Biological Significance of 18F-FDG PET/CT Maximum Standard Uptake Value for Predicting EGFR Mutation Status in Non-Small Cell Lung Cancer Patients.
To investigate the potential of maximum standardized uptake value (SUVmax) in predicting epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC) patients. Clinical data of 311 NSCLC patients who had undergone both EGFR mutation test and 18F-FDG PET/CT scans between January 2013 and December 2017 at our hospital were retrospectively analyzed. Patients were sub-grouped by their origin of SUVmax. Univariate and multivariate analyses were performed to investigate the association between clinical factors and EGFR mutations. Receiver operating characteristic curve (ROC) analysis was performed to confirm the predictive value of clinical factors. In vitro experiments were performed to confirm the correlation between EGFR mutations and glycolysis. EGFR-mutant patients had higher SUVmax than the wild-type patients in both primary tumors and metastases. In the multivariate analysis, SUVmax, gender and histopathologic type were determined as independent predictors of EGFR mutation status for patients whose SUVmax were obtained from the primary tumors; while for patients whose SUVmax were obtained from the metastases, SUVmax, smoking status and histopathologic type were regarded as independent predictors. ROC analysis showed that SUVmax of the primary tumors (cut off >10.92), not of the metastases, has better predictive value than other clinical factors in predicting EGFR mutation status. The predict performance was improved after combined SUVmax with other independent predictors. In addition, our in vitro experiments demonstrated that lung cancer cells with EGFR mutations have higher aerobic glycolysis level than wild-type cells. SUVmax of the primary tumors has the potential to serve as a biomarker to predict EGFR mutation status in NSCLC patients.


Conjugated estrogens and breast cancer risk in women.
The relationship between conjugated estrogen(s) (CE) and breast cancer was investigated by the examination of the records of 345 women with newly diagnosed breast cancer and 611 healthy controls belonging to a prepaid health plan. Use of CE was associated with a 40% elevation in risk [relative risk (RR) = 1.4; 95% confidence interval-1.0-2.0]. The RR was 1.3 for menopausal women with intact ovaries and 1.5 for those with ovaries removed. There was statistically significant evidence of a dose-response relationship with the three measures of dose evaluated. RR's rose to about twofold for women with 10 or more CE prescriptions noted in their charts, for those with 5 years or more between their first and last prescription, and for those with a usual daily dose of 1.25 mg or more. The RR associated with having ever used CE and with long-term use was highest among those women with a family history of breast cancer. These data support the hypothesis that long-term use of CE is associated with increased breast cancer risk.


Relaxation-Assisted Magnetization Transfer Phenomena for a Sensitivity-Enhanced 2D NMR.
2D NOESY and TOCSY play central roles in contemporary NMR. We have recently discussed how solvent-driven exchanges can significantly enhance the sensitivity of such methods when attempting correlations between labile and nonlabile protons. This study explores two scenarios where similar sensitivity enhancements can be achieved in the absence of solvent exchange: the first one involves biomolecular paramagnetic systems, while the other involves small organic molecules in natural abundance. It is shown that, in both cases, the effects introduced by either differential paramagnetic shift and relaxation or by polarization sharing among networks of protons can provide a similar sensitivity boost, as previously discussed for solvent exchange. The origin and potential of the resulting enhancements are analyzed, and experiments that demonstrate them in protein and natural products are exemplified. Limitations and future improvements of these approaches are also briefly discussed.


Transformation of the {Fe(NO)2}9 dinitrosyl iron complexes (DNICs) into S-nitrosothiols (RSNOs) triggered by acid-base pairs.
S-nitrosation of the coordinated thiolate of dinitrosyl iron complexes (DNICs) to generate S-nitrosothiols (RSNOs) was demonstrated. Transformation of [{(NO)(2)Fe(μ-StBu)}(2)] (1-tBuS) into the {Fe(NO)(2)}(9) DNIC [(NO)(2)Fe(StBu)(MeIm)] (2-MeIm) occurs under addition of 20 equiv of 1-methylimidazole (MeIm) into a solution of 1-tBuS in THF. The dynamic interconversion between {Fe(NO)(2)}(9) [(NO)(2)Fe(S-NAP)(dmso)] (2-dmso) (NAP = N-acetyl-D-penicillamine) and [{(NO)(2)Fe(μ-S-NAP)}(2)] (1-NAP) was also observed in a solution of complex 1-NAP in DMSO. In contrast to the reaction of complex 2-MeIm and bis(dimethylthiocarbamoyl) disulfide ((DTC)(2)) to yield {Fe(NO)}(7)[(NO)Fe(DTC)(2)] (3) (DTC = S(2)CNMe(2)) accompanied by (tBuS)(2) and NO(g), transformation of {Fe(NO)(2)}(9) 2-MeIm (2-dmso) into RSNOs (RS = tBuS, NAP-S) along with complex 3 induced by the Brønsted acid solution of (DTC)(2) demonstrated that Brønsted acid may play a critical role in triggering S-nitrosation of the coordinated thiolate of DNICs 2-MeIm (or 2-dmso) to produce RSNOs. That is, DNIC-mediated S-nitrosation requires a Brønsted acid-Lewis base pair to produce RSNO. Transformation of DNICs into RSNOs may only occur on the one-thiolate-containing {Fe(NO)(2)}(9) DNICs, in contrast to protonation of the two-thiolate-containing DNICs [(NO)(2)Fe(SR)(2)](-) by Brønsted acid to yield [{(NO)(2)Fe(μ-SR)}(2)]. These results might rationalize that the known protein-Cys-SNO sites derived from DNICs were located adjacent to acid and base motifs, and no protein-bound SNO characterized to date has been directly derived from [protein-(cysteine)(2)Fe(NO)(2)] in biology.


Identification of a novel Haemophilus parasuis-specific B cell epitope using monoclonal antibody against the OppA protein.
Monoclonal antibody (MAb) 1B3 against Haemophilus parasuis (H. parasuis) was generated by fusing SP2/0 murine myeloma cells and spleen cells from BALB/c mice immunized with the whole-bacterial-cell suspension of H. parasuis HS80 (serotype 5). The MAb 1B3 showed strong reactivity with 15 serotype reference strains of H. parasuis using Dot blot and Western blot analysis. Immunoprecipitation and protein spectral analysis indicated that MAb 1B3 recognized by Oligopeptide permease A (OppA) belongs to the ATP binding cassette transporter family. In addition, a linear B-cell epitope recognized by MAb 1B3 was identified by the screening of a phage-displayed 12-mer random peptide library. Sequence analysis showed that MAb 1B3 was recognized by phages-displaying peptides with the consensus motif KTPSEXR (X means variable amino acids). Its amino acid sequence matched (469)KTPAEAR(475) of H. parasuis OppA protein. A series of progressively truncated peptides were synthesized to define the minimal region that was required for MAb 1B3 binding. The epitope was highly conserved in OppA protein sequences from the isolated H. parasuis strains, which was confirmed by alignment analysis. Furthermore, the minimal linear epitope was highly specific among 75 different bacterial strains as shown in sequence alignments. These results indicated MAb 1B3 might be potentially used to develop serological diagnostic tools for H. parasuis.


New Species and Eight Undescribed Species Belonging to the Families Aspergillaceae and Trichocomaceae in Korea.
During a survey of fungal diversity associated with insects, mud, soil, and freshwater niches in different areas in Korea, nine interesting fungal strains were isolated. Based on their morphological characteristics and molecular phylogeny analyses, using a combined data set of β-tubulin (BenA), calmodulin (CaM), and second largest subunit of RNA polymerase (RPB2) sequences, the strains CNUFC AM-44, CNUFC JCW3-4, CNUFC S708, CNUFC WT202, CNUFC AS1-29, CNUFC JCW3-5, CNUFC JDP37, and CNUFC JDP62 were identified as Aspergillus alabamensis, A. floridensis, A. subversicolor, Penicillium flavigenum, P. laevigatum, P. lenticrescens, Talaromyces adpressus, and T. beijingensis, respectively. The strain CNUFC JT1301 belongs to series Westlingiorum in section Citrina and is phylogenetically related to P. manginii. However, slow growth when cultivated on CYA, MEA, CREA is observed and the property can be used to easily distinguish the new species from these species. Additionally, P. manginii is known to produce sclerotia, while CNUFC JT1301 strain does not. Herein, the new fungal species is proposed as P. aquadulcis sp. nov. Eight species, A. alabamensis, A. floridensis, A. subversicolor, P. flavigenum, P. laevigatum, P. lenticrescens, T. adpressus, and T. beijingensis, have not been previously reported in Korea. The present study expands the known distribution of fungal species belonging to the families Aspergillaceae and Trichocomaceae in Korea.


A comparison of the prenatal health behaviors of women from four cultural groups in Turkey: an ethnonursing study.
This research was conducted to uncover women's health behaviors during prenatal periods using a transcultural approach. The qualitative ethnonursing method was used, and the research was conducted at the family health center in Bornova District in Izmir. The data were collected between November 2007 and August 2008 using the purposive sampling method. Eighteen pregnant women were included in the study and in-depth face-to-face semi-structured interviews were recorded on an audio recording device. A thematic analysis revealed four main themes: family, social learning-tradition transfer, perceptions, and behavioral changes.


Athlete atypicity on the edge of human achievement: performances stagnate after the last peak, in 1988.
The growth law for the development of top athletes performances remains unknown in quantifiable sport events. Here we present a growth model for 41351 best performers from 70 track and field (T&F) and swimming events and detail their characteristics over the modern Olympic era. We show that 64% of T&F events no longer improved since 1993, while 47% of swimming events stagnated after 1990, prior to a second progression step starting in 2000. Since then, 100% of swimming events continued to progress.We also provide a measurement of the atypicity for the 3919 best performances (BP) of each year in every event. The secular evolution of this parameter for T&F reveals four peaks; the most recent (1988) followed by a major stagnation. This last peak may correspond to the most recent successful attempt to push forward human physiological limits. No atypicity trend is detected in swimming. The upcoming rarefaction of new records in sport may be delayed by technological innovations, themselves depending upon economical constraints.


