De-escalation, adequacy of antibiotic therapy and culture positivity in septic patients: an observational study.
To evaluate the prevalence of antibiotic de-escalation in patients diagnosed with severe sepsis or septic shock at a public academic tertiary hospital and to evaluate antibiotic adequacy and culture positivity. The prevalence of antibiotic de-escalation, the adequacy of antibiotic treatment and the rates of culture positivity were analyzed in patients with severe sepsis and septic shock between April and December 2013 at an intensive care unit in a tertiary university hospital. Among the 224 patients included in the study, de-escalation was appropriate in 66 patients (29.4%) but was implemented in 44 patients (19.6%). Among the patients who underwent de-escalation, half experienced narrowing of the antimicrobial spectrum. The mortality rate was 56.3%, with no differences between the patients with or without de-escalation (56.8% versus 56.1%; p = 0.999) nor in the length of hospital stay. Empirical antibiotic therapy was appropriate in 89% of cases. Microorganisms were isolated from total cultures in 30% of cases and from blood cultures in 26.3% of cases. The adequacy rate of empirical antibiotic therapy was high, reflecting an active institutional policy of monitoring epidemiological profiles and institutional protocols on antimicrobial use. However, antibiotic de-escalation could have been implemented in a greater number of patients. De-escalation did not affect mortality rates.


[Evaluation of the Effectiveness of the Clarification-Oriented Psychotherapy in Persons with a Narcissistic Personality Disorder According to DSM-IV - A Naturalistic Longitudinal Study with Pre-Post Design].
The treatment of patients diagnosed with a narcissistic personality disorder (NPS) is considered to be extra challenging. Well-controlled studies on the effectiveness of psychotherapy in NPS patients are not available; so many interventions are based on theoretical constructs. The clarification-oriented psychotherapy (COP) is a psychotherapeutic approach, which emerged from concepts of the cognitive behavioral therapy, client-centered psychotherapy and various process-oriented procedures. The present ambulatory therapy-evaluation of COP aimed to evaluate the effectiveness of a psychotherapeutic treatment for patients suffering from NPS. Retrospective cohort-study including 173 treatment-seeking NPS-patients. Via pre-post per-protocol-analysis, significant improvements mostly with medium effect sizes were found in all relevant parameters after completion of the COP (58.6±10.5 sessions). In particular, the ambitious/narcissistic personality style in the "Personality Style and Disorders Inventory (PSSI)" (primary outcome) was improved (medium effect size: d=-0.49 [-0.67; -0.31], p<0.001). Analyses revealed even high effect sizes in terms of the improvement of depressive "states" and "traits", neuroticism as well as self-acceptance. The lowest effect sizes however were found for improvements in self-regulation (d=0.2 [0.03; 0.36], p=0.02). As no intention-to-treat analysis has been carried out, the effect sizes of COP in the treatment of NPS might be overestimated. Nevertheless, our findings support the use of COP for the treatment of NPS. In light of evidence-based medicine, the present so far most comprehensive study on this topic warranted an increase of the evidence of COP in the treatment of NPS from level IV to level III.


Radiologic-Pathologic Correlation for Nondiagnostic CT-Guided Lung Biopsies Performed for the Evaluation of Lung Cancer.
OBJECTIVE. For nondiagnostic CT-guided lung biopsies, we tested whether radiologicpathologic correlation could identify patients who may benefit from repeat biopsy. MATERIALS AND METHODS. In this retrospective study, 1525 lung biopsies were performed between July 2013 and June 2017, 243 of which were nondiagnostic. Of these 243 lung biopsies, 98 were performed to evaluate for lung malignancy; 17 were excluded because of insufficient follow-up, leaving a total of 81 cases. The Brock and Herder models were used to calculate risk; in addition, cases were independently blindly reviewed by two thoracic radiologists who assigned a score from 1 (probably benign) to 5 (probably malignant). The final diagnosis was established by pathology results or benignancy was established if the lesion resolved or remained stable for at least 2 years. RESULTS. Of the 81 nondiagnostic lung biopsies, initial pathology results included 33 cases of inflammation, 28 cases of normal lung tissue or insufficient sample, 10 cases of organizing pneumonia, and 10 cases of atypical cells. 42% (34/81) of cases were eventually determined to be malignant (negative predictive value [NPV] of 58%). Pathology results of organizing pneumonia had the lowest rate of malignancy (2/10 = 20%), and pathology results of atypical cells had the highest rate of malignancy (5/10 = 50%, p = 0.51). Within this highly selected cohort, the Brock and Herder models were not predictive of malignancy, with areas under the ROC curve (AUCs) of 0.52 and 0.52, respectively. Evaluation by thoracic radiologists yielded AUCs of 0.85 and 0.77. When radiologist-assigned scores of 1 and 2 were considered as benign, the NPV was 90% and 95%. CONCLUSION. Review of nondiagnostic lung biopsies for radiologic-pathologic concordance by thoracic radiologists can triage patients who may benefit from repeat biopsy.


