Impact of interferon-free regimens on the glomerular filtration rate during treatment of chronic hepatitis C in a real-life cohort.
Little data are available on renal toxicity exerted by direct-acting antivirals (DAAs) in real life. The aim of this study was to assess the impact of direct-acting antivirals against hepatitis C virus infection currently used in Spain and Portugal on the estimated glomerular filtration rate (eGFR) in clinical practise. From an international, prospective multicohort study, patients treated with DAAs for at least 12 weeks and with eGFR ≥30 mL/min per 1.73 m2 at baseline were selected. eGFR was determined using the CKD-EPI formula. A total of 1131 patients were included; 658 (58%) were HIV/HCV-coinfected patients. Among the 901 patients treated for 12 weeks, median (interquartile range) eGFR was 100 (87-107) at baseline vs 97 (85-105) mL/min per 1.73 m2 at week 12 of follow-up (FU12) post-treatment (P < .001). For HIV-coinfected subjects who received tenofovir plus a ritonavir-boosted HIV protease inhibitor (PI/r), baseline vs FU12 eGFR were 104 (86-109) vs 104 (91-110) mL/min per 1.73 m2 (P = .913). Among subjects receiving ombitasvir/paritaprevir with or without dasabuvir, eGFR did not show any significant change. Of 1100 subjects with eGFR >60 mL/min per 1.73 m2 at baseline, 22 (2%) had eGFR <60 mL/min per 1.73 m2 at FU12, but none presented with eGFR <30 mL/min per 1.73 m2 . In conclusion, eGFR slightly declines during therapy with all-oral DAAs and this effect persists up to 12 weeks after stopping treatment in subjects with normal to moderately impaired renal function, regardless of HIV status. Concomitant use of tenofovir plus PI/r does not seem to have an impact on eGFR.


Validation of the 16S rDNA and COI DNA barcoding technique for rapid molecular identification of stored product psocids (Insecta: Psocodea: Liposcelididae).
Psocids are serious storage pests, and their control is hampered by the fact that different species respond differently to insecticides used for the control of stored-product insect pests. Additionally, psocids of genus Liposcelis that are commonly associated with stored-products are difficult to identify using morphological characteristics. The goal of this study was to validate molecular identification of stored-product psocids of genus Liposcelis based on 16S rDNA and cytochrome oxidase I (COI) DNA barcoding. Unidentified liposcelids (Liposcelis DK) imported from Denmark to China were compared with 14 population samples of seven common species (L. bostrychophila, L. brunnea, L. corrodens, L. decolor, L. entomophila, L. mendax, and L. paeta). The explored species (DK) liposcelids shared >98% sequence similarity for both the 16S rDNA and COI genes with the reference L. corrodens samples (98.32 and 98.94% for 16S rDNA and COI, respectively). A neighbor-joining tree revealed that the explored DK sample and the reference L. corrodens samples belong to the same clade. These molecular results were verified by morphological identification of DK specimens, facilitated by SEM microphotography. The DNA barcoding method and the neighbor-joining phylogenetic analyses indicated that both the 16S rDNA and COI genes were suitable for Liposcelis species identification. DNA barcoding has great potential for use in fast and accurate liposcelid identification.


The application of hospice concepts to neonatal care.
Despite impressive improvements in outcome for infants cared for in neonatal intensive care units (NICUs), large tertiary-care referral units still admit a substantial number of infants who will not survive or, because of a predictably very poor outcome, should not be offered modern life-support techniques. Dealing with these infants can be extremely taxing on both the family and the staff. We have recently adapted the concepts first described in adult hospice care to the care of the dying neonate and his family. By providing a "Family Room" that is private yet close to the NICU and by training the staff in more supportive approaches toward these families, we have been able to deal with the problem of the dying newborn in a manner that has been beneficial to both families and staff.


Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance.
Defects in apoptosis contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), calling for novel strategies that counter apoptosis resistance. Here, we demonstrate for the first time that small molecule inhibitors of the antiapoptotic protein XIAP cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, synergize with TRAIL to trigger apoptosis and to inhibit clonogenic survival of acute leukemia cells, whereas they do not affect viability of normal peripheral blood lymphocytes, suggesting some tumor selectivity. Analysis of signaling pathways reveals that XIAP inhibitors enhance TRAIL-induced activation of caspases, loss of mitochondrial membrane potential, and cytochrome c release in a caspase-dependent manner, indicating that they promote a caspase-dependent feedback mitochondrial amplification loop. Of note, XIAP inhibitors even overcome Bcl-2-mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Importantly, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In vivo, they significantly reduce leukemic burden in a mouse model of pediatric ALL engrafted in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood ALL.


Current and future therapies for targeting HER2 mutations in gastrointestinal cancer.
Gastrointestinal (GI) cancers altogether represent the most common cancer type. HER2 is found to be present in nearly all histologic types of GI cancers in variable degrees of expression. Over the last decade, substantial advances have been made in targeting HER2-positive cancers. Areas covered: The present review summarizes the current progress and future directions for HER2 targeted therapies in GI cancers, including esophagogastric, pancreaticobiliary, and colon cancers. To date trastuzumab is the only anti-HER2 therapy approved for metastatic esophagogastric adenocarcinoma. Efforts are ongoing to expand the therapeutic role of HER2 to other GI cancers and overcome mechanisms of drug resistance. Novel agents and combinations are being tested in most HER2 positive GI cancers including early stage disease. These are of recent interest in colorectal cancer with studies indicating that HER2 overexpression might increase resistance to anti-EGFR therapy and may be potentially targeted. Expert commentary: With the current ability to sequence tumors and detect genetic alterations, emphasis should be put on genomically-selected pan-tumor targeted therapies. HER2 is a perfect example of a promising drug target in GI cancers.


Underreduced supracondylar fracture of the humerus in children: clinical significance at skeletal maturity.
Although supracondylar fractures of the humerus in children are common, the literature is sparse regarding acceptable limits of reduction of these fractures in the sagittal plane. We retrospectively reviewed 223 pediatric cases of supracondylar fractures of the elbow treated in our hospital between the years 1996 and 2000. In 30 patients, we found some degree of underreduction of the extension component of the fracture. Twenty-two of them were followed and evaluated at or close to skeletal maturity. The mean age at the time of fracture was 5.4 years, the mean follow-up was 8.2 years. Radiographic remodeling, range of elbow motion, and awareness of the patients to the functional limitation were evaluated. At final follow-up, 17 (77%) of the patients had radiographic abnormality of the humerocondylar angle (a difference of 5 degrees or more compared with the uninjured side). Eleven patients (50%) had limited elbow flexion, and 7 (31%) were aware of this deficit. Most of the underreductions occurred when reduction was attempted in the emergency department, when the angulation was not appreciated, and when the cast was applied without any reduction attempt. Patients who were left to heal with some degree of extension developed limited end-elbow flexion and were aware of it. Although only 3 patients felt minor subjective functional disability at the last follow-up, 10 patients had unsatisfactory results according to Flynn criteria for motion restriction. The treating surgeon must be aware of this possible outcome and be more demanding in the reduction of the extension component of the fracture. Otherwise, clinically significant limitation in elbow flexion may occur. Although the reduction of moderately displaced fractures may seem simple, it should be performed under general anesthesia and with radiographic control of reduction and pin placement.


Three-dimensional hierarchical Ni3Se2 nanorod array as binder/carbon-free electrode for high-areal-capacity Na storage.
A three-dimensional hierarchical Ni3Se2 nanorod array (NA) grown in situ on foam Ni is the first to act as a carbon/binder-free electrode of SIBs via a one-step reversible conversion reaction. By a special decomposition-fusion process, the morphology and composition of the NA are regulated to obtain ultrahigh areal capacity, which is three times greater than that reported for other metal selenides.


Remote life-style causes of cancer.
Most epidemiologists regard more or less proximal variables as life-style factors--smoking, diet, sex behavior, occupation. Within this framework, life-style factors making for high risk of cancer are defined and presented. Three estimates of the contribution to cancer incidence by the major proximal causes are presented, using the variables specified by each estimator. For purposes of completeness and possible prevention action, however, intermediate and distant precursors should be considered--local ecology, culture, industrialization, etc. The possibility that stress may affect cancer risk is addressed and evidence presented to suggest that any contribution to risk, if it exists at all, is probably small.


The stretching force on a tethered polymer in pressure-driven flow.
We use mesoscopic lattice-Boltzmann/molecular dynamics simulations to study the stretching behavior of a single tethered polymer in micro- and nanochannels. In particular, we are interested in the connection between fluid flow properties and the force on the polymer chain. An analytical expression for the stretching force is proposed, which linearly depends on the number of monomers and the boundary shear rate. In agreement with theory, the numerical findings reveal that the influence of hydrodynamic interactions can be ignored, which is also supported by results of additional Langevin dynamics simulations. Our simulation data coincide with the analytical expression for the fractional extension of the chain and further indicate that even weak Poiseuille flow profiles induce a strong alignment of the chain along the channel walls. The numerical results are in good agreement with experimental data obtained by microfluidic stretching of tethered λ-DNA.


Identity of the B56.5 protein, the A-protein, and the groE gene product of Escherichia coli.
Protein B56.5 is a major Escherichia coli protein, originally identified on two-dimensional gels as an abundant cellular protein with unique regulation. The groE gene product is a bacterial protein essential for the assembly of many diverse bacteriophages. The ribosomal A-protein is a large, acidic protein of unknown function associated with isolated, washed ribosomes. On the basis of comigration in two-dimensional gels, oligopeptide map patterns, amino acid composition, immunological specificity, physical properties, and genetic analysis, protein B56.5 has now been shown to be the groE gene product and to be identical with the A-protein.


[Secretory carcinoma of the breast: clinicotherapeutic considerations and a review of the literature].
Prompted by the observation of a case of secretory (juvenile) secretory carcinoma of the breast, the Authors review the literature on this extremely rare disease. In view of the biological characteristics of this type of tumour, the Authors maintain that to ensure radical surgery and correct staging a quadrantectomy operation combined with emptying of the axillary cavity should be performed in those cases complying with the tumour size indication (2 cm). In larger tumours they regard the Helsted operation as the only form of surgery guaranteeing an adequate degree of radicality.