Spontaneous modulations of high-frequency cortical activity.
We clarified the clinical and mechanistic significance of physiological modulations of high-frequency broadband cortical activity associated with spontaneous saccadic eye movements during a resting state. We studied 30 patients who underwent epilepsy surgery following extraoperative electrocorticography and electrooculography recordings. We determined whether high-gamma activity at 70-110 Hz preceding saccade onset would predict upcoming ocular behaviors. We assessed how accurately the model incorporating saccade-related high-gamma modulations would localize the primary visual cortex defined by electrical stimulation. The dynamic atlas demonstrated transient high-gamma suppression in the striatal cortex before saccade onset and high-gamma augmentation subsequently involving the widespread posterior brain regions. More intense striatal high-gamma suppression predicted the upcoming saccade directed to the ipsilateral side and lasting longer in duration. The bagged-tree-ensemble model demonstrated that intense saccade-related high-gamma modulations localized the visual cortex with an accuracy of 95%. We successfully animated the neural dynamics supporting saccadic suppression, a principal mechanism minimizing the perception of blurred vision during rapid eye movements. The primary visual cortex per se may prepare actively in advance for massive image motion expected during upcoming prolonged saccades. Measuring saccade-related electrocorticographic signals may help localize the visual cortex and avoid misperceiving physiological high-frequency activity as epileptogenic.


Interactive effects of plant-available soil silicon and herbivory on competition between two grass species.
The herbivore defence system of true grasses (Poaceae) is predominantly based on silicon that is taken up from the soil and deposited in the leaves in the form of abrasive phytoliths. Silicon uptake mechanisms can be both passive and active, with the latter suggesting that there is an energetic cost to silicon uptake. This study assessed the effects of plant-available soil silicon and herbivory on the competitive interactions between the grasses Poa annua, a species that has previously been reported to accumulate only small amounts of silicon, and Lolium perenne, a high silicon accumulator. Plants were grown in mono- and mixed cultures under greenhouse conditions. Plant-available soil silicon levels were manipulated by adding silicon to the soil in the form of sodium silicate. Subsets of mixed culture pots were exposed to above-ground herbivory by desert locusts (Schistocerca gregaria). In the absence of herbivory, silicon addition increased biomass of P. annua but decreased biomass of L. perenne. Silicon addition increased foliar silicon concentrations of both grass species >4-fold. Under low soil-silicon availability the herbivores removed more leaf biomass from L. perenne than from P. annua, whereas under high silicon availability the reverse was true. Consequently, herbivory shifted the competitive balance between the two grass species, with the outcome depending on the availability of soil silicon. It is concluded that a complex interplay between herbivore abundance, growth-defence trade-offs and the availability of soil silicon in the grasses' local environment affects the outcome of inter-specific competition, and so has the potential to impact on plant community structure.


[Patients with diaphragmatic pacemakers].
Due to the implantation of diaphragmatic pacemakers, the hope and quality of life for those with upper spinal column injuries has increased considerably. Until about 10 years ago, these patients depended on a mechanical ventilator with all of its corresponding limitations. Nurses have had to learn how to use diaphragmatic pacemakers so they may provide patients with the specific treatment these make available and so that they may offer adequate health education to relatives of these patients. The greatest challenge for our profession is to succeed in having these patients abandon the hospital and integrate into society again. This article analyzes how diaphragmatic pacemakers work and the specific nursing treatment these patients require, placing emphasis on psycho-sociological aspects.


Genomic imprints of unparalleled growth.
Chlorella ohadii was isolated from desert biological soil crusts, one of the harshest habitats on Earth, and is emerging as an exciting new green model for studying growth, photosynthesis and metabolism under a wide range of conditions. Here, we compared the genome of C. ohadii, the fastest growing alga on record, to that of other green algae, to reveal the genomic imprints empowering its unparalleled growth rate and resistance to various stressors, including extreme illumination. This included the genome of its close relative, but slower growing and photodamage sensitive, C. sorokiniana UTEX 1663. A larger number of ribosome-encoding genes, high intron abundance, increased codon bias and unique genes potentially involved in metabolic flexibility and resistance to photodamage are all consistent with the faster growth of C. ohadii. Some of these characteristics highlight general trends in Chlorophyta and Chlorella spp. evolution, and others open new broad avenues for mechanistic exploration of their relationship with growth. This work entails a unique case study for the genomic adaptations and costs of exceptionally fast growth and sheds light on the genomic signatures of fast growth in photosynthetic cells. It also provides an important resource for future studies leveraging the unique properties of C. ohadii for photosynthesis and stress response research alongside their utilization for synthetic biology and biotechnology aims.


Understanding the role of nano-topography on the surface of a bone-implant.
Bone-implant material development is proceeding at a high pace, and has shifted from straightforward biomaterial testing to more advanced cell-targeted approaches for surface modification and design. It has been long known that cells can recognize and respond to topographical features by changing their morphology and behavior. The progress in surface analytical devices, as well as in techniques for production of topographical features on the nanometer scale allow for the characterization of natural tissues and the reproduction of biomimetic nanofeatures in material surfaces. In this review some of the most common surface-characterization and surface-manufacturing techniques will be addressed and results from in vitro and in vivo studies will be presented. Knowledge on biomaterial nanotopography can be exploited for active stimulation and control of cellular behavior like attachment, migration, spreading, gene expression, proliferation, differentiation and secretion of matrix components.


Pattern formation on a sphere.
Pattern formation on the surface of a sphere is described by equations involving interactions of spherical harmonics of degree l. When l is even, the leading-order equations are determined uniquely by the symmetry, regardless of the physical context. Existence and stability results are found for even l up to l=12. Using either a variational or eigenvalue criterion, the preferred solution has icosahedral symmetry for l=6, l=10, and l=12. Numerical simulations of a model pattern-forming equation are in agreement with these theoretical predictions near onset and show more complex patterns further from onset.


Oral cancer diagnosis and perspectives in India.
Globally, oral cancer is the sixth most common type of cancer with India contributing to almost one-third of the total burden and the second country having the highest number of oral cancer cases. Oral squamous cell carcinoma (OSCC) dominates all the oral cancer cases with potentially malignant disorders, which is also recognized as a detectable pre-clinical phase of oral cancer. Tobacco consumption including smokeless tobacco, betel-quid chewing, excessive alcohol consumption, unhygienic oral condition, and sustained viral infections that include the human papillomavirus are some of the risk aspects for the incidence of oral cancer. Lack of knowledge, variations in exposure to the environment, and behavioral risk factors indicate a wide variation in the global incidence and increases the mortality rate. This review describes various risk factors related to the occurrence of oral cancer, the statistics of the distribution of oral cancer in India by various virtues, and the socio-economic positions. The various conventional diagnostic techniques used routinely for detection of the oral cancer are discussed along with advanced techniques. This review also focusses on the novel techniques developed by Indian researchers that have huge potential for application in oral cancer diagnosis.


Inhibition of etoposide-induced apoptosis with peptide aldehyde inhibitors of proteasome.
Recent investigations have indicated the involvement of proteasome in programmed cell death. The present studies show that although peptide aldehyde inhibitors of proteasome are by themselves weak inducers of apoptosis, they inhibit the apoptotic effect of the anticancer drug etoposide in rat thymocytes. Acetyl-Leu-Leu-norvalinal (LLnV-al) and other related peptide aldehydes inhibited the increase in caspase activity and DNA fragmentation that followed treatment with etoposide and their effect was related to their potency as proteasome inhibitors. To inhibit etoposide-induced apoptosis, LLnV-al must be present within 3 h of treatment with etoposide, in the same way as the inhibitor of protein synthesis cycloheximide must be. Etoposide caused a rapid accumulation of p53 protein that was not inhibited by LLnV-al, which was also a strong inducer of p53. Peptide aldehydes were also weak activators of caspase activity, suggesting that the same mechanism, i.e. the blocking of proteasome function, both triggers apoptosis and inhibits the effect of etoposide. These results are consistent with a model in which proteasome is selectively involved in the pathway used by etoposide to induce cell suicide.


Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial.
There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma.


Electronic structure manipulation of graphene dots for effective hydrogen evolution from photocatalytic water decomposition.
This paper presents a heteroatom doping strategy to manipulate the structure of graphene-based photocatalysts for effective hydrogen production from aqueous solution. Oxygenation of graphene creates a bandgap to produce semiconducting graphene oxide, nitrogen doping extends the resonant π-conjugation to prolong the charge lifetime, and sulfur doping breaks the electron neutrality to facilitate charge transfer. Accordingly, ammonia-treated sulfur-nitrogen-co-doped graphene oxide dots (A-SNGODs) are synthesized by annealing graphene oxide sheets in sulfur-ammonia, oxidizing the sheets into dots, and then hydrothermally treating the dots in ammonia. The A-SNGODs exhibit a high nitrogen content in terms of quaternary and amide groups that are formed through sulfur-mediated reactions. The peripheral amide facilitates orbital conjugations to enhance the photocatalytic activity, whereas the quaternary nitrogen patches vacancy defects to improve stability. The simultaneous presence of electron-withdrawing S and electron-donating N atoms in the A-SNGODs facilitates charge separation and results in reactive electrons. When suspended in an aqueous triethanolamine solution, Pt-deposited A-SNGODs demonstrate a hydrogen-evolution quantum yield of 29% under monochromatic 420 nm irradiation. The A-SNGODs exhibit little activity decay under 6-day visible-light irradiation. This study demonstrates the excellence of the heteroatom-doping strategy in producing stable and active graphene-based materials for photoenergy conversion.