Beta-adrenergic stimulation of c-fos gene expression in the mouse submandibular gland.
Isoproterenol (IPR), a beta-adrenergic agonist, induces division of acinar cells in the parotid and submandibular glands of adult rodents and produces hyperplastic and hypertrophic enlargements of these organs. We analyzed the effects of IPR on thymidine incorporation, c-fos mRNA levels, and the immunocytochemical localization of c-fos protein in the submandibular glands of adult and of 5- and 14-day-old mice. In the glands of untreated mice c-fos transcripts were not detectable. In all experimental groups, administration of IPR led to a rapid, transient increase in the c-fos mRNA level. Propranolol blocked the IPR effect, while treatment with IPR and cycloheximide led to superinduction. We observed no correlation between the effect of IPR on cell replication or organ growth and stimulation of c-fos expression, and conclude that the latter is the result of beta-adrenergic receptor-IPR interaction. The c-fos protein was localized immunocytochemically in both the cytoplasm and the nuclei of acinar cells and in the nuclei of duct cells.


Judging a man by the width of his face: the role of facial ratios and dominance in mate choice at speed-dating events.
Previous research has shown that men with higher facial width-to-height ratios (fWHRs) have higher testosterone and are more aggressive, more powerful, and more financially successful. We tested whether they are also more attractive to women in the ecologically valid mating context of speed dating. Men's fWHR was positively associated with their perceived dominance, likelihood of being chosen for a second date, and attractiveness to women for short-term, but not long-term, relationships. Perceived dominance (by itself and through physical attractiveness) mediated the relationship between fWHR and attractiveness to women for short-term relationships. Furthermore, men's perceptions of their own dominance showed patterns of association with mating desirability similar to those of fWHR. These results support the idea that fWHR is a physical marker of dominance. This is the first study to show that male dominance and higher fWHRs are attractive to women for short-term relationships in a controlled and interactive situation that could actually lead to mating and dating.


Effects of glucocorticoid treatment given in early or late gestation on growth and development in sheep.
Antenatal corticosteroids are used to augment fetal lung maturity in human pregnancy. Dexamethasone (DEX) is also used to treat congenital adrenal hyperplasia of the fetus in early pregnancy. We previously reported effects of synthetic corticosteroids given to sheep in early or late gestation on pregnancy length and fetal cortisol levels and glucocorticoids alter plasma insulin-like growth factor (IGF) and insulin-like growth factor binding protein (IGFBP) concentrations in late pregnancy and reduce fetal weight. The effects of administering DEX in early pregnancy on fetal organ weights and betamethasone (BET) given in late gestation on weights of fetal brain regions or organ development have not been reported. We hypothesized that BET or DEX administration at either stage of pregnancy would have deleterious effects on fetal development and associated hormones. In early pregnancy, DEX was administered as four injections at 12-hourly intervals over 48 h commencing at 40-42 days of gestation (dG). There was no consistent effect on fetal weight, or individual fetal organ weights, except in females at 7 months postnatal age. When BET was administered at 104, 111 and 118 dG, the previously reported reduction in total fetal weight was associated with significant reductions in weights of fetal brain, cerebellum, heart, kidney and liver. Fetal plasma insulin, leptin and triiodothyronine were also reduced at different times in fetal and postnatal life. We conclude that at the amounts given, the sheep fetus is sensitive to maternal administration of synthetic glucocorticoid in late gestation, with effects on growth and metabolic hormones that may persist into postnatal life.


In vitro remineralization effects of grape seed extract on artificial root caries.
Grape seed extract (GSE) contains proanthocyanidins (PA), which has been reported to strengthen collagen-based tissues by increasing collagen cross-links. We used an in vitro pH-cycling model to evaluate the effect of GSE on the remineralization of artificial root caries. Sound human teeth fragments obtained from the cervical portion of the root were stored in a demineralization solution for 96 h at 37 degrees C to induce artificial root caries lesions. The fragments were then divided into three treatment groups including: 6.5% GSE, 1,000 ppm fluoride (NaF), and a control (no treatment). The demineralized samples were pH-cycled through treatment solutions, acidic buffer and neutral buffer for 8 days at 6 cycles per day. The samples were subsequently evaluated using a microhardness tester, polarized light microscopy (PLM) and confocal laser scanning microscopy (CLSM). Data were analyzed using ANOVA and Fisher's tests (p<0.05). GSE and fluoride significantly increased the microhardness of the lesions (p<0.05) when compared to a control group. PLM data revealed a significantly thicker mineral precipitation band on the surface layer of the GSE-treated lesions when compared to the other groups (p>0.05), which was confirmed by CLSM. We concluded that grape seed extract positively affects the demineralization and/or remineralization processes of artificial root caries lesions, most likely through a different mechanism than that of fluoride. Grape seed extract may be a promising natural agent for non-invasive root caries therapy.


Knockdown of lncRNA TP73-AS1 inhibits gastric cancer cell proliferation and invasion via the WNT/β-catenin signaling pathway.
Long non-coding RNAs (lncRNAs) function as tumor suppressors or oncogenes in tumor development and progression. The purpose of the present study was to investigate the clinical significance and functional role of lncRNA TP73-AS1 in gastric cancer (GC). Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that TP73-AS1 was significantly upregulated in GC tissues compared with adjacent normal tissues. The higher expression of TP73-AS1 was closely associated with lymph node metastasis and tumor-node-metastasis stage in patients with GC. Those patients with GC showing a higher expression of TP73-AS1 were predicted to have shorter disease-free survival and overall survival rates. The knockdown of TP73-AS1 was shown to markedly inhibit cell proliferation, cell colony formation and cell invasion. In addition, the downregulation of TP73-AS1 suppressed the expression of transcription factor 4 and β-catenin, which suggested that a decrease in TP73-AS1 suppressed the WNT/β-catenin signaling pathway in GC. Therefore, these results indicated that TP73-AS1 may be a target for GC treatment.