Kinetics of thermal activation of an ultraviolet cone pigment.
Visual pigments can be thermally activated via isomerization of the retinyl chromophore and hydrolysis of the Schiff base (SB) through which the retinyl chromophore is bound to the opsin protein. Here, we present the first combined experimental and theoretical study of the thermal activation of a Siberian hamster ultraviolet (SHUV) pigment. We measured the rates of thermal isomerization and hydrolysis in the SHUV pigment and bovine rhodopsin. We found that these rates were significantly faster in the UV pigment than in rhodopsin due to the difference in the structural and electrostatic effects surrounding the unprotonated Schiff base (USB) retinyl chromophore in the UV pigment. Theoretical (DFT-QM/MM) calculations of the cis-trans thermal isomerization revealed a barrier of ∼23 kcal/mol for the USB retinyl chromophore in SHUV compared to ∼40 kcal/mol for protonated Schiff base (PSB) chromophore in rhodopsin. The lower barrier for thermal isomerization in the SHUV pigment is attributed to the (i) lessening of the steric restraints near the β-ionone ring and SB ends of the chromophore, (ii) displacement of the transmembrane helix 6 (TM6) away from the binding pocket toward TM5 due to absence of the salt bridge between the USB and the protonated E113 residue, and (iii) change in orientation of the hydrogen-bonding networks (HBNs) in the extracellular loop 2 (EII). The results in comparing thermal stability of UV cone pigment and rhodopsin provide insight into molecular evolution of vertebrate visual pigments in achieving low discrete dark noise and high photosensitivity in rod pigments for dim-light vision.


Utility and tolerability of the long-pulsed 1064-nm neodymium:yttrium-aluminum-garnet (LP Nd:YAG) laser for treatment of symptomatic or disfiguring vascular malformations in children and adolescents.
Vascular malformations manifest with pain, bleeding, disability, and disfigurement in a subset of children. There are scant data available on the utility and tolerability of laser surgery for symptomatic or disfiguring non-port-wine stain vascular malformations in children. The objective of this study was to determine the utility and tolerability of the 1064-nm long-pulsed neodymium:yttrium-aluminum-garnet (LP Nd:YAG) laser for treatment of symptomatic or disfiguring vascular malformations in children. We conducted a retrospective review of 29 pediatric patients with non-port-wine stain vascular malformations who were treated with the LP Nd:YAG laser at our institution. We report patient characteristics, treatment parameters, outcomes, and complications. Blinded assessment of clinical efficacy revealed good to excellent results in 66.7% of patients treated and poor to fair results in 25%. The overall rate of complications was 27%, with minor skin breakdown and blistering being the most common. Our conclusions are limited by small sample size, pretreatment and posttreatment photographs in only a subset of patients, and lack of long-term follow-up. The LP Nd:YAG laser is a well-tolerated and effective treatment modality for a variety of non-port-wine stain vascular malformations in children.


Temperature-sensitive mutants of Abelson murine leukemia virus deficient in protein tyrosine kinase activity.
The effect of two missense mutations in abl on transformation by Abelson murine leukemia virus was evaluated. These mutations led to the substitution of a histidine for Tyr-590 and a glycine for Lys-536. Both changes gave rise to strains that were temperature dependent for transformation of both NIH 3T3 cells and lymphoid cells when expressed in the context of a truncated Abelson protein. In the context of the prototype P120 v-abl protein, the Gly-536 substitution generated a host range mutant that induced conditional transformation in lymphoid cells but had only a subtle effect on NIH 3T3 cells. The combination of both substitutions gave rise to a P120 strain that was temperature sensitive for both NIH 3T3 and lymphoid cell transformation. The Abelson proteins encoded by the temperature-sensitive strain displayed in vitro kinase activities that were reduced when compared with those of wild-type proteins. In vivo, levels of phosphotyrosine were reduced only at the restrictive temperature. Analysis of cells expressing either the wild-type P160 v-abl protein or the P210 bcr/abl protein and an Abelson protein encoded by a temperature-sensitive strain failed to correct this defect, suggesting either that tyrosine phosphorylation in vivo is an intramolecular reaction or that the protein encoded by the temperature-sensitive strain is a poor substrate for tyrosine phosphorylation in vivo. These results raise the possibility that tyrosine phosphorylation of Abelson protein plays a role in transformation.


Acute Appendicitis with Appendicolith and its Complication and Management: A Case Report.
Acute appendicitis is a common cause of acute abdominal pain requiring urgent surgery. Despite characteristic clinical signs, diagnosis can be challenging, leading to unnecessary appendectomies. This case report focuses on a 34-year-old male with escalating right lower quadrant abdominal pain. Imaging revealed acute appendicitis with a substantial appendicolith. Surgical intervention involved a open appendectomy with possible ileocecal resection due to cecal inflamation. Surgical findings indicated successful resection, and the patient recovered without complications. While urgent appendectomy is the norm, conservative approaches are gaining traction for peri-appendiceal abscesses. Interval appendectomy post-conservative treatment is a debated strategy. Management decisions are influenced by patient factors and disease severity. Future research is needed to establish standardized treatment protocols for complicated appendicitis. The case illustrates the evolving landscape of acute appendicitis management.


Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice.
The MTHFD1 gene encodes for methylenetetrahydrofolate dehydrogenase 1, an enzyme that has an important role in folate-mediated one-carbon metabolism. In people, a single nucleotide polymorphism of this gene (1958G>A; rs2236225) is associated with increased risk for bipolar disorder and schizophrenia, neural tube and other birth defects. Mice homozygous for a loss of Mthfd1 via a gene-trap mutation are not viable, and heterozygotes, though they appear healthy, have metabolic imbalances in the folate- and choline-mediated 1-carbon metabolic pathways. In this study, we evaluated cognitive function in Mthfd1gt/+ male and female mice using a behavioral battery composed of eight different tests. We found that these mice display impaired cue-conditioned learning, while other behaviors remain intact.


Antimicrobial activities of emulsion-based edible solutions incorporating lemon essential oil and sodium caseinate against some food-borne bacteria.
The antimicrobial properties of two different emulsion formulations contained lemon essential oil (coarse emulsion; CE and nanoemulsion; NE) and emulsions based edible solutions incorporated with lemon essential oil and sodium caseinate (coarse emulsion based solution; CESC and nanoemulsion based solution; NESC) on food-related microorganisms (Photobacterium damselae, Pseudomonas luteola, Salmonella Paratyphi A NCTC13, and Listeria monocytogenes ATCC19112) were investigated. The chemical compositions of lemon essential oils were identified by GC-MS. Physical parameter of different formulations was also analyzed at different time intervals. The antimicrobial properties of solutions were determined by using well diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration, and time-kill assay. The major identified component in lemon essential oil was D limonene (38.38%). NE showed a stronger antimicrobial effect against S. Paratyphi A and L. monocytogenes with 36.50 and 38.75 mm diameter zone compared to all other formulations. Listeria monocytogenes had the highest sensitivity towards NE and NESC formulations with 3.12 mg/ml MIC values in comparison to other two formulations. The nanoemulsion and nanoemulsion based coating solution were more effective than other formulations in killing bacterial cell within a short period time.


Coarse-Grained Simulations of Heme Proteins: Validation and Study of Large Conformational Transitions.
Heme proteins are ubiquitous in nature and perform many diverse functions in all kingdoms of life. Many of these functions are related to large-scale conformational transitions and allosteric processes. Sampling of these large conformational changes is computationally very challenging. In this context, coarse-grain simulations emerge as an efficient approach to explore the conformational landscape. In this work, we present a coarse-grained model of the heme group and thoroughly validate this model in different benchmark examples, which include the monomeric heme proteins myoglobin and neuroglobin and the tetrameric human hemoglobin where we evaluated the method's ability to explore conformational changes (as the formation of hexacoordinated species) and allosteric transitions (as the well-known R → T transition). The obtained results are compared with atomistic molecular dynamics simulations. Overall, the results indicate that this approach conserves the essential dynamical information on different allosteric processes.


Glutamine synthetase isoforms in nitrogen-fixing soybean nodules: distinct oligomeric structures and thiol-based regulation.
Legume root nodule glutamine synthetase (GS) catalyzes the assimilation of ammonia produced by nitrogen fixation. Two GS isoform subtypes (GS1β and GS1γ) are present in soybean nodules. GS1γ isoforms differ from GS1β isoforms in terms of their susceptibility to reversible inhibition by intersubunit disulfide bond formation between C159 and C92 at the shared active site at subunit interfaces. Although nodule GS enzymes share 86% amino acid sequence identity, analytical ultracentrifugation experiments showed that GS1γ is a dodecamer, whereas the GS1β is a decamer. It is proposed that this difference contributes to the differential thiol sensitivity of each isoform, and that GS1γ1 may be a target of thiol-based regulation.


Food protein-induced enterocolitis syndrome in children: what's known? What's new?
Food protein-induced enterocolitis syndrome (FPIES) is an under-recognized and frequently misdiagnosed non-IgE mediated food allergy syndrome. Affected infants show gastrointestinal symptoms few hours after ingestion of the incriminating food. Pathophysiology of FPIES has not yet been clearly defined and needs further characterization. The common allergy tests are not helpful for this disorder and tests for food specific IgE are usually negative. A diagnostic oral food challenge (OFC) is the method to confirm the diagnosis of FPIES. This review summarizes what is known about epidemiology, pathophysiology, clinical characteristics and diagnosis and what's new about therapeutic options of FPIES.


Rhabdomyolysis with Acute Kidney Injury Caused by Bilateral Iliopsoas Hematoma in a Patient with Atrial Fibrillation.
Rhabdomyolysis is a relatively common and life-threatening disease that is sometimes complicated by acute kidney injury (AKI). Several causes have been reported, divided into traumatic and non-traumatic causes. We herein report a patient with rhabdomyolysis with AKI caused by bilateral iliopsoas hematoma. This patient had atrial fibrillation that was poorly controlled with warfarin, and bilateral iliopsoas hematoma was caused by turnover without a history of high-energy injury. Treatment with the rapid neutralization of warfarin improved his clinical condition without complications. We should pay close attention to episodes of turnover among elderly patients receiving anticoagulant therapy.


Multisystemic Manifestations of Hyaline Fibromatosis Syndrome: Implications for Diagnosis and Management.
Hyaline fibromatosis syndrome (HFS) is a rare autosomal recessive disorder characterized by the deposition of hyaline material in the skin, soft tissues, and bones. In this report, we discuss a case of a six-month-old male with HFS who presented with faltering growth, chronic diarrhea, multiple joint contractures, joint stiffness, hyperpigmented skin over bony prominences, gingival hypertrophy, patent foramen ovale, and symmetric periventricular hyperintensities on brain MRI. The diagnosis of HFS was confirmed by skin biopsy and genetic testing, which identified a homozygous mutation in the anthrax toxin receptor 2 (ANTXR2) gene. The patient was managed symptomatically with nutritional support, physiotherapy, analgesics, and regular dental care. He also received intralesional corticosteroid therapy, which significantly decreased the size of the skin nodules. His hyperpigmented skin and gingival hypertrophy remained stable, and the patent foramen ovale was managed conservatively. This case report highlights the importance of early diagnosis and management of HFS and the benefits of involving a multidisciplinary team to improve the quality of life of affected individuals.


BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases.
It is estimated that more than 20% of ovarian cancer cases are associated with a genetic predisposition that is only partially explained by germline mutations in the BRCA1 and BRCA2 genes. Recently, several pieces of evidence showed that mutations in three genes involved in the homologous recombination DNA repair pathway, i.e., BRIP1, RAD51C, and RAD51D, are associated with a high risk of ovarian cancer. To more precisely estimate the ovarian cancer risk attributed to BRIP1, RAD51C, and RAD51D mutations, we performed a meta-analysis based on a comparison of a total of ~ 29,400 ovarian cancer patients from 63 studies and a total of ~ 116,000 controls from the gnomAD database. The analysis allowed precise estimation of ovarian cancer risks attributed to mutations in BRIP1, RAD51C, and RAD51D, confirming that all three genes are ovarian cancer high-risk genes (odds ratio (OR) = 4.94, 95%CIs:4.07-6.00, p < 0.0001; OR = 5.59, 95%CIs:4.42-7.07, p < 0.0001; and OR = 6.94, 95%CIs:5.10-9.44, p < 0.0001, respectively). In the present report, we show, for the first time, a mutation-specific risk analysis associated with distinct, recurrent, mutations in the genes. The meta-analysis provides evidence supporting the pathogenicity of BRIP1, RAD51C, and RAD51D mutations in relation to ovarian cancer. The level of ovarian cancer risk conferred by these mutations is relatively high, indicating that after BRCA1 and BRCA2, the BRIP1, RAD51C, and RAD51D genes are the most important ovarian cancer risk genes, cumulatively contributing to ~ 2% of ovarian cancer cases. The inclusion of the genes into routine diagnostic tests may influence both the prevention and the potential treatment of ovarian cancer.


[Morphological studies on lower margins of nasal aperture in the skull of Hokkaido Japanese].
It is well-known that the lower margins of nasal aperture in the human skull may be classified into the following four types, i.e., Forma anthropina, Forma infantilis, Fossae praenasales and Clivus nasoalveolaris, and that the rates of appearance of these four types differ with races. In the present study we made morphological studies on the lower margins of nasal aperture of 465 Hokkaido Japanese skulls, 463 skulls with symmetrical nasal aperture and 2 skulls with asymmetrical one, and compared the findings with those of all races in the world, especially of the Japanese, Ainu, Moyoro Man, Hamanaka Site Man and Eskimo. Forma anthropina was found in 330 skulls (71.27 +/- 2.10%) among the 463, marking the highest rate. Forma infantilis, found in 74 skulls (15.98 +/- 1.70%) among the 463, marked the second highest rate. Fossae praenasales, found in 42 skulls (9.07 +/- 1.33%) among the 463, marked the third highest rate. These 42 cases of Fossae praenasales were further classified into three types, i.e., sub-Forma infantilis, 17 (40.48%), typical Fossae prenasales, 23 (54.76%) and sub-Clivus nasoalveolaris, 2 (4.76%). Clivus nasoalveolaris, found in 17 skulls (3.67 +/- 0.87%) among the 463, marked the lowest rate. As a whole, the rates of the four types in the Hokkaido Japanese were close to those in the other groups of the Japanese in Kinai and Hokkaido (Ito).


KCl cotransport regulation and protein kinase G in cultured vascular smooth muscle cells.
K-Cl cotransport is activated by vasodilators in erythrocytes and vascular smooth muscle cells and its regulation involves putative kinase/phosphatase cascades. N-ethylmaleimide (NEM) activates the system presumably by inhibiting a protein kinase. Nitrovasodilators relax smooth muscle via cGMP-dependent activation of protein kinase G (PKG), a regulator of membrane channels and transporters. We investigated whether PKG regulates K-Cl cotransport activity or mRNA expression in normal, PKG-deficient-vector-only-transfected (PKG-) and PKG-catalytic-domain-transfected (PKG+) rat aortic smooth muscle cells. K-Cl cotransport was calculated as the Cl-dependent Rb influx, and mRNA was determined by semiquantitative RT-PCR. Baseline K-Cl cotransport was higher in PKG+ than in PKG- cells (p <0.01). At 0.5 mM, NEM stimulated K-Cl cotransport by 5-fold in PKG- but not in PKG+ cells. However, NEM was more potent although less effective to activate K-Cl cotransport in normal (passage 1-3) and PKG+ than in PKG- cells. In PKG- cells, [(dihydroindenyl) oxy] alkanoic acid (300 mM) but not furosemide (1 mM) inhibited K-Cl cotransport. Furthermore, no difference in K-Cl cotransport mRNA expression was observed between these cells. In conclusion, this study shows that manipulation of PKG expression in vascular smooth muscle cells affects K-Cl cotransport activity and its activation by NEM.


A report on preparation, expansion and future outlook of COVID-19 testing in Gambia.
The outbreak of COVID-19 disease and rapid spread of the virus outside China led to its declaration as a Public Health Emergency of International Concern (PHEIC) in January 2020. Key elements of the early intervention strategy focused on laboratory diagnosis and screening at points of entry and imposition of restrictions in crossborder activities. We report the role the Medical Research Council Unit, The Gambia (MRCG) played in the early implementation of molecular testing for COVID-19 in The Gambia as part of the national outbreak response. Laboratory staff members, with experience in molecular biology assays, were identified and trained on COVID-19 testing at the Africa CDC training workshop in Dakar, Senegal. Thereafter risks assessments, drafting of standard operating procedures (SOPs) and inhouse training enabled commencement of testing using commercial RTPCR kits. Subsequently, testing was expanded to the National Public Health Laboratroy and also implemented across field sites for rapid response across the country. Capacity for COVID-19 testing at MRCG was developed and can process aproximately 350 tests per day, which can be further scaled up as the demand for testing increases. The long presence of the Unit in The Gambia and strong collaborative relationship with the National Health Ministry, allowed for a synergistc approach in mounting an effective response that contributed in delaying the establishment of community transmission in the country.


TiO2-graphene oxide nanocomposite as advanced photocatalytic materials.
Graphene oxide composites with photocatalysts may exhibit better properties than pure photocatalysts via improvement of their textural and electronic properties. TiO2-Graphene Oxide (TiO2 - GO) nanocomposite was prepared by thermal hydrolysis of suspension with graphene oxide (GO) nanosheets and titania peroxo-complex. The characterization of graphene oxide nanosheets was provided by using an atomic force microscope and Raman spectroscopy. The prepared nanocomposites samples were characterized by Brunauer-Emmett-Teller surface area and Barrett-Joiner-Halenda porosity, X-ray Diffraction, Infrared Spectroscopy, Raman Spectroscopy and Transmission Electron Microscopy. UV/VIS diffuse reflectance spectroscopy was employed to estimate band-gap energies. From the TiO2 - GO samples, a 300 μm thin layer on a piece of glass 10×15 cm was created. The photocatalytic activity of the prepared layers was assessed from the kinetics of the photocatalytic degradation of butane in the gas phase. The best photocatalytic activity under UV was observed for sample denoted TiGO_100 (k = 0.03012 h-1), while sample labeled TiGO_075 (k = 0.00774 h-1) demonstrated the best activity under visible light.


Conservation of complex knotting and slipknotting patterns in proteins.
While analyzing all available protein structures for the presence of knots and slipknots, we detected a strict conservation of complex knotting patterns within and between several protein families despite their large sequence divergence. Because protein folding pathways leading to knotted native protein structures are slower and less efficient than those leading to unknotted proteins with similar size and sequence, the strict conservation of the knotting patterns indicates an important physiological role of knots and slipknots in these proteins. Although little is known about the functional role of knots, recent studies have demonstrated a protein-stabilizing ability of knots and slipknots. Some of the conserved knotting patterns occur in proteins forming transmembrane channels where the slipknot loop seems to strap together the transmembrane helices forming the channel.


Hormone replacement therapy does not augment gains in muscle strength or fat-free mass in response to weight-bearing exercise.
Lower extremity strength and fat-free mass were examined in 58 postmenopausal women aged 60-72 yr. Subjects were studied before and after an 11-mo control period (n = 16) or before and after an 11-mo weight-bearing exercise training program designed to generate relatively high ground reaction forces (n = 42). Twenty-two of the exercisers initiated hormone replacement therapy (HRT) at the outset of exercise and continued HRT for 11 mo. Hip extension and abduction strength were assessed using a hand-held dynamometer. Force production during knee extension and flexion was evaluated on an isokinetic dynamometer at 60, 90, and 180 degrees/s. Simultaneous knee and hip extension strength was also assessed on a leg press machine. Total body and lower extremity fat-free mass were determined using dual-energy x-ray absorptiometry. There were no significant changes in muscle strength or body composition in control subjects. Both exercise groups had significant increases in fat-free mass and in all strength measures. Fat-free mass increased from 38.8 +/- 4.3 to 39.7 +/- 4.3 kg in the exercise group and from 37.7 +/- 3.9 to 38.9 +/- 4.6 kg in the exercise-plus-HRT group. The average relative increase in strength was 16.2 +/- 11.0% in the exercise group and 17.0 +/- 13.0% in the exercise-plus-HRT group. Women receiving HRT did not have a gain in fat-free mass or in strength over and above that demonstrated by the women not on HRT. Our results provide evidence that HRT does not augment the increases in muscle mass or strength that occur in response to weight-bearing exercise in older women.


Intrinsic Traits Such as Personality and Decision-Making Style are Predictive of Stress in Surrogate Decision-Makers.
Introduction: Despite its prominence in psychology, little is known about how personality traits play a role in the stress experiences of surrogate decision-makers. We tested the hypothesis that intrinsic traits (personality and decision-making styles) would be related to surrogates' stress in order to learn whether screening or tailoring interventions based on personality traits could help support surrogate decision-makers. Methods: This pre-specified secondary analysis evaluated data from an interventional study with dyads of patients with advanced chronic illness and their spokespersons. Measures included stress after decision-making or patient death (Impact of Events-Revised), personality (Big Five Index; BFI) and decision-making style (maximization and regret scales). Multivariate linear regressions explored the impact of personality on the stress experience; linear regressions independently modeled the impact of maximization and regret on the stress experience. Results: Of 38 spokespersons, 89.5% were women, 97.4% non-Hispanic, and 29.0% had a college degree or higher. In univariate analyses, total stress was correlated with neuroticism (r = .56, P < .01), higher scores on the regret (r = .55, P < .01) and maximization (r = .48, P < .05). In adjusted models, BFI was significantly associated with total stress (R2 = 27.08, P = .02). However, only neuroticism was independently associated with total stress. Conclusions: Personality traits, particularly neuroticism, and decision-making styles predicted heightened stress in spokespersons of patients with advanced chronic illness. If ACP interventions are intended to reduce spokesperson stress, personality and decision-making style scales may help identify spokespersons most likely to benefit from ACP interventions.


