; OR (noncardiac surgery): 0.43, 95% CI 0.14-1.37], and myocardial ischemia [OR (cardiac surgery): 0.49, 95% CI 0.17-1.4; OR (noncardiac surgery): 0.38, 95% CI 0.21-0.69]. Length of hospitalization was not reduced [weighted mean difference (cardiac surgery): -0.35 days, 95% CI -0.77-0.07; weighted mean difference (noncardiac surgery): -5.59 days, 95% CI -12.22-1.04] and, in contrast to previous reports, beta-blockers did not reduce mortality [OR (cardiac surgery): 0.55, 95% CI 0.17-1.83; OR (noncardiac surgery): 0.78, 95% CI 0.33-1.87], and they had no influence on the occurrence of perioperative myocardial infarction [OR (cardiac surgery): 0.89, 95% CI 0.53-1.5; OR (noncardiac surgery): 0.59; 0.25-1.39]. Beta-blockers reduced perioperative arrhythmias and myocardial ischemia, but they had no effect on myocardial infarction, mortality, or length of hospitalization.


Longitudinal Study of Three microRNAs in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy.
Our objective was to investigate the potential of three microRNAs, miR-181a-5p, miR-30c-5p, and miR-206 as prognostic biomarkers for long-term follow up of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients. We analyzed the expression of three microRNAs in serum of 18 patients (DMD 13, BMD 5) and 13 controls using droplet digital PCR. Over 4 years a minimum of two and a maximum of three measurements were performed at different time points in the same patient. Correlations between microRNA serum levels, age, and functional outcome measures were analyzed. We show the individual evolution of the levels of the three microRNAs in 12 patients and also the effect of corticosteroid treatment on microRNAs expression. We measure the expression of three microRNAs in the muscle of six DMD patients and also the expression of target genes for miR-30c. We found that levels of miR-30c and miR-206 remained significantly elevated in DMD patients relative to controls over the entire study length. The introduction of the corticosteroid treatment did not significantly influence the levels of these microRNAs. We report a trend for microRNA levels to decrease with age. Moreover, miR-206 expression levels are capable to distinguish DMD from BMD patients according to ROC analysis. We found miR-30c expression decreased in the muscle of DMD patients and marked upregulation of the target genes for this microRNA. MiR-30c and miR-206 represent sensitive biomarkers for DMD, while miR-206 may have an additional value to distinguish the DMD and BMD phenotype. This may be particularly relevant to assess the effectiveness of treatments aimed at converting the DMD to the less-severe BMD like phenotype.


Pharmacokinetics of piperaquine after single and multiple oral administrations in healthy volunteers.
The aim of this work was to study the pharmacokinetics of piperaquine in healthy volunteers. Healthy volunteers received piperaquine and tablets of Artekin by oral administration. The plasma samples were analyzed for piperaquine by liquid-liquid extraction and determined by HPLC-UV. The results demonstrated that the plasma drug concentration-time curves of single and multiple dose of piperaquine were fitted to a two-compartment open model. The pharmacokinetics parameters of piperaquine alone in a single dose were: t(1/2(beta))=(317.2-/+126.6)h, AUC(0-->infinity)=(44293-/+12636)h x ng/ml, V(d)=(9490.9-/+2161.9)ml/kg, and Cl=(22.83-/+9.83)ml/h/kg. In Artekin in a single dose these parameters were: t(1/2(beta))=(302.8-/+180.7)h, AUC(0-->infinity)=(46419-/+13670)h x ng/ml, V(d)=(10188.6-/+3520.3)ml/kg, and Cl=(25.48-/+10.89)ml/h/kg, while in Artekin in multiple doses they were: t(1/2(beta))=(298.9-/+101.9)h, AUC(0-->infinity)=(227692-/+56294)h x ng/ml, V(d)=(5031.5-/+1097.8)ml/kg, Cl=(11.91-/+3.046)ml/h/kg, respectively. The absorption and distribution of piperaquine were quick while the elimination was quite slow. There were significant differences in the pharmacokinetics parameters of piperaquine in Artekin between a single dose and multiple doses (p<0.001), suggesting that piperaquine might accumulate in vivo and that attention should be given to its possible adverse drug reactions in clinical treatment.


