Role of insulin-like growth factor 1 (IGF1) in the regulation of mitochondrial bioenergetics in zebrafish oocytes: lessons from in vivo and in vitro investigations.
Optimal mitochondrial functioning is indispensable for acquiring oocyte competence and meiotic maturation, whilst mitochondrial dysfunction may lead to diminished reproductive potential and impaired fertility. The role of the intra-ovarian IGF system in ovarian follicular dynamics has been implicated earlier. Although several studies have demonstrated the role of the IGF axis in facilitating mitochondrial function over a multitude of cell lines, its role in oocyte energy metabolism remains largely unexplored. Here using zebrafish, the relative importance of IGF1 in modulating oocyte mitochondrial bioenergetics has been investigated. A dramatic increase in ovarian lhcgr and igf1 expression accompanied heightened ATP levels and mitochondrial polarization in full-grown (FG) oocytes resuming meiotic maturation and ovulation in vivo. Concomitant with elevated igf1 expression and IGF1R phosphorylation, hCG (LH analog) stimulation of FG follicles in vitro prompted a sharp increase in NRF-1 and ATP levels, suggesting a positive influence of gonadotropin action on igf1 expression vis-à-vis oocyte bioenergetics. While recombinant IGF1 administration enhanced mitochondrial function, IGF1R immunodepletion or priming with PI3K inhibitor wortmannin could abrogate NRF-1 immunoreactivity, expression of respiratory chain subunits, ΔΨM, and ATP content. Mechanistically, activation of PI3K/Akt signaling in IGF1-treated follicles corroborated well with the rapid phosphorylation of GSK3β at Ser9 (inactive) followed by PGC-1β accumulation. While selective inhibition of GSK3β promoted PGC-1β, Akt inhibition could abrogate IGF1-induced p-GSK3β (Ser9) and PGC-1β immunoreactive protein indicating Akt-mediated GSK3β inactivation and PGC-1β stabilization. The IGF1-depleted follicles showed elevated superoxide anions, subdued steroidogenic potential, and attenuated G2-M1 transition. In summary, this study highlights the importance of IGF1 signaling in oocyte bioenergetics prior to resumption of meiosis.


Clinical efficacy of Shilajatu (Asphaltum) processed with Agnimantha (Clerodendrum phlomidis Linn.) in Sthaulya (obesity).
Obesity is defined as the condition in which excessive amount of fat is accumulated in the body. Classical Ayurvedic texts describe eight types of despicable designated as 'Nindita purusha' including atisthaulya. Corpulent people are characterized by short in longevity, slow movement, difficult to indulge in sex, weak, emission of bad body odor, profuse perspiration, excessive hunger and excessive thirst. Sixty to seventy percent of cardiac patients die of obesity and contribute to develop coronary artery disease, diabetes mellitus, hypertension, hyperlipidaemia. In the present study, 66 patients of obesity were treated with Shilajatu processed with Agnimantha. After complition of therapy, 5.09 ± 0.24 kg and 2.06 ± 0.10 kg/m(2) reduction of body weight and body mass index, respectively were noted. The result was found to be statistically highly significant (P<0.001). No adverse effects were observed in any of the treated patients.


Comparison of reverse transcription polymerase chain reaction, immunohistochemistry, and in situ hybridization for the detection of porcine epidemic diarrhea virus in pigs.
Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and in situ hybridization were compared for the detection of porcine epidemic diarrhea virus (PEDV). Fifteen piglets experimentally infected with PEDV were used in the study. In addition, 94 diarrheic piglets submitted to the Department of Veterinary Pathology in Seoul National University for diagnosis of PEDV infection were used to compare the 3 methods. Antigen and nucleic acid of PEDV were detected in 15/15, 13/15, and 14/15 of the intestinal and fecal samples from the PEDV-inoculated pigs by RT-PCR, immunohistochemistry, and in situ hybridization, respectively. The virus was isolated from 15/15 of the jejunal samples from the PEDV-inoculated pigs. Neither PEDV antigen nor PEDV nucleic acid was detected in the intestinal and fecal samples from mock-infected control pigs. Of the 94 samples, 63 were positive for PEDV by all 3 techniques. Six samples were positive for PEDV by immunohistochemistry and in situ hybridization. Three samples were positive for PEDV by in situ hybridization and RT-PCR. Seven samples were positive for PEDV by RT-PCR. Although RT-PCR identified the presence of PEDV more frequently than the other methods, when only formalin-fixed tissues are submitted, immunohistochemistry and in situ hybridization would be useful methods for the detection of PEDV antigen and nucleic acid.


Case III: Managing conflict--the case of the faculty stuck in the middle.
The need for administrative faculty members to have superior leadership and management skills to handle their increasingly complex responsibilities is well established. As a part of the 2000-01 ADEA Leadership Institute curriculum, fellows were responsible for developing situational case studies for a faculty development workshop to develop participants' leadership and management skills. The case presented here involved managing conflicts in the dental academic setting. The foundation of conflict management centers on communication techniques including transparent communication, open discussion, open confrontation, and active listening. Management options such as avoidance, accommodation, competition, negotiation, and collaboration are potential strategies for the faculty leader. This case study involves a fictitious public dental school, New Horizons University, which has embarked on solutions to address limited resources, but unwittingly has created conflicts between individuals and groups of faculty members. The case discussion analyzes the cause of conflicts, presents the positive and negative potential of the conflicts, reviews techniques of conflict management, and discusses specific management concepts regarding resource allocation and equity theory.


Synthesis and Biological Evaluation of Polar Functionalities Containing Nitrodihydroimidazooxazoles as Anti-TB Agents.
Novel polar functionalities containing 6-nitro-2,3-dihydroimidazooxazole (NHIO) analogues were synthesized to produce a compound with enhanced solubility. Polar functionalities including sulfonyl, uridyl, and thiouridyl-bearing NHIO analogues were synthesized and evaluated against Mycobacterium tuberculosis (MTB) H37Rv. The aqueous solubility of compounds with MIC values ≤0.5 μg/mL were tested, and six compounds showed enhanced aqueous solubility. The best six compounds were further tested against resistant (Rif(R) and MDR) and dormant strains of MTB and tested for cytotoxicity in HepG2 cell line. Based on its overall in vitro characteristics and solubility profile, compound 6d was further shown to possess high microsomal stability, solubility under all tested biological conditions (PBS, SGF and SIF), and favorable oral in vivo pharmacokinetics and in vivo efficacy.


Vertical Habitat Stratification in Sympatric and Allopatric Populations of Aedes hendersoni and Aedes triseriatus (Diptera: Culicidae).
Vertical habitat stratification in populations of Aedes hendersoni Cockerell (Diptera: Culicidae) and Aedes triseriatus (Say) (Diptera: Culicidae) has been observed to varying degrees throughout the species' sympatric range, and potential causes of the phenomenon, including species competition and interaction, have been debated extensively. Stratification patterns in oviposition in allopatric, sympatric, and marginally sympatric populations of both species were investigated and compared in this research to detect any pattern differences related to species composition. Expected patterns were observed in sympatric populations, with Ae. hendersoni preferentially ovipositing in canopy habitats, whereas Ae. triseriatus preferred basal habitats. Allopatric populations presented a strong shift toward basal preference in the former and a slighter but significant shift toward canopy in the latter. Marginal populations of Ae. hendersoni showed intermediate height preferences, whereas preferences of marginal and sympatric Ae. triseriatus did not differ. The convergence of habitat selection in allopatric populations and corresponding divergence in sympatric populations support interspecific competition-based hypotheses regarding the origin of the stratification phenomenon, although plausible alternative or contributing explanations are numerous and warrant further study.


Role of the teneurins, teneurin C-terminal associated peptides (TCAP) in reproduction: clinical perspectives.
In humans, the teneurin gene family consists of four highly conserved paralogous genes that are the result of early vertebrate gene duplications arising from a gene introduced into multicellular organisms from a bacterial ancestor. In vertebrates and humans, the teneurins have become integrated into a number of critical physiological systems including several aspects of reproductive physiology. Structurally complex, these genes possess a sequence in their terminal exon that encodes for a bioactive peptide sequence termed the 'teneurin C-terminal associated peptide' (TCAP). The teneurin/TCAP protein forms an intercellular adhesive unit with its receptor, latrophilin, an Adhesion family G-protein coupled receptor. It is present in numerous cell types and has been implicated in gamete migration and gonadal morphology. Moreover, TCAP is highly effective at reducing the corticotropin-releasing factor (CRF) stress response. As a result, TCAP may also play a role in regulating the stress-associated inhibition of reproduction. In addition, the teneurins and TCAP have been implicated in tumorigenesis associated with reproductive tissues. Therefore, the teneurin/TCAP system may offer clinicians a novel biomarker system upon which to diagnose some reproductive pathologies.


Primary PNET of kidney: report of two cases and review of literature.
PNET of the kidney is a rare tumor with only a few published reports. In view of poorer prognosis and different therapeutic approach, renal PNET should therefore be differentiated from other primary renal neoplasma such as Wilms tumor, renal neuroblastoma and malignant rhabdoid tumor which on histology resemble renal PNET. Two cases of renal PNET have been described in this report. Cut surface of the tumor in both cases was greyish white lobulated, with multiple tiny cystic areas. Histologically, tumor consisted of loosely cohesive sheets of small to medium sized monomorphic cells with round nuclei and little cytoplasm. Tumor cells showed diffuse strong membrane positivity for MIC2 and focal weak to moderate positivity for NSE and vimentin. Renal PNET should therefore be included in differential diagnosis of rapidly enlarging renal lumps presenting with local infiltration and aggressive behaviour, particularly in children and young adults. Diffuse strong membrane positivity for MIC2 in PNET is helpful in differentiating it from other primary renal neoplasms.


