Multidrug-resistant MCF-7 breast cancer cells contain deficient intracellular calcium pools.
Emergence of resistance to antineoplastic drugs poses a major impediment to the successful treatment of breast cancer. We previously reported that human breast carcinoma MCF-7 cells selected for resistance against doxorubicin (MCF-7/DOX cells) expressed high levels of tissue-type transglutaminase (tTGase), a calcium-dependent protein cross-linking enzyme that plays a role in apoptosis. The purpose of this study was to determine the mechanisms by which MCF-7/DOX cells survive and proliferate despite high levels of tTGase expression. Our results demonstrate that the MCF-7/DOX cells contain deficient intracellular calcium pools, which may explain their ability to survive and tolerate the high levels of tTGase expression. Treatment with thapsigargin failed to induce any significant killing of MCF-7/DOX cells. Similar treatment of the drug-sensitive MCF-7 wild-type (MCF-7/WT) cells, however, induced significant apoptosis. Treatment with the ionophore A23187, on the other hand, killed a large percentage of both the MCF-7/DOX and the MCF-7/WT cells. We also established a revertant cell line, MCF-7/RT, from MCF-7/DOX cells to rule out the involvement of P-glycoprotein (P-gp) in these phenomena. Unlike the MCF-7/DOX cells, the MCF-7/RT cells showed no detectable P-gp expression; the MCF-7/RT cells, however, continued to express high levels of tTGase. Moreover, like MCF-7/DOX cells, the MCF-7/RT cells were highly resistant to thapsigargin-induced apoptosis but were sensitive to the ionophore A23187-induced apoptosis. These results suggest that the resistance of MCF7/DOX cells to thapsigargin is linked to their defective intracellular Ca2+ stores, a notion that was directly confirmed by single-cell spectrofluorometric analysis.


Expression Levels of Genes Encoding Proteins Involved in the Cell Wall-Plasma Membrane-Cytoskeleton Continuum Are Associated With the Maturation-Related Adventitious Rooting Competence of Pine Stem Cuttings.
Stem cutting recalcitrance to adventitious root formation is a major limitation for the clonal propagation or micropropagation of elite genotypes of many forest tree species, especially at the adult stage of development. The interaction between the cell wall-plasma membrane and cytoskeleton may be involved in the maturation-related decline of adventitious root formation. Here, pine homologs of several genes encoding proteins involved in the cell wall-plasma membrane-cytoskeleton continuum were identified, and the expression levels of 70 selected genes belonging to the aforementioned group and four genes encoding auxin carrier proteins were analyzed during adventitious root formation in rooting-competent and non-competent cuttings of Pinus radiata. Variations in the expression levels of specific genes encoding cell wall components and cytoskeleton-related proteins were detected in rooting-competent and non-competent cuttings in response to wounding and auxin treatments. However, the major correlation of gene expression with competence for adventitious root formation was detected in a family of genes encoding proteins involved in sensing the cell wall and membrane disturbances, such as specific receptor-like kinases (RLKs) belonging to the lectin-type RLKs, wall-associated kinases, Catharanthus roseus RLK1-like kinases and leucine-rich repeat RLKs, as well as downstream regulators of the small guanosine triphosphate (GTP)-binding protein family. The expression of these genes was more affected by organ and age than by auxin and time of induction.


Ce4+/Ce3+ Redox Effect-Promoted CdS/CeO2 Heterojunction Photocatalyst for the Atom Economic Synthesis of Imines under Visible Light.
The employment of stoichiometric alcohols and amines for imine synthesis under mild and green reaction conditions is still a challenge in the field. In this work, based on our research foundation in the thermocatalytic synthesis of imines over ceria, a CdS/CeO2 heterojunction photocatalyst was constructed and successfully realized the atom-economic synthesis of imines under visible light without additives at room temperature. Mechanistic experiments and corresponding characterizations indicated that the CdS/CeO2 heterojunction can improve the separation efficiency of photogenerated carriers, which can be further enhanced by the Ce4+/Ce3+ redox pair by rapidly combining photogenerated e-. The in situ-reduced Ce3+ can better activate O2 to form Ce-O-O·, which, together with h+, efficiently accelerates alcohol oxidation, which is the rate-determined step for the synthesis of imines via oxidative coupling reaction of alcohol and amine. In addition, our photocatalyst exhibited fairly decent reusability and substrate universality. This work solves problems of using base additives and excess amine or alcohol in the reported photocatalytic systems and provides new insight for designing CeO2-based photocatalytic oxidation catalysts.


The anti-inflammation effect of strontium ranelate on rat chondrocytes with or without IL-1β in vitro.
Temporomandibular joint osteoarthritis (TMJ-OA) is a common disease with a high level of inflammation in the joint micro-environment and cartilage degradation. Anti-inflammation and cartilage regeneration are the key therapies for TMJ-OA, but currently, there are no novel medicines or treatments that can control its pathogenic progression. Strontium ranelate (SrR) is an anti-osteoporosis drug and is now considered a promising anti-OA drug, but the anti-inflammatory effect of SrR remains to be elucidated. In the present study, the anti-inflammatory effect of SrR in a normal or high IL-1β environment was observed. Cell viability under the treatment of SrR was tested using Cell Counting Kit-8. Toluidine blue staining, immunofluorescence staining, hydroxyproline assay, PCR assay and western blotting were used to detect the expression of collagen (Col)II, proteoglycans (PG) and aggrecan as a reflection of extracellular matrix synthesis and MMP-9,13 hydroxyproline was used as an inflammation indicator. IL-1β of 10 ng/ml was added to the culture medium as inflammation environment and the tests of those biomarkers were done again. Then, the changes in β-catenin were also studied by immunofluorescence staining, PCR assay and western blotting to explore the possible involvement of the Wnt/β-catenin pathway. The results showed a significant inhibition of MMP-9, MMP-13, β-catenin and promotion of Col-II, PG and aggrecan in normal chondrocytes. The presence of IL-1β markedly upregulated the expression of MMP-9, MMP-13 and β-catenin while suppressing Col-II and PG and SrR partially reversed this trend. In conclusion, SrR decreased MMPs but promoted Col-II, aggrecan and PG synthesis in rat chondrocytes with or without the presence of IL-1β and SrR attenuated the IL-1β-induced increase in β-catenin, thus reducing the inflammatory reaction.


Selection of allografts for impaction bone grafting for bone defect reconstruction on the acetabular side.
To review the choices of allografts for bone defect reconstruction in acetabular revision surgery using the technique of impaction bone grafting. The data cited in this review were mainly obtained from articles listed in PubMed that were published from January 1993 to July 2009. The search terms were "impaction bone grafting", "particle size", "mechanical property" and "biological behavior". Articles relevant to the choices of allografts and their results for bone defect reconstruction on the acetabular side were selected. Different choices of allografts, including the particle size, process of irradiation or fat reduction, composition and particle grade, are made to improve the survival rate of a prosthesis in acetabular revision surgery. This review, which compares both mechanical and biological factors, summarizes the experimental and clinical results for different techniques. Fresh frozen cancellous allografts with particle sizes ranging from 7 to 10 mm are a favorable choice for reconstruction of bone defects of American Academy of Orthopedic Surgeons (AAOS) types II (cavitary defect) and III (combined cavitary and segmental defect) on the acetabular side. A fat-reducing procedure with saline or solvent/detergent is controversial. Adding autologous marrow into irradiated allografts, which provides reliable mechanical stability and biological safety, may be a substitute for fresh frozen allografts. Cortical bone can be a supplementary material in cases of insufficiency of cancellous allografts. Cartilage should be excluded from the graft material. Further research is required to demonstrate the best particle grade, and randomized controlled trials in clinical practice are required to obtain more information about the selection of allografts.


Vascular effects of endothelin-1 in the cat; modification by indomethacin and L-NAME.
Intravenous infusion of endothelin-1 (ET-1) in the cat, 60 pmol x kg body wt-1 x min-1 for 5 min, induced an increase in mean arterial blood pressure (MAP) of 41.3 +/- 4.8 mmHg (n = 6; P < 0.001). Blood flow, as determined with radioactive microspheres, was reduced in many tissues. Reductions by 70-80% were observed in the choroid plexus, pineal and pituitary glands. Total cerebral blood flow was reduced by 18-23%. Pre-treatment with indomethacin or a combination of indomethacin and L-NAME caused vasoconstriction in many tissues and modified the responses to ET-1 in a variable way, suggesting that normally, ET-1 tends to release arachidonic acid metabolites and nitric oxide with great variations between different tissues. Intracerebroventricular infusion (i.c.v.) of ET-1, 10 pmol x kg body wt-1 x min-1, caused an increase in MAP of 79 +/- 11 mmHg (n = 6; P < 0.001). Regional blood flow in the medulla oblongata, medulla spinalis, choroid plexus, pineal and pituitary glands was reduced by 60-80%. Heart rate, cardiac output and coronary blood flow were significantly increased after 30 min i.c.v. infusion, indicating an activation of the heart, most probably as part of a central ischaemic response. Our results indicate that in many tissues the vasoconstrictive effect of ET-1 is influenced by indomethacin- and L-NAME-sensitive vasodilator mechanisms that are activated by the peptide. In the CNS, there may be marked effects on regional blood flow after i.c.v. infusion.


Ozone therapy in extractive surgery on patients treated with bisphosphonates.
It is certain that oral extractive surgery is a remarkable trigger to avascular osteonecrosis of the jaw in patients treated with pyrophosphate analogous. This acquisition limits the use of endo-oral surgery in those patients, even when they have already developed the lesions. In this study, we present the results obtained in a group of 15 patients deriving from a 33-patient cluster with osteonecrosis of the jaw in treatment at our department with a new protocol based on ozone therapy. The object of this article is to demonstrate how dental extraction becomes possible in a patient with avascular bisphosphonate-related jaw osteonecrosis or in those who simply received pyrophosphate analogous when proper treatment with ozone therapy has been done.