Identification of a novel microtubule-destabilizing motif in CPAP that binds to tubulin heterodimers and inhibits microtubule assembly.
We have previously identified a new centrosomal protein, centrosomal protein 4.1-associated protein (CPAP), which is associated with the gamma-tubulin complex. Here, we report that CPAP carries a novel microtubule-destabilizing motif that not only inhibits microtubule nucleation from the centrosome but also depolymerizes taxol-stabilized microtubules. Deletion mapping and functional analyses have defined a 112-residue CPAP that is necessary and sufficient for microtubule destabilization. This 112-residue CPAP directly recognizes the plus end of a microtubule and inhibits microtubule nucleation from the centrosome. Biochemical and functional analyses revealed that this 112-residue CPAP also binds to tubulin dimers, resulting in the destabilization of microtubules. Using the tetracycline-controlled system (tet-off), we observed that overexpression of this 112-residue CPAP inhibits cell proliferation and induces apoptosis after G2/M arrest. The possible mechanisms of how this 112-residue motif in CPAP that inhibits microtubule nucleation from the centrosome and disassembles preformed microtubules are discussed.


Two different mechanisms of calcium spike modulation by dopamine.
Dopamine (10 to 50 microM) modulates in two different ways the duration of the Ca2+-dependent action potential recorded in the cell body of identified neurons of the snail Helix aspersa. In some neurons (cells E13 and F1) dopamine increases the amplitude of their Ca2+-dependent spike plateau by decreasing the S-current (Klein, M., J.S. Camardo, and E. R. Kandel (1982) Proc. Natl. Acad. Sci. U.S.A. 79: 5713-5717), a K+ current controlled by cyclic AMP. In another neuron (cell D2), dopamine decreases the Ca2+-dependent plateau of the somatic action potential by evoking a decrease in Ca2+-current resulting from a decrease in Ca2+ conductance. Both modulatory effects could be observed in the same single neuron in which dopamine induces decreases of both the Ca2+ conductance and cyclic AMP-dependent K+ conductance. Nevertheless, in these cells (such as cell F5) dopamine only evokes a decrease of the amplitude of the Ca2+ spike plateau. Since the modulation of the duration of the Ca2+ action potential recorded in the neuronal soma has been shown to constitute a good model of events taking place at synaptic endings, it is suggested that these modulatory mechanisms evoked by dopamine may be involved in processes of presynaptic facilitation and inhibition.


[A simple method for counting Rickettsia cells].
A simple modification of the method for counting Rickettsiae is described. The Escherichia coli cells (ECC) which served as reference particles were stained in suspension with methylene blue mixed with Rickettsia prowazekii (RP) and quickly sprayed over the glass slide. After fixation the samples were stained according to the technique of Gimenez and examined in the light microscope under oil immersion. Through a grid in the eye-piece it was not so difficult to count red-coloured RP and dark-blue ECC against a background formed by impurities. To calculate RP concentration, the reference particles' concentration was multiplied by the dilution factor of RP suspension by the ratio of RP to ECC enumerated. The statistical approach has shown that the wash of the slides during staining procedure does not change this ratio. Differential staining of Rickettsiae with fuchsin is the main clue of this new method to count them even in the crude preparations of infected yolk sacs.


Regulatory mechanisms of group distributions in a gregarious arthropod.
In a patchy environment, how social animals manage conspecific and environmental cues in their choice of habitat is a leading issue for understanding their spatial distribution and their exploitation of resources. Here, we experimentally tested the effects of environmental heterogeneities (artificial shelters) and some of their characteristics (size and fragmentation) on the aggregation process of a common species of terrestrial isopod (Crustacea). One hundred individuals were introduced into three different heterogeneous set-ups and in a homogeneous set-up. In the four set-ups, the populations split into two aggregates: one large (approx. 70 individuals) and one smaller (approx. 20 individuals). These aggregates were not randomly distributed in the arena but were formed diametrically opposite from one another. The similarity of the results among the four set-ups shows that under experimental conditions, the environmental heterogeneities have a low impact on the aggregation dynamics and spatial patterns of the isopod, merely serving to increase the probability of nucleation of the larger aggregation at these points. By contrast, the regulation of aggregate sizes and the regular distribution of groups are signatures of local amplification processes, in agreement with the short-range activator and long-range inhibitor model (scale-dependent feedbacks). In other words, we show how small-scale interactions may govern large-scale spatial patterns. This experimental illustration of spatial self-organization is an important step towards comprehension of the complex game of competition among groups in social species.


A CD40 Agonist and PD-1 Antagonist Antibody Reprogram the Microenvironment of Nonimmunogenic Tumors to Allow T-cell-Mediated Anticancer Activity.
In cancers with tumor-infiltrating lymphocytes (TILs), monoclonal antibodies (mAbs) that block immune checkpoints such as CTLA-4 and PD-1/PD-L1 promote antitumor T-cell immunity. Unfortunately, most cancers fail to respond to single-agent immunotherapies. T regulatory cells, myeloid derived suppressor cells (MDSCs), and extensive stromal networks within the tumor microenvironment (TME) dampen antitumor immune responses by preventing T-cell infiltration and/or activation. Few studies have explored combinations of immune-checkpoint antibodies that target multiple suppressive cell populations within the TME, and fewer have studied the combinations of both agonist and antagonist mAbs on changes within the TME. Here, we test the hypothesis that combining a T-cell-inducing vaccine with both a PD-1 antagonist and CD40 agonist mAbs (triple therapy) will induce T-cell priming and TIL activation in mouse models of nonimmunogenic solid malignancies. In an orthotopic breast cancer model and both subcutaneous and metastatic pancreatic cancer mouse models, only triple therapy was able to eradicate most tumors. The survival benefit was accompanied by significant tumor infiltration of IFNγ-, Granzyme B-, and TNFα-secreting effector T cells. Further characterization of immune populations was carried out by high-dimensional flow-cytometric clustering analysis and visualized by t-distributed stochastic neighbor embedding (t-SNE). Triple therapy also resulted in increased infiltration of dendritic cells, maturation of antigen-presenting cells, and a significant decrease in granulocytic MDSCs. These studies reveal that combination CD40 agonist and PD-1 antagonist mAbs reprogram immune resistant tumors in favor of antitumor immunity.