Current Status of Family Medicine Faculty Development in Sub-Saharan Africa.
Reducing the shortage of primary care physicians in sub-Saharan Africa requires expansion of training programs in family medicine. Challenges remain in preparing, recruiting, and retaining faculty qualified to teach in these pioneering programs. Little is known about the unique faculty development needs of family medicine faculty within the sub-Saharan African context. The purpose of this study was to assess the current status and future needs for developing robust family medicine faculty in sub-Saharan Africa. The results are reported in two companion articles. A cross-sectional study design was used to conduct a qualitative needs assessment comprising 37 in-depth, semi-structured interviews of individual faculty trainers from postgraduate family medicine training programs in eight sub-Saharan African countries. Data were analyzed according to qualitative description. While faculty development opportunities in sub-Saharan Africa were identified, current faculty note many barriers to faculty development and limited participation in available programs. Faculty value teaching competency, but institutional structures do not provide adequate support. Sub-Saharan African family physicians and postgraduate trainee physicians value good teachers and recognize that clinical training alone does not provide all of the skills needed by educators. The current status of limited resources of institutions and individuals constrain faculty development efforts. Where faculty development opportunities do exist, they are too infrequent or otherwise inaccessible to provide trainers the necessary skills to help them succeed as educators.


The treatment of fistulas following irradiation damage.
Fistulas following irradiation treatment of uterine cancer present special problems. They are seldom isolated injuries. Because of the depressed response of connective tissue, direct repair can seldom be carried out. For rectovaginal fistulas a defunctioning colostomy is the usual first stage, and this may in time result in spontaneous closure. Repair can only be achieved by carefully planned operations where non-irradiated tissue is used to close the defect.


Cyclic changes in the pituitary gland in correlation with the testicular cycle in a hill-stream teleost, Schizothorax richardsonii (Gray and Hard).
In Schizothorax richardsonii, the pituitary gland has been studied in correlation with the phases of the testicular cycle. The cyanophils of the proximal pars distalis show hypertrophy, hyperplasia, granulation, degranulation and vacuolisation in concurrence with the spermatogenic cycle. Secretory activity of the cyanophils controls the maturation of testes, which indicates that these cyanophils are gonadotrops. The formation of sperm mother cells, however, does not appear to depend on the secretory activity of the pituitary. During spawning and regression phases, the azocarminophilous granules in the cytoplasm of the cyanophils show quantitative variation. The migratory chromophil cells show numerical variation, suggesting their involvement in the reproductive cycle. Neurosecretory material also appears to play some part in reproduction.


Electrospun nanofiber supported optodes: scaling down the receptor layer thickness to nanometers - towards 2D optodes.
A novel type of optode sensor is proposed using electrospun nanofibers as the supporting inert material. The proposed arrangement offers the possibility of a significant extension of the surface area of the probe while also minimizing the thickness of the receptor layer. This novel, close to 2D, optode configuration results in a sensor free from limitations related to analyte transport in the receptor phase. Unlike other formats, low analyte ion concentrations (10-8-10-5 M) were recorded, which are typically inaccessible for other formats of optodes, with a linear dependence of the emission signal on the logarithm of the analyte concentration. This effect results from a significant exhaustion of the analyte in the sample close to the interface with the sensor. On the other hand, as the ionophore surface concentration in the receptor was close to saturation, for a high concentration of the analyte (>10-5 M) in solution, the optode responses were observed with a sigmoidal dependence of the emission intensity on the logarithm of analyte concentration, independent of the applied ionophore contents in the 2D receptor phase. It was also shown that the response of the nanofiber supported liquid optode layer is reversible for the sigmoidal response range.


Collagen suppresses the proliferative phenotype of allylamine-injured vascular smooth muscle cells.
Repeated cycles of oxidative injury by allylamine induce proliferative rat vascular smooth muscle cell (vSMC) phenotypes characterized by enhanced secretion of osteopontin (OPN). The present study was designed to evaluate the role of extracellular matrix (ECM) interactions in the induction of proliferative phenotypes in this model of oxidant injury. Because OPN is involved in ECM/integrin signaling, and may participate in proliferative control, the proliferation profiles of control and allylamine vSMCs seeded on different matrices were compared. Allylamine cells exhibited a proliferative advantage over controls when seeded on plastic, Pronectin, or fibronectin, but not type I collagen. Addition of GRGDS peptide selectively enhanced [3H]-thymidine incorporation in allylamine vSMCs, while anti-OPN antibodies nullified their proliferative advantage. Allylamine cells exhibited altered expression of alpha1, alpha5 and beta3 integrin subunits and enhanced downstream integrin-coupled increases in focal adhesion kinase, AP-1 and NF-kappaB binding activity. Inhibition of NF-kappaB by pyrrolidine dithiocarbamate selectively compromised proliferation of allylamine vSMCs, while seeding on a non-permissive collagen matrix ablated enhancement of NF-kappaB inducibility. These results implicate ECM interactions in the deregulation of vSMC proliferation following repeated cycles of oxidative chemical injury.


Non-human primates: a comparative developmental perspective on yawning.
There is a long history of yawning in Old World monkeys being viewed as a form of communication, in particular, as a kind of threat. Yawning in agonistic and tense situations is seen in adult males, in particular, and it varies with male hormonal levels and social status. Experiments are reviewed that demonstrate operant control of the rate of yawning in adult male macaques, using food rewards. This indicates a degree of flexibility in the production of yawning. However, although adult male Old World monkeys often engage in 'canine contests', there is little evidence for the contagious yawning seen in humans. Experiments are reviewed showing that chimpanzees tested under comparable conditions to human adults, namely exposed to video sequences showing yawns, may yawn contagiously to yawn stimuli. Chimpanzees also yawn to computer animations of yawns. There is controversy in the literature over whether other species, including dogs and some monkeys, may also show contagious yawning. Further research is required to address unresolved issues. A hypothesis is put forward that in modern industrial society adults' natural pattern of yawning is inhibited, and that being reminded to yawn by seeing another individual yawn (contagious yawning) can help us to catch up on missed yawns. This would explain the lack of contagious yawning reported in young children and chimpanzees in natural surroundings, as these populations do not have the same social constraints on yawning.


Short and long-term effects of Baccharis articulata on glucose homeostasis.
In this study, the in vivo effect of the crude extract and n-butanol and aqueous residual fractions of Baccharis articulata (Lam.) Pers. on serum glucose levels, insulin secretion and liver and muscle glycogen content, as well as in vitro action on serum intestinal disaccharidase activity and albumin glycation were investigated. Oral administration of the extract and fractions reduced glycemia in hyperglycemic rats. Additionally, the n-butanol fraction, which has high flavonoids content, stimulated insulin secretion, exhibiting an insulinogenic index similar to that of glipizide. Also, the n-butanol fraction treatment significantly increased glycogen content in both liver and muscle tissue. In vitro incubation with the crude extract and n-butanol and aqueous residual fractions inhibited maltase activity and the formation of advanced glycation end-products (AGEs). Thus, the results demonstrated that B. articulata exhibits a significant antihyperglycemic and insulin-secretagogue role. These effects on the regulation of glucose homeostasis observed for B. articulata indicate potential anti-diabetic properties.


Population outcomes, trends and the future of pouch surgery for ulcerative colitis: a 19-year New South Wales data linkage study.
Ileal pouch-anal anastomosis (IPAA) is considered the gold standard reconstructive option in ulcerative colitis (UC). Recent efforts to improve pouch outcomes have seen a push towards centralisation of surgery. This study aimed to document outcomes following pouch surgery at a population level within New South Wales (NSW), and identify factors associated with, and temporal trends of these outcomes. A retrospective data linkage study of the NSW population over a 19-year period was performed. The primary outcome was pouch failure in patients with UC who underwent IPAA. The influence of hospital level factors (including annual volume) and patient demographic variables on this outcome were assessed using Cox proportional hazards modelling. Temporal trends in annual volume and evidence for centralisation over the studied period were assessed using Poisson regression analysis. The annual volume of UC pouches reduced over the study period. The pouch failure rates were 8.6% (95% CI 6.3-10.8%) and 10.6% (95% CI 8.0-13.1%) at 5- and 10-years, respectively. Increasing age and non-elective admission were associated with higher failure rates. One-third of UC pouches (31.6%) were performed in a single institution, which averaged 6.5 pouches/year throughout the study period. Three-quarters (19/25) of NSW public hospitals who performed pouches performed less than one UC pouch annually. The outcomes following UC pouch surgery in NSW are comparable with global standards. Concentrating IBD pouch surgery with the aim of producing specialist surgical teams may be a reasonable way forward in NSW and would ensure equity of access and facilitate research and training collaboration.


PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection.
The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-gamma-producing alloreactive T cells and expansion of effector CD8(+) T cells in the periphery, and a decline in the percentage of Foxp3(+) graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.


Freshwater fish diversity in the western Amazon basin shaped by Andean uplift since the Late Cretaceous.
South America is home to the highest freshwater fish biodiversity on Earth, and the hotspot of species richness is located in the western Amazon basin. The location of this hotspot is enigmatic, as it is inconsistent with the pattern observed in river systems across the world of increasing species richness towards a river's mouth. Here we investigate the role of river capture events caused by Andean mountain building and repeated episodes of flooding in western Amazonia in shaping the modern-day richness pattern of freshwater fishes in South America, and in Amazonia in particular. To this end, we combine a reconstruction of river networks since 80 Ma with a mechanistic model simulating dispersal, allopatric speciation and extinction over the dynamic landscape of rivers and lakes. We show that Andean mountain building and consequent numerous small river capture events in western Amazonia caused freshwater habitats to be highly dynamic, leading to high diversification rates and exceptional richness. The history of marine incursions and lakes, including the Miocene Pebas mega-wetland system in western Amazonia, played a secondary role.