Measuring tracheal tube cuff pressures--tool and technique.
A three-part study identified factors essential to accurate determination of pressure exerted against the lateral wall of the trachea by three types of endotracheal tube cuffs. Part I compared 31 mercury sphygmomanometer measurements of tracheal cuff pressures to those of pressure-sensitive aneroid Portex manometer during simulated intubation and found 99.28% of mercury manometer readings accurate to within 2 mm Hg of Portex readings. Part II demonstrated that cuff compliance (i.e., the distensibility of the cuff material) influences such pressure determinations. Part III compared two methods of obtaining tracheal cuff pressure readings with the mercury sphygmomanometer during simulated intubation. Accurate measurement was made only with a stopcock system that simultaneously opened to the cuff, the manometer, and the inflator syringe and when a separate cuff distensibility factor was used in the computation.


A YAP/TAZ-ARHGAP29-RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions.
Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for EPB41L5 (Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss of Yurt in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human EPB41L5 knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by TEADi led to the identification of ARGHAP29 as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of EPB41L5 and TEADi expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA-YAP/TAZ signaling in podocyte physiology and disease.


Aerosol-assisted controlled packing of silica nanocolloids: templateless synthesis of mesoporous silicates with structural tunability and complexity.
A template-free synthesis method for mesoporous and macro-/mesoporous hierarchically porous silicates with remarkable structural tunability and complexity is presented. SiO2 nanocolloids having diameters of 3.0-29 nm were prepared as a primary building block by using extended Stöber synthesis, and they were subsequently assembled by an aerosol-assisted drying. The silica pore structure can be rationally controlled depending on the initial diameter of SiO2 colloids and the aerosol-assembly temperature that determines the packing density of SiO2 colloids (i.e., amounts of packing defects) in the resultant materials. The present method could produce mesoporous silica spheres with remarkable pore-structural tunability (291 < BET surface area <807 m(2) g(-1), 0.42 < pore volume <0.92 cm(3) g(-1), 3.1 < pore size <26 nm). Hierarchically porous materials can also be synthesized by the evaporation-induced phase separation of solvent medium during the aerosol-assisted assembly of SiO2 colloids. By adding aluminum and Pt precursors into the SiO2 colloid suspensions before the aerosol-assisted assembly, mesoporous aluminosilicates supporting uniform Pt nanoclusters (∼2 nm) can also be synthesized. This indicates that the synthesis strategy can be used for the direct synthesis of functional silicate materials.


Comparative cytotoxicity of Al2O3, CeO2, TiO2 and ZnO nanoparticles to human lung cells.
The increased applications of nanoparticles in a wide range of industrial fields raise the concern about their potential toxicity to human. The aim of this study was to assess and compare the toxicity of four different oxide nanoparticles (Al2O3, CeO2, TiO2 and ZnO) to human lung epithelial cells, A549 carcinoma cells and L-132 normal cells, in vitro. We focused on the toxicological effects of the present nanoparticles on cell proliferation, cell viability, membrane integrity and oxidative stress. The long-term cytotoxicity of nanoparticles was also evaluated by employing the clonogenic assay. Among four nanoparticles tested, ZnO exhibited the highest cytotoxicity in terms of cell proliferation, cell viability, membrane integrity and colony formation in both cell lines. Al2O3, CeO2 and TiO2 showed little adverse effects on cell proliferation and cell viability. However, TiO2 induced oxidative stress in a concentration- and time-dependent manner. CeO2 caused membrane damage and inhibited colony formation in long-term, but with different degree depending on cell lines. Al2O3 seems to be less toxic than the other nanoparticles even after long time exposure. These results highlight the need for caution during manufacturing process of nanomaterials as well as further investigation on the toxicity mechanism.


Probing Metabolism and Viscosity of Cancer Cells using Fluorescence Lifetime Imaging Microscopy.
Viscosity is an important physical property of a biological membrane, as it is one of the key parameters for the regulation of morphological and physiological state of living cells. Plasma membranes of tumor cells are known to have significant alterations in their composition, structure, and functional characteristics. Along with dysregulated metabolism of glucose and lipids, these specific membrane properties help tumor cells to adapt to the hostile microenvironment and develop resistance to drug therapies. Here, we demonstrate the use of fluorescence lifetime imaging microscopy (FLIM) to sequentially image cellular metabolism and plasma membrane viscosity in live cancer cell culture. Metabolic assessments are performed by detecting fluorescence of endogenous metabolic cofactors, such as reduced nicotinamide adenine dinucleotide NAD(P)H and oxidized flavins. Viscosity is measured using a fluorescent molecular rotor, a synthetic viscosity-sensitive dye, with a strong fluorescence lifetime dependence on the viscosity of the immediate environment. In combination, these techniques enable us to better understand the links between membrane state and metabolic profile of cancer cells and to visualize the changes induced by chemotherapy.