Ethnic Differences in Maternal Adipokines during Normal Pregnancy.
Two adipokines (adiponectin and resistin) have opposite relations with insulin resistance and inflammation. Our major focus was to determine whether there were detectable ethnic differences in maternal adipokines during pregnancy. We also explored the correlation of the adipokines with maternal glucose homeostasis, blood pressure and anthropometric parameters. Pregnant women (n = 1634) were from a large prospective cohort study in Camden NJ (African-American 36.8%; Hispanic 47.6%; Caucasian 15.6%). Serum adiponectin and resistin were measured at entry (week 16.8) and the 3rd trimester (week 30.7) using the Luminex xMapTechnology. Significant differences were observed among ethnic groups, controlling for confounding variables. African American women were exceptional in that they had decreased adiponectin and increased resistin throughout the course of pregnancy (p < 0.05 to p < 0.0001) and a greater than two fold risk of simultaneously exhibiting low adiponectin (lowest tertile) and high resistin (highest tertile) compared to Caucasians and/or Hispanics. The cohort as a whole and each ethnic group showed similar negative correlations between adiponectin, and glucose homeostasis, blood pressure and anthropometric parameters but there was lesser correspondence with resistin. Our data underscore the need for further research on ethnic variation in adipokines and other physiologic biomarkers during complicated and uncomplicated pregnancy.


Transfer of Phase Information between Microwave and Optical Fields via an Electron Spin.
We demonstrate the coherent coupling and the resulting transfer of phase information between microwave and optical fields in a single nitrogen vacancy center in diamond. The relative phase of two microwave fields is encoded in a coherent superposition spin state. This phase information is then retrieved with a pair of optical fields. A related process is also used for the transfer of phase information from optical to microwave fields. These studies show the essential role of dark states, including optical pumping into the dark states, in the coherent microwave-optical coupling and open the door to the full quantum state transfer between microwave and optical fields in a solid-state spin ensemble.


Authentication of Surveillance Videos: Detecting Frame Duplication Based on Residual Frame.
Nowadays, surveillance systems are used to control crimes. Therefore, the authenticity of digital video increases the accuracy of deciding to admit the digital video as legal evidence or not. Inter-frame duplication forgery is the most common type of video forgery methods. However, many existing methods have been proposed for detecting this type of forgery and these methods require high computational time and impractical. In this study, we propose an efficient inter-frame duplication detection algorithm based on standard deviation of residual frames. Standard deviation of residual frame is applied to select some frames and ignore others, which represent a static scene. Then, the entropy of discrete cosine transform coefficients is calculated for each selected residual frame to represent its discriminating feature. Duplicated frames are then detected exactly using subsequence feature analysis. The experimental results demonstrated that the proposed method is effective to identify inter-frame duplication forgery with localization and acceptable running time.


Dual suppression with oral contraceptives and gonadotrophin releasing-hormone agonists improves in-vitro fertilization outcome in high responder patients.
Certain patients have a tendency for high response to gonadotrophin therapy which is often not ameliorated with prior gonadotrophin-releasing hormone agonist (GnRHa) suppression. As a result, these patients are frequently cancelled and often experience ovarian hyperstimulation syndrome (OHSS) episodes during in-vitro fertilization (IVF)-embryo transfer cycles. Patients with polycystic ovarian syndrome (PCOS) have been noted to be particularly sensitive to exogenous gonadotrophin therapy. We have developed a protocol which is effective in improving IVF outcome in high responder patients, including those with PCOS. Oral contraceptive pills (OCP) are taken for 25 days followed by s.c. leuprolide acetate, 1 mg/day, which is overlapped with the final 5 days of oral contraceptive administration. Low-dose gonadotrophin stimulation is then initiated on the third day of withdrawal bleeding in the form of either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone at a dosage of 150 IU/day. Over a 5 year period, we reviewed our experience utilizing this dual method of suppression in 99 cycles obtained in 73 high responder patients. There were only 13 cancellations prior to embryo transfer (13.1%). The clinical and ongoing pregnancy rates per initiated cycle were 46.5 and 40.4% respectively. Only eight patients experienced mild-moderate OHSS following treatment. For those patients who had undergone previous IVF-embryo transfer cycles at our centre, significant improvements were noted in oocyte fertilization rates, embryo implantation rates and clinical/ongoing pregnancy rates with this protocol. Hormonal analyses revealed that the chief mechanism may be through an improved luteinizing hormone/follicle-stimulating hormone ratio following dual suppression. An additional feature of this dual method of suppression is significantly lower serum androgen concentrations, particularly dehydroepiandrosterone sulphate.


Regulation of PP2A by Sphingolipid Metabolism and Signaling.
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is a primary regulator of cellular proliferation through targeting of proliferative kinases, cell cycle regulators, and apoptosis inhibitors. It is through the regulation of these regulatory elements that gives PP2A tumor suppressor functions. In addition to mutations on the regulatory subunits, the phosphatase/tumor suppressing activity of PP2A is also inhibited in several cancer types due to overexpression or modification of the endogenous PP2A inhibitors such as SET/I2PP2A. This review focuses on the current literature regarding the interactions between the lipid signaling molecules, selectively sphingolipids, and the PP2A inhibitor SET for the regulation of PP2A, and the therapeutic potential of sphingolipids as PP2A activators for tumor suppression via targeting SET oncoprotein.


Psycho-social problems of the HIV positive and negative mothers.
People affected with HIV face numerous psycho-social problems in their families and work place. The present study attempted to identify various psychosocial problems faced by HIV positive mothers and their comparison was made with those without HIV. In the study, 320 HIV positive and as many negative mothers, attending OPD of Govt Rajaji Hospital and Meenakshi Mission Hospital & Research Centre, Madurai (TN) having children, were included as subjects. All HIV mothers were aware of their HIV status. It was found that majority of HIV positive mothers faced more social problems vis-a-vis HIV negative mothers.


[Diagnostic value of ultrasound in malignant melanoma].
High-resolution real-time sonography enables visualisation of the morphology of the cutis and of cutaneous tumours. Evaluation of 26 malignant melanomas showed that there is a high degree of correlation between the sonographically measured values of maximal tumour thickness with those determined postoperatively by histometry. As malignant melanomas have very few internal echos, they can be easily differentiated from benign tumours. High-resolution sonography is thus the only diagnostic imaging method which helps to evaluate preoperatively malignant melanomas.


When beggars are choosers-How nesting of a solitary bee is affected by temporal dynamics of pollen plants in the landscape.
Wild bees are declining in intensively farmed regions worldwide, threatening pollination services to flowering crops and wild plants. To halt bee declines, it is essential that conservation actions are based on a mechanistic understanding of how bee species utilize landscapes. We aimed at teasing apart how foraging resources in the landscape through the nesting season affected nesting and reproduction of a solitary bee in a farmland region. We investigated how availability of floral resources and potentially resource-rich habitats surrounding nests affected nest provisioning and reproduction in the solitary polylectic bee Osmia bicornis. The study was performed in 18 landscape sectors dominated by agriculture, but varying in agricultural intensity in terms of proportion of organic crop fields and seminatural permanent pastures. Pasture-rich sectors contained more oak (Quercus robur), which pollen analysis showed to be favored forage in early season. More oaks ≤100 m from nests led to higher proportions of oak pollen in nest provisions and increased speed of nest construction in early season, but this effect tapered off as flowering decreased. Late-season pollen foraging was dominated by buttercup (Ranunculus spp.), common in various noncrop habitats. Foraging trips were longer with more oaks and increased further through the season. The opposite was found for buttercup. Oak and buttercup interacted to explain the number of offspring; buttercup had a positive effect only when the number of oaks was above the mean for the studied sectors. The results show that quality of complex and pasture-rich landscapes for O. bicornis depends on preserving existing and generating new oak trees. Lignose plants are key early-season forage resources in agricultural landscapes. Increasing habitat heterogeneity with trees and shrubs and promoting suitable late-flowering forbs can benefit O. bicornis and other wild bees active in spring and early summer, something which existing agri-environment schemes seldom target.


New luminescence-based approach to measurement of luciferase gene expression reporter activity and adenosine triphosphate-based determination of cell viability.
The assay employing firefly luciferase as the end-point reporter is one of the most popular gene reporter systems. However, the physiological conditions of cells may affect the reporter gene expression, which makes an assessment of cell viability desirable. Estimates of cell viability may be based on different principles. We tested for correlations between various cell viability assessments, including luminescent determination of adenosine triphosphate in whole-cell lysate, and the reporter luciferase activity in pluripotent embryonic and colon adenocarcinoma cells. Luciferase activity in cell lysate from both cell lines cultured under different conditions correlated with the amount of viable cells assessed by all of the methods employed. Importantly, it was also possible to carry out adenosine triphosphate determination in cell lysates prepared in the buffer originally designed for determining luciferase activity; it correlated significantly with adenosine triphosphate determination in cells lysed in the buffer originally designed for adenosine triphosphate determination. The results suggest that the assessment of live cells by determining adenosine triphosphate can be multiplexed with a luciferase reporter gene assay, which allows independent monitoring of both reporter expression and cell viability.