Guidelines for preventing thromboembolism.
Clinicians, units and hospitals in the UK should develop written policies for thromboembolic prophylaxis. Deep-vein thrombosis is both life-threatening and costly. The use of prophylaxis should be included in clinical audit and plans for patient care. The implementation of research-based and agreed guidelines can reduce the incidence of postoperative deep-vein thrombosis.


Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and the risk of developing rheumatoid arthritis in antihypertensive drug users.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are effective in the treatment of cardiovascular disease. Next to effects on hypertension and cardiac function, these drugs have anti-inflammatory and immunomodulating properties which may either facilitate or protect against the development of autoimmunity, potentially resulting in autoimmune diseases. Therefore, we determined in the current study the association between ACE inhibitor and ARB use and incident rheumatoid arthritis (RA). A matched case-control study was conducted among patients treated with antihypertensive drugs using the Netherlands Information Network of General Practice (LINH) database in 2001-2006. Cases were patients with a first-time diagnosis of RA. Each case was matched to five controls for age, sex, and index date, which was selected 1 year before the first diagnosis of RA. ACE inhibitor and ARB exposure was considered to be any prescription issued in the period before index date. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CI). Our study included 211 cases and 667 matched controls. After controlling for potential confounders, ever use of ACE inhibitors or ARBs was not associated with incident RA (adjusted ORs [95%CI], 0.99 [0.55-1.79] and 1.02 [0.67-1.56], respectively). The adjusted ORs (95%CI) for current and past use of ACE inhibitors were 1.18 (0.75-1.85) and 0.61 (0.28-1.35). For current and past use of ARBs, these adjusted ORs (95%CI) were 1.40 (0.80-2.45) and 0.29 (0.05-1.67), respectively. No duration and dose-effect relationship was observed. ACE inhibitor or ARB use is not associated with incident RA.


Intraocular lens implantation: should we abandon intracapsular surgery?
The most important late complication of a longitudinal study of iris-supported lens was bullous keratopathy. Endothelial cell loss after using the closed chamber technique for lens insertion was more than halved. The cell loss rate after intracapsular extraction with a Federov I lens was compared with that after extracapsular extraction with an iridocapsular lens. The intermediate results did not show any significant difference between groups and there were eyes in both groups with a large initial loss which appeared to lose cells at a faster rate.


[Effects of Radix Astragali and Fructus Corni on urinary protein pattern in nephropathy mice by microfluidic chip].
To study the urinary protein patterns of nephropathy mice induced by dextran and the effects of aquesous extract of Fructus Corni (AEFC) and Radix Astragali (AERA). Nephropathy model was established by administrated with dextran to mice. Some of the dextran treated mice were given AERA (20 g x kg(-1) x d(-1)) as AERA group, other mice were given AEFC (10 g x kg(-1) x d(-1)) as AEFC group. Some of the dextran treated mice were given water as model group, some normal mice as normal control group. After a 12 weeks' treatment, 24 hour urine of four groups was collected, respectively. Each urinary sample was divided into two parts, one was non-concentrated urine sample, another was used as concentrated urine sample. Two kinds of urinary sample of four groups were analyzed with microfluidic chips on Agilent 2100 Bioanalyzer instrument. Each group's urinary protein patterns were obtained, more than 20 proteins were were detected. Compared with normal group, about five kinds of protein were found in urinary sample of model group, among which M > 43 x 10(3) proteins were increased. Compared with model group, significant treated-related protein's kind and quantitative changes in AERA treated group and AEFC group were found. Urinary protein kinds were reduced, especially certain the proteins (M > 50 x 10(3)) were significantly decreased approach to normal patterns. Non-concentrated urine samples' protein pattern mainly included were proteins (M=29, 32, 43, 52, 68, 76 x 10(3) and concentrated urine samples mainly included the proteins (M=22, 24, 32, 46 x 10(3)). AERA and AEFC could reduce the urinary protein and made protein pattern different, which showed that radix astragali and fructus corni could play an important role in protecting renal function of nephropathy mice and finding the target protein markers related to AERA and AEFC effects on nephropathy mice.


Matrix isolation and theoretical study of the reaction of substituted phosphines with CrCl2O2.
The reactions between CrO2Cl2 and a series of substituted phosphines have been investigated using matrix isolation infrared spectroscopy. For all of the phosphines except PF3, twin jet co-deposition of the two reagents into argon matrices at 14 K initially led to the formation of weak bands due to the corresponding phosphine oxide. For all of the phosphines, subsequent irradiation with light of lambda > 300 nm led to the growth of a number of intense new bands that have been assigned to the phosphine oxide complexed to CrCl2O, following an oxygen atom transfer reaction. Gas-phase, merged jet reactions prior to matrix deposition led to a significant yield of the uncomplexed phosphine oxide. Theoretical calculations at the B3LYP/6-311++g(d,2p) level were carried out in support of the experimental work, to support product band assignments and clarify the nature of the molecular complexes.


In vitro cultivation of Toxoplasma gondii cysts in astrocytes in the presence of gamma interferon.
Long-term culturing of Toxoplasma gondii cysts was accomplished in vitro in association with murine astrocytes and intermittent additions of gamma interferon to the media. Phase-contrast microscopy was used to follow the stages of cyst development, and electron microscopy confirmed the presence of morphologic characteristics of T. gondii cysts. T. gondii cysts formed in vitro had a single trilaminar membrane during both intracellular and extracellular existence and contained amorphous electron-dense material either throughout the cyst or in a uniform layer under the trilaminar membrane. The bradyzoites were similar to previous descriptions of tachyzoites in vitro except that they were smaller and contained numerous electron-lucent vacuoles. Gamma interferon is not necessary for cyst formation, but it controls the division of tachyzoites and may allow cysts to remain for prolonged periods without rupturing. In vitro-cultivated T. gondii cysts will be useful for producing bradyzoite and cyst antigens and for measuring the effects of antimicrobial agents and immune modulators on the viability of intracystic T. gondii.


[Development of the vascular prosthesis research].
The search for a nonthrombogenic material with the potential for use in small diameter vascular graft applications continues to be a field of extensive investigation. This article describes the choice of biomaterials used as vascular prosthesis, the innovation of construction of tissue-engineered blood vessels, the indispensability, methods and the effect produced by surface modification of vascular prosthesis. The article also points out that research achievements of vascular prosthesis must be made with the exploitation of new nonthrombogenic biomaterial and the development of tissue engineering.


Nitecapone and selegiline as effective adjuncts to L-DOPA in reserpine-induced catatonia in mice.
Reserpine-induced catatonia is a widely accepted animal model of Parkinson's disease. In the present study, reserpine (5 mg/kg i.p.) and alpha-methylpara-tyrosine (AMPT) (200 mg/kg i.p.) induced catatonia in mice 20 h and 1 h before the experiment, respectively, as assessed using the rota-rod and bar tests after reserpine treatment. There was a significant decrease in fall-off time in the rota-rod test and a significant increase in time spent on the bar in the bar test as compared to the untreated control mice. Combination therapy with L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) was less effective in reversing catatonia as compared to higher doses of L-DOPA (200 mg/kg i.p.) and carbidopa (20 mg/kg i.p.), which showed intense hyperactivity in reserpinized mice. Pretreatment with nitecapone (30 mg/kg i.p.), a COMT inhibitor, or selegiline (10 mg/kg i.p.), a MAO-B inhibitor potentiated the motor stimulant actions of subthreshold doses of the L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) combination. Amantadine (40 mg/kg i.p.), but not bromocriptine, potentiated the effects of L-DOPA treatment. The NMDA antagonistic action of amantadine may have beneficial effects. It is concluded that COMT and MAO-B enzymes play an important role in the metabolism of dopamine and administration of a COMT or MAO-B inhibitor may prove to be a better adjunct to L-DOPA therapy than a dopamine receptor agonist in Parkinson's disease.


Association of polygenic score with tumor molecular subtypes in papillary thyroid carcinoma.
The primary goal of the present study is to determine whether germline genetic risk, as assessed using a polygenic risk score (PGS) is associated with molecular subtypes of PTC, defined based on tumor driver mutation status. This study was carried out using data from The Cancer Genome Atlas (TCGA) thyroid cancer study. A previously validated 10-SNP PGS for PTC derived from GWAS hits was calculated to ascertain germline genetic risk. The primary molecular subtypes of interest were defined by tumor driver mutation status (BRAFV600E-mutated vs. RAS-mutated vs "other"). We also explored associations between PGS and molecular subtypes defined by mRNA expression, microRNA expression, and DNA methylation patterns. Polytomous logistic regression analysis was used to assess the association between PGS and PTC molecular subtype with and without adjustment for clinical variables. Odds ratios (ORs) with their 95% confidence intervals were estimated. A total of 359 patients were included in the study. PGS was significantly associated specific tumor molecular subtypes defined by tumor driver mutation status. Increasing germline risk was associated with having a higher odd of BRAFV600E-mutated PTC compared to PTCs without driver mutations in the "other" category. No significant difference was detected in terms of PGS tumor categorization in the RAS subtype compared to BRAFV600E. In exploratory analyses, PGS was also associated with mRNA, microRNA, and DNA methylation defined molecular subtypes, as defined by the TCGA PTC study. PGS has molecular subtype-specific associations in PTC, which has implications for their use in risk prediction.


Mindfulness training increases cooperative decision making in economic exchanges: Evidence from fMRI.
Emotions have been shown to exert influences on decision making during economic exchanges. Here we investigate the underlying neural mechanisms of a training regimen which is hypothesized to promote emotional awareness, specifically mindfulness training (MT). We test the hypothesis that MT increases cooperative economic decision making using fMRI in a randomized longitudinal design involving 8weeks of either MT or active control training (CT). We find that MT results in an increased willingness to cooperate indexed by higher acceptance rates to unfair monetary offers in the Ultimatum Game. While controlling for acceptance rates of monetary offers between intervention groups, subjects in the MT and CT groups show differential brain activation patterns. Specifically, a subset of more cooperative MT subjects displays increased activation in the septal region, an area linked to social attachment, which may drive the increased willingness to express cooperative behavior in the MT cohort. Furthermore, MT resulted in attenuated activity in anterior insula compared with the CT group in response to unfair monetary offers post-training, which may suggest that MT enables greater ability to effectively regulate the anterior insula and thereby promotes social cooperation. Finally, functional connectivity analyses show a coupling between the septal region and posterior insula in the MT group, suggesting an integration of interoceptive inputs. Together, these results highlight that MT may be employed in contexts where emotional regulation is required to promote social cooperation.