Conformational coupling between the cytoplasmic carboxylic acid and the retinal in a fungal light-driven proton pump.
Many fungal rhodopsins, eukaryotic structural homologues of the archaeal light-driven proton pump bacteriorhodopsin, have been discovered in the course of genome sequencing projects. Recently, two fungal rhodopsins were characterized in vitro and exhibited very different photochemical behavior. Neurospora rhodopsin possesses a slow photocycle and shows no ion transport, reminiscent of sensory rhodopsins, while Leptosphaeria rhodopsin has a fast bacteriorhodopsin-like photocycle and pumps protons light-dependently. Such a dramatic difference is surprising considering the very high degree of sequence homology of the two proteins. In this paper, we investigate whether the chemical structure of a cytoplasmic carboxylic acid, the homologue of Asp-96 of bacteriorhodopsin serving as a proton donor for the retinal Schiff base, can define the photochemical properties of fungal rhodopsins. We studied mutants of Leptosphaeria rhodopsin in which this aspartic acid was replaced with Glu or Asn using spectroscopy in the infrared and visible ranges. We show that Glu at this position is inefficient as a proton donor similar to a nonprotonatable Asn. Moreover, this replacement induces long-range structural perturbations of the retinal environment, as evidenced by changes in the vibrational bands of retinal (especially, hydrogen-out-of-plane modes) and neighboring aspartic acids and water molecules. The conformational coupling of the mutation site to the retinal may be mediated by helical rearrangements as suggested by the changes in amide and proline vibrational bands. We conclude that the difference in the photochemical behavior of fungal rhodopsins from Leptosphaeria and Neurospora may be ascribed, to some extent, to the replacement of the cytoplasmic proton donor Asp with Glu.


Analysis of intra-uterine fluid motion induced by uterine contractions.
Evaluation of the fluid flow pattern in a non-pregnant uterus is important for understanding embryo transport in the uterus. Fertilization occurs in the fallopian tube and the embryo (fertilized ovum) enters the uterine cavity within 3 days of ovulation. In the uterus, the embryo is conveyed by the uterine fluid for another 3 to 4 days to a successful implantation site at the upper part of the uterus. Fluid movements within the uterus may be induced by several mechanisms, but they seem to be dominated by myometrial contractions. Intra-uterine fluid transport in a sagittal cross-section of the uterus was simulated by a model of wall-induced fluid motion within a two-dimensional channel. The time-dependent fluid pattern was studied by employing the lubrication theory. A comprehensive analysis of peristaltic transport resulting from symmetric and asymmetric contractions is presented for various displacement waves on the channel walls. The results provide information on the flow field and possible trajectories by which an embryo may be transported before implantation at the uterine wall.


Flow karyotyping of wheat-Aegilops additions facilitate dissecting the genomes of Ae. biuncialis and Ae. geniculata into individual chromosomes.
Breeding of wheat adapted to new climatic conditions and resistant to diseases and pests is hindered by a limited gene pool due to domestication and thousands of years of human selection. Annual goatgrasses (Aegilops spp.) with M and U genomes are potential sources of the missing genes and alleles. Development of alien introgression lines of wheat may be facilitated by the knowledge of DNA sequences of Aegilops chromosomes. As the Aegilops genomes are complex, sequencing relevant Aegilops chromosomes purified by flow cytometric sorting offers an attractive route forward. The present study extends the potential of chromosome genomics to allotetraploid Ae. biuncialis and Ae. geniculata by dissecting their M and U genomes into individual chromosomes. Hybridization of FITC-conjugated GAA oligonucleotide probe to chromosomes suspensions of the two species allowed the application of bivariate flow karyotyping and sorting some individual chromosomes. Bivariate flow karyotype FITC vs. DAPI of Ae. biuncialis consisted of nine chromosome-populations, but their chromosome content determined by microscopic analysis of flow sorted chromosomes indicated that only 7Mb and 1Ub could be sorted at high purity. In the case of Ae. geniculata, fourteen chromosome-populations were discriminated, allowing the separation of nine individual chromosomes (1Mg, 3Mg, 5Mg, 6Mg, 7Mg, 1Ug, 3Ug, 6Ug, and 7Ug) out of the 14. To sort the remaining chromosomes, a partial set of wheat-Ae. biuncialis and a whole set of wheat-Ae. geniculata chromosome addition lines were also flow karyotyped, revealing clear separation of the GAA-rich Aegilops chromosomes from the GAA-poor A- and D-genome chromosomes of wheat. All of the alien chromosomes represented by individual addition lines could be isolated at purities ranging from 74.5% to 96.6% and from 87.8% to 97.7%, respectively. Differences in flow karyotypes between Ae. biuncialis and Ae. geniculata were analyzed and discussed. Chromosome-specific genomic resources will facilitate gene cloning and the development of molecular tools to support alien introgression breeding of wheat.


Clopidogrel, prasugrel, or ticagrelor use and clinical outcome in patients with acute coronary syndrome: A nationwide long-term registry analysis from 2009 to 2014.
The beneficial use of dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and P2Y12 õinhibitors has been established for patients after acute coronary syndrome (ACS). However, the optimal duration of DAPT is under debate. The aim of the present study was to investigate the long-term utilization and clinical outcome of clopidogrel, prasugrel, and ticagrelor in patients with ACS from 2009 to 2014 in Austria. We analysed data from 13 Austrian health insurance funds for the years 2009 to 2014, on 72,676 patients with a hospital discharge diagnosis of ACS. The primary end point was recurrence of ACS or death >30days after the index event. 32,830 subjects received a prescription of a P2Y12 inhibitor within 30days after the index ACS. 18,640 (56.8%) subjects were discharged with clopidogrel, 6683 (20.4%) with prasugrel, and 7507 (22.9%) with ticagrelor, respectively. Data from 32,174 patients with 4975 events during a median follow-up period of 24.9months were available for survival analysis. The cumulative incidence for recurrence of ACS or death at two years was 18.7% in patients receiving clopidogrel, and 8.7% and 12.0% in those receiving prasugrel or ticagrelor, respectively. Utilization of P2Y12 inhibitors in patients with ACS was consistent with guideline recommendations. Prasugrel and ticagrelor are increasingly used in ACS patients and associated with a lower number of recurrence of ACS or death compared to clopidogrel. However, clopidogrel was predominantly used in older patients with more co-morbidities.


Children's needs during hospitalization: an observational study of hospitalized boys.
Twenty-one boys (age range 5 months to 16 years) were followed during their stay at hospital. Total observation time was 120 h. Field notes were made immediately after each observation. These were then transcribed into a narrative text, which was analysed by content analysis. Six categories of needs were identified during non-threatening situations at the hospital: the need for activity, the need for new experiences, the need for information, the need for participation, the need for praise and recognition, and needs related to physical resources. Four categories of needs were found during episodes of threat, discomfort and pain: the need for control, the need for having their parents nearby, the need for what is familiar, and the need for integrity. These results indicate that those involved in the care of children should be alert to the fact that as circumstances change, different needs have to be met. During non-threatening situations efforts should be made to inform children and to allow them to continue with their everyday lives. During threatening situations the children should be assisted and supported in keeping the situation under control.


Orbital complications associated with paranasal sinus infections - A 10-year experience in Israel.
Orbital involvement is the most common complication of sinus infections. The epidemiology of the disease is continuously changing in the antibiotic era. Data on patients who were hospitalized due to acute sinusitis and orbital complications were retrospectively collected and analyzed from four medical centers in Israel during the years 2002-2012. 288 patients were included in the study, the average age was 14.4 years, 180 were males, and 220 were children. No significant annual increase in the number of patients was noted. The lowest number of patients was found during the summer 19.4%. A linear direct correlation was found between older age and prolonged hospital stay. Children were presented with a significantly higher Chandler score than adults. No patient had cavernous sinus thrombosis. 101 (35%) patients received antibiotics before hospital admission. Their average hospital stay was similar to those who were not treated prior to admission. 106 patients (39.8%) had fever. A direct correlation was found between older age and the presence of fever. 102 (35.4%) patients had leukocytosis. The difference in white blood cell count between patients younger than two years of age to the other groups was statistically significant. Forty four (15.3%) patients underwent surgical intervention. A direct correlation was found between leukocytosis and older age to surgery. Periorbital cellulitis occurs mainly in children and males and is less frequent in the summer. Children tend to have worse orbital involvement with lower temperatures than adults. Older age and leukocytosis are associated with surgical intervention.


High-Throughput 3D Tumor Spheroid Screening Method for Cancer Drug Discovery Using Celigo Image Cytometry.
Oncologists have investigated the effect of protein or chemical-based compounds on cancer cells to identify potential drug candidates. Traditionally, the growth inhibitory and cytotoxic effects of the drugs are first measured in 2D in vitro models, and then further tested in 3D xenograft in vivo models. Although the drug candidates can demonstrate promising inhibitory or cytotoxicity results in a 2D environment, similar effects may not be observed under a 3D environment. In this work, we developed an image-based high-throughput screening method for 3D tumor spheroids using the Celigo image cytometer. First, optimal seeding density for tumor spheroid formation was determined by investigating the cell seeding density of U87MG, a human glioblastoma cell line. Next, the dose-response effects of 17-AAG with respect to spheroid size and viability were measured to determine the IC50 value. Finally, the developed high-throughput method was used to measure the dose response of four drugs (17-AAG, paclitaxel, TMZ, and doxorubicin) with respect to the spheroid size and viability. Each experiment was performed simultaneously in the 2D model for comparison. This detection method allowed for a more efficient process to identify highly qualified drug candidates, which may reduce the overall time required to bring a drug to clinical trial.


Mycobacterial infection of the parotid gland: an unusual cause of parotid swelling.
Six cases of mycobacterial infection of the parotid gland are reviewed. All six cases presented solely with a slowly enlarging parotid swelling clinically indistinguishable from a parotid tumour. All of the swellings required surgical removal, superficial parotidectomy in four cases, and enucleation in two cases to obtain a definitive diagnosis.


Latent class versus two-part models in the demand for physician services across the European Union.
Using three waves of data from the European Community Household Panel, this paper estimates demand for physician services equations for 12 European countries. We focus on the selection of the most appropriate econometric specification for visits to general practitioners and to specialists among two-part and latent class models. The distinction between the demand of services from these two types of physicians allows us to distinguish cases in which two-part perform better than latent class models, evidence which is different from previous findings in the literature. The results suggest that latent class models are more appropriate than two-part models to estimate general practitioners utilisation while the opposite is found for visits to the specialists.