Chilean university students: knowledge and concern about HIV/AIDS.
According to a 2004 report by the Joint United Nations Programme on HIV/AIDS, Chile has an incipient HIV/AIDS epidemic. Regardless of the classification, every year the cumulative incidence of HIV/AIDS increases. Young Chileans have been the most affected group; still, their knowledge, attitudes, and concerns about HIV/AIDS are not known. This study describes Chilean university students' HIV/AIDS-related knowledge, their worry about getting the virus, and the correlation between both variables. A convenience sample of 45 university students responded to an anonymous self-administered questionnaire after orally consenting to participate in this study. Overall, students had good levels of HIV/AIDS-related knowledge, with 77% responding correctly to at least 85% of the questions. Despite this knowledge, almost 56% of students stated that they were not worried about getting HIV/AIDS. The situation was corroborated by a nonsignificant statistical correlation between both variables (p > .05). These results are congruent with literature from other countries and strengthen the need for further research to clarify why university students, the majority of whom are well-educated and engage in behaviors that place them at risk for contracting the virus, do not worry about HIV.


Functional characterization of AATF transcriptome in human leukemic cells.
The study, addressed to explore the transcriptional expression and regulation of Apoptosis-antagonizing transcription factor (AATF) gene within various types of human leukemic cell lines, revealed that AATF gene was overexpressed ubiquitously in all the leukemic cell lines studied and this upregulation was accompanied by c-myc gene overamplification in these cells. Downregulation of AATF gene transcription within leukemic cells not only resulted in the downregulation of c-myc gene and vice-versa but also contributed to apoptosis leading to cell death. Further, the link between AATF expression and leukemic cellular apoptosis involved PI3K/Akt pathway. Based on these results we propose that AATF gene may be of crucial importance in maintaining the leukemic state of a cell compartment through its ability to initiate cell proliferation coupled with repression of cellular apoptosis.


Apolipoprotein A-IV is involved in detection of lipid in the rat intestine.
Long chain triglyceride (>C12) in the intestinal lumen potently inhibits gastric emptying and acid secretion via the vagal afferent pathway. While the mechanism of inhibition involves the formation of chylomicrons, the essential role of the apolipoprotein apo A-IV is unclear. Using apo A-IV(-/-) mice, we tested the hypothesis that inhibition of gastric emptying and gastric acid secretion in response to dietary lipid is dependent upon apo A-IV. As measured by nuclear scintigraphy in awake mice, gastric emptying of an ingested whole-egg meal was significantly faster in apo A-IV(-/-) knockout versus A-IV(+/+) controls (34 +/- 1 versus 54 +/- 3 min, P < 0.0001). In anaesthetized A-IV(+/+) mice, meal-stimulated gastric acid secretion was 59% inhibited by intestinal lipid infusion; this was abolished in apo A-IV(-/-) mice. Oral gavage of lipid in awake mice activated neurones throughout the nucleus of the solitary tract (NTS) in A-IV(+/+) mice, measured by immunohistochemical localization of Fos protein expression. However, in the mid region of the NTS (bregma -7.32 to -7.76 mm), Fos expression in response to intestinal lipid was significantly decreased by 50% in apo A-IV(-/-) mice compared to A-IV(+/+) controls. We conclude that activation of the vagal afferent pathway and inhibition of gastric function in response to dietary lipid is partly dependent upon apo A-IV.


Prognostic Value of Soluble ST2 After Myocardial Infarction: A Community Perspective.
Soluble ST2 (sST2) is a marker of cardiac mechanical strain hypothesized to adversely impact short-term prognosis after myocardial infarction. We examined the association of sST2 with longer-term outcomes after myocardial infarction in a geographically defined community. Olmsted County, Minnesota residents who experienced an incident (first-ever) myocardial infarction between November 1, 2002 and December 31, 2012 were prospectively enrolled; sST2 levels were measured. Patients were followed for heart failure and death. We studied 1401 patients with incident myocardial infarction (mean age 67 years; 61% men; 79% non-ST-elevation myocardial infarction). Median sST2 (ng/mL) was 48.7 (25th-75th percentile 32.5-103.3). Soluble ST2 was elevated in 51% of patients. Higher values of sST2 were associated with increased age, female sex, and comorbidities. During 5 years of follow-up, 388 persons died and 360 developed heart failure. After adjustment for age, sex, comorbidities, Killip class, and troponin T, the hazard ratios for death were 1.73 (95% confidence interval [CI], 1.22-2.45) and 3.57 (95% CI, 2.57-4.96) for sST2 tertiles 2 and 3, respectively (Ptrend <.001). For heart failure, the hazard ratios were 1.67 (95% CI, 1.18-2.37) and 2.88 (95% CI, 2.05-4.05), respectively (Ptrend <.001). Results were similar among 30-day survivors. In the community, sST2 elevation is present in half of myocardial infarctions. Higher values of sST2 are associated with a large excess risk of death and heart failure independently of other prognostic indicators. Measurement of sST2 should be considered for risk stratification after myocardial infarction.


Identification of potential driver mutations in glioblastoma using machine learning.
Glioblastoma is a fast and aggressively growing tumor in the brain and spinal cord. Mutation of amino acid residues in targets proteins, which are involved in glioblastoma, alters the structure and function and may lead to disease. In this study, we collected a set of 9386 disease-causing (drivers) mutations based on the recurrence in patient samples and experimentally annotated as pathogenic and 8728 as neutral (passenger) mutations. We observed that Arg is highly preferred at the mutant sites of drivers, whereas Met and Ile showed preferences in passengers. Inspecting neighboring residues at the mutant sites revealed that the motifs YP, CP and GRH, are preferred in drivers, whereas SI, IQ and TVI are dominant in neutral. In addition, we have computed other sequence-based features such as conservation scores, Position Specific Scoring Matrices (PSSM) and physicochemical properties, and developed a machine learning-based method, GBMDriver (GlioBlastoma Multiforme Drivers), for distinguishing between driver and passenger mutations. Our method showed an accuracy and AUC of 73.59% and 0.82, respectively, on 10-fold cross-validation and 81.99% and 0.87 in a blind set of 1809 mutants. The tool is available at https://web.iitm.ac.in/bioinfo2/GBMDriver/index.html. We envisage that the present method is helpful to prioritize driver mutations in glioblastoma and assist in identifying therapeutic targets.


In vitro and in vivo potentiation of radiosensitivity of malignant gliomas by antisense inhibition of the RAD51 gene.
The mammalian RAD51 gene is a homologue of the yeast RAD51 and E. coli RecA genes, which are related to the repair of DNA double-strand breaks and are also involved in recombination repair and various SOS responses to DNA damage by gamma-irradiation and alkylating reagents. In this study, we investigated both in vitro and in vivo whether inhibition of the RAD51 gene by antisense oligonucleotides (ODNs) enhances the radiosensitivity of mouse malignant gliomas. A volume of 100 nM of RAD51 antisense ODNs inhibited the level of mRNA by more than 95% and reduced the protein expression by about 70%. Treatment of mouse 203G glioma cells with 100 nM of RAD51 antisense ODNs significantly enhanced the radiation-induced cell kill compared to control cells, and cells treated with sense or scrambled ODNs. When the glioma cells were implanted in the cisterna magna of mice followed by treatment with RAD51 antisense ODNs, the survival time of the mice was markedly prolonged compared to that of the untreated group (p < 0.001, logrank test). In addition, the combination of antisense ODNs and irradiation extended the survival time of the glioma-bearing mice much longer than could be achieved with radiation alone (p < 0.0001, logrank test). These results suggest that inhibition of RAD51 can be expected to serve as a novel potentiator for radiation therapy in malignant gliomas by inhibiting DNA double-strand break repair.


Electrosynthesized molecularly imprinted polyscopoletin nanofilms for human serum albumin detection.
Molecularly imprinted polymers (MIPs) rendered selective solely by the imprinting with protein templates lacking of distinctive properties to facilitate strong target-MIP interaction are likely to exhibit medium to low template binding affinities. While this prohibits the use of such MIPs for applications requiring the assessment of very low template concentrations, their implementation for the quantification of high-abundance proteins seems to have a clear niche in the analytical practice. We investigated this opportunity by developing a polyscopoletin-based MIP nanofilm for the electrochemical determination of elevated human serum albumin (HSA) in urine. As reference for a low abundance protein ferritin-MIPs were also prepared by the same procedure. Under optimal conditions, the imprinted sensors gave a linear response to HSA in the concentration range of 20-100 mg/dm3, and to ferritin in the range of 120-360 mg/dm3. While as expected the obtained limit of detection was not sufficient to determine endogenous ferritin in plasma, the HSA-sensor was successfully employed to analyse urine samples of patients with albuminuria. The results suggest that MIP-based sensors may be applicable for quantifying high abundance proteins in a clinical setting.


An International Survey Comparing Different Physician Models for Health Care Delivery to Critically Ill Children With Heart Disease.
To explore relationships between the training background of cardiac critical care attending physicians and self-reported perceived strengths and weaknesses in their ability to provide clinical care. Cross-sectional observational survey sent worldwide to ~550 practicing cardiac ICU attending physicians. Hospitals providing cardiac critical care. Practicing cardiac critical care physicians. None. We received responses from 243 ICU attending physicians from 82 centers (14 countries). The primary training background of the respondents included critical care (62%), dual training in critical care and cardiology (16%), cardiology (14%), and other (8%). We received 49 responses from medical directors in nine countries, who reported that the predominant training background for attending physicians who provide cardiac intensive care at their institutions were critical care (58%), dual trained (18%), cardiology (12%), and other (11%). A greater proportion of physicians trained in either critical care or dual-training reported feeling confident managing multiple organ failure, neurologic conditions, brain death, cardiac arrest, and performing procedures like advanced airway placement and inserting chest- and abdominal-drains. In contrast, physicians with cardiology and dual-training reported feeling more confident managing intractable arrhythmias, understanding cardiopulmonary interactions, and interpreting echocardiogram, electrocardiogram, and cardiac catheterization. Overall, only 57% of the respondents felt comfortable based on their current training background to manage patients with complex cardiac issues without collaboration with other specialists. Our survey demonstrates that intensivists trained in critical care are more comfortable with critical care skills, cardiology-trained intensivists are more comfortable with cardiology skills, and dual-trained physicians are comfortable with both critical care skills and cardiology skills. These findings may help inform future efforts to optimize the educational curriculum and training pathways for future cardiac intensivists. These data may also be used to shape continuing medical education activities for cardiac intensivists who have already completed their training.