Hospital length of stay on a diabetes cluster unit.
To determine whether the length of hospital stay for patients with either a primary or a secondary diagnosis of diabetes mellitus can be reduced by use of a diabetes cluster unit. For a period of 12 months, we compared the length of hospital stay for 462 patients with diabetes who were admitted to a diabetes cluster unit and for 1,855 patients with diabetes who were admitted to the other medical and surgical units during the same period. Statistical analysis was done by comparing the calculated average length of stay for patients with primary and secondary diagnoses of diabetes admitted to both types of hospital accommodations and comparing these values with the expected lengths of hospital stay based on the New York Group Standard. The mean length of hospital stay for patients who were admitted to the diabetes unit for a primary diagnosis of diabetes was 5.8 days shorter than for those admitted to regular medical and surgical units (7.6 days or 1% below the expected duration versus 13.4 days or 70% longer than the expected duration, respectively; P<0.0002). For a secondary diagnosis of diabetes, patients in the diabetes unit had an average length of stay of 15.5 days (35% longer than the expected duration) in comparison with 17 days (45% longer than expected) for patients on the other medical and surgical units (no significant difference). For hospitalization of patients with diabetes, geographic clustering seems to reduce the length of stay for patients with a primary diagnosis of diabetes mellitus.


Advancements in Drug Repurposing: Examples in Psychiatric Medications.
Because there are a limited number of animal models for psychiatric diseases that can be extrapolated to humans, drug repurposing has been actively pursued. This study was aimed at uncovering recent trends in drug repurposing approaches and new technologies that can predict efficacy on humans based on animal models used in psychiatric drug development. Psychiatric drugs that were approved by the FDA between 2002 and 2022 were listed, and the method of how the drug repurposing has been applied was analyzed. Drug repurposing has been increasingly applied to recently approved psychiatric drugs. The development concepts of psychiatric drugs that have been developed through drug repurposing over the past 20 years were found to be divided into six categories: new application exploration, reduction of side effects, improvement of symptom control, improvement of medication compliance, enhancement of drug efficacy, and reduction of drug-drug interactions. All repurposed drugs approved before 2016 used either prodrugs or active metabolites, while all drugs approved in 2021 and beyond used fixed-dose combinations with sophisticated ideas. SmartCube®, which uses artificial intelligence to predict human drug efficacy from animal phenotypes, was developed and produced novel drugs that show clinical efficacy. Well-designed drug repurposing approaches and new technologies for predicting human drug efficacy based off of animal models would contribute to novel psychiatric drug development.


Patient and clinician communication of self-reported insomnia during ambulatory cancer care clinic visits.
Insomnia, the most commonly reported sleep-wake disturbance in people with cancer, has an adverse effect on quality of life including emotional well-being, distress associated with other symptoms, daily functioning, relationships, and ability to work. The aim of this study was to describe the content of discussions between clinicians and 120 patients with self-reported insomnia and to examine the associations of sociodemographic, clinical, and environmental factors with insomnia. A secondary analysis was conducted with self-reported symptom data and sociodemographic, clinical, and environmental factors. Recordings of clinician and patient discussions during clinic visits were examined by conducting a content analysis. Severe insomnia was more likely to be reported by women, minority, and lower-income individuals. Seven major topics were identified in the discussions. The clinicians did not always discuss insomnia; discussion rates differed by diagnosis and clinical service. Reporting of insomnia by the patient and clinician communication about insomnia may have differed by demographic and clinical characteristics. Clinicians attended to insomnia about half the time with management strategies likely to be effective. Explanations may be that insomnia had a low clinician priority for the clinic visit or lack of clear evidence to support insomnia interventions. A better understanding is needed about why insomnia is not addressed even when reported by patients; it is well known that structured assessments and early interventions can improve quality of life. Research is warranted to better understand potential disparities in cancer care.