Urinary free cortisol during pregnancy.
Adrenocortical function was measured during early and late normal pregnancies by determining urinary free cortisol on three consecutive days. A marked intra-individual variation in urinary free cortisol excretion was found. This pattern did not differ in early and late pregnancy. No correlation was demonstrated between the excretion of free cortisol, estrogen levels and creatinine clearances.


First-line treatment for osteoarthritis. Part 2: Nonpharmacologic interventions and evaluation.
Because of the chronic nature of osteoarthritis, nonpharmacologic interventions provide the client with self-care strategies that may lessen pain, improve physical functioning, and increase independence and sense of control. Nonpharmacologic interventions include exercise, rest and joint protection, heat and cold, hydrotherapy, therapeutic touch, acupuncture/acupressure, biofeedback, hypnotherapy, cognitive-behavioral techniques, activity and home maintenance modification, nutrition, and transportation interventions. Most of these therapies are very useful for nurses as independent interventions. Suggestions for evaluation of interventions are made.


The Added Value of Patient Engagement in Early Dialogue at EMA: Scientific Advice as a Case Study.
The European Medicines Agency provides Scientific Advice to medicines developers and patient input has been an integral part of this process for many years. As end users of medicines, patients bring their perspectives to many different processes along EMA's regulatory pathway, complementing the scientific expertise. While the value of including patients has been well-demonstrated over the years, requests for evidence of their impact continue. Using Scientific Advice as a case study, data was collected over a four-year period to assess the number of patients involved, where they contributed, as well as the impact and added value of their input. In this paper, we show that patients' contributions have a tangible impact on the recommendations provided to developers and in over half of the cases, this led to further discussion on relevant patient perspectives. These data provide quantitative evidence of the value of patient input in medicines development and supports EMA's continued inclusion of their voice throughout the medicine's lifecycle.


Simplified hypertension screening methods across 60 countries: An observational study.
Simplified blood pressure (BP) screening approaches have been proposed. However, evidence is limited to a few countries and has not documented the cardiovascular risk amongst missed hypertension cases, limiting the uptake of these simplified approaches. We quantified the proportion of missed, over-diagnosed, and consistently identified hypertension cases and the 10-year cardiovascular risk in these groups. We used 60 WHO STEPS surveys (cross-sectional and nationally representative; n = 145,174) conducted in 60 countries in 6 world regions between 2004 and 2019. Nine simplified approaches were compared against the standard (average of the last 2 of 3 BP measurements). The 10-year cardiovascular risk was computed with the 2019 World Health Organization Cardiovascular Risk Charts. We used t tests to compare the cardiovascular risk between the missed and over-diagnosed cases and the consistent hypertension cases. We used Poisson multilevel regressions to identify risk factors for missed cases (adjusted for age, sex, body mass index, and 10-year cardiovascular risk). Across all countries, compared to the standard approach, the simplified approach that missed the fewest cases was using the second BP reading if the first BP reading was 130-145/80-95 mm Hg (5.62%); using only the second BP reading missed 5.82%. The simplified approach with the smallest over-diagnosis proportion was using the second BP reading if the first BP measurement was ≥140/90 mm Hg (3.03%). In many countries, cardiovascular risk was not significantly different between the missed and consistent hypertension groups, yet the mean was slightly lower amongst missed cases. Cardiovascular risk was positively associated with missed hypertension depending on the simplified approach. The main limitation of the work is the cross-sectional design. Simplified BP screening approaches seem to have low misdiagnosis rates, and cardiovascular risk could be lower amongst missed cases than amongst consistent hypertension cases. Simplified BP screening approaches could be included in large screening programmes and busy clinics.


Elucidation of the Binding Mode of the Carboxyterminal Region of Peptide YY to the Human Y2 Receptor.
Understanding the agonist-receptor interactions in the neuropeptide Y (NPY)/peptide YY (PYY) signaling system is fundamental for the design of novel modulators of appetite regulation. We report here the results of a multidisciplinary approach to elucidate the binding mode of the native peptide agonist PYY to the human Y2 receptor, based on computational modeling, peptide chemistry and in vitro pharmacological analyses. The preserved binding orientation proposed for full-length PYY and five analogs, truncated at the amino terminus, explains our pharmacological results where truncations of the N-terminal proline helix showed little effect on peptide affinity. This was followed by receptor mutagenesis to investigate the roles of several receptor positions suggested by the modeling. As a complement, PYY-(3-36) analogs were synthesized with modifications at different positions in the common PYY/NPY C-terminal fragment (32TRQRY36-amide). The results were assessed and interpreted by molecular dynamics and Free Energy Perturbation (FEP) simulations of selected mutants, providing a detailed map of the interactions of the PYY/NPY C-terminal fragment with the transmembrane cavity of the Y2 receptor. The amidated C-terminus would be stabilized by polar interactions with Gln2886.55 and Tyr2195.39, while Gln1303.32 contributes to interactions with Q34 in the peptide and T32 is close to the tip of TM7 in the receptor. This leaves the core, α-helix of the peptide exposed to make potential interactions with the extracellular loops. This model agrees with most experimental data available for the Y2 system and can be used as a basis for optimization of Y2 receptor agonists.


Comparative uptake of polyamines by prostate and non-prostate cancer cell lines.
The Km and Vmax of [14C]-radiolabeled polyamines were determined for PC-3 and AT3B-1 cell lines. With PC-3 Km values are in the following order: ornithine> spermidine> spermine> putrescine, while with AT3B-1 it was spermidine> ornithine> spermine> putrescine. To determine which of these polyamines exhibit higher accumulation, the relative uptake of all the four amines was studied with prostate (PC-3, AT3B-1, LNCaP) and non-prostate (MCF-7, KLN-205, OVCAR) cell lines at 10 and 20 microM after 1 hour. Spermine and spermidine accumulated at higher levels in prostate (AT3B-1 and LNCaP) over non-prostate cell lines (p < 0.01). Putrescine accumulated more in PC-3 and LNCaP than the non-prostate cancer cells.


Clinical effectiveness and cost-effectiveness of fissure sealants in children and adolescents with a high caries risk.
In Germany, the application of resin-based pits and fissures sealants on the occlusal surfaces of permanent molars is part of individual prophylaxis for children and adolescents between six and 18 years. The individual prophylaxis is covered by the Statutory Health Insurance since 1993. The report addresses questions on medical effectiveness, cost-effectiveness, as well as ethical, social, and legal implications of pit and fissure sealants in preventing dental caries for children and adolescents at high caries risk. The results of the studies indicate a protective effect of pit and fissure sealants, particularly for children and adolescents at high caries risk. Additionally, the economic evaluation suggests a tendency for cost savings in this group. Nevertheless, a general expansion of the intervention cannot be recommended. All studies show a risk of bias in favour of pit and fissure sealing and a limited transferability to the German health care system. Studies included in the economic evaluation revealed methodological flaws. Both the economic models and primary studies do not provide reliable results.


Radiation-associated circulatory disease mortality in a pooled analysis of 77,275 patients from the Massachusetts and Canadian tuberculosis fluoroscopy cohorts.
High-dose ionising radiation is associated with circulatory disease. Risks associated with lower-dose (<0.5 Gy) exposures remain unclear, with little information on risk modification by age at exposure, years since exposure or dose-rate. Tuberculosis patients in Canada and Massachusetts received multiple diagnostic x-ray fluoroscopic exposures, over a wide range of ages, many at doses <0.5 Gy. We evaluated risks of circulatory-disease mortality associated with <0.5 Gy radiation exposure in a pooled cohort of 63,707 patients in Canada and 13,568 patients in Massachusetts. Under 0.5 Gy there are increasing trends for all circulatory disease (n = 10,209; excess relative risk/Gy = 0.246; 95% CI 0.036, 0.469; p = 0.021) and for ischaemic heart disease (n = 6410; excess relative risk/Gy = 0.267; 95% CI 0.003, 0.552; p = 0.048). All circulatory-disease and ischaemic-heart-disease risk reduces with increasing time since exposure (p < 0.005). Over the entire dose range, there are negative mortality dose trends for all circulatory disease (p = 0.014) and ischaemic heart disease (p = 0.003), possibly due to competing causes of death over this dose interval.These results confirm and extend earlier findings and strengthen the evidence for circulatory-disease mortality radiation risk at doses <0.5 Gy. The limited information on well-known lifestyle/medical risk factors for circulatory disease implies that confounding of the dose trend cannot be entirely excluded.


Machine Learning Approaches in Brillouin Distributed Fiber Optic Sensors.
This paper presents reported machine learning approaches in the field of Brillouin distributed fiber optic sensors (DFOSs). The increasing popularity of Brillouin DFOSs stems from their capability to continuously monitor temperature and strain along kilometer-long optical fibers, rendering them attractive for industrial applications, such as the structural health monitoring of large civil infrastructures and pipelines. In recent years, machine learning has been integrated into the Brillouin DFOS signal processing, resulting in fast and enhanced temperature, strain, and humidity measurements without increasing the system's cost. Machine learning has also contributed to enhanced spatial resolution in Brillouin optical time domain analysis (BOTDA) systems and shorter measurement times in Brillouin optical frequency domain analysis (BOFDA) systems. This paper provides an overview of the applied machine learning methodologies in Brillouin DFOSs, as well as future perspectives in this area.