Chronic activation of spinal adenosine A1 receptors results in hypersensitivity.
Spinally administered adenosine reduces hypersensitivity in animals and humans with nerve injury, but also causes transient pain in humans and reduces tonic inhibition in spinal neurons. Nerve injury results in increased tonic spinal cord adenosine A1 receptor activation, consistent with a role for adenosine to generate hypersensitivity. Here, we demonstrate that chronic intrathecal adenosine induces hypersensitivity in normal animals and that chronic blockade of spinal adenosine A1 receptors by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine partially prevents nerve injury-induced hypersensitivity. In contrast, chronic blockade of spinal adenosine A1 receptors failed to reduce increased tonic G-protein signaling in the spinal cord after nerve injury. These data support a role for chronic adenosine A1 receptor stimulation after nerve injury to result in hypersensitivity.


Reliable HPLC separation, vibrational circular dichroism spectra, and absolute configurations of isoborneol enantiomers.
Resolution of chiral compounds has played an important role in the pharmaceutical field, involving detailed studies of pharmacokinetics, physiological, toxicological, and metabolic activities of enantiomers. Herein, a reliable method by high-performance liquid chromatography (HPLC) coupled with an optical rotation detector was developed to separate isoborneol enantiomers. A cellulose tris(3, 5-dimethylphenylcarbamate)-coated chiral stationary phase showed the best separation performance for isoborneol enantiomers in the normal phase among four polysaccharide chiral packings. The effects of alcoholic modifiers and column temperature were studied in detail. Resolution of the isoborneol racemate displayed a downward trend along with an increase in the content of ethanol and column temperature, indicating that less ethanol in the mobile phase and lower temperature were favorable to this process. Moreover, two isoborneol enantiomers were obtained via a semipreparative chiral HPLC technique under optimum conditions, and further characterized by analytical HPLC, and experimental and calculated vibrational circular dichroism (VCD) spectroscopy, respectively. The solution VCD spectrum of the first-eluted component was consistent with the Density Functional Theory (DFT) calculated pattern based on the SSS configuration, indicating that this enantiomer should be (1S, 2S, 4S)-(+)-isoborneol. Briefly, these results have provided reliable information to establish a method for analysis, preparative separation, and absolute configuration of chiral compounds without typical chromophoric groups.


High-Efficiency and High-Color-Rendering-Index Semitransparent Polymer Solar Cells Induced by Photonic Crystals and Surface Plasmon Resonance.
Semitransparent polymer solar cells (ST-PSCs) show attractive potential in power-generating windows or building-integrated photovoltaics. However, the development of ST-PSCs is lagging behind opaque PSCs because of the contradiction between device efficiency and transmission. Herein, Ag/Au alloy nanoparticles and photonic crystals (PCs) were simultaneously introduced into ST-PSCs, acting compatibly as localized surface plasmon resonances and distributed Bragg reflectors to enhance light absorption and transmission. As a result, ST-PSCs based on a hybrid PTB7-Th:PC71BM active layer contribute an efficiency as high as 7.13 ± 0.15% and an average visible transmission beyond 20%, which are superior to most of the reported results. Furthermore, PCs can partly compensate valley range of transmission by balancing reflection and transmission regions, yielding a high color rendering index of 95. We believe that the idea of two light management methods compatibly enhancing the performance of ST-PSCs can offer a promising path to develop photovoltaic applications.


Adult ventricular myocytes isolated from CHF 146 and CHF 147 cardiomyopathic hamsters.
Single ventricular myocytes have been isolated from normal and cardiomyopathic hamsters using a collagenase method. The procedure produces calcium-tolerant myocytes that are viable and appear on light and electron microscopic examination to be healthy. These cells respond to electrical stimulus and have normal intracellular resting and action potentials.


The ontogeny of biochemical markers of cardiac dysfunction.
Biochemical markers are available to detect cardiac involvement in many pediatric disease states and should be considered. Analyses of three markers are readily available in clinical laboratories for improved diagnosis. Increased workload of the heart has been associated with the release of biochemical markers (natriuretic peptides and cardiac enzymes) that indicate that a new genetic program has been activated and maladaptation is occurring in the atria, ventricles, or both. This review summarizes those that have been identified in fetal and pediatric practice. The expression of such markers is traced from early embryonic development to fetal life, to the neonate, to childhood, and then to adult life.


A Bayesian approach to subgroup identification.
This article discusses subgroup identification, the goal of which is to determine the heterogeneity of treatment effects across subpopulations. Searching for differences among subgroups is challenging because it is inherently a multiple testing problem with the complication that test statistics for subgroups are typically highly dependent, making simple multiplicity corrections such as the Bonferroni correction too conservative. In this article, a Bayesian approach to identify subgroup effects is proposed, with a scheme for assigning prior probabilities to possible subgroup effects that accounts for multiplicity and yet allows for (preexperimental) preference to specific subgroups. The analysis utilizes a new Bayesian model selection methodology and, as a by-product, produces individual probabilities of treatment effect that could be of use in personalized medicine. The analysis is illustrated on an example involving subgroup analysis of biomarker effects on treatments.


Galactose oxidase-glucan binding domain fusion proteins as targeting inhibitors of dental plaque bacteria.
In order to inhibit the growth of bacteria present in the human oral cavity, a novel system which targets antimicrobial agents to dental plaque has been developed. This system involves a hybrid protein consisting of a peptide expressing the bactericidal properties of galactose oxidase (GAO) fused to the glucan binding domain (GBD) of the Streptococcus mutans glucosyltransferase-S enzyme. A gene encoding GAO from the fungus Fusarium sp. has been inserted into an Escherichia coli expression vector and fused to sequences encoding the GBD, which binds to the glucans synthesized by oral streptococci. Bacterial extracts expressing the hybrid protein were tested for their ability to target the GAO activity to an in vitro plaque model consisting of streptococcal cells bound to microtiter plate wells. The binding of the hybrid protein to the streptococcal cells through its GBD and the dependence of binding on the production of glucans by bacteria were demonstrated. Furthermore, killing of three different species of oral streptococci by bound hybrid protein in conjunction with the galactose-lactoperoxidase-iodide cytotoxic system has been demonstrated. These results suggest a novel strategy for controlling dental plaque formation as well as dental caries in humans.


Commensal microbiota modulate gene expression in the skin.
The skin harbors complex communities of resident microorganisms, yet little is known of their physiological roles and the molecular mechanisms that mediate cutaneous host-microbe interactions. Here, we profiled skin transcriptomes of mice reared in the presence and absence of microbiota to elucidate the range of pathways and functions modulated in the skin by the microbiota. A total of 2820 genes were differentially regulated in response to microbial colonization and were enriched in gene ontology (GO) terms related to the host-immune response and epidermal differentiation. Innate immune response genes and genes involved in cytokine activity were generally upregulated in response to microbiota and included genes encoding toll-like receptors, antimicrobial peptides, the complement cascade, and genes involved in IL-1 family cytokine signaling and homing of T cells. Our results also reveal a role for the microbiota in modulating epidermal differentiation and development, with differential expression of genes in the epidermal differentiation complex (EDC). Genes with correlated co-expression patterns were enriched in binding sites for the transcription factors Klf4, AP-1, and SP-1, all implicated as regulators of epidermal differentiation. Finally, we identified transcriptional signatures of microbial regulation common to both the skin and the gastrointestinal tract. With this foundational approach, we establish a critical resource for understanding the genome-wide implications of microbially mediated gene expression in the skin and emphasize prospective ways in which the microbiome contributes to skin health and disease.


G16R single nucleotide polymorphism but not haplotypes of the β(2)-adrenergic receptor gene alters cardiac output in humans.
Variation in genes encoding the β(2)-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with β(2)-mediated vasodilation, but the effect of ADRB2 haplotypes on Q has not been studied. Five SNPs within ADRB2 (46G>A, 79C>G, 491C>T, 523C>A and 1053G>C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise. Only the G16R polymorphism was associated with Q. In carriers of the Arg(16) allele, Q(rest) (resting Q) was 0.4 [95% CI (confidence interval), 0.0-0.7] l/min lower than in G16G homozygotes (P=0.048). During exercise, the increase in Q was by 4.7 (95% CI, 4.3-5.2) l/min per litre increase in pulmonary Vo(2) (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0-0.9) l/min lower in Arg16 carriers (P=0.035). A similar effect size was observed for the Arg16 haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in Q was 0.5 (CI, 0.0 -1.0) l/min greater in ACE I/I carriers compared with I/D and D/D subjects (P=0.054). In conclusion, the ADRB2 Arg16 allele in humans is associated with a lower Q both at rest and during exercise, overriding the effects of haplotypes.


High-order harmonic spectroscopy for molecular imaging of polyatomic molecules.
High-order harmonic generation is a powerful and sensitive tool for probing atomic and molecular structures, combining in the same measurement an unprecedented attosecond temporal resolution with a high spatial resolution of the order of an angstrom. Imaging of the outermost molecular orbital by high-order harmonic generation has been limited for a long time to very simple molecules, like nitrogen. Recently we demonstrated a technique that overcame several of the issues that have prevented the extension of molecular orbital tomography to more complex species, showing that molecular imaging can be applied to a triatomic molecule like carbon dioxide. Here we report on the application of such a technique to nitrous oxide (N(2)O) and acetylene (C(2)H(2)). This result represents a first step towards the imaging of fragile compounds, a category which includes most of the fundamental biological molecules.


Macrocyclic DNA-encoded chemical libraries: a historical perspective.
While macrocyclic peptides are extensively researched for therapeutically relevant protein targets, DNA-encoded chemical libraries (DELs) are developed at a quick pace to discover novel small molecule binders. The combination of both fields has been explored since 2004 and the number of macrocyclic peptide DELs is steadily increasing. Macrocycles with high affinity and potency were identified for diverse classes of proteins, revealing DEL's huge potential. By giving a historical perspective, we would like to review the methods which permitted the rise of macrocyclic peptide DELs, describe the different DELs which were created and discuss the achievements and challenges of this emerging field.