Opioid-induced constipation: pathophysiology, clinical consequences, and management.
Although opioids offer potent analgesia for severe acute and chronic noncancer pain, adverse gastrointestinal effects potentially undermine their clinical utility. In particular, between 40% and 95% of patients develop opioid-induced constipation (OIC). Therefore, there is a consensus that patients should commence laxatives at the start of opioid therapy and continue throughout treatment. Nevertheless, laxatives are not routinely coprescribed with opioids. Even when concurrent laxatives are prescribed, approximately half the patients treated for OIC do not achieve the desired improvement. Moreover, laxatives do not target the underlying cause of OIC (opioid binding to the μ -receptors in the enteric system) and as such are not very effective at managing OIC. The failure of lifestyle modification and laxatives to treat adequately many cases of OIC led to the concurrent use of peripherally acting opioid antagonists (such as methylnaltrexone bromide and naloxone) to reduce the incidence of gastrointestinal adverse events without compromising analgesia. Judicious use of the various options to manage OIC should allow more patients to benefit from opioid analgesia. Therefore, this paper reviews the causes, consequences, and management of OIC to help clinicians optimise opioid analgesia.


Predictive factors of long-term rectal toxicity following permanent iodine-125 prostate brachytherapy with or without supplemental external beam radiation therapy in 2216 patients.
We analyzed factors associated with rectal toxicity after iodine-125 prostate brachytherapy (BT) with or without external beam radiation therapy (EBRT). In total, 2216 prostate cancer patients underwent iodine-125 BT with or without EBRT between 2003 and 2013. The median followup was 6.9 years. Cox proportional hazards modeling was used for univariate and multivariate analyses to assess clinical and dosimetric factors associated with rectal toxicity. Dosimetric parameters from 1 day after implantation (Day 1) and 1 month after implantation (Day 30) were included in the analyses. The 7-year cumulative incidence of Grade 2 or higher rectal toxicity was 5.7% in all patients. The multivariate analysis revealed that antiplatelet or anticoagulant therapy, neoadjuvant androgen deprivation therapy, treatment modality, Day 1 rectal volume receiving 100% of the prescribed dose (RV100), and the Day 30 minimal percent of the prescribed dose delivered to 30% of the rectum (RD30) were associated with rectal toxicity. Day 1 RV100 was a common predictor in both BT-alone and the BT + EBRT groups. The 5-year cumulative incidence of Grade 2 or higher rectal toxicity was 12.6%, 5.9%, and 1.7% for BT + 3-dimensional conformal radiation therapy, BT + intensity-modulated radiation therapy, and the BT-alone groups, respectively (p < 0.001). Rectal dosimetric parameters in BT were associated with late rectal toxicity. Although the risk of rectal toxicity was higher when EBRT was combined with BT, with proper and achievable rectal dose constraints intensity-modulated radiation therapy yielded less toxicity than 3-dimensional conformal radiation therapy.


Positive drug screen for benzodiazepine due to a chinese herbal product.
A female athlete tested positive for benzodiazepine on a random drug screen. She denied taking any illicit or prescription drugs. The positive screen was found to be caused by undeclared addiction of diazepam to a Chinese herbal product, "Miracle Herb." Some foreign vitamins, health care products, or herbal tea may contain banned or dangerous additives unknown to the consumer. These additives may include ingredients such as benzodiazepine, mefenamic acid, or corticosteroids. Possible physical harm may result when using products containing these undeclared additives. Team physicians and athletic trainers should educate athletes about the purchase and use of vitamins, herbal teas, and substances that are perceived to be performance-enhancing products, especially those manufactured outside the United States.


Sonic hedgehog is not required for polarising activity in the Doublefoot mutant mouse limb bud.
The mouse mutant Doublefoot (Dbf) shows preaxial polydactyly of all four limbs. We have analysed limb development in this mutant with respect to morphogenesis, gene expression patterns and ectopic polarising activity. The results reveal a gain-of-function mutation at a locus that mediates pattern formation in the developing limb. Shh expression is identical with that of wild-type embryos, i.e. there is no ectopic expression. However, mesenchyme from the anterior aspects of Dbf/+ mutant limb buds, when transplanted to the anterior side of chick wing buds, induces duplication of the distal skeletal elements. Mid-distal mesenchymal transplants from early, but not later, Dbf/+ limb buds are also able to induce duplication. This demonstration of polarising activity in the absence of Shh expression identifies the gene at the Dbf locus as a new genetic component of the Shh signalling pathway, which (at least in its mutated form) is able to activate signal transduction independently of Shh. The mutant gene product is sufficient to fulfil the signalling properties of Shh including upregulation of the direct Shh target genes Ptc and Gli, and induction of the downstream target genes Bmp2, Fgf4 and Hoxd13. The expression domains of all these genes extend from their normal posterior domains into the anterior part of the limb bud without being focused on a discrete ectopic site. These observations dissociate polarising activity from Shh gene expression in the Dbf/+ limb bud. We suggest that the product of the normal Dbf gene is a key active constituent of the polarising region, possibly acting in the extracellular compartment.


Isolation and characterization of murine orthologue of PTP-BK.
We isolated and characterized a murine orthologue of PTP-BK, a receptor-type protein tyrosine phosphatase expressed in brain and kidney. The deduced amino acid sequences showed 89, 95, and 92% identities with human, rabbit, and chicken homologues of PTP-BK. Mouse PTP-BK encodes a polypeptide of 1,226 amino acids with calculated molecular weight of 138,598 Da. The mature form of PTP-BK constitutes of 3 domain structures including extracellular, transmembrane, and a single intracellular PTPase domain. Western blot analysis indicated that anti-PTP-BK antibody specifically immunoreacted to 2 distinct molecules of 200 kDa and 220 kDa in COS cells, possibly due to differential glycosylation. The recombinant PTP-BK showed the phosphatase activity specific for the phosphotyrosine, but not for the phosphoserine residue of phosphopeptides in vitro. Radiation hybrid panel assigned mouse PTP-BK gene to 5.02cR distal to from the marker D6Mit339 on chromosome 6. Mouse PTP-BK was classified in PTPRO family in novel nomenclature. We discuss here the diversity and physiological functions of PTPRO family of PTP.


Control of transgenesis in higher cells: the procell transposon Tn10 TetR mRNA has several major hairpins and can be unstable in eucells.
The TetR regulatory gene from the transposon Tn10 has some excellent characteristics for transgenic control in higher cells. However, we experienced severe problems with mRNA instability for this gene in eucells (CHO cells). This may be connected with the existence within the Tn10 TetR mRNA of several sizeable hairpins. They resemble canonical RNase E sites for mRNA destabilisation in procells and possibly also in eucells. Two of the hairpins also included sequences resembling eucell hnRNA polyadenylation or processing signals. The TetR counterpart from the plasmid RA1 appears to have less of the hairpin secondary structure; perhaps because of this, it did not present these mRNA instability problems in CHO cells, and it may prove a valuable alternative for transgene control in gene therapy and biotechnology.


Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription.
Over 15 inherited diseases are caused by expansion of triplet-repeats. Friedreich ataxia (FRDA) patients are homozygous for an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. The expanded GAA triplet-repeat results in deficiency of FXN gene transcription, which is reversed via administration of histone deacetylase inhibitors indicating that transcriptional silencing is at least partially due to an epigenetic abnormality. We found a severe depletion of the chromatin insulator protein CTCF (CCCTC-binding factor) in the 5'UTR of the FXN gene in FRDA, and coincident heterochromatin formation involving the +1 nucleosome via enrichment of H3K9me3 and recruitment of heterochromatin protein 1. We identified FAST-1 (FXNAntisense Transcript - 1), a novel antisense transcript that overlaps the CTCF binding site in the 5'UTR, which was expressed at higher levels in FRDA. The reciprocal relationship of deficient FXN transcript and higher levels of FAST-1 seen in FRDA was reproduced in normal cells via knockdown of CTCF. CTCF depletion constitutes an epigenetic switch that results in increased antisense transcription, heterochromatin formation and transcriptional deficiency in FRDA. These findings provide a mechanistic basis for the transcriptional silencing of the FXN gene in FRDA, and broaden our understanding of disease pathogenesis in triplet-repeat diseases.


A Simple High Efficiency Protocol for Pancreatic Islet Isolation from Mice.
Pancreatic islets, also called the Islets of Langerhans, are a cluster of endocrine cells which produces hormones for glucose regulation and other important biological functions. The islets primarily consist of five types of hormone-secreting cells: α cells secrete glucagon, β cells secrete insulin, δ cells secrete somatostatin, ε cells secrete ghrelin, and PP cells secrete pancreatic polypeptide. Sixty to 80% of the cells in the islets are β cells, which are the most important cell population to study insulin secretion. Pancreatic islets are a crucial model system to study ex vivo insulin secretion. Acquiring high quality islets is of great importance for diabetes research. Most islet isolation procedures require technically difficult to access site of collagenase injection, harsh and complex digestion procedures, and multiple density gradient purification steps. This paper features a simple high yield mouse islet isolation method with detailed descriptions and realistic demonstrations, showing the following specific steps: 1) injection of collagenase P at the ampulla of Vater, a small area joining the pancreatic duct and the common bile duct, 2) enzymatic digestion and mechanical separation of the exocrine pancreas, and 3) a single gradient purification step. The advantages of this method are the injection of digestive enzyme using the more accessible ampulla of Vater, more complete digestion using combination of enzymatic and mechanical approaches, and a simpler single gradient purification step. This protocol produces approximately 250-350 islets per mouse; and islets are suitable for various ex vivo studies. Possible caveats of this procedure are potentially damaged islets due to enzymatic digestion and/or prolonged gradient incubation, all of which can be largely avoided by careful ad justification of incubation time.


[Modified warden procedure for partial anomalous pulmonary venous connection in an adult].
A 46-year-old woman was admitted to our hospital because of congestive heart failure and atrial fibrillation. She had undergone atrial septal defect repair at the age of 7 years. Computed tomography( CT)scan revealed right upper pulmonary vein returned to superior vena cave and the left upper pulmonary vein returned to the innominate vein. Cardiac catheterization showed Qp/Qs of 2.6. Pulmonary venous drainage repair and right-sided maze procedure was planned. The right upper pulmonary vein was led to the left atrium using the modified Warden Procedure. The left upper pulmonary vein was divided and anastomosed to the left atrial appendage. Concomitantly right-sided maze procedure was performed. Postoperative course was uneventful and CT scan revealed no stenosis at anastomotic sites. Sinus rhythm was retained and she was discharged on postoperative day 30.