[Comparative study on metagenomics of esophageal flora in elderly and middle-aged esophageal squamous cell carcinoma patients].
Objective: To explore the flora characteristics and differences of esophageal tissues between elderly esophageal squamous cell carcinoma (ESCC) patients and young and middle-aged ESCC patients, so as to assist in studying the potential biomarkers of elderly ESCC patients. Methods: In this study, a retrospective study was adopted. 72 ESCC patients diagnosed in Taihe Hospital, Shiyan City, Hubei Province from July 2018 to July 2019 were selected, including 49 patients in the elderly group (≥ 60 years old, 40 males and 9 females), 23 patients in the young and middle-aged group (<60 years old, 21 males and 2 females). In the same period, 20 healthy persons without abnormal gastroscopy in endoscopy center were selected as the control group (aged 35-78 years old, median age 57 years old, 16 males and 4 females). The genomic DNA was extracted from the affected esophageal tissues of patients with ESCC and the middle esophageal samples of the control group. The V4 hypervariable region of bacterial 16SrRNA gene sequence was amplified. Illumina HiSeq sequencing technology was adopted. The flora characteristics of elderly, young and middle-aged ESCC patients was compared and analyzed. QIIME and Rstudio software were used to analyze the sequence data, and nonparametric Kruskal-Wallis test or Wilcoxon rank sum test were used for statistical methods. Results: Shannon index [5.17 (4.53, 5.95) vs. 4.79 (3.74, 5.97)], Simpson index [0.94 (0.91, 0.96) vs. 0.92 (0.83, 0.96)] and Chao1 index [343.55 (259.76, 570.59) vs. 329.16 (268.88, 648.00)] were similar in flora of two groups, and there was no significant difference (Z=-0.791, -1.057, -0.380, all P>0.05). There was no significant difference in β-diversity between the elderly group and the young and middle-aged group (PC1=19.14%, PC2=6.95%, PPC1=0.67, PPC2=0.42). At the phyla level, the top 5 phyla in abundance were as follows: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria and Fusobacteria in the young and middle-aged group, while the top 5 phyla in abundance were as follows: Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria and Actinobacteria in the elderly group; the significant difference between the two groups was Fusobacteria (Q=0.596, P<0.05). At the genus level, the top 5 genera in the young and middle-aged group in abundance were as follows: Prevotella, Bacteroides, Streptococcus, Selenomonas and Veillonella. In the elderly group, Prevotella, Bacteroides, Streptococcus, Selenomonas and Haemophilus were the top 5 in abundance, and there were significant difference in Fusobacterium between the two groups (Q=0.938, P<0.05). PICRUSt function prediction showed that the abundance of Aminoacyl.tRNA.biosynthesis, Nucleotide.excision.repair, RNA.polymerase, Ribosome, Clavulanic.acid.biosynthesis, Photosynthesis and Photosynthesis. proteins in the elderly group were lower than those in the young and middle-aged group (all Q=0.734, P<0.05). Conclusion: There is no significant difference in α-diversity and β-diversity between elderly ESCC patients and young and middle-aged patients, but the abundance of Fusobacterium flora increased.


Multiple levels of Notch signal regulation (review).
Notch is a vitally important signalling receptor controlling cell fate determination and pattern formation in numerous ways during development of both invertebrate and vertebrate species. An intriguing pathway for the Notch signal has emerged where, after ligand-dependent proteolysis, an intracellular fragment of the receptor itself translocates to the nucleus to regulate gene expression. The nuclear activity of the Notch intracellular domain is linked to complexes regulating chromatin organization through histone deacetylation and acetylation. To allow the Notch signal to be deployed in numerous contexts, many different mechanisms have evolved to regulate the level, duration and spatial distribution of Notch activity. Regulation occurs at multiple levels including patterns of ligand and receptor expression, Notch-ligand interactions, trafficking of the receptor and ligands, and covalent modifications including glycosylation, phosphorylation and ubiquitination. Several Notch regulatory proteins have conserved domains that link them to the ubiquitination pathway, and ubiquitination of the Notch intracellular domain has recently been linked to its degradation. Different proteolytically derived isoforms of Notch have also been identified that may be involved in alternative Notch-dependent signals or regulatory mechanisms, and differences between the four mammalian Notch homologues are beginning to be appreciated.


Urothelial carcinoma in a man with hereditary nonpolyposis colon cancer.
Although most upper tract urothelial carcinomas are believed to be acquired, patients with hereditary nonpolyposis colon cancer (HNPCC) may have more than 20 times the risk of the normal population for these cancers. Certain mismatch repair mutations are now known to be associated with the disease. Screening and surveillance regimens are still evolving, but urinalysis, urine cytology, cystoscopy, and periodic upper tract imaging are the mainstays. HNPCC should be considered in any patient who develops an upper tract urothelial cancer or has a suggestive family history.


Coalescence of charged droplets in outer fluids.
A controlled technique to produce a precise volume of fluid species, such as water droplets, has critical importance in a variety of industrial applications. Electric field provided a well-established method to produce charged water droplets with a controlled volume. The coalescence of produced charged water droplets, however, impedes the efficiency of electric field-assisted methods. Whereas the coalescence of stationary single droplets, often charged, is overwhelmingly studied in air or vacuum, the effects of surrounding medium and approaching velocity are neglected. Systematic series of experiments and simulations were designed to address the effect of viscosity as well as approaching velocity on the coalescence of charged water droplets in viscous surrounding mediums (μ = 100 & 1000 cSt). Results suggested that increasing the electrical conductivity of water droplets with lower approaching velocity diminishes the chance of coalescence between water droplets. The higher viscosity of surrounding medium resulted in a lower chance of coalescence between water droplets while droplets with stronger electrical conductivities underwent a lower deformation inside the dielectric medium. Finally, results suggested that water chain formation, which is reportedly a main retarding factor in electrocoalescers, took place for droplets with intermediate sizes in higher viscosities of surrounding medium.


The Impact of Saffron on Symptoms of Withdrawal Syndrome in Patients Undergoing Maintenance Treatment for Opioid Addiction in Sabzevar Parish in 2017.
Drug dependence is one of the serious problems around the world. Saffron is one of those beneficial medicinal plants which is embedded with a similar mechanism to methadone (e.g., inhibition of serotonin reuptake). Thus, it can be helpful in reducing the withdrawal symptoms. The aim of this study was to reduce the daily dose of methadone usage and reduce its side effects using saffron in the form of medicinal supplements. This study was categorized as a clinical trial. Accordingly, 44 clients of addiction treatment centers in Sabzevar parish were randomly selected to participate in this study in 2016-2017. While the experimental group was treated with methadone syrup and self-made saffron capsules, the control group received methadone syrup and placebo capsules. The results showed that the use of saffron and methadone alleviated the symptoms of withdrawal syndrome (p<0.001). Having reviewed the research participants, it was indicated that the introduction of saffron alleviated the symptoms of withdrawal syndrome in patients undergoing maintenance treatment for opioid addiction. Thus, it seems rational to make use of saffron in combination with methadone in order to alleviate the symptoms of withdrawal syndrome.


Monitoring Microcirculatory Blood Flow during Cardiopulmonary Bypass in Paediatric Cardiac Surgery Patients as a Predictor for Anaerobic Metabolism.
Improving tissue oxygenation is one of most important tasks in management of low cardiac output. Central venous oxygen saturation (ScvO2) and lactate are established criteria for monitoring the adequacy of tissue oxygenation. The venous-to-arterial carbon dioxide difference [P(v-a)CO2] is inversely associated with cardiac output. To study the use of P(v-a)CO2/C(a-v)O2 ratio as a marker of low cardiac output during Cardiopulmonary Bypass (CPB) in paediatric cardiac surgical patients. The present study was a prospective observational study conducted over a period of nine months from 1st August 2015 to 30th April 2016. A total of 110 children were enrolled, who underwent CPB during cardiac surgery. The CPB time, Mean Arterial Pressure (MAP), flow rate, cross clamp time, were recorded for all the patients as well as Arterial Blood Gas (ABG) and Venous Blood Gas (VBG) were checked at four different points of time: 1) Before CPB, 2) 10 minutes after initiation of CPB, 3) 30 minutes on CPB and 4) off CPB. The results indicated that Receiver Operating Characteristic curve (ROC curve) at 30 minute of CPB time P(v-a)CO2/C(a-v)O2 was more specific and sensitive than lactate to detect anaerobic metabolism. Decrease platelet count was significant on second postoperative day. The present study suggests the use of P(v-a)CO2/C(a-v)O2 ratio as a marker to detect low flow on CPB. Our study was single centric and with a small size, studies involving large population and multiple centers are required to support the recent findings.


Validity of equivalent square field concept in small field dosimetry.
The equivalent square (ES) concept has been used for traditional radiation fields defined by the machine collimating system. For small fields, the concept Sclin was introduced based on measuring dosimetric field width (full-width half maximum, FWHM) of the cardinal axis of the beam profiles. The pros and cons of this concept are evaluated in small fields and compared with the traditional ES using area and perimeter (4A/P) method based on geometric field size settings, for example, light field settings. One hundred thirty-seven square and rectangular fields from 5-50 mm with every possible permutation (keeping one jaw fixed and varying other jaw from 5 to 50 mm) were utilized to measure FWHM for the validation of Sclin . Using a microSilicon detector and a scanning water tank, measurements were performed on an Elekta (Versa) machine with Agility head and a Varian TrueBeam with different MLC/Jaw design to evaluate the Sclin concept and to understand the effect of exchange factor in small fields. Field output factors were also measured for all 137 fields. The data fitting for fields ranging from 5-50 mm between the traditional 4A/P method and Sclin shows differences and indicates a linear relationship with distinct separation of slope for Elekta and Varian machines. For Elekta Agility machine ES based on 4A/P < Sclin and for the VarianTrueBeam 4A/P > Sclin for square fields. Our measured data show that both methods are equally valid but does vary by the machine design. The field output factor is dependent on the elongation factor as well as machine design. For fields with sides ≥10 mm, the exchange factor is nearly identical in both machines with magnitude up to 4%, which is close to measurement uncertainty (±3%), but for small fields (< 10 mm), the Elekta machine has higher exchange factors compared to the Varian machine. The results demonstrate that the two concepts for defining equivalent field (Sclin and 4A/P) are equivalent and can be directly related through an empirical equation. This study confirms that 4A/P is still valid for small fields except for very small fields (≤10 mm) where source occlusion is a dominating factor. The Sclin method is potentially sensitive to measurement uncertainty due to measurement of FWHM which is machine-, detector- and user-dependent, while the 4A/P method relies mainly on geometry of the machine and has less dependency on type of machine, detector, and user. The exchange factors are comparable for both types of machines. The conclusion is based on data from an Elekta with Agility head and a Varian TrueBeam machine that may have potential for bias due to light field/collimator set up and alignment. Care should be taken in extrapolating these data to any other machine.