Osteoimmune-modulating and BMP-2-eluting anodised 3D printed titanium for accelerated bone regeneration.
3D printing of titanium (Ti) metal has potential to transform the field of personalised orthopaedics and dental implants. However, the impacts of controlled surface topographical features of 3D printed Ti implants on their interactions with the cellular microenvironment and incorporation of biological growth factors, which are critical in guiding the integration of implants with bone, are not well studied. In the present study, we explore the role of surface topological features of 3D printed Ti implants using an anodised titania nanotube (TiNT) surface layer in guiding their immune cell interaction and ability to deliver bioactive form of growth factors. TiNT layers with precisely controlled pore diameter (between 21and 130 nm) were anodically grown on 3D printed Ti surfaces to impart a nano-micro rough topology. Immune biomarker profiles at gene and protein levels show that anodised 3D Ti surfaces with smaller pores resulted in classical activation of macrophages (M1-like), while larger pores (i.e., >100 nm) promoted alternate activation of macrophages (M2-like). The in vitro bone mineralisation studies using the conditioned media from the immunomodulatory studies elucidate a clear impact of pore diameter on bone mineralisation. The tubular structure of TiNTs was utilised as a container to incorporate recombinant human bone morphogenetic protein-2 (BMP-2) in the presence of various sugar and polymeric cryoprotectants. Sucrose offered the most sustainable release of preserved BMP-2 from TiNTs. Downstream effects of released BMP-2 on macrophages as well as bone mineralisation were assessed showing bioactivity retention of the released rhBMP-2. Overall, the TiNT surface topography in combination with controlled, sustained, and local release of bioactive growth factors can potentially enhance the osseointegration outcomes of custom 3D printed Ti implants in the clinic.


Induction of apoptosis by vitamin D3 analogue EB1089 in NCI-H929 myeloma cells via activation of caspase 3 and p38 MAP kinase.
EB1089, a novel 1,25-dihydroxyvitamin D3 analogue, has been known to have potent antiproliferative properties in a variety of malignant cells both in vitro and in vivo. In the present study, we analysed the effect of EB1089 on NCI-H929 human myeloma cells. EB1089 inhibited cell growth of NCI-H929 and efficiently induced the G1 phase arrest of the cell cycle in a dose-dependent manner. We could also detect apoptosis in NCI-H929 cells exposed to EB1089 (1 x 10-7 M for 72 h) using the sub-G1 group of the cell cycle by FACS and annexin V binding assays. Induction of apoptosis by EB1089 was associated with down-regulation of the Bcl-2 protein without change of the Bax protein. Regarding caspase activity, which plays a crucial role in apoptosis, EB1089-treated NCI-H929 cells revealed an increased activity of caspase 3 protease accompanied by degradation of the PARP protein in a dose- and time-dependent manner. In addition, EB1089 caused the down-regulation of p44 extracellular signal-related kinase (ERK) activity and up-regulation of the p38 kinase activity during apoptosis of NCI-H929 cells. These results suggest that EB1089 inhibits growth of NCI-H929 cells via G1 cell cycle arrest as well as apoptosis by activating p38 kinase and suppressing ERK activity.


Metabolomic assessment of the effect of dietary cholesterol in the progressive development of fatty liver disease.
Nonalcoholic fatty liver disease is considered to be the hepatic manifestation of metabolic syndrome and is usually related to high-fat, high-cholesterol diets. With the rationale that the identification and quantification of metabolites in different metabolic pathways may facilitate the discovery of clinically accessible biomarkers, we report the use of (1)H NMR metabolomics for quantitative profiling of liver extracts from LDLr(-/-) mice, a well-documented mouse model of fatty liver disease. A total of 55 metabolites were identified, and multivariate analyses in a diet- and time-comparative strategy were performed. Dietary cholesterol increased the hepatic concentrations of cholesterol, triglycerides, and oleic acid but also decreased the [PUFA/MUFA] ratio as well as the relative amount of long-chain polyunsaturated fatty acids in the liver. This was also accompanied by variations of the hepatic concentration of taurine, glutathione, methionine, and carnitine. Heat-map correlation analyses demonstrated that hepatic inflammation and development of steatosis correlated with cholesterol and triglyceride NMR derived signals, respectively. We conclude that dietary cholesterol is a causal factor in the development of both liver steatosis and hepatic inflammation.


Use of the Escherichia coli transposon Tn1000 (gamma delta) to generate mutations in Bacillus subtilis DNA.
Plasmid pHM2 contains a Bacillus subtilis spoIIA gene and is able to replicate in both Escherichia coli and B. subtilis. The plasmid was mobilized at low frequency by the E. coli F plasmid. Nearly 30% of the mobilized plasmids contained an insert of Tn1000 (gamma delta). Fourteen of the inserts were in the B. subtilis DNA portion of pHM2. Of these, two adjacent inserts abolished expression of the plasmid spoIIA gene in B. subtilis. From the map positions of flanking inserts that do not abolish spoIIA gene expression, it is estimated that the gene is probably not more than 700 bp long.