Optical Signatures of Quantum Emitters in Suspended Hexagonal Boron Nitride.
Hexagonal boron nitride (h-BN) is rapidly emerging as an attractive material for solid-state quantum engineering. Analogously to three-dimensional wide-band-gap semiconductors such as diamond, h-BN hosts isolated defects exhibiting visible fluorescence at room temperature, and the ability to position such quantum emitters within a two-dimensional material promises breakthrough advances in quantum sensing, photonics, and other quantum technologies. Critical to such applications is an understanding of the physics underlying h-BN's quantum emission. We report the creation and characterization of visible single-photon sources in suspended, single-crystal, h-BN films. With substrate interactions eliminated, we study the spectral, temporal, and spatial characteristics of the defects' optical emission. Theoretical analysis of the defects' spectra reveals similarities in vibronic coupling to h-BN phonon modes despite widely varying fluorescence wavelengths, and a statistical analysis of the polarized emission from many emitters throughout the same single-crystal flake uncovers a weak correlation between the optical dipole orientations of some defects and h-BN's primitive crystallographic axes, despite a clear misalignment for other dipoles. These measurements constrain possible defect models and, moreover, suggest that several classes of emitters can exist simultaneously throughout free-standing h-BN, whether they be different defects, different charge states of the same defect, or the result of strong local perturbations.


Combination therapy in psoriasis: an evidence-based review.
Psoriasis is a chronic, systemic, inflammatory condition for which a variety of treatment modalities exist. Combinations of therapies are used often in clinical practice to enhance efficacy and reduce drug toxicities. The purpose of this review is to assess the literature on the efficacy and safety of combination therapy in the treatment of psoriasis. MEDLINE was reviewed to identify English-language publications from 1966 to 2011 examining combination therapy in psoriasis. Fifty-three articles met inclusion criteria and were included in this review. Randomized controlled trials addressing various combinations of treatment modalities for psoriasis were included. Data from these clinical studies were summarized and the outcomes were discussed. Large-scale, randomized controlled trials investigating the use of various combination therapies in psoriasis are limited. The strongest data support the use of combinations of vitamin D derivatives and corticosteroids as topical combinations and, to a lesser extent, the combination of other topical agents. Phototherapy and topical vitamin D derivatives as well as phototherapy in combination with oral retinoids are well supported in the literature. Combinations of systemic medications, though often used clinically, have little data to support their efficacy or safety. Our data were limited by the small number of clinical trials examining the multiple available combinations that are used in clinical practice. The use of combination treatments falls within the standard of care for psoriasis, even if these combinations have not been extensively studied in clinical trials.


Brain-derived neurotrophic factor acutely depresses excitatory synaptic transmission to GABAergic neurons in visual cortical slices.
Brain-derived neurotrophic factor (BDNF) acutely modulates synaptic transmission to excitatory neurons in hippocampus and neocortex. The question of whether BDNF acts similarly on excitatory synaptic transmission to GABAergic neurons was eluded in previous studies using cortical slices. To address this question, we used transgenic mice in which expression of green fluorescence protein (GFP) is regulated by glutamic acid decarboxylase 67 (GAD67) promoter. In cortical slices prepared from these GAD67-GFP knock-in mice, we could detect GABAergic neurons under a fluorescent microscope. An application of BDNF rapidly depressed excitatory postsynaptic currents (EPSCs) evoked by layer IV stimulation in most GFP-positive neurons in layer II/III of the cortex. This effect was seen at synapses activated during the BDNF application and blocked by anti-TrkB IgG, indicating that the acute inhibitory action of BDNF is activity-dependent and mediated through TrkB. Paired-pulse ratios of the amplitude of EPSCs to paired stimulation at intervals of 10-100 ms were not significantly changed after BDNF application, suggesting that the site of depression may be postsynaptic. Responses to directly applied glutamate were also depressed by BDNF in most of neurons, being consistent with the interpretation of postsynaptic action of BDNF. The depressive action of BDNF was blocked by an intracellular injection of a Ca(2+) chelator, suggesting that a rise in Ca(2+) is involved in the acute depression of EPSCs. This action of BDNF was seen in 67% of parvalbumin (PV)-positive neurons, but in only 19% of PV-negative neurons, indicating that the depressive action is biased to PV-positive GABAergic neurons.