Trichrome staining for detection of intestinal protozoa a better screening method.
Intestinal protozoal infections are common in our country because of poor hygiene and tropical conditions. The efficacy of trichrome staining to screen stool smear was compared with commonly used methods i.e. concentrated iodine mount and direct wet mount to test its better effectiveness. All Stool samples were first examined by routine methods i.e. direct wet mount and iodine staining. A portion of stool sample was also inoculated in vial containing polyvinyl alcohol (PVA) fixative. From PVA preserved samples, slides were prepared and stained by modified wheately's trichrome method. The results of both methods were compared and relative accuracy was calculated. 1054 stool specimens were examined and 259 parasites detected, of which 20.7% were protozoa and 3.7% helminthde. Trichrome staining detected 19.1% protozoa while routine methods detected 12.9% protozoa. For identification of protozoa, accuracy was 91.8% in favor trichrome staining and 61.8% by wet mount and iodine staining. Trichrome stained smear alone can be used as screening method in those geographic areas where protozoa infections are common.


Iodide excess exerts oxidative stress in some target tissues of the thyroid hormones.
Environmental iodine deficiency continues to be a significant public health problem worldwide. On the other hand, iodide excess results principally from the use of iodine-containing medicinal preparations or radiographic contrast media. For this reason we intended to explore iodide excess impairment on prooxidant/antioxidant balance of the thyroid gland, hepatic tissue and in blood and the effect of selenium administration on oxidative stress markers under the same circumstances. Experiments were performed for 10 days with white, male, Wistar rats, as follows: group 1: control-normal iodine supply group; 2: high iodine diet, group; 3: high iodine diet and selenium; group 4: high iodine diet and Carbimasole. Oxidative stress markers such as lipid peroxides were determined in thyroid gland, hepatic tissue and in blood. Measuring H+ donor ability of the sera and catalase activity in thyroid gland and in hepatic tissue assessed antioxidant defense. Iodide excess had prooxidant effects, leading to an increased lipid peroxides level and catalase activity in target tissues and in blood and to a decreased H+ donor ability of the sera. Selenium supplementation had opposite effects. Present data allow us to conclude that the alterations due to iodide excess in thyroid gland, hepatic tissue and in blood are mediated through oxidative stress.


Temporal stability of an endemic Mexican treefrog.
The demographic characteristics of an amphibian population fluctuate independently over time, mainly in response to the temporal variation of environmental factors, especially precipitation and temperature. These temporal fluctuations may contribute to the size of an amphibian population and could be used to determine the current conservation status of a species. During a five year (2004-2008) period, we studied the relative abundance, sex ratio, and age-sex structure of a population of metamorphosed individuals of the endemic treefrog Hyla eximia in Central Mexico. We also studied the species' relationship with climatic variables such as temperature and precipitation. We found an interannual constant abundance during the study period. However, interannual differences were observed in the population structure by age-sex category (males, females, or juveniles), with decreased abundance of males and juveniles during the rainy months (August-November). The annual abundance of H. eximia was positively correlated with rainfall, but negatively with monthly temperature. We found the sex ratio was male-biased (2:1), except for year 2008. Also, differences in snout-vent length (SVL) were found between years, suggesting changes in recruitment of new individuals. We conclude that variations in abundance, and frequencies by age-sex category, of H. eximia are related to seasonal variations in temperature and precipitation characteristics of temperate zones. However, this temporal stability may suggest that anurans have an unusual capacity to persist even in the face of human-induced habitat change.


HIF1α in aortic aneurysms and beyond.
Abdominal aortic aneurysm (AAA) is a permanent expansion of the vessel wall with a high prevalence in those 65 years of age and older. Aneurysms are prone to dissection and rupture that carry a mortality rate of over 85%. Currently, surgical repair is the only option to treat this disease. The need to intervene prior to these events has set off a flurry of basic studies in an effort to understand the cellular and molecular mechanisms that govern AAA formation, progression and rupture. In the present study, the role of myeloid cells in contributing to AAA development has been confirmed. More specifically, the transcription factor, hypoxia-inducible factor-1α (HIF1α), was demonstrated to be a necessary component for regulating the expression of extracellular matrix modifying enzymes and their endogenous inhibitors in these cells. This new discovery may lead to therapeutic targets to prohibit the degradation and weakening of the vessel wall with the hope of limiting AAA formation and/or growth.


Influence of maternal proximity on behavioral and physiological responses to separation in infant rhesus monkeys (Macaca mulatta).
The effects of maternal proximity on the behavioral and physiological responses of infant rhesus macaques during 4 days of total or adjacent separations from the mother were studied. The 6 infants tested showed behavioral responses that differentiated the two separation conditions. Major differences were found in the quantity and quality of vocalizations, the occurrence of cage-biting and cage-shaking behavior, object exploration, and hunched and freezing postures. In particular, the structure of coo vocalizations clearly discriminated between the presence or the absence of the mother during separation. Cerebrospinal fluid (CSF) concentrations of dopamine and serotonin metabolites did not discriminate between the two separation conditions but showed a transient elevation at 24 hr after separation and were not different from baseline by 96 hr after separation. In contrast, both the plasma cortisol and the CSF norepinephrine metabolite responses tended to be greater and to persist for a longer period of time when infants were totally isolated. The results are discussed within the context of attachment and coping theories.


Hyperbaric oxygen therapy for cognitive disorders after irradiation of the brain.
Analysis of the feasibility and effect of hyperbaric oxygen treatment (HBO) on cognitive functioning in patients with cognitive disorders after irradiation of the brain. Seven patients with cognitive impairment after brain irradiation, with an interval of at least 1.5 years after treatment, were treated with 30 sessions of HBO in a phase I-II study. A comprehensive neuropsychological test battery was performed before treatment, at 3 and 6 months thereafter. Patients were randomized into an immediate treatment group and a delayed treatment group. The delayed group had a second neuropsychological test at 3 months without treatment in that period and started HBO thereafter. All eligible patients completed the HBO treatment and the extensive neuropsychological testing. One out of seven patients had a meaningful improvement in neuropsychological functioning. At 3 months there was a small, but not significant benefit in neuropsychological performance for the group with HBO compared to the group without HBO treatment. Six out of seven patients eventually showed improvement after HBO in one to nine (median 2.5) of the 31 tests, although without statistical significance. HBO treatment was feasible and resulted in a meaningful improvement of cognitive functioning in one out of seven patients. Overall there was a small but not significant improvement.


Photostatic reporting in a hospital bacteriology laboratory.
A method of reporting results of tests performed in a hospital bacteriological laboratory is described in which a modified commercially available electrostatic copier is used. This device was designed for a hispital system in which more than one report per specimen is issued and in which rubber stamps are widely used and frequently changed. It has been working satisfactorily for more than six months. It increases accuracy and saves time and money. Attention to the clarity of reproduction is necessary. It is suggested that this system could be modified for other laboratory reporting systems.


Modality-Specific Modulation of Temperature Representations in the Spinal Cord after Injury.
Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality-specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the CNS encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated on ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push-pull mechanism in processing cold and heat inputs and reveal a synergic mechanism to shift thermosensation after injury.SIGNIFICANCE STATEMENT In this paper, we combine our novel in vivo spinal cord two-photon calcium imaging, mouse genetics, and persistent pain models to study how tissue injury alters the sensation of temperature. We discover modality-specific changes of spinal temperature responses in different models of injury. Chemotherapy medication oxaliplatin leads to cold hypersensitivity and heat hyposensitivity. By contrast, inflammation increases heat sensitivity and decreases cold sensitivity. This decrease in cold sensitivity results from the stronger crossover inhibition from the hyperactive heat inputs. Our work reveals the bidirectional change of thermosensitivity by injury and suggests that the crossover inhibitory circuit underlies the shifted thermosensation, providing a mechanism to the biased perception toward a unique thermal modality that was observed clinically in chronic pain patients.


Early Postoperative Parathyroid Hormone Level as a Predictor of Hypocalcaemia after Total Thyroidectomy.
Postoperative transient hypocalcaemia is a common squeal after total thyroidectomy usually due to parathyroid insufficiency. Objective of this study is to find out the optimum cut-off value of parathyroid hormone (PTH) level in early postoperative period as a best predictor for hypocalcaemia. This prospective observational study was carried out from July 2013 to July 2014 in the Department of Surgery Sir Salimullah Medical College & Mitford Hospital (SSMC&MH), in collaboration with department of Otolaryngology SSMC&MH, department of Otolaryngology Bangabandhu Sheikh Mujib Medical University (BSMMU) and department of Otolaryngology Dhaka Medical College & Hospital (DMC&H), Dhaka. Total 92 patients were selected those came for total thyroidectomy. PTH was measured at different percentile 6 hours after surgery to find out optimum cut-off point. In 47.5th percentile at 8.02 cut-off point of PTH found with good combination of sensitivity, specificity, positive and negative predictive value, accuracy and it was 83.33%, 91.66%, 90.90%, 84.62% and 91.30% respectively. We found PTH level as a predictor of hypocalcaemia and PTH 8.02pg/ml was the optimum cut-off point to predict hypocalcaemia within 6 hours after total thyroidectomy.