Retinoic acid and chick limb bud development.
The chick limb bud is a powerful experimental system in which to study pattern formation in vertebrate embryos. Exogenously applied retinoic acid, a vitamin A derivative, can bring about changes in pattern and, on several grounds, is a good candidate for an endogenous morphogen. As such, the local concentration of retinoic acid might provide cells with information about their position in relation to one axis of the limb. Alternatively, retinoic acid may be part of a more complex signalling system. Homeobox genes are possible target genes for regulation by retinoic acid in the limb. In particular, one homeobox gene, XlHbox 1 is expressed locally in the mesenchyme of vertebrate forelimbs and might code for an anterior position. When the pattern of the chick wing is changed by retinoic acid or by grafts of signalling tissue such that anterior cells now form posterior structures, the domain of XlHbox 1 expression expands rather than contracts. The expansion of XlHbox 1 expression correlates with shoulder girdle abnormalities. Retinoic acid application leads to visible changes in bud shape and this allows dissection of the way in which patterning is co-ordinated with morphogenesis. Results of recombination experiments and studies of changes in the apical ridge and proliferation in the mesenchyme suggest the following scheme: retinoic acid is involved in specification of position of mesenchyme cells; this specification determines their local interaction with the ridge that controls ridge morphology; the thickened apical ridge permits local proliferation in the underlying mesenchyme.(ABSTRACT TRUNCATED AT 250 WORDS)


A separability parameter for dielectrophoretic cell separation.
In this study, a separability parameter is introduced to determine the selection of optimum operating parameters for DEP separation of a cell pair. The separability parameter is defined as a function of cells' Clausius-Mossotti (CM) factors. T-cell leukemia Jurkat and mouse melanoma B16 cells are tested to validate the separability parameter. CM factors of cells are measured using a recently developed microfluidic impedance spectroscopy device. Separability maps are generated for varying values of field frequency and buffer conductivity. Cell separation is tested using a planar interdigitated electrode array at different buffer conductivities. Impedance measurements of the DEP device are performed at various buffer conductivities. Electrode polarization effects and energy allocation for dielectrophoretic manipulation of cells are computed from the impedance data utilizing an equivalent circuit model. Cell separation results are explained in the light of the impedance measurements.


Genomic organization and chromosomal assignment of the human beta1, 4-N-acetylgalactosaminyltransferase gene. Identification of multiple transcription units.
The beta1,4-N-acetylgalactosaminyltransferase (beta1,4GalNAc-T) (EC) gene is expressed in normal brain tissues and in various malignant transformed cells, such as malignant melanoma, neuroblastoma, and adult T cell leukemia. To analyze the regulatory mechanisms of gene expression, we determined the genomic organization of the beta1, 4GalNAc-T gene. The gene consists of at least 11 exons and spans >8 kilobase pairs. The coding region is located in exons 2-11. To determine the transcription initiation sites, 5'-rapid amplification of cDNA ends analysis and ribonuclease protection assays were performed using RNA obtained from the human melanoma cell line SK-MEL-31. Consequently, we defined three transcription initiation sites and the alternative usage of three exons. Exons 1a and 1b partially overlap; the latter is part (3'-side) of the former and corresponds to the 5'-noncoding region of the cDNA clone previously isolated. The third transcript, exon 1c, corresponds to nucleotides -520 to -412 (position +1 = A of ATG of beta1,4GalNAc-T cDNA), which are considered to be in intron 1 based on the cloned cDNA sequence. Ribonuclease protection assays revealed the corresponding protection bands in samples of the gene-expressing cell lines. 5'-Flanking regions of individual initiation sites showed promoter activity when analyzed by chloramphenicol acetyltransferase assay in SK-MEL-31 cells. The multiple transcription initiation sites and their promoters/enhancers identified here might be differentially involved in the cell type-specific expression of the beta1,4GalNAc-T gene. This gene was assigned to human chromosome 12q13.3 by means of fluorescence in situ hybridization.


E-cigarette advertising expenditures in the USA, 2014-2018.
Tobacco product advertising has been shown to reach youth and promote initiation. This study assessed trends in e-cigarette advertising expenditures in the USA during 2014-2018, overall and by manufacturer and media type. Data came from Kantar Media, which provides information on US advertising expenditures, including for e-cigarettes. Advertising expenditures were estimated as the dollar amount spent by e-cigarette companies to purchase advertising space in print, television, Internet, radio and outdoors. Dollar amounts were adjusted to 2017 dollars. Trends in e-cigarette advertising expenditures during 2014-2018 were analysed using Joinpoint regression overall, by media type, and by manufacturers based on 2017-2018 national sales. Total e-cigarette advertising expenditures in print, radio, television, Internet and outdoors decreased substantially from US$133 million in 2014 to US$48 million in 2017, followed by an increase to US$110 million in 2018. By media type, expenditures were highest for print advertising, irrespective of year. By manufacturer, Altria had the highest e-cigarette advertising expenditures, totalling over US$134 million during 2014-2018. Imperial Tobacco had the second highest, totalling over US$85 million during 2014-2018, while JUUL Labs had the highest single-year expenditures, spending over US$73 million in 2018 alone. E-cigarette advertising expenditures have been volatile in the USA, with declines in traditional advertising venues during 2014-2017 that may reflect a shift towards social media. However, an increase occurred in 2018 that is likely reflective of advertising by newer manufacturers. Continued monitoring of e-cigarette advertising is important to inform tobacco control strategies.