An industry in pain.
The pharmaceutical industry, buffeted by marketplace changes and unprecedented political pressure, is far from united as it heads into the mother of all lobbying battles.


Modeling admissible behavior using event signals.
We describe here how to obtain a model for the admissible behavior of a discrete event system that is represented by a safe Petri net (PN) model. The transitions of this PN model may be controllable or uncontrollable. Also given is a sequential specification which is modeled with a special state machine. Then, using the condition and event arcs of net condition/event systems, a combined model of plant and specification is obtained. We use only the structure of this combined model to develop a method which gives the admissible behavior of the system. Thus, we avoid the complexity of a complete state enumeration.


Structure of a Lys49-phospholipase A2 homologue isolated from the venom of Bothrops nummifer (jumping viper).
Lys49-Phospholipase A2 (Lys49-PLA2) homologues damage membranes by a Ca2+-independent mechanism which does not involve catalytic activity. We have solved the structure of myotoxin-I, a Lys49-PLA2 homologue isolated from the venom of Bothrops nummifer (jumping viper) at 2.4 A resolution using molecular replacement techniques. The final model has been refined to a final R-factor of 18.4% (R-free = 23.2%), and shows excellent geometry. The myotoxin-I from Bothrops nummifer is dimeric in the crystalline state as has been observed for other Lys49-PLA2 homologues. In addition, a continuous electron density in the active site and substrate binding channel could be successfully modeled as a fatty-acid molecule.


The initiation of the swing phase in human infant stepping: importance of hip position and leg loading.
Hip extension and low load in the extensor muscles are important sensory signals that allow a decerebrate or spinal cat to advance from the stance phase to the swing phase during walking. We tested whether the same sensory information controlled the phases of stepping in human infants. Twenty-two infants between the ages of 5 and 12 months were studied during supported stepping on a treadmill. Forces exerted by the lower limbs, surface electromyography (EMG) from muscles, and the right hip angle were recorded. The whole experimental session was videotaped. The hip position and the amount of load experienced by the right limb were manipulated during stepping by changing the position of the foot during the stance phase or by applying manual pressure on the pelvic crest. Disturbances with different combinations of hip position and load were used. The stance phase was prolonged and the swing phase delayed when the hip was flexed and the load on the limb was high. In contrast, stance phase was shortened and swing advanced when the hip was extended and the load was low. The results were remarkably similar to those in reduced preparations of the cat. They thus suggest that the behaviour of the brainstem and spinal circuitry for walking may be similar between human infants and cats. There was an inverse relationship between hip position and load at the time of swing initiation, indicating the two factors combine to regulate the transition.


Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins.
Regulators of G protein signaling (RGS) proteins are potent negative modulators of G protein signaling and have been proposed as potential targets for small-molecule inhibitor development. We report a high-throughput time-resolved fluorescence resonance energy transfer screen to identify inhibitors of RGS4 and describe the first reversible small-molecule inhibitors of an RGS protein. Two closely related compounds, typified by CCG-63802 [((2E)-2-(1,3-benzothiazol-2-yl)-3-[9-methyl-2-(3-methylphenoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]prop-2-enenitrile)], inhibit the interaction between RGS4 and Galpha(o) with an IC(50) value in the low micromolar range. They show selectivity among RGS proteins with a potency order of RGS 4 > 19 = 16 > 8 >> 7. The compounds inhibit the GTPase accelerating protein activity of RGS4, and thermal stability studies demonstrate binding to the RGS but not to Galpha(o). On RGS4, they depend on an interaction with one or more cysteines in a pocket that has previously been identified as an allosteric site for RGS regulation by acidic phospholipids. Unlike previous small-molecule RGS inhibitors identified to date, these compounds retain substantial activity under reducing conditions and are fully reversible on the 10-min time scale. CCG-63802 and related analogs represent a useful step toward the development of chemical tools for the study of RGS physiology.


Effect of Helicobacter pylori status on intragastric pH during administration of lafutidine or famotidine.
There has been no study attempting to compare the effects of lafutidine, a novel H2-receptor antagonist and other H2-receptor antagonists in the same subjects and relating them to H. pylori status. The first aim of this study was to investigate the effect of H. pylori status on intragastric pH in healthy volunteers receiving lafutidine or famotidine. The second aim was to compare the effects of the two antisecretory drugs. The study was carried out in 11 healthy asymptomatic male volunteers. H. pylori infection was present in 5 subjects. Subjects were first examined by an ambulatory pH monitoring for 24 hours without medication. The second and third 24-hour pH monitoring study was performed on all subjects. Subjects took 10 mg lafutidine or 20mg famotidine at 9:00 and 21:00. During administration of lafutidine or famotidine, the percentage of period holding intragastric pH >4 was not significantly different between the H. pylori-negative and -positive subjects. Among the H. pylori negative subjects, the percentage of daytime period holding intragastric pH >4 was significantly greater with lafutidine than with famotidine (p < 0.05). The effect of lafutidine to increase intragastric pH was not affected by the H. pylori status. Among H. pylori-negative subjects, lafutidine was proven to be more effective than famotidine for acid control during the daytime in Japanese healthy volunteers.


Microscope and Fiberscope-assisted Subarachnoid-Subarachnoid (S-S) Bypass: A Novel Surgical Technique to Reestablish Cerebrospinal Fluid Flow in Treating Dorsal Spinal Arachnoid Webs, Diagnosed by Cine-MRI.
A "dorsal spinal arachnoid web" is the thickened arachnoid band on the surface of the spinal cord which disturbs the cerebrospinal fluid (CSF) flow, known as a rare cause of thoracic myelopathy. The ideal treatment is controversial because of the risk of readhesion after simple resection of the web. A subarachnoid-subarachnoid bypass is a method to reestablish CSF flow through a silicon tube between the cranial and caudal subarachnoid space. This method is reported to be useful for traumatic syringomyelia, adhesive arachnoiditis, etc. We applied this technique for arachnoid webs with the assistance of a microscope and fiberscope. After a dura incision, the thickened arachnoid web can be seen fluttering within the CSF flow inside the arachnoid space, which partitions the subarachnoid space into cranial and caudal parts. After opening the subarachnoid space and resection of the web under a microscope, the fiberscope is inserted toward the cranial and caudal directions to check for the presence of another arachnoid web. If another web is found, it is penetrated using a guiding wire. Then, a silicone tube is inserted into the cranial and caudal normal subarachnoid space. In this paper, we would like to introduce this technique.


[Use of cryogenic technic for the treatment of tumors of the oral cavity and pharynx].
To achieve cryodestruction of neoplastic tissues or preliminary freezing tumours for reducing bleedings cryogenic technique was employed in the treatment of 60 patients with buccal and pharyngeal neoplasms. Cryogenic action on the buccal and pharyngeal newgrowths is a promising method of therapy, and for it most suitable is cryoprobe. Recommendations for further improvement of cryogenic instruments are given.


Heat-induced superaggregation of amphotericin B reduces its in vitro toxicity: a new way to improve its therapeutic index.
Superaggregation of amphotericin B (AmB) was previously shown to occur upon heating of solutions at 70 degrees C. In the present study, we demonstrate that heat pretreatment of Fungizone (deoxycholate salt of AmB [AmB-DOC]) solutions induces a drastic decrease in the in vitro toxicity of this antibiotic. Heated AmB-DOC colloidal solutions, which mainly contained superaggregated and monomeric forms of the antibiotic, were strongly less hemolytic than unheated solutions (aggregates and monomers). Thermal pretreatment of AmB-DOC solutions also reduced the toxicity to the cell line HT29, as deduced from two simultaneous cell viability assays (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release). These heated colloidal solutions were only slightly less efficient than the unheated ones at inhibiting the growth of Candida albicans cells in vitro. Such results suggest that mild heat treatment of AmB-DOC solutions could provide a new and simple solution for improving the therapeutic index of this antifungal agent by reducing its toxicity to mammalian cells.


Cristae undergo continuous cycles of membrane remodelling in a MICOS-dependent manner.
The mitochondrial inner membrane can reshape under different physiological conditions. How, at which frequency this occurs in living cells, and the molecular players involved are unknown. Here, we show using state-of-the-art live-cell stimulated emission depletion (STED) super-resolution nanoscopy that neighbouring crista junctions (CJs) dynamically appose and separate from each other in a reversible and balanced manner in human cells. Staining of cristae membranes (CM), using various protein markers or two lipophilic inner membrane-specific dyes, further revealed that cristae undergo continuous cycles of membrane remodelling. These events are accompanied by fluctuations of the membrane potential within distinct cristae over time. Both CJ and CM dynamics depended on MIC13 and occurred at similar timescales in the range of seconds. Our data further suggest that MIC60 acts as a docking platform promoting CJ and contact site formation. Overall, by employing advanced imaging techniques including fluorescence recovery after photobleaching (FRAP), single-particle tracking (SPT), live-cell STED and high-resolution Airyscan microscopy, we propose a model of CJ dynamics being mechanistically linked to CM remodelling representing cristae membrane fission and fusion events occurring within individual mitochondria.


Basic principles for reconstruction of problem skin defects: trunk, head, and neck.
When dealing with skin defects, the veterinary surgeon should always use the simplest, least time consuming, least expensive techniques first and use the more involved techniques only as they are necessary. For closing skin defects the 3 techniques that can be used are: shifting local tissue; flaps, or grafts. Shifting local tissue to close skin defects is the simplest means of reconstruction. Because of the abundance of loose elastic skin on dogs and cats, many defects can be closed using either this technique or local skin flaps.