Intersectional Epistemologies of Ignorance: How Behavioral and Social Science Research Shapes What We Know, Think We Know, and Don't Know About U.S. Black Men's Sexualities.
Epistemologies of ignorance describe how ignorance influences the production of knowledge. Advancing an intersectional epistemologies of ignorance approach that examines how conscious (or unconscious) ignorance about racism, heterosexism, and classism shapes empirical knowledge about Black men's sexualities, we conducted a critical review of the behavioral and social science research on U.S. Black men, ages 18 and older, for two time frames: pre-1981 and the most recent decade, 2006-2016. Our search yielded 668 articles, which we classified into five categories: sexual violence, sexual experiences and expressions, sexual identities, cultural and social-structural influences, and sexual health and sexual risk. We found that most of the research, particularly pre-1981, centered the experiences of White heterosexual men as normative and implicitly constructed Black men as hypersexual or deviant. Most of the research also color-blinded White privilege and ignored how racism, heterosexism, and classism structured Black men's inequities. We also found notable exceptions to these trends. Black men who are gay, bisexual, or who have sex with men, and research on HIV risk were prominent in the past decade, as was research that emphasized the social-structural (e.g., poverty, heterosexism, racism) and cultural (e.g., masculinity, religion) contexts of Black men's lives and sexualities. We provide 10 recommendations to avoid intersectional epistemic ignorance in future research.


A molecularly imprinted polymer-based synthetic transaminase.
The design, synthesis, and evaluation of a molecularly imprinted polymer transaminase mimic is described. Methacrylic acid-ethylene glycol dimethacrylate copolymers were synthesized using, as a template, a transition state analogue (TSA) for the reaction of phenylpyruvic acid and pyridoxamine to yield phenylalanine and pyridoxal. Polymer suitability was established on the basis of (1)H NMR studies of template-functional monomer interactions. Polymer recognition characteristics were examined in a series of HPLC studies using the polymers as chromatographic stationary phases. Selectivity for the TSA, relative to substrates and products, was observed in both aqueous and nonpolar media. In the latter case (chloroform/AcOH, 96:4), an enantioseparation factor (alpha) of 2.1 was obtained, and frontal chromatographic studies revealed the presence of 11.9 +/- 0.2 micromol g(-1) (dry weight) of enantioselective sites. Polymers imprinted with the l-form of the oxazine-based TSA induced a 15-fold enhancement of the apparent reaction rate (app. V(max) 2.5 x 10(-7) mol s(-1); app. K(m) 8.2 x 10(-3) M) and enantioselective production of phenylalanine (32 +/- 4% ee) for reactions conducted in an aqueous buffer system. Substrate selectivity was evident, and a turnover number (k(cat)) of 0.1 s(-)(1) was determined. This is the first example of the catalysis of sigmatropic shifts in aqueous media by molecularly imprinted polymers.


A decade-long sour-taste sensation successfully treated with a proton-pump inhibitor.
We report a case study of a 54-year-old Japanese woman who persistently suffered from a sour-taste sensation in her mouth for 10 years, and was treated with a proton-pump inhibitor (PPI). She found sour-tasting meals irritable, and after eating such meals the sour-taste sensation worsened. She also complained of eructation and regurgitation. Upper gastrointestinal (GI) endoscopy showed duodenal erosion, superficial gastritis, and erosive oesophagitis. After 2 weeks of PPI therapy (lansoprazole, 30 mg day(-1)) the sour taste subjectively decreased to 70%, and after 6 weeks the symptoms disappeared. In addition to increased sensitivity of the mouth, gastro-oesophageal reflux might have created her obstinate sour-taste sensations. It is suggested that in such cases PPI therapy should be attempted.


Distribution of RET immunoreactivity in the rodent spinal cord and changes after nerve injury.
RET (for "rearranged during transfection") is a transmembrane tyrosine kinase signaling receptor for members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands. We used RET immunohistochemistry (IHC), double-labeling immunofluorescence (IF), and in situ hybridization (ISH) in adult naïve and nerve-injured rats to study the distribution of RET in the spinal cord. In the dorsal horn, strong RET-immunoreactive (-ir) fibers were abundant in lamina II-inner (II(i)), although this labeling was preferentially observed after an antigen-unmasking procedure. After dorsal rhizotomy, RET-ir fibers in lamina II(i) completely disappeared from the dorsal horn, indicating that they were all primary afferents. After peripheral axotomy, RET-ir in primary afferents decreased in lamina II(i) and appeared to increase slightly in laminae III and IV. RET-ir was also observed in neurons and dendrites throughout the dorsal horn. Some RET-ir neurons in lamina I had the morphological appearance of nociceptive projection neurons, which was confirmed by the finding that 53% of RET-ir neurons in lamina I colocalized with neurokinin-1. GDNF-ir terminals were in close proximity to RET-ir neurons in the superficial dorsal horn. In the ventral horn, RET-ir was strongly expressed by motoneurons, with the strongest staining in small, presumably gamma-motoneurons. Increased RET expression following peripheral axotomy was most pronounced in alpha-motoneurons. The expression and regulation pattern of RET in the spinal cord are in line with its involvement in regenerative processes following nerve injury. The presence of RET in dorsal horn neurons, including nociceptive projection neurons, suggests that RET also has a role in signal transduction at the spinal level. This role may include mediating the effects of GDNF released from nociceptive afferent fibers.


[Pulmonary hypertension in Russia: the first results of the national register].
To investigate the demographic and clinical characteristics of patients with pulmonary hypertension (PH) and chronic thromboembolic pulmonary hypertension (CTEPH), regions of their residence, the specific features of diagnosis and drug therapy, and the patients' survival within the framework of a multicenter open-label prospective study. The study enrolled patients over 18 years of age with PH classified as Group 1 (PH) and Group 4 (CTEPH). The follow-up was made in 9 expert centers of Russia on January 1 to February 28, 2014. The data of patients with PH and CTEPH were electronically entered at the register website: www.pul-hyp.medibase.ru. The study included 242 patients (183 women and 59 men) from 44 regions of the Russian Federation. PH of different etiologies was present in 79.3%, including 43.8% with idiopathic PH, 28.5% with congenital heart disease-associated PH, 6.2% with diffuse connective tissue-associated PH, 0.8% with hereditary PH; 20.7% were diagnosed with CTEPH. The patients' mean age at the inclusion in the register was 43.2 ± 15.8 years; the median PH duration was 4.4 years (1.4 to 10.6%). The distance covered during a 6-minute walk test was 395.2?111.1 m; the Borg dyspnea index was 3.4 ± 1.4 scores and the functional class was 2.5 ± 0.8. After right cardiac catheterization, the mean pulmonary artery pressure was 53.1 ± 19.5 mm Hg; cardiac output, 3.8 ± 1.2 l/ min; cardiac index, 2.1 ± 0.6 l/min/m2; pulmonary vascular resistance, 1105 ± 677.6 dyn·sec/cm5. A positive acute pharmacological test was seen in 16.3% of the patients. The most common comorbidity was erosive ulcerative lesion of the gastrointestinal tract (23.5%), hypertension (16.9%), and obesity (16.5%). 66% of the patients received PH-specific therapy: sildenafil (51.6%), bosentan (20.9%), or iloprost (7%); 7.4% of the patients were observed within the framework of clinical trials, 17.7% received combined therapy for PH: 16.3 and 1.4% had dual- or triple-component therapy, respectively; 55.8% of the patients took calcium antagonists, 61.4% had diuretics, 85.6% had antithrombotic drugs. The survival rates were 98% in the first year of the follow-up and 90.1% by the end of 2013. The formation of a national register of patients with PH and CTEPH makes it possible to introduce current approaches to diagnosing and treating the patients of this category and to evaluate the efficiency and quality of rendered medical care and will contribute to the estimation of required health care volumes and the expenditure of public health resources.


Long-term results in patients with idiopathic dilated cardiomyopathy after weaning from left ventricular assist devices.
Since our first successful left ventricular assist device (LVAD) explantation in a patient with idiopathic dilated cardiomyopathy (IDCM) in 1995, an additional 31 IDCM patients have been weaned in our department. Echocardiographic evaluations during repeated "off-pump" trials were the cornerstone for weaning decisions. After 9 years of experience, we assessed the reliability of our weaning criteria in light of the long-term results. We evaluated all of the IDCM patients who were weaned between March 1995 and March 2004 with regard to preservation of cardiac function without LVAD support and survival after weaning. Additionally, we reviewed our echocardiographic data to assess their predictive value for long-term stability of cardiac function after weaning. The 32 weaned IDCM patients showed a survival rate of 78.3%+/-8.1 at 5 years after LVAD explantation. Heart failure (HF) recurred during the first 3 years after weaning in 31.3%. Only 2 patients died because of HF after weaning; the other patients with HF recurrence were successfully transplanted. Off-pump LV end-diastolic diameter >55 mm and/or LVEF <45% before LVAD removal, as well as history of HF > or =5 years before LVAD implantation, appeared to be major risk factors for early recurrence of HF. Patients without any of these 3 risk factors showed no HF recurrence during the first 3 years after weaning, but at the same time, all of those with at least 2 of these 3 risk factors developed early recurrence of HF. In patients with HF recurrence during the first 3 postweaning years, a significant LVEF decrease already occurred during the first month after weaning, whereas in those with long-term stable cardiac function even at the end of the sixth postweaning month, the LVEF was not different from that before LVAD removal. For selected patients with IDCM, weaning from LVADs is a clinical option with good results over >9 years and should, therefore, be considered in those with cardiac recovery after LVAD implantation. Off-pump echocardiographic data are reliable for the detection of LV recovery and prediction of long-term cardiac stability after weaning.