Effects of active immunization against GnRH versus surgical castration on hypothalamic-pituitary function in boars.
The objective was to compare effects of anti-GnRH immunization (immunocastration) versus surgical castration on hypothalamic-pituitary function in boars. Thirty-six boars were randomly divided into three groups (n = 12/group): control, surgically castrated, or immunized against GnRH at 10 wk of age (boostered 8 wk later). Compared to intact boars, immunocastration reduced (P < 0.05) serum concentrations of LH, FSH, testosterone and inhibin B and caused severe testicular atrophy, whereas surgical castration increased (P < 0.05) serum concentrations of LH and FSH. Both immunocastration and surgical castration consistently reduced hypothalamic GnRH synthesis, with decreased (P < 0.05) mRNA expressions of GnRH, GnRH up-stream gatekeeper genes kiss1 and its receptor (GPR54), and androgen receptor in the hypothalamic arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV), as well as GnRH content in the median eminence. Inconsistently, mRNA expressions of gonadotropin-inhibitory hormone (GnIH) in ARC and AVPV as well as its receptor (GPR147) in pituitary were selectively reduced (P < 0.05), but mRNA expressions of estrogen receptor alpha and aromatase (CPY17A1) in pituitary were selectively increased (P < 0.05) in surgical castrates. In response to selectively attenuated suppressive signaling from GnIH and testosterone, mRNA expressions of GnRH receptor (GnRHR), LH-β and FSH-β in pituitary were increased (P < 0.05) in surgical castrates, whereas these pituitary gene expressions were decreased (P < 0.05) in immunocastrates, due to loss of hypothalamic GnRH signaling. We concluded that immunocastration and surgical castration consistently reduced hypothalamic GnRH synthesis due to a testosterone deficiency disrupting testosterone-Kisspeptin-GPR54-GnRH signaling pathways. Furthermore, selectively attenuated GnIH and testosterone signaling in the pituitary increased gonadotropin production in surgical castrates.


The Tentorium Cerebelli: A Comprehensive Review Including Its Anatomy, Embryology, and Surgical Techniques.
The tentorium cerebelli functions as a partition, dispelling the burden of weight from supratentorial structures upon inferior brain matter. Clinicians and neurosurgeons, when assessing pathological findings, should have knowledge regarding the tentorium cerebelli anatomy. This work of literature is a comprehensive review of the tentorium cerebelli, including its anatomy, embryology, and clinical and surgical implications. The evolutionary pattern demonstrates sequential stages to higher mammalian lineage. An understanding of the complexity of the neurovascular structures and the anatomy of the tentorium cerebelli is crucial for surgical procedures by neurosurgeons.


Acinar ATP8b1/LPC pathway promotes macrophage efferocytosis and clearance of inflammation during chronic pancreatitis development.
Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. PRSS1 transgenic (PRSS1Tg) mice were treated with caerulein to mimic CP development. Phospholipid metabolite profiling and epigenetic assays were performed with PRSS1Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA), and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analyze the proportion of pancreatic macrophages. Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated phospholipid pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulates phospholipid metabolism. Our study indicates that the acinar Atp8b1/LPC pathway acts as an important "find-me" signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1, and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.


[Micro-invasive glaucoma surgery].
Intraocular pressure (IOP) reduction is the current treatment in glaucoma. In recent years, minimally invasive glaucoma surgery (MIGS) has been added to the arsenal of surgical options. MIGS can reduce trabecular meshwork resistance to outflow and decrease the IOP with mild side effects. In this article, we review the clinical experience gathered with iSTENT, Bypass, Gold Micro Shunt and the Trabectome.


X-ray contact microscopy system for spectromicroscopy of biological specimens.
An X-ray contact microscopy system has been developed for the study of molecular and elemental distributions in biological specimens based on X-ray absorption characteristics. The system consists of a chamber for measuring XANES (X-ray absorption near-edge structure) of biomolecules, and a contact microscopy system for dried specimens with an electronic zooming tube. With this system the elemental distribution of carbon, nitrogen, oxygen, Ca and Fe in an HeLa cell has been studied, and the DNA-related image using a peak from the XANES profile of the DNA at the K-absorption edge of phosphorus has been obtained.


[Indices of the lipid peroxidation--antioxidant defense system as markers of chronic cardiac failure in cardiomyopathies].
Content of circulating products of lipid peroxidation (LPO), alpha-tocopherol (AT) and ceruloplasmin (CP), was studied in patients with hypertrophic and dilated cardiomyopathies (HTCMP and DCMP). The data obtained correlates with severity of chronic cardiac failure (CCF) and exercise tolerance of the patients. It is shown that the rise in LPO products level and simultaneous lowering of AT concentration in HTCMP and DCMP depend on the functional class of chronic cardiac failure by NYHA (1964). Content of lipoperoxides, AT and CP in the serum reflect the HTCMP patients' tolerance to exercise. Laboratory estimation of the levels of LPO products, AT and CP in patients with cardiomyopathies can substantially objectivize and supplement both clinical and functional-diagnostic assessment of CCF severity.


Therapists and quasi-therapists in a therapy analogue situation.
Evaluated an assumption from previous psychotherapy analogue studies, namely, that trained psychotherapists and untrained quasi-therapists with personality similarities will respond similarly to patient presentations. Ss were 24 male psychotherapists and 24 male undergraduate students, chosen partially on the basis of their responses to an A-B personality scale derived from the work of Whitehorn and Betz (1954). The three-factor experimental design included S personality type (A or B), S professional status (psychotherapist vs. student), and videotaped patient simulations (neurotic vs. schizoid), with all Ss exposed to both patient prototypes. Therapists demonstrated a higher degree of accurate empathy, were less active, made shorter responses, and used more declarative sentences (p less than .01 for each variable). Second-order interaction effects indicated that therapist personality type X patient type pairings produced opposite results for quasi-therapists when compared to professional therapists.


[Approval of HIV protease inhibitors as the AIDS therapeutics of next generation].
The long-term usages of reverse transcriptase inhibitors as anti-HIV drugs have induced serious side effects and emergence of resistant viruses. To overcome these problems, combination therapies are expected to be effective. Under such circumstances, HIV protease inhibitors have been rationally designed and synthesized based on the substrate transition state concept. HIV protease inhibitors act at the exact point in the life cycle of HIV, exhibited efficacy in the clinical trials and have been approved with high expectation. The introduction of anti-HIV drug with novel action mechanism evoked a new dramatic movement in the combination therapy of AIDS.


Sequencing of a new HLA-C allele, HLA-Cw*0742, with a novel HLA polymorphism at exon 3.
The new human leukocyte antigen (HLA)-C allele Cw*0742 was identified by sequence-based typing in a Caucasian bone marrow donor. HLA-Cw*0742 differs from Cw*070201 by a single nucleotide position at codon 113 (TAT --> TTT), giving rise to an amino acid substitution from Tyr to Phe.


Monitoring the microbial population dynamics at the start-up stage of wastewater treatment reactor by terminal restriction fragment length polymorphism analysis based on 16S rDNA and rRNA gene sequences.
The microbial population dynamics at the start-up stage of a wastewater treatment reactor was investigated using terminal restriction fragment length polymorphism (T-RFLP) analysis based on 16S rDNA and rRNA gene sequences. The results of fragment peaks suggested that the number and activity of nitrifying bacteria increased in association with the start of nitrification, and the relative ratios of 16S rRNA of these bacteria changed prior to those of the 16S rDNA. Furthermore, multidimensional scaling (MDS) analysis revealed that the 16S rRNA exhibited wider dispersion than the 16S rDNA at the start-up stage, indicating that the diversity of 16S rRNA in the microbial communities was strongly affected by environmental changes.


Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice.
Each of the olfactory sensory neurons (OSNs) chooses to express a single G protein-coupled olfactory receptor (OR) from a pool of hundreds. Here, we show the receptor transporting protein (RTP) family members play a dual role in both normal OR trafficking and determining OR gene choice probabilities. Rtp1 and Rtp2 double knockout mice (RTP1,2DKO) show OR trafficking defects and decreased OSN activation. Surprisingly, we discovered a small subset of the ORs are expressed in larger numbers of OSNs despite the presence of fewer total OSNs in RTP1,2DKO. Unlike typical ORs, some overrepresented ORs show robust cell surface expression in heterologous cells without the co-expression of RTPs. We present a model in which developing OSNs exhibit unstable OR expression until they choose to express an OR that exits the ER or undergo cell death. Our study sheds light on the new link between OR protein trafficking and OR transcriptional regulation.


Random capillary glucose levels throughout pregnancy, obstetric and neonatal outcomes, and long-term neurodevelopmental conditions in children: a group-based trajectory analysis.
Gestational diabetes mellitus (GDM) is associated with both short- and long-term risks, although it is unknown if risks vary by severity, timing, and duration of gestational hyperglycemia. We aimed to identify trajectories of random capillary glucose (RCG) levels throughout pregnancy and assess their associations with both obstetric/neonatal outcomes and children's risk of neurodevelopmental conditions (NDCs) (i.e., autism, intellectual disability, and attention-deficit/hyperactivity disorders [ADHD]). A population-based cohort study was conducted involving 76,228 children born to 68,768 mothers without pregestational diabetes. Group-based trajectory modeling was utilized to identify distinct glucose trajectories across RCG values throughout the course of pregnancy. The associations between these trajectory groups and obstetric/neonatal outcomes as well as children's NDCs were then assessed using generalized estimating equation models with a logit link. The Benjamini-Hochberg (BH) procedure was employed to adjust P-values for multiple comparisons, controlling the false discovery rate (FDR). Five distinct glucose trajectory groups were identified, each with varying percentages diagnosed with GDM. Their associations with obstetric/neonatal outcomes as well as children's NDCs varied. For example, when compared to the "Persistently Low" group, other groups exhibited varying degrees of increased risk for large-for-gestational-age babies, with the exception of the "High in Early Pregnancy" group. Compared to the "Persistently Low" group, all other trajectory groups were associated with NDC outcomes, except the "High in Mid-Pregnancy" group. However, none of the associations with offspring NDCs remained significant after accounting for the FDR correction. Persistent high glucose levels or moderately elevated glucose levels throughout pregnancy, as well as transient states of hyperglycemia in early or mid-pregnancy, were found to be associated with increased risks of specific obstetric and neonatal complications, and potentially offspring NDCs. These risks varied depending on the severity, timing, duration, and management of hyperglycemia. The findings underscore the need for continuous surveillance and individualized management strategies for women displaying different glucose trajectories during pregnancy. Limitations such as potential residual confounding, the role of mediators, and small sample size should be addressed in future studies.