Porous Co3O4 nanoplates with pH-switchable peroxidase- and catalase-like activity.
Porous Co3O4 nanoplates were synthesized via a soft template method. By using amphiphilic block copolymer F127 colloids as the pore producer, porous Co(OH)2 nanoplates were prepared. After the annealing procedure, the obtained Co3O4 reserved the hexagonal shape and a similar size to the Co(OH)2 precursor. The as-prepared porous Co3O4 nanoplates named Co3O4-F simultaneously possessed peroxidase and catalase mimetic activities. Interestingly, these two kinds of mimetic enzyme activities could be switched by pH. Meanwhile, temperature and the concentrations of Co3O4-F had a significant effect on the switch pH and the dual-enzyme mimetic catalytic ability. Moreover, Co3O4-F exhibited good peroxidase-like catalytic activity even in the neutral pH system, providing a new strategy for one-step analysis of glucose. A novel one-step colorimetric glucose biosensor was fabricated based on the Co3O4-F nanozyme, making the operation of detection simpler and easier.


Unmet Need of Antenatal Screening for Asymptomatic Bacteriuria: A Risk Factor for Adverse Outcomes of Pregnancy.
Recommended urine culture is unsuitable for screening pregnant women for asymptomatic bacteriuria due to long turn-around time, unaffordability, and user-unfriendliness. The objective of this review was to evaluate the suitability of various tests for this purpose. A PubMed-based systematic review of published articles irrespective of year and language was done. Search terms included asymptomatic bacteriuria, screening test, urinary tract infection, and diagnostic test. Diagnostic accuracy studies conducted on human populations comparing tests with urine culture were included. One author extracted predefined data fields, including quality indicators, another validated it. Of 78 records, 25 studies describing 15 tests were included. All tests were rapid, seven were valid and two of them were affordable and easy-to-use. No test provided comprehensive identification with antibiotic susceptibility. Despite publication bias, no test was found suitable for screening asymptomatic bacteriuria antenatally and providing evidence-based prescription. Further research is needed to develop tests which suit this purpose.


Neutralization of SARS-CoV-2 Variants by mRNA and Adenoviral Vector Vaccine-Elicited Antibodies.
The increasing prevalence of SARS-CoV-2 variants has raised concerns regarding possible decreases in vaccine effectiveness. Here, neutralizing antibody titers elicited by mRNA-based and adenoviral vector-based vaccines against variant pseudotyped viruses were measured. BNT162b2 and mRNA-1273-elicited antibodies showed modest neutralization resistance against Beta, Delta, Delta plus and Lambda variants whereas Ad26.COV2.S-elicited antibodies from a significant fraction of vaccinated individuals had less neutralizing titer (IC50 <50). The data underscore the importance of surveillance for breakthrough infections that result in severe COVID-19 and suggest a potential benefit by second immunization following Ad26.COV2.S to increase protection from current and future variants.


The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction.
A strong and independent association between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED) has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these two clinical identities. Although the efficacy of the most commonly used treatments for LUTS/BPH is well defined, the negative impact of these treatments on sexual function - in particular, on ED - has triggered the search for new treatment options. In this regard, a new role for phosphodiesterase type 5 inhibitors in the treatment of LUTS/BPH and ED has been claimed. Tadalafil is one of the most extensively investigated phosphodiesterase type 5 inhibitors for this new indication. All evidence reported to date suggests that tadalafil 5 mg once daily is a safe and effective treatment option for both LUTS/BPH and ED.


Four Covariance Structure Models for Canonical Correlation Analysis: A COSAN Modeling Approach.
The mathematical connection between canonical correlation analysis (CCA) and covariance structure analysis was first discussed through the Multiple Indicators and Multiple Causes (MIMIC) approach. However, the MIMIC approach has several technical and practical challenges. To address these challenges, a comprehensive COSAN modeling approach is proposed. Specifically, we define four COSAN-CCA models to correspond with four possible combinations of the data to be analyzed and the unique parameters to be estimated. In terms of the data, one can analyze either the unstandardized or standardized variables. In terms of the unique parameters, one can estimate either the weights or loadings. Besides the unique parameters of each COSAN-CCA model, all four COSAN-CCA models also estimate the canonical correlations as their common parameters. Taken together, the four COSAN-CCA models provide the correct point estimates and standard error estimates for all commonly used CCA parameters. Two numeric examples are used to compare the standard error estimates obtained from the MIMIC approach and the COSAN modeling approach. Moreover, the standard error estimates from the COSAN modeling approach are validated by a simulation study and the asymptotic theory. Finally, software implementation and future extensions are discussed.


Sex-based differences in the association between duration of type 2 diabetes and heart rate variability.
We examined the association between heart rate variability (HRV) and duration of type 2 diabetes among 155 female and 106 male subjects: mean+/-SD for duration=49.6+/-65.6 and 57.3+/-77.1 months, respectively, p=0.38. Among males, duration of diabetes was independently and inversely associated with vagal-heart rate modulation (high frequency (HF) power, 0.15-0.40 Hz, standardised ss = -0.32, p=0.001; root mean square of successive differences between R-R intervals, ss = -0.26, p=0.006) and total R-R variability (standard deviation of normal R-R intervals, ss = -0.36, p=0.001); but not among females (p> or =0.80 for each HRV index). In contrast, HF was inversely associated with age of diabetes diagnosis (ss = -0.16, p=0.04) and 10-year absolute risk for coronary heart disease (ss = -0.16, p=0.04) among female subjects. Longitudinal research is needed to establish whether risk factors for early cardiac autonomic impairment differ among men and women with type 2 diabetes.


Comparison of synthesis and secretion of plasma albumin, fibrinogen and alpha 2-macroglobulin by slices of Morris hepatomas and rat liver.
Slices of rat liver or Morris Hepatomas 5123 GVI and 7777 were incubated for 2 h with 14C-leucine. Newly synthesized labelled proteins were determined independently in the medium and tissue homogenate, total protein after precipitation with trichloro-acetic acid, and albumin, fibrinogen and alpha 2-macroglobulin after immuno-precipitation with monospecific antisera. In comparison with control rat liver, synthesis and secretion of albumin were reduced four- to five-fold in the 2 heptomas examined. On the other hand, synthesis and secretio of fibrinogen and alpha 2-macroglobulin in Hepatomas 5123 GVI annd 7777 were similar to rat liver, especially to the liver isolated from rats with turpentine-induced local inflammation.


Mechanical properties and cytocompatibility of dense and porous Zn produced by laser powder bed fusion for biodegradable implant applications.
In this work, the macrotexture of dense Zn produced by laser powder bed fusion (LPBF) was studied and the mechanical properties for different tensile bar orientations were measured. The compressive strength of LPBF Zn scaffolds with five different unit cells was measured for a relative density of 20-51%. In addition, the response of mesenchymal stem cells to the LPBF Zn scaffolds was studied. The elastic modulus and yield strength of dense LPBF Zn were 110.0 ± 0.2 GPa and 78.0 ± 0.4 MPa, respectively in the vertical and 81.0 ± 0.4 GPa and 55.0 ± 0.7 MPa in the horizontal direction. This could be explained by the preferential orientation of the 〈0001〉 direction in the building plane. For LPBF Zn scaffolds, the plateau stress for the different unit cells varied between 8 and 33 MPa for a 30% relative density. Calcein staining, lactate production and DNA measurements over a 13-day period showed that mesenchymal stem cell viability was low for Zn scaffolds. This work forms a basis for further research into the LPBF texture formation of metals with hexagonal crystal structure, guides implant designers in scaffold unit cell and relative density selection and motivates further research into the cytocompatibility of LPBF Zn. STATEMENT OF SIGNIFICANCE: Laser powder bed fusion (LPBF) is a manufacturing technology which allows the seamless combination of porous and non-porous volumes in a metallic implant and is used in the orthopedic manufacturing industry today. The production of highly dense Zn with LPBF has been described earlier, but the mechanical properties of the resulting material have not been studied in detail yet. This study is the first to report on (i) the influence of different scanning strategies on the macrotexture of dense LPBF Zn and the resulting anisotropy of its mechanical properties, (ii) the relationship between the relative density and strength for LPBF Zn scaffolds with five different unit cells and (iii) the in vitro response of mesenchymal stem cells to these scaffolds.


Transforming psychology education to include global mental health.
In recent years, the reality of global migration has brought the lack of understanding of mental health needs across different cultures into sharp focus. Psychology programs are not up to date on global issues and are often experienced as inadequate in preparing graduates to meet the challenges of society today. The field of education and training in psychology has hardly evolved since the last two decades. On the other hand, the mental health needs arising locally and globally require a knowledge base and a set of skills future psychologists need to have in order to be able to work and grow professionally. In addition, most psychologists in the western world are bound, at some point in their career, to be in contact with immigrants or refugees to offer them services and be a source of support for such a vulnerable population. Also, the field of psychology is witnessing more movement among psychologists than ever before, whereby many professionals move to another country, to work, volunteer, gain or provide training, consult and much more. This requires a certain level of preparation, which psychologists need to be aware of and ready to engage in before and after they move. This article highlights different psychology programs around the world that include global mental health in their programs. It discusses essential aspects and skills that psychologists need to learn to be prepared to work globally with various populations and to expand their skills beyond service providing to more management and policy work. Topics such as human rights and social justice, advocacy, health management and policymaking are addressed as important competencies to be gained during the education and training of future psychologists.


Inventors as investigators: the ethics of patents in clinical trials.
The Bayh-Dole Act and renewed emphasis on translational research have stimulated patenting activities at universities. To examine how different institutions manage possible patent-related conflicts of interest in human subjects research, and to provide an ethical analysis and recommendations. Policies of nine major professional organizations, 13 of the largest recipients of federal biomedical funding in the United States and Canada, and 17 biomedical journals were canvassed. Disagreements in policies were used as the basis for analyzing the ethics of inventorship in clinical trials. Policies varied along three lines. First, some policies did not define patent inventorship as a potential conflict of interest. Second, some of those that did define it as such used licensing as a trigger for conflict of interest management. Third, several policies imposed presumptive restrictions on an investigator's participation in a trial involving his or her invention. The author defends on ethical grounds restrictive policies on patent holding in clinical trials and rejects objections to restrictive policies. The author recommends five policies: (1) any related patent holding should always be disclosed to IRBs and research subjects, (2) investigators who hold conflicting patents should be presumptively barred from certain activities in a study, (3) institutional interests in patents should be managed and disclosed to research subjects, (4) IRBs should also be informed of an investigator's filed (not just held) patents on an experimental agent, and (5) the stringency of policies should be adjusted according to a patent's earning potential and the risk associated with a study.