I.4 Screening Experimental Designs for Quantitative Trait Loci, Association Mapping, Genotype-by Environment Interaction, and Other Investigations.
Crop breeding programs using conventional approaches, as well as new biotechnological tools, rely heavily on data resulting from the evaluation of genotypes in different environmental conditions (agronomic practices, locations, and years). Statistical methods used for designing field and laboratory trials and for analyzing the data originating from those trials need to be accurate and efficient. The statistical analysis of multi-environment trails (MET) is useful for assessing genotype × environment interaction (GEI), mapping quantitative trait loci (QTLs), and studying QTL × environment interaction (QEI). Large populations are required for scientific study of QEI, and for determining the association between molecular markers and quantitative trait variability. Therefore, appropriate control of local variability through efficient experimental design is of key importance. In this chapter we present and explain several classes of augmented designs useful for achieving control of variability and assessing genotype effects in a practical and efficient manner. A popular procedure for unreplicated designs is the one known as "systematically spaced checks." Augmented designs contain "c" check or standard treatments replicated "r" times, and "n" new treatments or genotypes included once (usually) in the experiment.


Streptomyces caeruleatus sp. nov., with dark blue diffusible pigment.
An actinomycete, designated strain GIMN4.002(T), was isolated from a tomato rhizosphere soil sample in Guangzhou, China. The strain produces white aerial mycelium and dark blue diffusible pigment on Gause's synthetic agar, and microscopic observation revealed that it produces looped chains of spiny spores. Morphological and chemotaxonomic characteristics of the strain are typical of the genus Streptomyces. Melanin was produced and antibacterial activity was detected against Gram-positive micro-organisms, such as Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus. The 16S rRNA gene sequence of strain GIMN4.002(T) had highest similarity (99.4 %) to Streptomyces lincolnensis B91; however, DNA-DNA relatedness between strain GIMN4.002(T) and S. lincolnensis NBRC 13054(T) was only 32.17 %. Further, the morphological, physiological and biochemical characteristics of strain GIMN4.002(T) are distinct from S. lincolnensis and other species of the genus Streptomyces with which this strain has high 16S rRNA gene sequence similarity (98-99 %). On the basis of the physiological and molecular properties observed, it is proposed that strain GIMN4.002(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces caeruleatus sp. nov. is proposed, with GIMN4.002(T) (=CCTCC M 208213(T) =NRRL B-24802(T)) as the type strain.


Does Surgical Treatment Affect the Degree of Anxiety or Depression in Patients With Degenerative Cervical Myelopathy?
Retrospective cohort study. Preoperative mental state has been reported as one of the factors affecting the surgical outcomes of spine surgery, but few studies have examined in detail how patients' mental state is affected by spine surgery. The purpose of this study was to investigate using the Hospital Anxiety and Depression Scale (HADS) whether surgery improves preoperative depression and anxiety in patients with degenerative cervical myelopathy. We investigated patient-reported outcomes (Mental Component Summary, Physical Component Summary of SF-12 Health Survey, and EQ-5D, Neck Disability Index, JOACMEQ, satisfaction with treatment) and HADS one year after surgery, comparing them before and after surgery between April 2017 and February 2020. Among the cases diagnosed as preoperative anxiety and depression, we additionally compared the patient-reported outcomes based on the presence or absence of postoperative improvement in mental state, having also investigated the correlation between patient-reported outcomes and HADS for sub-analysis. Among the 99 patients eligible for inclusion in the present study, we found that patient-reported outcomes and the HADS scores improved significantly after surgery. There was a moderate correlation between the amount of change in HADS-D score before and after surgery and the amount of change in NDI (moderate, r = .41), NRS of neck (moderate, r = .46), and JOACMEQ (cervical spine function; moderate, r = .43, upper extremity function; moderate, r = .41, QOL; moderate, r = .41). We found that surgical treatment for patients with degenerative cervical myelopathy may improve postoperative anxiety and depression as well as other patient-reported outcomes.


Effect of gramicidin D on the acidogenic properties of oral streptococci and human dental plaque.
The effect of gramicidin D, Gramicidin S, and carbonylcyanide p-trifluoromethoxyphenyl hydrazone on the glycolysis of various oral streptococci was investigated. Gramicidin D was the most effective and inhibited the glycolysis of all the streptococci studied in the presence of the most common sugars found in man's diet (sucrose, lactose, glucose, and fructose). A concentration of 2.5 X 10(-6) M gramicidin D was sufficient to decrease significantly the rate of glycolysis of human dental plaque in the presence of sucrose. The use of this ionophore as a caries preventive agent is discussed.


Alcoholic Cardiomyopathy: Multigenic Changes Underlie Cardiovascular Dysfunction.
Alcoholism is the third leading cause of preventable death in the United States. Aside from promoting cardiomyopathies, chronic alcohol consumption is associated with an increased risk of dementia, the development of liver or pancreas failure, and cancers of the oral cavity and pharynx. Although a J-shaped curve for all cause mortality has been identified for average alcohol consumption, irregular heavy drinking also carries significantly greater risks for cardiovascular disease. Alcohol induced cardiovascular disease has a complex multigenic etiology. There is significant variation in the initial presentation of alcoholic cardiomyopathy with diastolic dysfunction possibly being the first indication. Ethanol exposure generates toxic metabolites, primarily acetaldehyde and ROS, which activate several cell signaling systems to alter cell function across many levels. Sudden cardiac death is a known occurrence of alcoholism that may be linked to an arrhythmogenic effect of alcohol. Microscopic and molecular examination of diseased hearts has demonstrated abnormal alterations to various cellular components, including the mitochondria and myofibrils. These studies have shown not only the direct impact on myocardial contractility but also disrupted metabolism that determines the long-term survival of the myocardium. Significant variations in the response to chronic alcohol consumption may be related to unique genotypes that modify the metabolic response to ethanol. Future studies to further characterize the role of different genotypes will help indentify those genotypes are more susceptible to chronic alcohol consumption.


Diminazene aceturate--An antiparasitic drug of antiquity: Advances in pharmacology & therapeutics.
Diminazene aceturate (C14H15N7.2C4H7NO3) is an aromatic diamidine that was developed more than six decades ago and has been marketed until today for the control of trypanosomiasis. In recent years, however, this trypanocidal compound has been extensively studied with respect to its therapeutic potential and has consequently attracted much interest for the development of further research. The objective of this study was to conduct a systematic review on diminazene aceturate regarding its pharmacological properties. In this way, databases were searched for articles (ScienceDirect, Scopus, PubMed, Web of Science and SciFinder) and patents (INPI, USPTO, WIPO, DPMA, SIPO, DERWENT, CIPO and EPO). For the development of this review, 115 articles and 22 patents were selected and analyzed. It was thus possible to highlight several researches that have investigated alternatives in order to improve success in the treatment of animal trypanosomiasis, by using new drugs in associations with diminazene aceturate, as well as looking for new pharmacological applications for this compound, such as leishmanicidal, amebicidal, anti-pneumocystis, anti-rheumatoid arthritis, antihypertensive agent, and mainly as an activator of angiotensin-converting enzyme 2. Another pharmacological property still little studied is the inhibition of acid-sensitive ion channels (ASIC1a, ASIC1b, ASIC2a and ASIC3), which are related to the development of various diseases. Collectively, these studies conducted by several research groups extend the use of diminazene aceturate beyond the antitrypanosomal activity and suggest promising new applications.


Does antimicrobial use density at the ward level influence monthly central line-associated bloodstream infection rates?
The aim of this study was to elucidate risk factors, including ward antimicrobial use density (AUD), for central line-associated bloodstream infection (CLABSI) as defined by the Centers for Disease Control and Prevention in a 430-bed community hospital using central venous lines with closed-hub systems. We calculated AUD as (total dose)/(defined daily dose × patient days) ×1,000 for a total of 20 drugs, nine wards, and 24 months. Into each line day data, we inputed AUD and device utilization ratios, number of central line days, and CLABSI. The ratio of susceptible strains in isolates were subjected to correlation analysis with AUD. Of a total of 9,997 line days over 24 months, CLABSI was present in 33 cases (3.3 ‰), 14 (42.4%) of which were on surgical wards out of nine wards. Of a total of 43 strains isolated, eight (18.6%) were methicillin-resistant Staphylococcus aureus (MRSA); none of the MRSA-positive patients had received cefotiam before the onset of infection. Receiver-operating characteristic analysis showed that central line day 7 had the highest accuracy. Logistic regression analysis showed the central line day showed an odds ratio of 5.511 with a 95% confidence interval of 1.936-15.690 as did AUD of cefotiam showing an odds ratio of 0.220 with 95% confidence interval of 0.00527-0.922 (P=0.038). Susceptible strains ratio and AUD showed a negative correlation (R (2)=0.1897). Thus, CLABSI could be prevented by making the number of central line days as short as possible. The preventative role of AUD remains to be investigated.


In vitro effects of deoxynivalenol on small intestinal D-glucose uptake and absorption of deoxynivalenol across the isolated jejunal epithelium of laying hens.
Deoxynivalenol (DON) is a common mycotoxin contaminant in feedstuffs. It has been shown to cause diverse toxic effects in animals. The aim of the present study was to evaluate the effects of DON on the glucose transport capacity in chickens' jejunum and to investigate the permeation of DON itself by the Ussing chamber technique. Glucose uptake into chicken jejunal epithelia was measured after the addition of 200 mumol/L of (14)C-labeled glucose to the mucosal solution. Glucose uptake under control condition was 3.28 +/- 0.53 nmol/cm(2) x min. The contribution of sodium glucose-linked transporter 1 (SGLT-1) to total glucose uptake was estimated by inhibiting SGLT-1 with phlorizin (100 micromol/L). In the presence of phlorizin, glucose uptake was reduced (P < 0.05) to 1.21 +/- 0.19 nmol/cm(2) x min. Deoxynivalenol decreased (P < 0.05) the glucose uptake in the absence of phlorizin to 1.81 +/- 0.24 nmol/cm(2) x min but had no additional effect on the glucose uptake in the presence of phlorizin (0.97 +/- 0.17 nmol/cm(2) x min). Mucosal-to-serosal permeation of DON was proportional to the initial DON concentration over a concentration range from 1 to 10 mug/mL on the mucosal side. Apparent permeability at 10 microg/mL of DON measured 60 to 90 min after DON application was 1.7 x 10(-05) cm/s. It can be concluded that DON (10 mg/L) decreases glucose uptake almost as efficiently as phlorizin. The similarity between the effects of phlorizin and DON on glucose uptake evidences their common ability to inhibit Na(+)-D-glucose cotransport. In addition to local effects, DON can be absorbed from the jejunum. A predominant part of DON passes across the chicken intestinal epithelium by passive diffusion, which is likely on the paracellular pathway. The results imply that the exposure to DON-contaminated feeds may negatively affect animal health and performance by local (i.e., inhibition of intestinal SGLT-1) and systemic effects.


PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells.
Pyruvate kinase M2 (PKM2) is expressed at high levels during embryonic development and tumour progression and is important for cell growth. However, it is not known whether it directly controls cell division. Here, we found that Aurora B phosphorylates PKM2, but not PKM1, at T45; this phosphorylation is required for PKM2's localization and interaction with myosin light chain 2 (MLC2) in the contractile ring region of mitotic cells during cytokinesis. PKM2 phosphorylates MLC2 at Y118, which primes the binding of ROCK2 to MLC2 and subsequent ROCK2-dependent MLC2 S15 phosphorylation. PKM2-regulated MLC2 phosphorylation, which is greatly enhanced by EGF stimulation or EGFRvIII, K-Ras G12V and B-Raf V600E mutant expression, plays a pivotal role in cytokinesis, cell proliferation and brain tumour development. These findings underscore the instrumental function of PKM2 in oncogenic EGFR-, K-Ras- and B-Raf-regulated cytokinesis and tumorigenesis.


Redo tricuspid valve operation in patients with 1st-generation mitral prostheses.
Background In patients with remarkably enlarged cardiac chambers and history of implantation of older types of mitral valve prosthesis, the considerations for reoperative tricuspid valve surgery are not limited to the risks of sternal reentry but also include the dilemma of whether to carry out prophylactic replacement of the normal functioning but outdated prosthesis or leave it in situ. Methods We reviewed our surgical strategy and postoperative 5-year follow-up findings in two patients who underwent redo tricuspid surgery 3 to 4 decades after mechanical mitral valve replacement. Both patients presented with significant symptoms of progressive right heart failure due to severe tricuspid regurgitation, despite optimal medical therapy. Results We found the beating-heart approach to be an effective and safe method for redo tricuspid surgery. Both first-generation mitral mechanical prostheses were not replaced and have remained well functional upon the patients' postoperative 5-year follow-up, respectively. Conclusion For patients with normal functioning first-generation mechanical mitral prostheses, whether to prophylactically replace the prosthesis should be based on an individualized risk-benefit analysis.


What brings pericytes to tumor vessels?
Paracrine signaling via platelet-derived growth factor B (PDGFB), expressed by endothelial cells, and its receptor PDGFR-beta, expressed by pericytes, plays a central role in blood vessel maturation. A new study (see the related article beginning on page 1142) reveals that it is not just the presence of PDGFB, but how it is presented to pericytes, that determines the quality of the endothelium-pericyte interaction.


Normal cross-sectional dimensions of the thyroid gland on routine chest CT scans.
The purpose of this work was to determine the range of normal measurements for the thyroid gland on chest CT scans and relate it to the dimensions of the trachea. Chest CT scans in 118 patients were examined prospectively for visibility of the thyroid gland and its relationship to the trachea. The greatest transverse dimensions of the lobes and the transverse tracheal diameter were measured. A thyroid/trachea ratio was determined. The mean value for the transverse diameter of the thyroid gland was 28.79 mm (SD 6.57 mm). The right lobe averaged 15.05 mm (SD 3.51 mm). The left lobe averaged 13.74 mm (SD 3.91 mm). Measurements for the trachea showed a mean value of 19.97 mm (SD 2.37 mm). A thyroid/trachea index was calculated with a mean value of 1.46 (SD 0.39). Our investigation provides initial values for assessing the thyroid gland on CT scans, defining the limits of normal and the border zones of abnormal size.


Intravitreal ranibizumab versus isovolemic hemodilution in the treatment of macular edema secondary to central retinal vein occlusion: twelve-month results of a prospective, randomized, multicenter trial.
This is a prospective, randomized, multicenter, investigator-initiated trial to evaluate the 12-month effectiveness of isovolemic hemodilution (IH) with prompt versus deferred intravitreal injections (IVI) of ranibizumab 0.5 mg for the treatment of macular edema secondary to early central retinal vein occlusion (CRVO). Eyes with macular edema due to CRVO having occurred not more than 8 weeks previously received either monthly ranibizumab IVI in combination with IH (group I, n = 28) or IH alone (group II, n = 30). From month 2 to 12, the patients in both groups could be treated with monthly intravitreal ranibizumab. The main outcome variables were gain of visual acuity and the course of central retinal thickness as measured with optical coherence tomography. At 12 months, eyes in group I on average gained +28.1 (±19.3) letters compared to +25.2 (±20.9) letters in group II (p = 0.326). This result was achieved with significantly fewer injections in group II. Additionally, 30% of the eyes in group II did not need ranibizumab IVI during the 12 months of the trial. Ranibizumab IVI in addition to IH proved to be highly effective in increasing visual acuity and reducing macular edema secondary to CRVO. Initial IH in early CRVO may be a first treatment option in patients anxious about IVI.


Dietary eicosapentaenoic acid modulates CTLA-4 expression in murine CD4+ T-cells.
We have demonstrated that downregulation of proliferation by CD4(+) T-cells in mice fed n-3 PUFA diets is dependent on the involvement of CD28. Therefore, we hypothesized that the balance of co-stimulatory and downregulatory properties of CD28 and CTLA-4, respectively, would be altered by diet. Mice were fed a control corn oil (CO)-enriched diet devoid of n-3 PUFA, or diets enriched with either docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) for 14d. The proliferation of splenic CD4(+) T-cells was suppressed by DHA and EPA following stimulation with anti-CD3 and anti-CD28. Surprisingly, the number of surface CD28 molecules was not reduced in activated CD4(+) T-cells from either group of n-3 PUFA-fed mice. However, in mice fed EPA, CTLA-4 protein levels were enhanced significantly 72 h post-activation (P<0.01). Therefore, we conclude that dietary EPA may suppress CD4(+) T-cell activation by enhancing the downregulatory co-receptor CTLA-4, while not altering the levels of CD28.


Optimizing hereditary angioedema management through tailored treatment approaches.
Hereditary angioedema (HAE) is a rare but serious and potentially life threatening autosomal dominant condition caused by low or dysfunctional C1 esterase inhibitor (C1-INH) or uncontrolled contact pathway activation. Symptoms are characterized by spontaneous, recurrent attacks of subcutaneous or submucosal swellings typically involving the face, tongue, larynx, extremities, genitalia or bowel. The prevalence of HAE is estimated to be 1:50,000 without known racial differences. It causes psychological stress as well as significant socioeconomic burden. Early treatment and prevention of attacks are associated with better patient outcome and lower socioeconomic burden. New treatments and a better evidence base for management are emerging which, together with a move from hospital-centered to patient-centered care, will enable individualized, tailored treatment approaches.


Serum alpha-fetoprotein levels in acute viral hepatitis.
Serum alpha-fetoprotein levels were measured serially by radioimmunoassay in 32 patients with acute viral hepatitis. With one exception, the levels were increased during the course of the illness. Raised concentrations of the protein occurred almost equally in patients with and without the hepatitis-B antigen. In the majority of patients the rise was modest but in seven levels were reached at which alpha-fetoprotein could be detected by immunodiffusion. Very high levels were more likely to occur in children. In eight patients the concentration increased as the serum glutamic pyruvic transaminase (SGPT) level, used as an index of hepatocyte damage, was returning to normal, a pattern which favoured increased synthesis of the protein during hepatocellular regeneration. In the remainder, the alpha-fetoprotein level paralleled that of SGPT, suggesting rather an acutephase reaction to liver injury.


Relationship Between Physical Activity, Parental Psychological Control, Basic Psychological Needs, Anxiety, and Mental Health in Chinese Engineering College Students During the COVID-19 Pandemic.
The issue of mental health among college students is of increasing concern during the COVID-19 outbreak. Since course characteristics of engineering college students determine the particularities of their mental health, the specific objectives of this study were: (1) to analyze the relationship between physical activity, parental psychological control, basic psychological needs, anxiety, and mental health in Chinese engineering college students during COVID-19 pandemic; and (2) to examine the mediation effect of anxiety between the relationship of basic psychological needs and mental health. A cross-sectional study was conducted among several universities in Shandong Province, China. We randomly selected 254 Chinese engineering college students from these colleges. Participants who were given questionnaires completed the Physical Activity Rating Scale (PARS-3), Basic Needs Satisfaction in General Scale (BNSG-S), Parental psychological control Questionnaire, the Beck anxiety inventory (BAI), and the Kessler 10 (K10) scale. The mediation model was conducted to assess the mediation effect of anxiety between the relationship of basic psychological needs and mental health. Among 254 Chinese college students majoring in engineering, the results showed that their mental health was in the mid-level range. Besides, physical activity and basic psychological needs is positively correlated with mental health, respectively, while parental psychological control is not correlated with mental health. Anxiety is negatively associated with mental health. Mediation analysis revealed that anxiety played a mediation role in the relationship between basic psychological needs and mental health. In conclusion, mental health of Chinese engineering college students deserves extensive attention during the COVID-19 pandemic. Proper intervention on physical activity, basic psychological needs, and anxiety may be beneficial to improve their mental health. In addition, meeting basic psychological needs is beneficial to reduce anxiety and improve mental health further.


Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and Ginkgo biloba extracts in healthy subjects.
1. Ginkgo biloba extract (GBE) is one of the most commonly used herbal remedies worldwide. It is usually concomitantly administrated with statins to treat diseases in geriatric patients. We aim to determine the influence of GBE on the pharmacokinetics (PK) and pharmacodynamics of simvastatin, which is currently unknown. 2. An open-label, randomized, two-period, two-treatment, balanced, crossover study was performed in 14 healthy volunteers. Subjects received simvastatin 40 mg once daily, co-treated with placebo or GBE 120 mg twice daily. Each treatment was administered for 14 d, separated by a wash-out period of 1 month. Simvastatin, simvastatin acid and lipoprotein concentrations were assessed. 3. GBE administration reduced mean simvastatin area under the curve (AUC)0-24, AUC0-∞ and Cmax by 39% (p = 0.000), 36%(p = 0.001) and 32% (p = 0.002), respectively, but did not cause significant differences in simvastatin acid PK or its cholesterol-lowering efficacy. 4. GBE consumption decreased simvastatin system exposure, but did not affect simvastatin acid PK. However, we cannot rule out the possibility for a pharmacodynamic interaction between GBE and simvastatin in vivo.