[Sympathetic skin response in patients with severe motor and intellectual disabilities].
To elucidate autonomic function in individuals with severe motor and intellectual disabilities, we evaluated sympathetic skin response in 14 patients with severe motor and intellectual disabilities. The results of sympathetic skin response were compared with those of patients with mild or moderate motor and intellectual disabilities who could walk and had an intelligence quotient > or = 35 (7 cases) and neuromuscular diseases (3 cases). No sympathetic skin response was recorded in patients with severe motor and intellectual disabilities, whereas all patients with mild or moderate motor and intellectual disabilities defined above and neuromuscular diseases showed sympathetic skin response. The results suggested that all patients with severe motor and intellectual disabilities had autonomic dysfunction, and sympathetic skin response can be a useful test that can evaluate autonomic function in patients with severe motor and intellectual disabilities.


Loss to patient-reported outcome measure follow-up after hip arthroplasty and knee arthroplasty : patient satisfaction, associations with non-response, and maximizing returns.
The aim of this study was to determine satisfaction rates after hip and knee arthroplasty in patients who did not respond to postoperative patient-reported outcome measures (PROMs), characteristics of non-responders, and contact preferences to maximize response rates. A prospective cohort study of patients planned to undergo hip arthroplasty (n = 713) and knee arthroplasty (n = 737) at a UK university teaching hospital who had completed preoperative PROMs questionnaires, including the EuroQol five-dimension health-related quality of life score, and Oxford Hip Score (OHS) and Oxford Knee Score (OKS). Follow-up questionnaires were sent by post at one year, including satisfaction scoring. Attempts were made to contact patients who did not initially respond. Univariate, logistic regression, and receiver operator curve analysis was performed. At one year, 667 hip patients (93.5%) and 685 knee patients (92.9%) had undergone surgery and were alive. No response was received from 151/667 hip patients (22.6%), 83 (55.0%) of whom were ultimately contacted); or from 108/685 knee patients (15.8%), 91 (84.3%) of whom were ultimately contacted. There was no difference in satisfaction after arthroplasty between initial non-responders and responders for hips (74/81 satisfied vs 476/516 satisfied; p = 0.847) or knees (81/93 satisfied vs 470/561 satisfied; p = 0.480). Initial non-response and persistent non-response was associated with younger age, higher BMIs, and worse preoperative PROMs for both hip and knee patients (p < 0.050). Being in employment was associated with persistent non-response for hip patients (p = 0.047). Multivariate analysis demonstrated that younger age (p < 0.038), higher BMI (p = 0.018), and poorer preoperative OHS (p = 0.031) were independently associated with persistent non-response to hip PROMs. No independent associations were identified for knees. Using a threshold of > 66.4 years predicted a preference for contact by post (area under the curve 0.723 (95% confidence interval (CI) 0.647 to 0.799; p < 0.001, though this CI crosses the 0.7 limit considered reliable). The majority of initial non-responders were ultimately contactable with effort. Satisfaction rates were not inferior in patients who did not initially respond to PROMs. Cite this article: Bone Jt Open 2022;3(4):275-283.


Correlation between C-Reactive Protein to Albumin Ratio and Disease Activity in Patients with Axial Spondyloarthritis.
The C-reactive protein (CRP) to albumin (ALB) ratio (CAR) has emerged as a novel inflammatory biomarker. This study was designed to investigate the role of CAR in the disease activity of axial spondyloarthritis (axSpA). A total of 241 patients and 61 healthy controls were retrospectively enrolled in this study. AxSpA patients were further divided into the inactive group (n = 176) and active group (n = 65) according to Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) cutoff value of 4. Laboratory data and clinical assessment indices were recorded. Spearman's correlation analysis, receiver operation characteristic (ROC) curve analysis, and binary logistic regression analysis were performed. In axSpA patients, CAR was significantly higher than the healthy group (P < 0.001). Similarly, axSpA patients in the active group had higher CAR than the inactive group (P < 0.001). Besides, CAR was positively correlated with erythrocyte sedimentation rate (ESR) (r = 0.704, P < 0.001), CRP (r = 0.996, P < 0.001), BASDAI (r = 0.329, P < 0.001), and Bath Ankylosing Spondylitis Functional Index (BASFI) (r = 0.330, P < 0.001). ROC curve analysis suggested that the area under the curve (AUC) of CAR for axSpA of the active group was 0.701, which was higher than that of CRP and ESR. The optimal cutoff point of CAR for axSpA of the active group was 0.3644, with a sensitivity and specificity of 58.5% and 79.0%. Binary logistic analysis results revealed that CAR was an independent predictive factor for axSpA disease activity (odds ratio = 4.673, 95% CI: 1.423-15.348, P = 0.011). CAR was increased in axSpA and axSpA of the active group. CAR may be a novel and reliable indicator for axSpA disease activity.


Km mutants of the Chlorella monosaccharide/H+ cotransporter randomly generated by PCR.
The HUP1 gene codes for the monosaccharide/H+ cotransporter protein of Chlorella kessleri. The gene is functionally expressed in Schizosaccharomyces pombe. This heterologous system has been used to screen for Km mutants of the Chlorella symporter. Since S. pombe transformed with HUP1 cDNA showed a 1000-fold increase in sensitivity toward the toxic sugar analogue 2-deoxyglucose, we screened for transformants with a decreased 2-deoxyglucose sensitivity. The transformants were produced with HUP1 cDNA randomly mutagenized by PCR. From 73 transformants with decreased 2-deoxyglucose sensitivity, four mutants with increased Km values for D-glucose were obtained. The amino acid exchanges responsible for the increased Km values are located in the center of the putative transmembrane helices V (Q179E), VII (Q298R), and XI (V433L/N436Y). Q179N and Q299N had previously been shown by directed mutagenesis to affect the Km value of the transporter for D-glucose. The drastic mutational changes Q298R and N436Y gave rise to very high Km values; however, the corresponding conservative amino acid changes Q298N or N436Q obtained by directed mutagenesis also result in Km values increased by a factor of 10 or 20, respectively. The data therefore support the proposal that at least helices V, VII, and XI may line the sugar translocation path and determine its specificity. These results are discussed in relation to other sugar transporters and to the interaction of the yeast hexokinase B with D-glucose as known from published crystal structures.


The evolution of homeobox genes: Implications for the study of brain development.
The homeobox gene superfamily includes many genes implicated in brain development in vertebrates; for example, the Otx, Emx, Dmbx, Gbx, En and Hox gene families. We describe the evolutionary history of the homeobox gene superfamily, as inferred from molecular phylogenetics and chromosomal mapping. Studies of amphioxus, a close relative of vertebrates, have proven particularly informative because it has a genome uncomplicated by recent lineage-specific gene duplications and because in situ hybridisation techniques exist for mapping gene positions and gene expression patterns. We describe an ancient subdivision into gene classes (ANTP, PRD, LIM, POU, SIN, TALE), each containing multiple gene families. The original ANTP class gene duplicated to give distinct NK-like and Hox/ParaHox-related genes, both of which underwent tandem duplication, before the expanding Hox gene cluster duplicated to give Hox and ParaHox clusters. A chromosomal breakage event probably occurred to separate the NK-like and extended Hox genes. Finally, there was additional and extensive gene duplication and gene loss in the vertebrate lineage. We argue that understanding evolutionary history is important for establishing consistent gene nomenclature, and for comparing gene expression patterns and gene functions between species and between gene families.


Radionuclide localization of massive pulmonary hemorrhage.
Lung scans with technetium sulfur colloid were performed in ten patients with life-threatening hemoptysis and nondiagnostic chest roentgenograms. Localized deposition of radionuclide was demonstrated in five of the six patients who were studied during active bleeding. These abnormalities were confirmed bronchoscopically in four patients, and lung scans provided clinically useful information regarding the bleeding site that had not been available from the medical history, physical examination, or chest roentgenogram. Evaluation with radionuclide scanning may complement bronchoscopic and roentgenographic studies in selected patients with massive pulmonary hemorrhage.


Using the Biopsychosocial Approach to Identify Factors Associated with Major Depressive Disorder for Individuals with Hypothyroidism.
Previous research has found that major depressive disorder (MDD) commonly occurs in hypothyroid populations. The purpose of this study was to use the biopsychosocial model to investigate factors associated with MDD and hypothyroidism by comparing hypothyroid patients with MDD and without MDD. A sample of 386 participants with hypothyroidism completed both cognitive and psychosocial self-reported assessments along with a questionnaire rating the severity of common hypothyroid symptoms. Participants were divided into two groups (MDD and no MDD) using the diagnostic criteria of the Patient Health Questionnaire. Univariate comparisons were used to assess differences in the severity of physical, psychological, and social correlates in participants with and without MDD. Participants with MDD reported significantly worse symptom severity, increased stress, and disruptions of cognitive functioning. Compared to individuals without MDD, they also indicated poorer quality of life, doctor-patient relationships, and treatment adherence. Individuals with comorbid depression and hypothyroidism reported worse outcomes across physical symptoms, social factors, and psychological and cognitive states than individuals without MDD. Integrating depression screeners and independent treatment for MDD, in addition to the patient's hypothyroid treatment plan, may result in hypothyroid symptom relief and greater quality of life.


Synthesis and characterization of immunogens based on calix[4]arene-crown-6 for the generation of antibodies directed towards cesium ions.
With the aim of generating antibodies directed towards cesium, a calix[4]arene-crown-6 in the 1,3-alternate conformation bearing an N-hydroxysuccinimide function was synthesized. The calixarene was coupled to bovine serum albumin using different calixarene/protein ratios, and cesium was loaded. Conjugates were characterized using trinitrobenzenesulfonic acid derivatization, matrix assisted laser desorption ionisation-mass spectrometry (MALDI-TOF-MS), and inductively coupled plasma-mass spectrometry (ICP-MS). Targeted lysines were determined after enzymatic cleavage followed by MALDI-TOF-MS, and a progressive targeting related to lysines accessibility was observed.