Atrial fibrillation: epidemiology, prognosis and therapy.
Atrial fibrillation is the most common cardiac tachyarrhythmia encountered in clinical practice affecting 1% of the population. It is characterized by uncoordinated atrial activation that can lead to embolic complications and reduction in cardiac output resulting in significant morbidity, mortality and a reduction in quality of life. The three major goals in the management of atrial fibrillation are rate control, prevention of thromboembolism and correction of rhythm disturbance. This article will review up-to-date thinking about strategies for achieving each of these fundamental goals of AF care, with an emphasis on new drugs such as dabigatran and dronedarone and emerging non-pharmacologic therapies such as catheter ablation and left atrial appendage exclusion. After many years with relatively few new treatments, the past few years have seen a number of exciting developments which will hopefully improve clinician's ability to improve the outcomes of patients with this chronic and troublesome condition.


Idiopathic nephrotic syndrome in South African children.
Different histo-pathological types and treatment response patterns of Idiopathic nephrotic syndrome (INS) have been associated with differences in ethnicity and geographical location. To provide an update on the steroid response and renal histo-pathological pattern in children treated for INS. Medical records of children with INS treated at the Charlotte Maxeke Johannesburg Academic Hospital were reviewed. Mean age was 5.3 years ± 2.8. The majority (68.1%) of the 163 children were of the black racial group. The highest rate of INS was seen in the 2-6 year age group (71.2%). The black racial group had the highest rate (42/111; 37.8%) of focal segmental glomerulosclerosis (FSGS), and the white race had the highest rate (9/14; 64.3%) of minimal change disease (MCD). Ninety four (57.7%) patients were steroid sensitive (SSNS) while 69 patients (42.3%) were steroid resistant (SRNS). Minimal change disease was the most common histo-pathological type seen in SSNS (60%), while FSGS was the most common observed in patients who had SRNS (65.2%). There appears to be a higher rate of FSGS in all the racial groups, and also a higher rate of MCD in the black race group, when compared to previous reports.


Toward the Development of a Core Set of Outcome Domains to Assess Shared Decision-making Interventions in Rheumatology: Results from an OMERACT Delphi Survey and Consensus Meeting.
The aim of this Outcome Measures in Rheumatology (OMERACT) Working Group was to determine the core set of outcome domains and subdomains for measuring the effectiveness of shared decision-making (SDM) interventions in rheumatology clinical trials. Following the OMERACT Filter 2.0, and based on a previous literature review of SDM outcome domains and a nominal group process at OMERACT 2014, (1) an online Delphi survey was conducted to gather feedback on the draft core set and refine its domains and subdomains, and (2) a workshop was held at the OMERACT 2016 meeting to gain consensus on the draft core set. A total of 170 participants completed Round 1 of the Delphi survey, and 116 completed Round 2. Respondents came from 29 countries, with 49% being patients/caregivers. Results showed that 14 out of the 17 subdomains within the 7 domains exceeded the 70% criterion (endorsement ranged from 83% to 100% of respondents). At OMERACT 2016, only 8% of the 96 attendees were patients/caregivers. Despite initial votes of support in breakout groups, there was insufficient comfort about the conceptualization of these 7 domains and 17 subdomains for these to be endorsed at OMERACT 2016 (endorsement ranged from 17% to 68% of participants). Differences between the Delphi survey and consensus meeting may be explained by the manner in which the outcomes were presented, variations in participant characteristics, and the context of voting. Further efforts are needed to address the limited understanding of SDM and its outcomes among OMERACT participants.


NMDA receptors and nitric oxide regulate prostaglandin D2 synthesis in the rabbit hippocampus in vivo.
The aim of this in vivo microdialysis study was to characterise the regulation of prostaglandin D2 (PgD2) synthesis by NMDA receptors in the rabbit hippocampus in relation to changes in extracellular Ca2+ concentration ([Ca2+]e) and nitric oxide (NO) levels. Samples of dialysate were analysed for changes in PgD2 concentration, in [Ca2+]e and in the level of NO. The results demonstrated that a 20-min pulse application of 0.1-2.5 mM NMDA via a microdialysis probe induced a prolonged stimulation of PgD2 release that was sensitive to competitive NMDA receptor antagonists. An inhibitor of voltage-sensitive Na+ channels, tetrodotoxin, did not influence this effect but significantly suppressed basal PgD2 production, whereas a NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), prevented NMDA-evoked NO release and inhibited NMDA-induced PgD2 release in an L-arginine-sensitive manner. NO donors, S-nitroso-N-acetylpenicillamine and sodium nitroprusside, stimulated PgD2 release. NMDA-evoked decrease in [Ca2+]e was insensitive to TTX and L-NAME. These results demonstrate an in vivo NMDA receptor-mediated modulation of PgD2 synthesis in the brain, in which NO participates.