Sequence and functional expression of a single alpha subunit of an insect nicotinic acetylcholine receptor.
We report the isolation and sequence of a cDNA clone that encodes a locust (Schistocerca gregaria) nervous system nicotinic acetylcholine receptor (AChR) subunit (alpha L1). The calculated molecular weight of the unglycosylated polypeptide, which contains in the proposed extracellular domain two adjacent cysteine residues which are characteristic of alpha (ligand binding) subunits, is 60,641 daltons. Injection into Xenopus oocytes, of RNA synthesized from this clone in vitro, results in expression of functional nicotinic receptors in the oocyte membrane. In these, nicotine opens a cation channel; the receptors are blocked by both alpha-bungarotoxin (alpha-Bgt) and kappa-bungarotoxin (kappa-Bgt). Reversible block of the expressed insect AChR by mecamylamine, d-tubocurarine, tetraethylammonium, bicuculline and strychnine has also been observed. These data are entirely consistent with previously reported electrophysiological studies on in vivo insect nicotinic receptors and also with biochemical studies on an alpha-Bgt affinity purified locust AChR. Thus, a functional receptor exhibiting the characteristic pharmacology of an in vivo insect nicotinic AChR can be expressed in Xenopus oocytes by injection with a single subunit RNA.


[Radium-223 treatment of bone metastases from castration-resistant prostate cancer].
The alpha emitter Radium-223 ((22)3Ra-Cl2) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone refractory prostate cancer. More than 1,000 patients have been included in clinical phase I-III tests showing significant reduction in alkaline phosphatase- and PSA level and prolonged survival. Adverse events are usually mild to moderate and comprise gastrointestinal and myelotoxic symptoms. Intravenously administered (22)3Ra-Cl2 (half-life 11.4 days) will likely be given every four weeks for six treatments to out-patients.


Enzymes harboring unnatural amino acids: mechanistic and structural analysis of the enhanced catalytic activity of a glutathione transferase containing 5-fluorotryptophan.
The catalytic characteristics and structure of the M1-1 isoenzyme of rat glutathione (GSH) transferase in which all four tryptophan residues in each monomer are replaced with 5-fluorotryptophan are described. The fluorine-for-hydrogen substitution does not change the interaction of the enzyme with GSH even though two tryptophan residues (Trp7 and Trp45) are involved in direct hydrogen-bonding interactions with the substrate. The rate constants for association and dissociation of the peptide, measured by stopped-flow spectrometry, remain unchanged by the unnatural amino acid. The 5-FTrp-substituted enzyme exhibits a kcat of 73 s-1 as compared to 18 s-1 for the native enzyme toward 1-chloro-2,4-dinitrobenzene. That the increase in the turnover number is due to an enhanced rate of product release in the mutant is confirmed by the kinetics of the approach to equilibrium for binding of the product. The crystal structure of the 5-FTrp-containing enzyme was solved at a resolution of 2.0 A by difference Fourier techniques. The structure reveals local conformational changes in the structural elements that define the approach to the active site which are attributed to steric interactions of the fluorine atoms associated with 5-FTrp146 and 5-FTrp214 in domain II. These changes appear to result in the enhanced rate of product release. This structure represents the first of a protein substituted with 5-fluorotryptophan.


EACVI survey on the evaluation of infective endocarditis.
To evaluate the diagnosis and imaging of patients with suspected endocarditis and the management in routine clinical practice across Europe, the EACVI Scientific Initiatives Committee performed a survey across European centres. In particular, the routine use of echocardiography, advanced imaging modalities and multidisciplinary team was explored. A total of 100 European Echocardiography Laboratories from 29 different countries responded to the survey, which consisted of 20 questions. For most of the use of echocardiography and advanced imaging, answers from the centres were relatively homogeneous and demonstrated good adherence to current recommendations. In particular, two-thirds of centres report the use of a specific endocarditis team for decision-making. Echocardiography plays a key role in the diagnosis and management of endocarditis. Nuclear imaging modalities are broadly available among the centres and are mainly used in prosthetic valve endocarditis and cardiac device-related infective endocarditis. Computed tomography (CT) is widely available and used to assess for structural valve abnormalities, neurological complications, and to preoperative assessment of the coronary arteries. Most institutions provide structured patients follow-up following hospital discharge. In Europe, a relatively homogenous adherence to current recommendation was observed for most diagnostic and management including the follow-up of patients with endocarditis. Decision-making is most commonly performed by a multidisciplinary team. Echocardiography remains the first line and central imaging modality for patient diagnosis and assessment, but 60% of centres also commonly use CT, whilst positron emission tomography imaging is used in patients with prosthetic valve endocarditis or device infection.


Small bowel and liver pO2 during vasopressin infusion into the superior mesenteric artery.
In an earlier study we found that intravenous vasopressin infusion caused a profound decrease in intestinal and liver pO2. As vasopressin has been reported to be more effective when infused directly into the superior mesenteric artery, we have now studied the effects of this type of administration. Intestinal pO2 and pCO2 and liver pO2 were continuously recorded using a silicone elastomer tube as a tonometer. Vasopressin was infused in a dose of 2.75 mU/kg/min in twelve dogs for 45 minutes. Intestinal tissue pO2 decreased during 45 minute infusion period from 35 +/- 0.9 mmHg to 19 +/- 0.7 mmHg (p less than 0.001) and liver pO2 from 38 +/- 1.9 mmHg to 19 +/- 1.1 mmHg (p less than 0.005). Both values obtained in this study did not differ from those noted when the same dose of vasopressin was administered intravenously.


Biosynthesis of phenylpropanoid amides by an endophytic Penicillium brasilianum found in root bark of Melia azedarach.
Biosynthetic studies on brasiliamides, potently convulsive and bacteriostatic compounds from an endophytic Penicillium brasilianum isolated from Melia azedarach (Meliaceae), confirms their phenylpropanoid origin, which is very uncommon in fungi. Feeding experiments with [2-(13)C]- phenylalanine indicated the incorporation of two units of this amino acid on brasiliamide structures. The first step in the phenylpropanoid pathway to those compounds was evaluated through enzymatic bioassays and confirmed the phenylalanine ammonia-lyase (PAL) participation. The metabolism of phenylalanine in this fungus is discussed.


[Orthopedic problems in children caused by neuromuscular diseases].
In the child, neuromuscular diseases have an affect not only on the soft tissues but also on the skeleton, with consequences regarding statics and locomotion. Problems essentially involve the joints of the lower limb. Certain are due to muscular imbalance, eg. an unstable hip, coxa valga, hyperanteversion or miscellaneous abnormalities of the knee. Others are due to sensory denervation, resulting in "neurological joints". Vertebro-pelvic abnormalities also occur with manifestations, according to the individual case, including tilting of the pelvis, paralytic scoliosis or vertebral dysmorphism. It is easy to understand the importance of awareness of such abnormalities, which can be detected early radiologically, and then subjected to expert evaluation in order to be able to select in good time the most appropriate orthopedic management.


Spatiotemporal SERT expression in cortical map development.
The cerebral cortex is organized into morphologically distinct areas that provide biological frameworks underlying perception, cognition, and behavior. Profiling mouse and human cortical transcriptomes have revealed temporal-specific differential gene expression modules in distinct neocortical areas during cortical map establishment. However, the biological roles of spatiotemporal gene expression in cortical patterning and how cortical topographic gene expression is regulated are largely unknown. Here, we characterize temporal- and spatial-defined expression of serotonin (5-HT) transporter (SERT) in glutamatergic neurons during sensory map development in mice. SERT is transiently expressed in glutamatergic thalamic neurons projecting to sensory cortices and in pyramidal neurons in the prefrontal cortex (PFC) and hippocampus (HPC) during the period that lays down the basic functional neural circuits. We previously identified that knockout of SERT in the thalamic neurons blocks 5-HT uptake by their thalamocortical axons, resulting in excessive 5-HT signaling that impairs sensory map architecture. In contrast, here we show that selective SERT knockout in the PFC and HPC neurons does not perturb sensory map patterning. These data suggest that transient SERT expression in specific glutamatergic neurons provides area-specific instructions for cortical map patterning. Hence, genetic and pharmacological manipulations of this SERT function could illuminate the fundamental genetic programming of cortex-specific maps and biological roles of temporal-specific cortical topographic gene expression in normal development and mental disorders.


Diabetic glomerulopathy following unilateral nephrectomy in the dog.
To elucidate the important features of early renal disease in the diabetic dog, renal capillary permselectivity and fractional mesangial expansion with and without unilateral nephrectomy (NX) were examined. Pancreatectomized mongrel dogs (N = 9) received 10-20 U Regular and NPH insulin daily. Weekly blood glucose monitoring, 300 +/- 75 mg/dl (means +/- SD). Three dogs without NX had serial open needle biopsies 6-23 months post-pancreatectomy, revealing significant glomerular basement membrane widening and mesangial expansion. Without NX, inulin clearance increased from 2.55 +/- 0.89 (pre-diabetes) to 4.30 +/- 0.70 ml/min/kg body weight (N = 4, means +/- SD, p less than 0.05), whereas albuminuria, measured by radioimmunoassay, remained unchanged 2.57 +/- 1.03 (pre-diabetes) to 2.83 +/- 1.63 micrograms/min/kg body weight up to 23 months post-pancreatectomy. To determine whether altered renal capillary permselectivity occurred despite normal albuminuria, glomerular charge and size selectivity was analysed with serial fractional anionic dextran (20-44 A Stokes Einstein Radius) clearances. Furthermore, peritubular capillary permselectivity was probed with anionic and neutral 3H-dextran (26 A) using the multiple indicator dilution method. Fractional anionic dextran clearances remained unchanged up to 23 months, as did peritubular capillary permselectivity. Five diabetic dogs were compared to non-diabetic dogs with (N = 4) and without (N = 10) NX. To identify whether angiotensin II converting enzyme inhibition modified glomerular function or morphology, 3 diabetic + NX dogs received Captopril (5 mg/kg/day). At one year, diabetes + NX had an additive effect on renal hypertrophy, although fractional mesangial expansion was not enhanced by NX. Albuminuria was unaffected by NX or Captopril.(ABSTRACT TRUNCATED AT 250 WORDS)


Partial volume effect modeling for segmentation and tissue classification of brain magnetic resonance images: A review.
Quantitative analysis of magnetic resonance (MR) brain images are facilitated by the development of automated segmentation algorithms. A single image voxel may contain of several types of tissues due to the finite spatial resolution of the imaging device. This phenomenon, termed partial volume effect (PVE), complicates the segmentation process, and, due to the complexity of human brain anatomy, the PVE is an important factor for accurate brain structure quantification. Partial volume estimation refers to a generalized segmentation task where the amount of each tissue type within each voxel is solved. This review aims to provide a systematic, tutorial-like overview and categorization of methods for partial volume estimation in brain MRI. The review concentrates on the statistically based approaches for partial volume estimation and also explains differences to other, similar image segmentation approaches.