Yeast transformation mediated by Agrobacterium strains harboring an Ri plasmid: comparative study between GALLS of an Ri plasmid and virE of a Ti plasmid.
Agrobacterium strains containing a Ti plasmid can transfer T-DNA not only to plants but also to fungi, including the yeast Saccharomyces cerevisiae. However, no Agrobacterium strain harboring an Ri plasmid has been evaluated in fungal transformation. Some Ri plasmids have GALLS , instead of virE1 and virE2. GALLS protein can functionally substitute in plant transformation for a structurally different protein VirE2. In this study, we compared the yeast transformation ability among Agrobacterium donors: a strain containing a Ti plasmid, strains harboring either an agropine-type or a mikimopine-type Ri plasmid, and a strain having a modified Ri plasmid supplemented with a Ti plasmid type virE operon. Agrobacterium strains possessing GALLS transformed yeast cells far less efficiently than the strain containing virE operon. Production of GALLS in recipient yeast cells improved the yeast transformation mediated by an Agrobacterium strain lacking neither GALLS nor virE operon. A reporter assay to detect mobilization of the proteins fused with Cre recombinase revealed that VirE2 protein is much more abundant in yeast cells than GALLS. Based on these results, we concluded that the low yeast transformability mediated by Agrobacterium strains having the Ri plasmid is because of low amount of mobilized GALLS in yeast cells.


Compound Shuganjieyu Capsule on CYP450 Enzyme Activity.
To evaluate the potential drug-drug interactions of the Shuganjieyu capsule by establishing a Chronic Unpredictable Mild Stress (CUMS) depression model combined with the Cocktail probe substrate method. The whole study was divided into the single-dose and multiple-dose groups. Animals were randomly divided into further subgroups in each group. Following chronic unpredictable mild stress model development, Shuganjieyu capsules were administered to the drug administration group. The single-dose subgroup received the drug for one day, and the multiple-dose subgroup received the drug for three months. Liver microsomes of each group were extracted, and the effects of the Shuganjieyu capsule on the CYP450 enzyme were investigated by liquid chromatography-mass spectrometry (LC-MS) (LC-MS) based on the Cocktail probe substrate method. The immunohistochemical method and RT-qPCR were used to detect the activity of CYP450 immunoprotein in rat liver. In the single-dose subgroup, there were no statistical differences between the administration and model groups. In the multiple-dose subgroup, the conversion and protein expression rates of CYP1A2 and CYP2C19 were significantly increased in the model group compared with the blank group. In the administration group, the conversion and protein expression rates of CYP1A2 and CYP2C19 were inhibited. Long-term administration of the Shuganjieyu capsule could relieve depression-related behaviors in CUMS rats and downregulate the CYP1A2 and CYP2C19 enzyme activities in CUMS rats by inhibiting the expression of CYP1A2 and CYP2C19 protein. Long-term administration of the Shuganjieyu capsule may affect the bioavailability of other drugs metabolized by CYP1A2 and CYP2C19 enzymes, but the clinical guidance's specific significance needs to be clarified further.


Effect of polymerase mutations on packaging of primer tRNAPro during murine leukemia virus assembly.
The role of reverse transcriptase in selective encapsidation of the murine leukemia virus (MuLV) tRNA primer, tRNAPro, was investigated by examining the tRNA composition of several nonconditional pol mutants. One mutant, clone 23, which contains an altered polymerase about 40% smaller than the wild-type enzyme (B. I. Gerwin et al., J. Virol. 31:741-751, 1979) had a typical viral tRNA pattern, including normal levels of tRNAPro in free and 70S-associated 4S RNA. Another class of mutants, produced by Moloney murine leukemia virus-infected cell clone M13 and subclone M13/1, does not contain any detectable polymerase protein (A. Shields et al., Cell 14:601-609, 1978) and was found to have reduced amounts of tRNAPro in free 4S RNA. However, the level of tRNAPro associated with the genome was normal in the mutant virions. These results suggest that the reverse transcriptase protein is involved in the initial selection of tRNA primer during virus assembly, but not in the subsequent association of this tRNA with genomic RNA.


Oral disease-modifying therapies for relapsing-remitting multiple sclerosis.
The efficacy and safety of the three oral agents approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS) are reviewed. Limitations to parenteral disease-modifying therapies (DMTs) (interferon beta-1a, interferon beta-1b, and glatiramer acetate) for the treatment of RRMS have been addressed by the approval of three oral DMTs: fingolimod, teriflunomide, and dimethyl fumarate. In clinical trials, each of the oral DMTs was superior to placebo in annualized relapse rate, a key indicator of clinical efficacy, and in neuroradiological efficacy. A reduction in disability progression was evident with higher doses of teriflunomide but was not consistently demonstrated with fingolimod or dimethyl fumarate. Each of the oral DMTs demonstrated acceptable safety in clinical trials, with adverse-effect profiles that differ from injectable agents. The safety of both teriflunomide and dimethyl fumarate is supported by long-term use of related agents for other diseases; however, postmarketing surveillance studies are needed to determine the safety of each of the oral DMTs in patients with RRMS. Dimethyl fumarate seems to have the most innocuous safety profile of the three agents. Fingolimod requires first-dose inpatient monitoring due to cardiac safety concerns and multiple laboratory tests prior to initiation of therapy, while teriflunomide has been associated with hepatotoxicity and teratogenicity. With the approval of three oral drugs for RRMS-fingolimod, teriflunomide, and dimethyl fumarate-the therapeutic strategy for RRMS has evolved to include options that are efficacious and appear to have administration advantages over established parenteral treatments.


Gastric MALT lymphoma and Helicobacter pylori.
The majority of low grade gastric lymphomas arise within acquired organized lymphoid tissue, which has all the features of MALT. This MALT is specifically acquired most commonly in response to infection of the gastric mucosa by H pylori. The lymphocytes within this MALT are therefore programmed to respond to this organism and the neoplastic cells of the lymphoma that may develop within this acquired MALT retain the ability to respond to the immunological proliferative drive associated with the continued presence of the organism. Following the removal of this immunological drive by eradication of the organism in vivo, the lymphoma shows clinical and histological regression. The time required to see this response is unknown and there are some lymphomas that fail to respond to simple Helicobacter eradication. In some cases, there is continued molecular evidence of the presence of the lymphoma clone in low levels and the significance of this remains unknown. These factors are presently under detailed examination, and several clinical trials to assess the response of a large series of low grade gastric MALT lymphomas to anti-Helicobacter therapy and the requirement for additional chemotherapy are at present in progress.


Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria.
Liver transplantation (LT) for hepatocellular carcinoma (HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria (MC) (single HCC ≤ 5 cm or up to 3 HCCs ≤ 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy (LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCC-LT criteria models and pre-LT treatment strategies are required.


Medicaid Coverage for Routine Foot Care.
Despite national and international guidelines supporting podiatric services as a means of prevention for lower-extremity complications, especially in at-risk individuals, current coverage for these services under the US Medicaid program is not universal. The vast differences between state Medicaid programs regarding reimbursable foot care services is confusing and potentially serves as a barrier for the most vulnerable populations to receive preventative services. This article provides a brief discussion of "routine" podiatric services from a clinical perspective and provides a review of state Medicaid programs including optional services (eg, podiatric coverage). Using data from a national survey of state Medicaid programs, we present and discuss common Medicaid coverage schemes for routine foot care provided by podiatric physicians. Analysis demonstrated that states vary dramatically in basic descriptions of preventive foot care, levels of coverage, eligibility, and methods of documenting coverage details. The authors recommend bringing Medicaid in line with other federal health programs and including podiatric physicians in the definition of "physician" for coverage purposes. States should move away from describing preventative services as "routine" and choose language that more accurately reflects the true nature and purpose of the care.


Phosphatidylinositol 4-kinase IIIbeta regulates the transport of ceramide between the endoplasmic reticulum and Golgi.
The recently identified ceramide transfer protein, CERT, is responsible for the bulk of ceramide transport from the endoplasmic reticulum (ER) to the Golgi. CERT has a C-terminal START domain for ceramide binding and an N-terminal pleck-strin homology domain that binds phosphatidylinositol 4-phosphate suggesting that phosphatidylinositol (PI) 4-kinases are involved in the regulation of CERT-mediated ceramide transport. In the present study fluorescent analogues were used to follow the ER to Golgi transport of ceramide to determine which of the four mammalian PI 4-kinases are involved in this process. Overexpression of pleckstrin homology domains that bind phosphatidylinositol 4-phosphate strongly inhibited the transport of C5-BODIPY-ceramide to the Golgi. A newly identified PI 3-kinase inhibitor, PIK93 that selectively inhibits the type III PI 4-kinase beta enzyme, and small interfering RNA-mediated down-regulation of the individual PI 4-kinase enzymes, revealed that PI 4-kinase beta has a dominant role in ceramide transport between the ER and Golgi. Accordingly, inhibition of PI 4-kinase III beta either by wortmannin or PIK93 inhibited the conversion of [3H]serine-labeled endogenous ceramide to sphingomyelin. Therefore, PI 4-kinase beta is a key enzyme in the control of spingomyelin synthesis by controlling the flow of ceramide from the ER to the Golgi compartment.


True Chromogranin A concentrations in plasma from patients with small intestinal neuroendocrine tumours.
Objective: The incidence of enteropancreatic neuroendocrine tumours (NET) is increasing. Chromogranin A (CgA) in plasma is a marker in patients suspected of NET tumours. CgA, however, is a precursor protein subjected to cellular processing that challenges quantitation and hence the use of CgA in diagnostics.Materials and methods: CgA concentrations in plasma sampled from 130 well-characterized patients with small intestinal NETs and from 30 healthy subjects were measured with eight commercial CgA kits, an in-house radioimmunoassay (RIA) and a processing-independent assay (PIA). For the evaluation of diagnostic accuracy, we performed regression analyses and plotted receiver-operating characteristic curves (ROC). The specificity was further assessed by size chromatography.Results: Five commercial assays (Thermo-Fisher, DRG Diagnostics, Eurodiagnostica (RIA and ELISA), and Phoenix), displayed a diagnostic accuracy with area under the curve (AUC) values >0.90, whereas three immunoassays (Yanaihara, CisBio RIA, and CisBio ELISA) discriminated poorly between disease stages (AUC: 0.60-0.78). Compared with the in-house assays, however, even the most accurate commercial immunoassay still missed patients with metastatic disease. Chromatography showed non-uniform patterns of large and small CgA fragments in plasma.Conclusion: Available commercial immunoassays measure CgA in plasma with gross variability. Three commercial CgA immunoassays discriminate so poorly between health and disease that they should not be used. The highest diagnostic accuracy was obtained with processing-independent measurement of total CgA concentrations in plasma.