[Acute pancreatitis caused by salazopyrine. An unusual association].
A 28 year old patient with a moderate attack of ulcerative colitis was treated with sulfasalazine. Ten days after, the patient was admitted with clinical and laboratory symptoms of acute pancreatitis (serum amylase 631 u., serum lipase 1080 u. urine amylase, 910 u.). Upon recovery, sulfasalazine was reintroduced at lower dosage (2 Gm/day), and the patient repeated the clinical and biological picture of acute pancreatitis (serum amylase of 710 and lipase 1010 u.) CAT scan showed pancreatic edema and ultrasonography demonstrated a normal gallbladder. The symptoms and laboratory abnormalities disappeared in three days after stopping sulfasalazine. The patient has been followed-up for one year without recurrence of pancreatitis on maintenance treatment with 1.5 Gm 5-Aminosalicylic acid.


Control of Nanostructured Polysulfone Membrane Preparation by Phase Inversion Method.
The preparation of membranes from polymer solutions by the phase inversion method, the immersion-precipitation technique has proved since the beginning of obtaining technological membranes the most versatile and simple possibility to create polymeric membrane nanostructures. Classically, the phase inversion technique involves four essential steps: Preparation of a polymer solution in the desired solvent, the formation of the polymer solution film on a flat support, the immersion of the film in a coagulation bath containing polymer solvents, and membrane conditioning. All phase inversion stages are important for the prepared membrane's nanostructure and have been studied in detail for more than six decades. In this paper, we explored, through an electrochemical technique, the influence of the contact time with the polymer film's environment until the introduction into the coagulation bath. The system chosen for membrane preparation is polysulfone-dimethylformamide-aqueous ethanol solution (PSf-DMF-EW). The obtained nanostructured membranes were characterized morphologically and structurally by scanning electron microscopy (SEM) and thermal analysis (TA), and in terms of process performance through water permeation and bovine serum albumin retention (BSA). The membrane characteristics were correlated with the polymeric film exposure time to the environment until the contact with the coagulation bath, following the diagram of the electrochemical parameters provided by the electrochemical technique.


Semi-automatic 3D morphological reconstruction of neurons with densely branching morphology: Application to retinal AII amacrine cells imaged with multi-photon excitation microscopy.
Accurate reconstruction of the morphology of single neurons is important for morphometric studies and for developing compartmental models. However, manual morphological reconstruction can be extremely time-consuming and error-prone and algorithms for automatic reconstruction can be challenged when applied to neurons with a high density of extensively branching processes. We present a procedure for semi-automatic reconstruction specifically adapted for densely branching neurons such as the AII amacrine cell found in mammalian retinas. We used whole-cell recording to fill AII amacrine cells in rat retinal slices with fluorescent dyes and acquired digital image stacks with multi-photon excitation microscopy. Our reconstruction algorithm combines elements of existing procedures, with segmentation based on adaptive thresholding and reconstruction based on a minimal spanning tree. We improved this workflow with an algorithm that reconnects neuron segments that are disconnected after adaptive thresholding, using paths extracted from the image stacks with the Fast Marching method. By reducing the likelihood that disconnected segments were incorrectly connected to neighboring segments, our procedure generated excellent morphological reconstructions of AII amacrine cells. Reconstructing an AII amacrine cell required about 2h computing time, compared to 2-4days for manual reconstruction. To evaluate the performance of our method relative to manual reconstruction, we performed detailed analysis using a measure of tree structure similarity (DIADEM score), the degree of projection area overlap (Dice coefficient), and branch statistics. We expect our procedure to be generally useful for morphological reconstruction of neurons filled with fluorescent dyes.


Clinical and experimental studies on the treatment of senile constipation with shenshen wan.
From August 1988 through February 1991, we have successfully treated 400 cases of senile constipation with self-made Shenshen Wan with a total effective rate of 98%. A group of patients taking Maren Wan served as controls. Clinical practice has proved that Shenshen Wan can not only relax the bowels, but also improve renal function. Furthermore, no side effects whatever were observed after a prolonged administration of the pills.


[The 2002 hospital reform--physicians' views].
The Norwegian hospital reform of 2002 aimed at improving several aspects of the health-care service, i.e. the definition of responsibility between hospitals and their owners, equality in access to hospital-based health services, the quality of medical work, organisation of hospitals and productivity. This paper describes to what extent hospital-based physicians consider these aims to have been achieved. A postal questionnaire was disseminated to 2 500 hospital-based physicians in January 2006. The questions comprised work conditions and remuneration, organisational matters and the perceived results of the 2002 hospital reform. The respondents were asked to compare the situation in 2006 with the pre-reform situation, and to assess whether the situation was closer or further away from the aims. 1,298 of the doctors responded, i.e. a response rate of 53%. The average opinion was that the aims regarding organisation, access to hospital-based health services, and quality of medical work had become more distant. 38% stated that the aim to improve the quality of medical work was more distant than before the reform as opposed to 8% who perceived it as being closer. 58% of the physicians thought productivity had increased after the reform. There were some regional differences; e.g. the physicians in the southern region experienced stronger than those in the other four regions that responsibility between hospitals and hospital owners was less defined and the quality of medical work was worse than before the reform. 49% of the respondents felt that the hospital reform had mainly had a negative impact on hospitals, whereas 18% felt that the impact had been positive.