Dissociative Water Adsorption by Al3O4+ in the Gas Phase.
We use cryogenic ion trap vibrational spectroscopy in combination with density functional theory (DFT) to study the adsorption of up to four water molecules on Al3O4+. The infrared photodissociation spectra of [Al3O4(D2O)1-4]+ are measured in the O-D stretching (3000-2000 cm-1) as well as the fingerprint spectral region (1300-400 cm-1) and are assigned based on a comparison with simulated harmonic infrared spectra for global minimum-energy structures obtained with DFT. We find that dissociative water adsorption is favored in all cases. The unambiguous assignment of the vibrational spectra of these gas phase model systems allows identifying characteristic spectral regions for O-D and O-H stretching modes of terminal (μ1) and bridging (μ2) hydroxyl groups in aluminum oxide/water systems, which sheds new light on controversial assignments for solid Al2O3 phases.


Immunogenicity and protective efficacy of nanoparticle formulations of L-SseB against Salmonella infection.
Salmonella enterica, a Gram-negative pathogen, has over 2500 serovars that infect a wide range of hosts. In humans, S. enterica causes typhoid or gastroenteritis and is a major public health concern. In this study, SseB (the tip protein of the Salmonella pathogenicity island 2 type III secretion system) was fused with the LTA1 subunit of labile-toxin from enterotoxigenic E. coli to make the self-adjuvanting antigen L-SseB. Two unique nanoparticle formulations were developed to allow multimeric presentation of L-SseB. Mice were vaccinated with these formulations and protective efficacy determined via challenging the mice with S. enterica serovars. The polysaccharide (chitosan) formulation was found to elicit better protection when compared to the squalene nanoemulsion. When the polysaccharide formulation was used to vaccinate rabbits, protection from S. enterica challenge was elicited. In summary, L-SseB in a particulate polysaccharide formulation appears to be an attractive candidate vaccine capable of broad protection against S. enterica.


Through-the-knee amputation: an improved technique.
Through-the-knee amputation (TKA) is an excellent lower extremity treatment for the ischemic extremity when revascularization is not feasible and a prosthesis is not practical. Over the past 8 years 185 major amputations have been performed at our hospital of which 63 were of the TKA type. In 61 of these an improved technique was used that resulted in nonischemic, strong, and aesthetic stumps with 100 per cent primary healing. Our technique consists of removing the distal 2 cm of the femoral head with the two condyles and allowing the patella to ankylose to the new distal femoral end. In comparison with the other major amputations the TKA with this technique had significant advantages over the above-knee amputation and often was found to be superior to the below-knee amputation especially when rehabilitative ambulation with a prosthesis was not possible.


Proposal of an experimental model of fetal hydrocephalus.
There have been numerous experimental studies reported in literature that simulate congenital hydrocephalus. The various techniques that have been proposed present the obstacle of being difficult to reproduce and the results therefore, often do not match. We have proposed a new experimental model that is easily created, reproduced and that allows for precise monitoring of the hydrocephalic entity, in addiction to presenting itself as an example to follow in resolving the hydrocephalic pathology. The authors report the results relative to their case studies of 14 pregnant animals treated and they list and discuss the principal complications encountered.


Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse.
We have identified an excitatory synapse in cerebellar molecular layer interneurons at which the level of presynaptic activity determines the receptor type involved in the postsynaptic response. When small numbers of parallel fibers are activated, EPSCs are mediated solely by AMPA receptors (AMPARs), despite our finding that NMDA receptors (NMDARs) are present in the dendrites of these cells. The EPSC kinetics are fast (tau decay = 0.82 +/- 0.05 msec at room temperature), consistent with the role these interneurons are thought to play in precisely timed inhibitory control of Purkinje cells. NMDARs are activated only when glutamate release is increased either by facilitation with brief high-frequency trains or by recruiting more presynaptic fibers with higher stimulus intensities. Under these conditions, EPSCs consist of a fast-rising AMPAR-mediated current followed by a slow component mediated by both NMDARs and AMPARs. Inhibitors of glutamate transport increase the amplitude and prolong the time course of the compound EPSCs. In contrast, the properties of fast AMPAR EPSCs resulting from the activation of few inputs remain unchanged when glutamate uptake is blocked. Our results suggest that, at these synapses, the postsynaptic density contains AMPARs alone. It is only when transmitter release is high enough for glutamate to diffuse to the extrasynaptic space and to reach concentrations sufficient to activate extrasynaptic receptors that NMDARs are involved in the postsynaptic response. We suggest that such a spatial separation of receptor types may provide a mechanism for rapid changes in EPSC properties, depending on the amount of synaptic activity.


Immune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients.
Most demyelinating forms of Charcot-Marie-Tooth type 1 (CMT1) neuropathy are slowly progressive and do not respond to anti-inflammatory treatment. In nerve biopsy samples, overt lymphocytic infiltration is absent, but pathological features typical of macrophage-related demyelination have been reported. In mouse models of CMT1, demyelination was substantially reduced when the mutants were backcrossed into an immunodeficient genetic background. A few individual patients with CMT1 respond to anti-inflammatory treatment; however, unlike most patients with CMT1, these patients show accelerated worsening of symptoms, inflammatory infiltrates in nerve biopsies, and clinical features resembling chronic inflammatory demyelinating polyneuropathy as well as CMT1. We conclude that in patients with typical CMT1 and in animal models, a cryptic and mild inflammatory process not responsive to standard anti-inflammatory treatment fosters genetically mediated demyelination.


Effect of H2-receptor antagonists on the pharmacokinetics of 5-fluorouracil in the rat and monkey.
The effect of short term (7 days) and long term (28 days) pretreatment with the imidazole H2-receptor antagonist, cimetidine (CMT), on the pharmacokinetics of 5-fluorouracil (5-FUra) has been studied in the rat and cynomolgus monkey. Short-term pretreatment of rats with CMT significantly increased t1/2.z by 29 per cent and AUC by 40 per cent: total body clearance was decreased by 30 per cent. Long-term pretreatment exaggerated these effects. By contrast, short- and long-term pretreatment with the furan H2-receptor antagonist, ranitidine, caused no significant effect on 5-FUra kinetics. In the monkey, 7 days pretreatment with CMT increased t1/2.z by 32 per cent leaving other 5-FUra kinetic parameters unchanged; 28 days pretreatment increased both t1/2.z by 41 per cent and AUC by 100 per cent with a decrease in total body clearance of 5-FUra of 48 per cent. CMT, but not RNT, inhibited cytosolic dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FUra catabolism. It is proposed that the observed effects of CMT on 5-FUra kinetics are the result of inhibition of DPD. This interaction has the potential for increasing systemic drug toxicity and it is therefore advisable that where H2-receptor blockade is administered concurrently with 5-FUra that a non-imidazole based H2-receptor antagonist such as RNT should be substituted for CMT.


Improvements in chemical carriers of proteins and peptides.
The successful intracellular delivery of biologically active proteins and peptides plays an important role for therapeutic applications. Indeed, protein/peptide delivery could overcome some problems of gene therapy, for example, controlling the expression levels and the integration of transgene into the host cell genome. Thus, protein/peptide drug delivery showed a promising and safe approach for treatment of cancer and infectious diseases. Due to the unique physical and chemical properties of proteins, their production (e.g., isolation, purification & formulation) and delivery represented significant challenges in pharmaceutical studies. Modification in the structural moieties of these protein/peptide drugs could improve their solubility, stability, crystallinity, lipophilicity, enzymatic susceptibility and targetability, and subsequently, therapies and cures against various diseases. Using the structural modification of protein/peptide, their delivery provided overall higher success rates including high specificity, high activity, bioreactivity and safety. Recently, biotechnological and pharmaceutical companies have tried to find novel techniques for the modifications and improve delivery systems/carriers. However, each carrier has its own benefits and drawbacks, and an appropriate carrier is often established by the physicochemical properties of protein or peptide, the ideal route of injection, and clinical characteristics of therapy. In this review, an attempt was made to give an overview on the chemical carriers for proteins and peptides as well as the recent advances in this field.


Objective auditory brainstem response classification using machine learning.
The objective of this study was to use machine learning in the form of a deep neural network to objectively classify paired auditory brainstem response waveforms into either: 'clear response', 'inconclusive' or 'response absent'. A deep convolutional neural network was constructed and fine-tuned using stratified 10-fold cross-validation on 190 paired ABR waveforms. The final model was evaluated on a test set of 42 paired waveforms. The full dataset comprised 232 paired ABR waveforms recorded from eight normal-hearing individuals. The dataset was obtained from the PhysioBank database. The paired waveforms were independently labelled by two audiological scientists in order to train the network and evaluate its performance. The trained neural network was able to classify paired ABR waveforms with 92.9% accuracy. The sensitivity and the specificity were 92.9% and 96.4%, respectively. This neural network may have clinical utility in assisting clinicians with waveform classification for the purpose of hearing threshold estimation. Further evaluation using a large clinically obtained dataset would provide further validation with regard to the clinical potential of the neural network in diagnostic adult testing, newborn testing and in automated newborn hearing screening.


Echography in the post-natal diagnosis of congenital urinary tract disorders.
The lecture concerns itself specifically with post-natal diagnosis of urinary tract disorders in a child, investigation of the siblings and parents and monitoring of children "at risk". The author describes the advantages of ultrasonography compared with other imaging techniques and gives a description of the appearance of major congenital conditions (infantile type polycystic disease, adult type polycystic disease, medullary cystic disease, nephrocalcinosis and lucent crystal deposits). The author hints at the necessity to screen the parents of children presenting with infantile polycystic disease, as this research was done for the relatives of cases of adult polycystic disease.