Adipokinetic hormone-induced mobilization of fat body triglyceride stores in Manduca sexta: role of TG-lipase and lipid droplets.
Triglycerides (TG) stores build up in the insect fat body as lipid droplets at times of excess of food. The mobilization of fat body triglyceride (TG) is stimulated by adipokinetic hormones (AKH). The action of AKH involves a rapid activation of cAMP-dependent protein kinase (PKA). Recent in vitro studies have shown that PKA phosphorylates and activates the TG-lipase substrate, the lipid droplets. Conversely, purified TG-lipase from Manduca sexta fat body is phosphorylated by PKA in vitro but is not activated. This study was directed to learn whether or not AKH promotes a change in the state of phosphorylation of the lipase in vivo, and what are the relative contributions of cytosol and lipid droplets to the overall increase of lipolysis triggered by AKH. TG-lipase activity of fat body cytosols isolated from control and AKH-treated insects was determined against the native substrate, in vivo [3H]-TG radiolabeled lipid droplets, obtained from control and AKH-treated insects. The lipase activity of the system composed of AKH-cytosol and AKH-lipid droplets (11.1 +/- 2.1 nmol TG/min-mg) was 3.1-fold higher than that determined with control cytosol and lipid droplets (3.6 +/- 0.5 nmol TG/min-mg). Evaluation of the role of AKH-induced changes in the lipid droplets on lipolysis showed that changes in the lipid droplets are responsible for 70% of the lipolytic response to AKH. The remaining 30% appears to be due to AKH-dependent changes in the cytosol. However, the phosphorylation level of the TG-lipase was unchanged by AKH, indicating that phosphorylation of the TG-lipase plays no role in the activation of lipolysis induced by AKH.


The interconnected rhizosphere: High network complexity dominates rhizosphere assemblages.
While interactions between roots and microorganisms have been intensively studied, we know little about interactions among root-associated microbes. We used random matrix theory-based network analysis of 16S rRNA genes to identify bacterial networks associated with wild oat (Avena fatua) over two seasons in greenhouse microcosms. Rhizosphere networks were substantially more complex than those in surrounding soils, indicating the rhizosphere has a greater potential for interactions and niche-sharing. Network complexity increased as plants grew, even as diversity decreased, highlighting that community organisation is not captured by univariate diversity. Covariations were predominantly positive (> 80%), suggesting that extensive mutualistic interactions may occur among rhizosphere bacteria; we identified quorum-based signalling as one potential strategy. Putative keystone taxa often had low relative abundances, suggesting low-abundance taxa may significantly contribute to rhizosphere function. Network complexity, a previously undescribed property of the rhizosphere microbiome, appears to be a defining characteristic of this habitat.


[SAGA complex subunit Spt20 involves in the calcineurin-mediated Cl- homeostasis in Schizosaccharomyces pombe].
SAGA (Spt-Ada-Gcn5 acetyltransferase) is a highly conserved protein complex in eukaryotes, which plays a role in many important cellular processes, including transcriptional activation and mRNA exportation. In order to investigate the potential biological function of SAGA subunit, we performed a yeast two-hybrid screen using a core structural subunit of SAGA in fission yeast, Spt20, as the bait. Ppbl, catalytic subunit of calcineruin was identified in the test. Calcineurin is a key regulator of signal transduction. The interaction between Spt20 and Ppb1 was confirmed by yeast two-hybrid assay and co-immunoprecipitation. In S. pombe, ppb1delta was hypersensitive to high concentration of Cl-. In contrast, spt20delta could resist high concentration of Cl-, which maintained normal growth of cells. Fluorescent colocalization analysis showed that Ppb1 was translocated from cytoplasm to nucleus and colocalized with Spt20 upon the increase of extracellular Cl-. Further genetic analysis revealed that loss of spt20+ suppressed the hypersensitive phenotype to Cl- of ppbldelta. Thus, spt20+ and ppb1+ stayed in the same pathway of regulating Cl- homeostasis and spt20+ functioned downstream of ppb1+. Our data suggest that spt20delta is able to resist high concentration of extracellular Cl- and Spt20 involves in the calcineurin-mediated Cl- homeostasis. The aberrant up-regulation of intracellular Cl- is correlated with the diseases like myocardial ischemia reperfusion injury in higher organism. As Spt20 is highly conserved in eukaryotes, it might serve as a potential drug target in Cl- imbalance related diseases.


Qiliqiangxin reduced cardiomyocytes apotosis and improved heart function in infarcted heart through Pink1/Parkin -mediated mitochondrial autophagy.
Qiliqiangxin (QLQX) is a preparation refined from a traditional Chinese medicine compound. It plays an important role in protecting cardiac function after myocardial infarction (MI). However, the underline mechanism of QLQX action is not clear. The purpose of this study was to detect the effects of QLQX on mitophagy after MI. Male FVB/NJ mice aged 8-10 weeks were underwent left coronary artery ligation and were orally administered either QLQX (0.25 g/kg/d) or saline. Twenty-eight days after surgical operation, the cardiac function of mice was detected by echocardiography. Electron Microscopy was used to observe the microstructure of cardiomyocytes. Myocardial apoptosis was examined by TdT-mediated dUTP Nick-End Labeling (TUNEL) and western blot. H9c2 cells were cultured in a hypoxic incubator chamber (5% CO2, 1% O2, 94% N2) for 12 h and pretreated with or without QLQX (0.5 mg/mL). The cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential and mitophagy were detected. When compared to sham group, the cardiac function of MI mice decreased significantly, and their cardiomyocyte apoptosis and mitochondrial damage were more serious. These MI-induced cardiac changes could be reversed by QLQX treatment. In vitro experiments also confirmed that QLQX could protect cardiomyocytes from hypoxia-induced apoptosis and mitochondrial damage. Further study indicated that QLQX could increase the expression of Pink1 and Parkin in cardiomyocytes. Qiliqiangxin could reduce cardiomyocytes apotosis and improved heart function in infarcted heart through Pink1-mediated mitochondrial autophagy.


Lower working heights decrease contraction intensity of shoulder muscles in a herringbone 30° milking parlor.
Musculoskeletal disorders have been a main concern in milkers for many years. To improve posture, a formula was developed in a previous study to calculate ergonomically optimal working heights for various milking parlor types. However, the working height recommendations based on the formula for the herringbone 30° parlor were broad. To clarify the recommendations for the optimal working height, we investigated the effect of working height on upper limb and shoulder muscle contraction intensities. We evaluated 60 milking cluster attachment procedures in a herringbone 30° milking parlor in 7 men and 9 women. Specifically, we examined the effect of working height on muscle contraction intensity of 4 arm and shoulder muscles bilaterally (flexor carpi ulnaris, biceps brachii, deltoideus anterior, and upper trapezius) by using surface electromyography. The working heights (low, medium, and high), which reflect the ratio of the subject's height to the height of the udder base, were used in the milking health formula to determine and fit individual depth of pits. Data were evaluated for each muscle and arm side in the functions holding and attaching. Statistical analysis was performed using linear mixed effects models, where muscle contraction intensity served as a target variable, whereas working height coefficient, sex, subject height, and repetition were treated as fixed effects, and repetition group nested in working height nested in subject was considered a random effect. Contraction intensities decreased with decreasing working height for the deltoideus anterior and upper trapezius, but not for the flexor carpi ulnaris or the biceps brachii muscles in both holding and attaching arm functions. We found that milking at a lower working height reduced muscle contraction intensities of the shoulder muscles. Women showed higher contraction intensities than men, whereas subject height had no effect. The study demonstrated that a lower working height decreased muscular load during milking. These lower working heights should be used within the recommendations made by the milking health formula for the herringbone 30°. Working heights could be adjusted effectively for milkers of varying body height. Future studies should therefore use the milking health formula as a tool to objectively compare and improve the accuracy of the working height coefficients.


[Preoperative oral information prior to planned thyroid surgery: the surgeon, physician, lawyer and judge's point of view].
Analysis of the consequence of the preoperative information delivered orally to patients requiring surgery for benign pathology of the thyroid gland from various perspective (head and neck surgeon, physician, judge, lawyer). Prospective study conducted in an academic tertiary care referral center. Inception cohort of 123 patients with benign pathology of the thyroid gland consecutively informed orally and by the same surgeon during the years 2003-2004. Analysis of the consequences of the preoperative information, degree of memorization regarding the surgical related risks as well as the patient's opinion regarding this information. Due to the information regarding the risks related to surgery 14.6% of patients refused to undergo surgery. None of the patients remembered more than 4 out of the 6 main surgical risks. 68.8% of patients remembered only one or two surgical related risks. 12.2% of patients did not remember a single surgical related risk, 85.5% of patients remembered the risk of a unilateral laryngeal nerve paralysis, 41.1% the risk of death related to the completion of a general anesthesia and 21.1% the risk of a bilateral laryngeal nerve paralysis. Less than 11% of patients remembered the other risks (general risks related to any open field surgical approach, hypocalcemia and loss of breast feeding) Among the patients who had an opinion postoperatively, 87.6% had a positive opinion and 41.9% a negative opinion regarding the preoperative information related to the surgical related risks. Also, 28.4% of patients expressed simultaneously a positive and a negative opinion. Oral information of the patient regarding the surgical risks resulted in an important stress for the patient and modified the relation patient-surgeon. Due to the information, a non-neglectable group of patients elicited not to follow the advice of the surgeon. Various measures are discussed since the information on the surgical related risks is a must from a legal point of view but is also highly appreciated and requested by most of the patients.


Inflammation and Inflammatory Cells in Myocardial Infarction and Reperfusion Injury: A Double-Edged Sword.
Myocardial infarction (MI) is the most common cause of cardiac injury, and subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Therefore, inflammation and inflammatory cell infiltration are the hallmarks of MI and reperfusion injury. Ischemic cardiac injury activates the innate immune response via toll-like receptors and upregulates chemokine and cytokine expressions in the infarcted heart. The recruitment of inflammatory cells is a dynamic and superbly orchestrated process. Sequential infiltration of the injured myocardium with neutrophils, monocytes and their descendant macrophages, dendritic cells, and lymphocytes contributes to the initiation and resolution of inflammation, infarct healing, angiogenesis, and ventricular remodeling. Both detrimental effects and a beneficial role in the pathophysiology of MI and reperfusion injury may be attributed to the subset heterogeneity and functional diversity of these inflammatory cells.