Remeasuring man.
Samuel George Morton (1799-1851) was the most highly regarded American scientist of the early and middle 19th century. Thanks largely to Stephen Jay Gould's book The Mismeasure of Man, Morton's cranial capacity measurements of different races is now held up as a prime example of and cautionary tale against scientific racism. A team of anthropologists recently reevaluated Morton's work and argued that it was Gould, not Morton, who was biased in his analysis. This article is a reexamination of the Morton and Gould controversy. It argues that most of Gould's arguments against Morton are sound. Although Gould made some errors and overstated his case in a number of places, he provided prima facia evidence, as yet unrefuted, that Morton did indeed mismeasure his skulls in ways that conformed to 19th century racial biases. Gould's critique of Morton ought to remain as an illustration of implicit bias in science.


On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease.
Different types of human gene mutation may vary in size, from structural variants (SVs) to single base-pair substitutions, but what they all have in common is that their nature, size and location are often determined either by specific characteristics of the local DNA sequence environment or by higher order features of the genomic architecture. The human genome is now recognized to contain "pervasive architectural flaws" in that certain DNA sequences are inherently mutation prone by virtue of their base composition, sequence repetitivity and/or epigenetic modification. Here, we explore how the nature, location and frequency of different types of mutation causing inherited disease are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment. The mutability of a given gene or genomic region may also be influenced indirectly by a variety of noncanonical (non-B) secondary structures whose formation is facilitated by the underlying DNA sequence. Since these non-B DNA structures can interfere with subsequent DNA replication and repair and may serve to increase mutation frequencies in generalized fashion (i.e., both in the context of subtle mutations and SVs), they have the potential to serve as a unifying concept in studies of mutational mechanisms underlying human inherited disease.


[Results of surgical treatment of epilepsy with bilateral temporal lesions].
Nineteen patients with recurrence of paroxysmal syndrome after temporal focus resection and 37--after stereotaxic destruction of amygdala nuclei from both sides operated in the periods of 1967-1984 and 1989-1999, respectively, were studied. Duration of follow up study was from 1 to 35 years. The results of the study were compared to a level of patient's "real work-status" at the moment of examination. Dynamic postoperative EEG investigation revealed a number of focal activity features. Specifically, there were lost of leading focus signs, moving of intensive epileptogenesis focus to the opposite side or primary revealing of contralateral focus in different postoperative periods. Such patients are in need of anticonvulsive medicine because of possibility of a relapse within 2 or 6 years after surgery. According to the results obtained, open surgical intervention in the leading epileptic focus (anterotemporal lobectomy) in patients with bilateral temporal foci seems to be inexpedient. One of the treatment methods is stereotaxic bilateral amygdalotomy.


[Reaction of intercellular contacts of the intestinal epithelium to a non-specific stress].
The influence of a short-term ischemia on the small intestinal epithelial cell contacts was studied in the rat. The cell contact condition was evaluated by the parameters of the paracellular ionic permeability and the cell adhesion. A severe diminution of the adhesion is noted immediately after the ischemia and during the next 4-8 h, after what it is replaced by an increase above the control values while the mitotic index is reduced. On the 4th day an increase of the mitotic index is accompanied by a new reduction of the cell adhesion. The fluctuation of the cell adhesion is always accompanied by a fall of the transepithelial resistance and a modification of the relative ionic permeability PNa/PCl. These and other data may be a sign of deep and long alterations in the enterocyte plasmic membranes as an answer to the ischemic trauma, as well as a proof of the influence of the cell contact state on the cellular turn-over.


High abundance of ammonia-oxidizing Archaea in coastal waters, determined using a modified DNA extraction method.
Molecular characterizations of environmental microbial populations based on recovery and analysis of DNA generally assume efficient or unbiased extraction of DNA from different sample matrices and microbial groups. Appropriate controls to verify this basic assumption are rarely included. Here three different DNA extractions, performed with two commercial kits (FastDNA and UltraClean) and a standard phenol-chloroform method, and two alternative filtration methods (Sterivex and 25-mm-diameter polycarbonate filters) were evaluated, using the addition of Nitrosopumilus maritimus cells to track the recovery of DNA from marine Archaea. After the comparison, a simplified phenol-chloroform extraction method was developed and shown to be significantly superior, in terms of both the recovery and the purity of DNA, to other protocols now generally applied to environmental studies. The simplified and optimized method was used to quantify ammonia-oxidizing Archaea at different depth intervals in a fjord (Hood Canal) by quantitative PCR. The numbers of Archaea increased with depth, often constituting as much as 20% of the total bacterial community.


Candida funiuensi sp. nov., a cellobiose-fermenting yeast species isolated from rotten wood.
Two strains of an asexual cellobiose-fermenting yeast species were isolated from rotten wood samples collected in Funiu Mountain Nature Reserve in Henan Province, central China. Molecular phylogenetic analysis that included the nearly complete small subunit (SSU), the internal transcribed spacer (ITS) region and the D1/D2 domains of the large subunit (LSU) rDNA showed that these strains belonged to the Candida kruisii clade, with Candida kruisii and Candida cretensis as their closest phylogenetic neighbours. The nucleotide differences between the novel strains and the type strains of C. kruisii and C. cretensis were 30 and 36 substitutions, respectively, in the D1/D2 LSU rDNA, 40 and 44 substitutions, respectively, in the ITS region and 19 and 23 substitutions, respectively, in the SSU rDNA. The novel strains can also be distinguished from their closest described species, C. kruisii and C. cretensis, by a number of physiological characteristics, and represent a novel species of the genus Candida, for which the name Candida funiuensis sp. nov. is proposed. The type strain is NYNU 14625T ( = CICC 33050T = CBS 13911T). The Mycobank number is MB 811503.


Differentiated hemodynamic changes controlled by splanchnic nerve.
The splanchnic (SPL) nerve is a postganglionic sympathetic nerve involved in the tonic regulation of the cardiovascular system. Electrical stimulation of this nerve produces mesenteric vasoconstriction and it has been assumed that vasodilatory responses are dependent on inhibition of the vasoconstrictor tone. Several different central stimuli have been shown to dilate the hindquarter vascular bed and constrict the mesenteric vascular bed. To determine whether vasodilatory and vasoconstrictor effects in different vascular beds are elicited by activation of different sympathetic nerves, we investigated the hemodynamic changes in hindquarter, mesenteric and renal vascular beds evoked by electrical stimulation of the SPL nerve. Stimulation of the intact or sectioned SPL nerve in chloralose-anesthetized, artificially ventilated rats evoked increases in the hindquarter vascular conductance and simultaneously decreased the mesenteric and renal vascular conductance. Intravenous (i.v.) administration of L-NAME prior to stimulation of the proximal end of the sectioned SPL nerve abolished the increase in hindquarter conductance, suggesting the involvement of nitric oxide in this response. In assessing the hemodynamic effects of tonic activity on the SPL nerves, no significant changes were observed after unilateral section of the SPL nerve, but bilateral section of the SPL nerves decreased hindquarter conductance and did not significantly change the mesenteric conductance simultaneously. No consistent response was observed in the renal vascular bed after unilateral and subsequent contralateral section of the SPL nerves. These findings demonstrate that electrical stimulation of the SPL nerve produces mesenteric vasoconstriction and simultaneous hindquarter vasodilatation, which is mediated by nitric oxide. Moreover, the present data suggest that SPL nerves may provide a tonic vasodilatory tone in the hindquarter vascular bed and simultaneously a vasoconstrictor tone in another, undetermined vascular bed.


GASTON: an architecture for the acquisition and execution of clinical guideline-application tasks.
Recently, studies have shown the benefits of using clinical guidelines in the practice of medicine. There have been numerous efforts to develop clinical decision support systems that support guideline-based care in an automated fashion, covering a wide range of clinical settings and tasks. Despite these efforts, only a few systems progressed beyond the prototype stage and the research laboratory. For guideline-based clinical decision support systems to be successful, a balance must be made between intuitive but imprecise representations usually encountered by most of today's systems and representations that support a strong underlying clinical performance model. The project described in this paper tries to achieve such a balance. It presents the GASTON architecture that contains a set of reusable software components for the application of guidelines, including design-time components to facilitate the guideline authoring process based on guideline representation models along with execution-time components for building decision support systems that incorporate these guidelines. This architecture was used to develop several guideline representation models such as a rule-based representation to model rule-based guidelines and guideline representation models that address more complex tasks. Also, decision support systems that incorporate these models were developed with the architecture. For the representation and application of various classes of guidelines, rules were also viewed as instances of more complex tasks. By identifying similar characteristics of sets of rules, we developed several tasks such as a drug intera ction and drug contraindication task. Based on these models, we have developed and validated guidelines and decision support systems for use in several application domains such as intensive care, family physicians and psychiatry. In order to be able to represent more complex time-oriented plans, new guideline representation models are being developed.


Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: impact on staging, disease-free survival, and outcome: a plea for adaptation of TNM classification in upper-half esophageal carcinoma.
To determine the impact of esophagectomy with 3-field lymphadenectomy on staging, disease-free survival, and 5-year survival in patients with carcinoma of the esophagus and gastroesophageal junction (GEJ). Esophagectomy with 3-field lymphadenectomy is mainly performed in Japan. Data from Western experience with 3-field lymphadenectomy are scarce and dealing with relatively small numbers. As a result, its role in the surgical practice of cancer of the esophagus and GEJ remains controversial. Between 1991 and 1999, primary surgery with 3-field lymphadenectomy was performed in 192 patients, of whom a cohort of 174 R0 resections was used for further analysis. Hospital mortality of the whole series was 1.2%. Overall morbidity was 58%. Pulmonary complications occurred in 32.8%, cardiac dysrhythmias in 10.9%, and persistent recurrent nerve problems in 2.6%. pTNM staging was as follows: stage 0, 0.6%; stage I, 9.2%; stage II, 27.6%; stage III, 28.7%; and stage IV, 33.9%. Overall 3- and 5-year survival was 51% and 41.9%, respectively. The 3- and 5-year disease-free survival was 51.4% and 46.3%, respectively. Locoregional lymph node recurrence was 5.2%; no patient developed an isolated cervical lymph node recurrence. Five-year survival for node-negative patients was 80.2% versus 24.5% for node-positive patients. Five-year survival by stage was 100% in stages 0 and I, 59.1% in stage II, 36.8% in stage III, and 13.3% in stage IV. Twenty-three percent of the patients with adenocarcinoma (25.8% distal third and 17.6% GEJ) and 25% of the patients with squamous cell carcinoma (26.2% middle third) had positive cervical nodes resulting in a change of pTNM staging specifically related to the unforeseen cervical lymph node involvement in 12%. Cervical lymph node involvement was unforeseen in 75.6% of patients with cervical nodes at pathologic examinations. Five-year survival for patients with positive cervical nodes was 27.7% for middle third squamous cell carcinoma. For distal third adenocarcinomas, 4-year survival was 35.7% and 5-year survival 11.9%. No GEJ adenocarcinoma with positive cervical nodes survived for 5 years. Esophagectomy with 3-field lymph node dissection can be performed with low mortality and acceptable morbidity. The prevalence of involved cervical nodes is high, regardless of the type and location of tumor resulting in a change of final staging specifically related to the cervical field in 12% of this series. Overall 5-year and disease-free survival after R0 resection of 41.9% and 46.3%, respectively, may indicate a real survival benefit. A 5-year survival of 27.2% in patients with positive cervical nodes in middle third carcinomas indicates that these nodes should be considered as regional (N1) rather than distant metastasis (M1b) in middle third carcinomas. These patients seem to benefit from a 3-field lymphadenectomy. The role of 3-field lymphadenectomy in distal third adenocarcinoma remains investigational.


Hyperglycaemia at admission in acute coronary syndrome patients: prognostic value in diabetics and non-diabetics.
To evaluate the impact of admission glycaemia on short-term and long-term prognosis in diabetic and non-diabetic patients admitted for acute coronary syndromes (ACS), and to identify the independent predictors of post-ACS mortality in this population. This study included 1149 consecutive patients admitted to a single coronary care unit for ACS between May 2004 and December 2006. Our population was divided into four groups according to the quartiles of glycaemia at admission [Q1 <5.77 mmol/l, Q2 (5.77-7.0) mmol/l, Q3 (7.0-9.22) mmol/l and Q4 > or =9.22 mmol/l]. Diabetic (n = 396) and non-diabetic (n = 753) subgroups were then separately analysed. Hyperglycaemia at admission was associated with worse cardiovascular risk profile, high levels of necrosis and inflammation biomarkers and low left ventricle ejection fraction. Considering overall population, in-hospital, 30-day and 3-year mortalities were higher in more elevated glycaemia quartiles. In diabetic patients, there were no significant differences in mortality among glycaemia quartiles; however, in non-diabetic group higher admission glucose levels were associated with successively higher in-hospital and 3-year mortalities. After multivariate regression analysis, glycaemia at admission > or =5.77 mmol/l, age > or =72 years, Killip class >1 and troponin I > or =6.0 ng/ml were independent predictors of in-hospital mortality. This study suggests that, in a broad ACS population, hyperglycaemia at admission is a short-term and long-term bad prognosis marker, particularly in non-diabetic patients, being a strong independent predictor of in-hospital mortality.


Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?
Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system. Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic). Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation. One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia . Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells. The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release. This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R's role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception. We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoidmediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons. This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.


Secondary psychosis induced by metabolic disorders.
Metabolic disorders are not well-recognized by psychiatrists as a possible source of secondary psychoses. Inborn errors of metabolism (IEMs) are not frequent. Although their prompt diagnosis may lead to suitable treatments. IEMs are well-known to pediatricians, in particular for their most serious forms, having an early expression most of the time. Recent years discoveries have unveiled later expression forms, and sometimes very discreet first physical signs. There is a growing body of evidence that supports the hypothesis that IEMs can manifest as atypical psychiatric symptoms, even in the absence of clear neurological symptoms. In the present review, we propose a detailed overview at schizophrenia-like and autism-like symptoms that can lead practitioners to bear in mind an IEM. Other psychiatric manifestations are also found, as behavioral, cognitive, learning, and mood disorders. However, they are less frequent. Ensuring an accurate IEM diagnosis, in front of these psychiatric symptoms should be a priority, in order to grant suitable and valuable treatment for these pathologies.


The effect of Parkinson's disease and Huntington's disease on human visuomotor learning.
Visuomotor adaptation is often driven by error-based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning-free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB-independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non-EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia.


Transhemispheric exchange of Lyme disease spirochetes by seabirds.
Lyme disease is a zoonosis transmitted by ticks and caused by the spirochete Borrelia burgdorferi sensu lato. Epidemiological and ecological investigations to date have focused on the terrestrial forms of Lyme disease. Here we show a significant role for seabirds in a global transmission cycle by demonstrating the presence of Lyme disease Borrelia spirochetes in Ixodes uriae ticks from several seabird colonies in both the Southern and Northern Hemispheres. Borrelia DNA was isolated from I. uriae ticks and from cultured spirochetes. Sequence analysis of a conserved region of the flagellin (fla) gene revealed that the DNA obtained was from B. garinii regardless of the geographical origin of the sample. Identical fla gene fragments in ticks obtained from different hemispheres indicate a transhemispheric exchange of Lyme disease spirochetes. A marine ecological niche and a marine epidemiological route for Lyme disease borreliae are proposed.


European Code against Cancer 4th Edition: Ultraviolet radiation and cancer.
Ultraviolet radiation (UVR) is part of the electromagnetic spectrum emitted naturally from the sun or from artificial sources such as tanning devices. Acute skin reactions induced by UVR exposure are erythema (skin reddening), or sunburn, and the acquisition of a suntan triggered by UVR-induced DNA damage. UVR exposure is the main cause of skin cancer, including cutaneous malignant melanoma, basal-cell carcinoma, and squamous-cell carcinoma. Skin cancer is the most common cancer in fair-skinned populations, and its incidence has increased steeply over recent decades. According to estimates for 2012, about 100,000 new cases of cutaneous melanoma and about 22,000 deaths from it occurred in Europe. The main mechanisms by which UVR causes cancer are well understood. Exposure during childhood appears to be particularly harmful. Exposure to UVR is a risk factor modifiable by individuals' behaviour. Excessive exposure from natural sources can be avoided by seeking shade when the sun is strongest, by wearing appropriate clothing, and by appropriately applying sunscreens if direct sunlight is unavoidable. Exposure from artificial sources can be completely avoided by not using sunbeds. Beneficial effects of sun or UVR exposure, such as for vitamin D production, can be fully achieved while still avoiding too much sun exposure and the use of sunbeds. Taking all the scientific evidence together, the recommendation of the 4th edition of the European Code Against Cancer for ultraviolet radiation is: "Avoid too much sun, especially for children. Use sun protection. Do not use sunbeds."


Effect of antimicrobials administered via liquid feed on the occurrence of sulphonamide and trimethoprim resistant Enterobacteriaceae: case-control study.
Drugs for the treatment of groups of pigs receiving liquid feed are frequently mixed into the feed and administered via the pipelines of the feeding installations. In-feed antimicrobials may select antimicrobial resistant strains among the bacteria which form the biofilm of these pipelines and are shed into the liquid feed. In order to evaluate the risk of selecting antimicrobial resistant bacteria in the biofilm of liquid feeding installations, the effect of the administration of antimicrobials via the pipelines on the occurrence of antimicrobial resistance in the feed was examined in a case-control study. A premix containing either sulphonamide plus trimethoprim or sulphonamide plus chlortetracycline plus tylosin or chlortetracycline was administered via the pipelines to each batch of bought-in fattening pigs in 7, 3 and 3 case farms respectively, whereas antimicrobials had not been administered via the liquid feeding installation for at least 2 years in the 14 control farms. Enterobacteriaceae and sulphonamide-trimethoprim resistant Enterobacteriaceae were counted in twelve and eight feed samples collected in each case and in each control farm respectively during one fattening period. The semiparametric Generalized Estimating Equations (GEE) method was used for the statistical data analysis. The ratio of sulphonamide and trimethoprim resistant to total Enterobacteriaceae was higher in the feed of the case farms compared to the control farms (P < 0.001) and did not decrease after treatment during the fattening period. The administration of antimicrobials via the liquid feeding installation selects antibiotic resistant bacteria in the biofilm lining the pipelines, which may contaminate the liquid feed for extended periods and transmit their resistance genes to the gastrointestinal flora of the pigs. Alternatives to the administration of antimicrobials via pipelines of liquid feeding installations for group treatment should be developed.


Circulating microRNAs as biomarkers of acute stroke.
MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. Due to the complexity of the pathology, identifying stroke specific microRNAs has been a challenge. This study shows that microRNA profiles reflect not only the temporal progression of stroke but also the specific etiologies. A panel of 32 microRNAs, which could differentiate stroke etiologies during acute phase was identified and verified using a customized TaqMan Low Density Array (TLDA). Furthermore we also found 5 microRNAs, miR-125b-2*, -27a*, -422a, -488 and -627 to be consistently altered in acute stroke irrespective of age or severity or confounding metabolic complications. Differential expression of these 5 microRNAs was also observed in rat stroke models. Hence, their specificity to the stroke pathology emphasizes the possibility of developing these microRNAs into accurate and useful tools for diagnosis of stroke.