Anti-MuSK-Positive Myasthenic Crisis in a 7-Year-Old Female.
A seven-year-old African American female with anti-MuSK-positive Juvenile Myasthenia Gravis collapsed while at school from progressively worsening weakness and dyspnea. On initial emergency department presentation, she required 15 liters per minute of supplemental oxygen to maintain oxygen saturation above 92%. Initial pulmonary function tests and venous blood gas led to the decision to place her on noninvasive positive pressure ventilation (NPPV) with BiPAP in the emergency department. Due to worsening hypercarbia, she later required mechanical intubation in the PICU and underwent IVIG therapy followed by plasmapheresis in order to achieve a stable discharge from the hospital. A respiratory virus panel PCR was positive for influenza A, influenza B, and rhinovirus, likely precipitating the respiratory failure and myasthenic crisis in this seven-year-old patient. Given the rarity of this condition, this case report is to provide further education to the clinician managing severe, prepubertal Juvenile Myasthenia Gravis and myasthenic crisis.


[Editorial introduction: from the structure and functions of the neuromuscular junction to the diseases].
The neuromuscular junction has been recognized as a site for autoimmune and genetic disorders. Myasthenia gravis (MG) is mainly caused by postsynaptic nicotinic acetylcholine receptor (AChR) IgG1 antibodies that are directed against α-subunit 67-76 and 125-147 and activate complement. Thymic abnormalities are present in the autoimmune background. A proportion of MG patients without conformation-dependent AChR antibodies assayed by the cell-based method have muscle-specific tyrosine kinase (MuSK) antibodies which are largely IgG4 and partially IgG1. MuSK is activated by Dok-7 and Lrp4 (agrin receptor) and contributes to AChR clustering at the postsynaptic membrane via various kinase cascades in collaboration with Wnt-MuSK/Frizzled-Dishevelled signaling. Rapsyn interacts with MuSK-linked chaperones to stabilize postsynaptic architecture and also contributes to AChR phosphorylation. MG-associated thymomas express antigens that trigger antibody responses which play a part in disease generation and modification. Among these, ryanodine receptor-1 (RyR1; acts on sarcoplasmic Ca2+ release) antibodies cause muscle contractile weakness. Transient receptor potential canonical-3 (TRPC3) antibodies are also detected in thymoma-associated MG patients; they may participate in muscle contractile weakness because TRPC3 acts on RyR1, and may also impair the refill of sarcoplasmic Ca2+ stores since TRPCs contribute to the receptor-operated Ca2+ influx via the phospholipase C (PLC)-diacylglycerol (DAG) pathway in cooperation with the store-operated, STIM1/Orai1-mediated Ca2+ influx and TRPCs-Homerl-IP3R interaction. Lambert-Eaton myasthenic syndrome (LEMS) is caused by reduced ACh quantal release that occurs mainly because of presynaptic P/Q-type voltage-gated Ca2+ channel (VGCC) antibodies. Physicians should be vigilant for LEMS because it may predict an underlying malignancy, particularly small-cell lung carcinoma; SOX-1 antibodies are usually present in these patients and are absent in those who do not have caucer. Some patients with LEMS have antibodies against synaptotagmin-1, which associates with SNARE complex and functions as Ca2+ sensor for exocytosis. The stimulation of the M1-type presynaptic muscarinic AChR (mAChR)(G-proterin-coupled receptor) can compensate for the deficiency of Ca2+-mediated ACh quantal release via the PLC/DAG-mediated mechanism; This acts in a manner similar to the BDNF/NT4-TrkB interaction. The detection of M1 mAChR antibodies in LEMS suggests an impaired compensatory mechanism and corresponds, at least in part, to autonomic symptoms. Congenital myasthenic syndromes are classified into presynaptic, synaptic basal lamina and postsynaptic defects.


P-type ATPase from the cyanobacterium Synechococcus 7942 related to the human Menkes and Wilson disease gene products.
DNA encoding a P-type ATPase was cloned from the cyanobacterium Synechococcus 7942. The cloned ctaA gene encodes a 790-amino acid polypeptide related to the CopA Cu(2+)-uptake ATPase of Enterococcus hirae, to other known P-type ATPases, and to the candidate gene products for the human diseases of copper metabolism, Menkes disease and Wilson disease. Disruption of the single chromosomal gene in Synechococcus 7942 by insertion of an antibiotic-resistance cassette results in a mutant cell line with increased tolerance to Cu2+ compared with the wild type.