Benign adult familial myoclonic epilepsy (BAFME) with night blindness.
This is the first report of benign adult familial myoclonic epilepsy (BAFME) with night blindness. Our cases of BAFME (mother, son, and daughter) demonstrated night blindness with a reduced b-wave response on electroretinography (ERG) suggesting an alteration in calcium-mediated neurotransmitter release from photoreceptors in response to light. Several familial epilepsies have been shown to be due to a channelopathy. On the other hand, the mutation of a calcium-channel gene in Xp11.23 was recently reported in incomplete X-linked congenital stationary night blindness (CSNB). Although the gene locus of BAFME was recently assigned to 8q23.3-q24.1, the causative gene has yet to be identified. The present familial case suggests that BAFME may also be a disease of the calcium channel that is present in the retina and the central nervous system (CNS).


Letter to the Editor.
The editorial in BJN 24(15) written by BJN Editor in Chief, Ian Peate, challenged the Nursing and Midwifery Council's (NMC) Chief Executive and Registrar's assertion that the progress her organisation has achieved over the past 12 months is something to be 'delighted' about. The NMC responded and their letter is below. If you would like to comment on the issue email us: firstname.lastname@example.com.


Analytic solution of the two-star model with correlated degrees.
Exponential random graphs are important to model the structure of real-world complex networks. Here we solve the two-star model with degree-degree correlations in the sparse regime. The model constraints the average correlation between the degrees of adjacent nodes (nearest neighbors) and between the degrees at the end-points of two-stars (next nearest neighbors). We compute exactly the network free energy and show that this model undergoes a first-order transition to a condensed phase. For non-negative degree correlations between next nearest neighbors, the degree distribution inside the condensed phase has a single peak at the largest degree, while for negative degree correlations between next nearest neighbors the condensed phase is characterized by a bimodal degree distribution. We calculate the degree assortativities and show they are nonmonotonic functions of the model parameters, with a discontinuous behavior at the first-order transition. The first-order critical line terminates at a second-order critical point, whose location in the phase diagram can be accurately determined. Our results can help to develop more detailed models of complex networks with correlated degrees.


[Bronchiolitis obliterans organizing pneumonia associated with dermatomyositis and antiphospholipid syndrome].
Dermatomyositis and antiphospholipid syndrome are rare diseases that can be associated pulmonary damage. We report a case of anti-phospholipid syndrome that presented with bilateral pulmonary embolism and subsequently developed pulmonary infiltrates in association with the characteristic muscular and cutaneous features of dermatomyositis. Histological examination of trans-bronchial biopsies revealed bronchiolitis obliterans organizing pneumonia.


High power ultrasound standard.
A sensitive radiation force balance for laboratory measurement of ultrasonic power is presented. The principle of the system is based on measuring the ultrasonic radiation force exerted on a conical float suspended in water. Technical details of the implementation of the economically attractive system are described. The operation of the system is automated with the aid of the IEEE-488 bus and a desktop computer. Design aspects that affect measurement uncertainty are investigated. A theoretical model for the measurement of ultrasonic power with a conical reflector target is discussed. The expanded uncertainty (95% confidence level) of the above radiation force conical float system is estimated to be between 5% to 10%.


Low-pH-induced membrane fusion mediated by human metapneumovirus F protein is a rare, strain-dependent phenomenon.
Membrane fusion promoted by human metapneumovirus (HMPV) fusion (F) protein was suggested to require low pH (R. M. Schowalter, S. E. Smith, and R. E. Dutch, J. Virol. 80:10931-10941, 2006). Using prototype F proteins representing the four HMPV genetic lineages, we detected low-pH-dependent fusion only with some lineage A proteins and not with lineage B proteins. A glycine at position 294 was found responsible for the low-pH requirement in lineage A proteins. Only 6% of all HMPV lineage A F sequences have 294G, and none of the lineage B sequences have 294G. Thus, acidic pH is not a general trigger of HMPV F proteins for activity.


VIM thalamotomy in the treatment of Holmes' tremor secondary to HIV-associated midbrain lesion: a case report.
Holmes' tremor (rubral tremor, cerebellar outflow tremor) is characterized by rest, intention and postural tremor, often localized to one upper extremity, associated with ipsilateral dysmetria and dysdiadochokinesia. We describe a case of successful treatment of Holmes' tremor with unilateral nucleus ventralis intermedius (VIM) thalamotomy. The subject is a 43-year-old woman with unremarkable previous medical history. She presented with complete left hemiparesis in the context of human immunodeficiency syndrome and the magnetic resonance image disclosed a contrast-enhancing lesion in right brain peduncle, in topography of red nucleus. She developed a progressive rest, intention and postural tremor in left upper limb. She was submitted to a stereotactic biopsy and the tremor became worse. She performed awake right VIM thalamotomy, with immediate complete resolution of tremor. There were no complications after procedure, and the result is stable after six months. We highlight the role of thalamotomy in cases like ours, once patient recovered well and, due to HIV, will need further neuroimage studies to evaluate neurologic complications of HIV. Deep brain stimulation in such cases may interfere with coming neuroimage quality and may act like a foreign body.


Two young sisters with spinocerebellar ataxia type 2 showing different clinical progression of disease.
Spinocerebellar ataxia type 2 is a neurodegenerative disease caused by a CAG repeat expansion in the ataxin-2 gene. Gain-of-toxic effects caused by expanded polyglutamine tracts are important for the disease pathogenesis and there is an inverse relationship between the number of CAG repeats and the age of onset and clinical severity. Previously, we reported an extended Turkish family with spinocerebellar ataxia type 2 with several affected members in three generations. Two sisters in this generation showed an earlier age of onset (5 and 7 years, respectively) than their father (30 years). In this paper, we present a further interesting finding regarding the disease onset and manifestation in the two sisters. Interestingly, the age of onset was delayed and the clinical severity of the disease was milder in the child who had more CAG repeats (84 vs. 70). This finding suggests that there are other factors contributing to the age of onset and clinical severity in spinocerebellar ataxia type 2 other than the increased CAG repeat.


Compound-specific isotope analysis resolves the dietary origin of docosahexaenoic acid in the mouse brain.
DHA (22:6n-3) may be derived from two dietary sources, preformed dietary DHA or through synthesis from α-linolenic acid (ALA; 18:3n-3). However, conventional methods cannot distinguish between DHA derived from either source without the use of costly labeled tracers. In the present study, we demonstrate the proof-of-concept that compound-specific isotope analysis (CSIA) by GC-isotope ratio mass spectrometry (IRMS) can differentiate between sources of brain DHA based on differences in natural 13C enrichment. Mice were fed diets containing either purified ALA or DHA as the sole n-3 PUFA. Extracted lipids were analyzed by CSIA for natural abundance 13C enrichment. Brain DHA from DHA-fed mice was significantly more enriched (-23.32‰ to -21.92‰) compared with mice on the ALA diet (-28.25‰ to -27.49‰). The measured 13C enrichment of brain DHA closely resembled the dietary n-3 PUFA source, -21.86‰ and -28.22‰ for DHA and ALA, respectively. The dietary effect on DHA 13C enrichment was similar in liver and blood fractions. Our results demonstrate the effectiveness of CSIA, at natural 13C enrichment, to differentiate between the incorporation of preformed or synthesized DHA into the brain and other tissues without the need for tracers.


Does stage of labor at time of cesarean delivery affect risk of subsequent preterm birth?
The effect of a cesarean delivery in different stages of labor on spontaneous preterm birth (sPTB) in a subsequent pregnancy has not been studied extensively. The objective of the study was to evaluate the risk of subsequent sPTB after a first-stage or second-stage cesarean delivery compared with a vaginal delivery. This was a planned secondary analysis of a large retrospective cohort study of women with 2 consecutive deliveries from 2005-2010. Women with a previous sPTB were excluded. First-stage (<10 cm) and second-stage (≥10 cm) cesarean deliveries were compared with vaginal deliveries. Data were obtained through chart abstraction. The primary outcome was sPTB (<37 wk) in a subsequent pregnancy. Categoric variables were compared with the use of χ(2) analyses, and logistic regression was used to calculate odds and control for confounders. Eight hundred eighty-seven women were included (721 vaginal deliveries; 129 first-stage and 37 second-stage cesarean deliveries). The sPTB rate varied between groups (7.8%, 2.3%, and 13.5%, respectively; P = .03). When compared with women with a vaginal delivery, women with a first-stage cesarean delivery had a decreased risk of sPTB, which remained after adjustment for confounders (adjusted odds ratio, 0.30; 95% confidence interval, 0.09-0.99; P = .049). There was a nonsignificant increase in odds of sPTB after a second-stage cesarean delivery compared with a vaginal delivery (adjusted odds ratio, 2.4; 95% confidence interval, 0.77-7.43; P = .13). Women with a second-stage cesarean delivery had a 6-fold higher odds of sPTB compared with women with a first-stage cesarean delivery, which remained after adjustment for confounders (adjusted odds ratio, 5.8; 95% confidence interval, 1.08-30.8; P = .04). Women with a full-term second-stage cesarean delivery have a significantly higher than expected rate of subsequent sPTB (13.5%) compared with both the overall national sPTB rate (7-8%) and to a first-stage cesarean delivery (2.3%). As the cesarean delivery rate continues to rise, this potential impact on pregnancy outcomes cannot be ignored.


Is p53 polymorphism maintained by natural selection?
We present here a new interesting feature of the human tumor suppressor gene p53: a very pronounced ethnic and clinal variation of polymorphic codon 72 alleles. The frequency of the A1 (Pro) allele showed a north-south cline from 17% in Swedish Saamis to 63% in African Blacks (Nigerians), and there was a significant (p < 0.001) correlation (r = 0.95) between the A2 frequency and latitude. In the Finnish and Swedish populations no significant differences were found with respect to the genotype and allele distributions in spontaneously aborted fetuses and liveborn children, which makes differential intrauterine selection unlikely. However, the ethnic and clinal variations suggest that the codon 72 polymorphism is balanced and maintained by natural selection.