The Molecular Structure of Fibrinogen.
Seminars in Thrombosis and Hemostasis (STH) celebrates 50 years of publishing in 2024. To celebrate this landmark event, STH is republishing some archival material. This manuscript represents the first full paper ever published in STH. The manuscript published without an abstract, and essentially covered in considerable detail the molecular structure of fibrinogen, as was known at that time. Fittingly, it covers some historical perspectives, the physicochemical properties and structure of fibrinogen across several species of animals (including humans) and its transformation into fibrin. We hope the readers of STH enjoy this journey into the past. This manuscript is accompanied by a Commentary that reflects on this past, as well as the journey towards contemporary understanding of the molecular structure of fibrinogen. As this is a republication of archival material, transformed into a modern format, we apologise in advance for any errors introduced during this transformation.


[Immunomorphological identification of myoepithelial cells in mixed tumors of the mammary gland in dogs].
Myoepithelial cells (MC) in mixed tumors of the mammary gland in dogs were identified with the Coons indirect method with the aid of monospecific antiserum to smooth muscle myosin. In 2 of 5 observations, anaplastic carcinoma and adenocarcinomas were detected in the presence of a mixed tumor. Immunochemical study of the myoepithelium demonstrated varying fluorescence intensity and ununiform pattern of MC distribution in tumor tissue of the mammary gland. MC were detected in lobular structures in the form of islet accumulations or diffuse vegetations from cells with a poorly fluorescent rim of the cytoplasm. In the ducts with papillary epimyoepithelial proliferations, MC occupied the peripheral position, showing bright fluorescence of the cytoplasm and hypertrophied processes. The fluorescence intensity decreased as MC displaced towards the stroma or lumen of the ducts. The changeability of specific staining of the myoepithelium may attest to different levels of cell differentiation. The presence of immature forms of MC in mixed tumors is likely to be due to the modulatory character of cell differentiation and is determined by the totality of factors that apparently play the triggerring part in derepression of the genes of specific synthesis of smooth muscle proteins in undifferentiated cells of the epithelium of the terminal ducts and alveoli.


Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development.
Introduction: Over a decade of research and development culminated in the 2017 United States (US) Food and Drug Administration (FDA) approval of voretigene neparvovec-rzyl (VN) for RPE65 mutation-associated inherited retinal disease (IRD), the first approved gene therapy for a hereditary genetic disease in the US, and the first and only pharmacologic treatment for an IRD.Areas covered: VN serves as a model for ocular gene therapy development, while RPE65 mutation-associated IRD serves as an example of a well-suited candidate disorder. This review also discusses development considerations for viral vector gene augmentation, and, studies that led to VN's FDA approval. Subretinal injection of VN resulted in improved performance on the novel multi-luminance mobility test (MLMT), light sensitivity, and visual fields in patients with RPE65 mutation-associated IRD, which predominantly impairs rod function. Additionally, the dosage, administration technique, pharmacokinetics, and safety data of VN are reviewed.Expert Opinion: As a model for development, special challenges associated with the introduction of this first ocular gene therapy include limited genetic testing in clinical practice, novel surgical complexity of ocular gene therapy administration, new functional vision endpoints, as well as unique development, launch, and reimbursement considerations associated with orphan therapies and one-time gene therapies.


Single lung transplantation with cardiopulmonary bypass.
Single lung transplantation can rarely become complicated by hypoxia, hypercarbia and haemodynamic instability which requires extracorporeal support in order to conduct the transplant safely. The decision to use cardiopulmonary bypass must be taken by the surgeon and anaesthetist together after assessing the circumstances but should then be executed without delay. The need for bypass can sometimes be predicted before surgery or becomes obvious most often after induction of anaesthesia or at the time of clamping the pulmonary artery. The use of cardiopulmonary bypass for single lung transplantation is becoming less frequent as its use becomes increasingly confined to patients who have deteriorated significantly on the waiting list or those who are older. Peripheral cannulation of the femoral artery and vein with transoesophageal echocardiographic guidance of venous cannula position and the use of venous assisted drainage allows for rapid institution of cardiopulmonary bypass and an unobstructed operative field in the thorax. Alternatively, cannulation of the main pulmonary artery can be used to effect venous drainage or direct cannulation of the right atrium can be used if the transplant is to be undertaken on that side. Left thoracotomy permits cannulation of the aortic arch or descending aorta for arterial return. Under conditions of cardiopulmonary bypass with modest hypothermia single lung transplantation can proceed in safety. Although many have suggested adverse outcomes when lung transplantation is undertaken with bypass, several series have not indicated high incidences of significant complications. The likelihood of needing bypass may be suggested preoperatively by low right ventricular ejection fraction and poor 6-min walk test results in patients with restrictive lung pathology. This allows the surgeon and anaesthetist to predict problems and be more prepared to intervene with extracorporeal circulation.


[The effect of whole-body controlled hyperthermia on the energy resources of cancer patients].
The results of examination of 120 patients with advanced malignant melanoma, soft tissue sarcomas and lung and renal cancer suggest disturbance in mechanisms of energy supply during whole-body guided hyperthermia. Cell glucose uptake was inhibited in hyperglycemic patients. High energy loss in due to utilization of such alternative substrates as lipids and proteins which, in turn, potentiates peroxidation of lipids toxic to cell membranes. These data provide biochemical rationale for developing procedures aimed at managing biochemical dysbalance, increase in carbohydrate utilization included.


Isolation and properties of a Bacillus subtilis mutant unable to produce fructose-bisphosphatase.
A Bacillus subtilis mutation (gene symbol fdpA1), producing a deficiency of D-fructose-1,6-bisphosphate 1-phosphohydrolase (EC 22.214.171.124, fructose-bisphosphatase), was isolated and genetically purified. An fdpA1-containing mutant did not produce cross-reacting material. It grew on any carbon source that allowed growth of the standard strain except myo-inositol and D-gluconate. Because the mutant could grow on D-fructose, glycerol, or L-malate as the sole carbon source, B. subtilis can produce fructose-6-phosphate and the derived cell wall precursors from these carbon sources in the absence of fructose-bisphosphatase. In other words, during gluconeogenesis B. subtilis must be able to bypass this reaction. Fructose-bisphosphatase is also not needed for the sporulation of B., subtilis. The fdpA1 mutation has the pleiotropic consequence that mutants carrying it cannot produce inositol dehydrogenase (EC 22.214.171.124) and gluconate kinase (EC 126.96.36.199) under conditions that normally induce these enzymes.


Comparison of LCST-transitions of homopolymer mixture, diblock and statistical copolymers of NIPAM and VCL in water.
The LCST-transitions of linear, well-defined polymers of N-isopropylacrylamide (NIPAM) and N-vinylcaprolactam (VCL), including a homopolymer mixture, diblock and statistical copolymers, in water are explored and compared by applying turbidity and FTIR measurements in combination with two-dimensional correlation spectroscopy (2Dcos). Only one transition is observed in all polymer systems, suggesting a dependent aggregation of poly(N-isopropylacrylamide) (PNIPAM) and poly(N-vinylcaprolactam) (PVCL) parts in the phase transition processes. With the help of 2Dcos analysis, it is discovered that the hydrophobic interaction among C-H groups is the driving force for simultaneous collapse of the two distinct thermo-responsive segments. Additionally, the delicate differences within the LCST-transitions thereof have been emphasized, where the phase separation temperatures of the homopolymer mixture and the diblock copolymer are close while that of the statistical copolymer is relatively higher. Moreover, both diblock and statistical copolymers exhibit rather sharp phase transitions while the homopolymer mixture demonstrates a moderately continuous one.


Resistance to Plum pox virus strain C in Arabidopsis thaliana and Chenopodium foetidum involves genome-linked viral protein and other viral determinants and might depend on compatibility with host translation initiation factors.
Research performed on model herbaceous hosts has been useful to unravel the molecular mechanisms that control viral infections. The most common Plum pox virus (PPV) strains are able to infect Nicotiana species as well as Chenopodium and Arabidopsis species. However, isolates belonging to strain C (PPV-C) that have been adapted to Nicotiana spp. are not infectious either in Chenopodium foetidum or in Arabidopsis thaliana. In order to determine the mechanism underlying this interesting host-specific behavior, we have constructed chimerical clones derived from Nicotiana-adapted PPV isolates from the D and C strains, which differ in their capacity to infect A. thaliana and C. foetidum. With this approach, we have identified the nuclear inclusion a protein (VPg+Pro) as the major pathogenicity determinant that conditions resistance in the presence of additional secondary determinants, different for each host. Genome-linked viral protein (VPg) mutations similar to those involved in the breakdown of eIF4E-mediated resistance to other potyviruses allow some PPV chimeras to infect A. thaliana. These results point to defective interactions between a translation initiation factor and the viral VPg as the most probable cause of host-specific incompatibility, in which other viral factors also participate, and suggest that complex interactions between multiple viral proteins and translation initiation factors not only define resistance to potyviruses in particular varieties of susceptible hosts but also contribute to establish nonhost resistance.


An unusual lightning flash at kennedy space center.
A lightning flash that struck the 150-meter weather tower at Kennedy Space Center was studied by several research groups using varioul techniques. The flash had unusually large peak currents and a stepped leader of relatively short duration. The charged regions neutralized by the three return strokes were located within a horizontal layer between heights of about 6 and 8 kilometers, where environmental temperatures were about -10 degrees to -20 degrees C. The charge source for the first return stroke coincided with a vertical shaft of precipitation inferred to have been graupel or hail. Charge sources for subsequent strokes were near the edge of the detectable precipitation echo. The overall channel length was about 10 kilometers. A Vertically oriented intracloud discharge occurred after the three return strokes.