Responsiveness of raised pulmonary vascular resistance to oxygen assessed by pulsed Doppler echocardiography.
To assess whether changes in Doppler echocardiographic indices in the pulmonary artery correlated with changes in pulmonary vascular resistance. Acceleration time, ejection time, maximal flow velocity, and velocity time integrals were measured at the same time as pressure and oxygen saturation measurements in room air and during 10 minutes of oxygen breathing in the catheterisation laboratory. Pulmonary vascular resistance and pulmonary blood flow (Qp) were calculated from catheterisation data by use of the Fick principle. 14 consecutive patients with a congenital heart defect and a left to right shunt associated with raised pulmonary artery pressure who underwent routine diagnostic cardiac catheterisation to assess their pulmonary vascular resistance. Though pulmonary vascular resistance and systolic pulmonary artery pressure fell significantly during oxygen administration, there was no significant change in the acceleration time or ejection time. Peak velocity increased significantly during oxygen administration. During oxygen breathing Doppler derived measurements of pulmonary flow showed a significant increase in Qp similar to the increase in Qp measured by the Fick principle. There was no significant correlation between the fall in pulmonary vascular resistance and the increase in acceleration time or ejection time, increase in peak velocity, increase in pulmonary artery diameter, or increase in Doppler derived pulmonary blood flow. Measurements of acceleration and ejection time by Doppler echocardiography did not predict the response of pulmonary artery pressure and resistance to oxygen. Though changes in maximal flow velocity across the pulmonary artery and in Doppler derived pulmonary blood flow measurements became significant during oxygen breathing, the correlation of these changes with fall in pulmonary vascular resistance was poor.


Legion: An Instrument for High-Throughput Electrochemistry.
Electrochemical arrays promise utility for accelerated hypothesis testing and breakthrough discoveries. Herein, we report a new high-throughput electrochemistry platform, colloquially called "Legion," for applications in electroanalysis and electrosynthesis. Legion consists of 96 electrochemical cells dimensioned to match common 96-well plates that are independently controlled with a field-programmable gate array. We demonstrate the utility of Legion by measuring model electrochemical probes, pH-dependent electron transfers, and electrocatalytic dehalogenation reactions. We consider advantages and disadvantages of this new instrumentation, with the hope of expanding the electrochemical toolbox.


Synthesis and antimicrobial properties of guanidine-functionalized labdane type diterpenoids.
The occurrence of increased antibiotic resistance has reduced the availability of drugs effective in the control of infectious diseases, especially those caused by various combinations of bacteria and/or fungi that are often associated with poorer patient outcomes. In the hunt for novel antibiotics of interest to treat polymicrobial diseases, molecules bearing guanidine moieties have recently come to the fore in designing and optimizing antimicrobial agents. Due to their remarkable antibacterial and antifungal activities, labdane diterpenes are also attracting increasing interest in antimicrobial drug discovery. In this study, six different guanidines prenylated with labdanic fragments were synthesized and evaluated for their antimicrobial properties. Assays were carried out against both non-resistant and antibiotic-resistant bacteria strains, while their possible antifungal activities have been tested on the yeast Candida albicans. Two of the synthesized compounds, namely labdan-8,13(R)-epoxy-15-oyl guanidine and labdan-8,13(S)-epoxy-15-oyl guanidine, were finally selected as the best candidates for further developments in drug discovery, due to their antimicrobial effects on both Gram-negative and Gram-positive bacterial strains, their fungicide action, and their moderate toxicity in vivo on zebrafish embryos. The study also provides insights into the structure-activity relationships of the guanidine-functionalized labdane-type diterpenoids.


Focal and abnormally persistent paralysis associated with congenital paramyotonia.
Mutations of the skeletal muscle voltage-gated sodium channel (NaV1.4) are an established cause of several clinically distinct forms of periodic paralysis and myotonia. Focal paresis has sometimes already been described. We report a case with atypical clinical manifestation comprising paramyotonia and cold-induced persistent and focal paralysis. A 27-year-old woman presented with paramyotonia congenita since her childhood. She experienced during her childhood one brief episode of generalised weakness. At the age of 27, she experienced a focal paresis lasting for several months. The known mutation p.Val1293Ile was found in the muscle sodium channel gene (SCN4A). Channel inactivation is involved in most Na(+) channelopathies. Fast inactivation is known to be responsible for the myotonia phenotype. We hypothesise that the V1293I mutation may also alter the slow inactivation in specific conditions, for example, prolonged cold exposure or prolonged and intensive exercise. This observation broadens the spectrum of clinical manifestations of this sodium channel mutation.


Morphological and functional abnormalities in the inner retina of the rd/rd mouse.
We investigated the effects of photoreceptor degeneration on the anatomy and physiology of inner retinal neurons in a mouse model of retinitis pigmentosa, the retinal degeneration (rd) mutant mouse. Although there is a general assumption that the inner retinal cells do not suffer from photoreceptor death, we confirmed major changes both accompanying and after this process. Changes include sprouting of horizontal cells, lack of development of dendrites of rod bipolar cells, and progressive atrophy of dendrites in cone bipolar cells. Electrophysiological recordings demonstrate a selective impairment of second-order neurons that is not predictable on the basis of a pure photoreceptor dysfunction. Our data point out the necessity to prove integrity of the inner retina before attempting restoring visual function through photoreceptor intervention. This is even more important when considering that although intervention can be performed before the onset of any symptoms in animals carrying inherited retinopathies, this is obviously not true for human subjects.


Microemulsion-based synthesis of nanocrystalline materials.
Microemulsion-based synthesis is found to be a versatile route to synthesize a variety of nanomaterials. The manipulation of various components involved in the formation of a microemulsion enables one to synthesize nanomaterials with varied size and shape. In this tutorial review several aspects of microemulsion based synthesis of nanocrystalline materials have been discussed which would be of interest to a cross-section of researchers working on colloids, physical chemistry, nanoscience and materials chemistry. The review focuses on the recent developments in the above area with current understanding on the various factors that control the structure and dynamics of microemulsions which can be effectively used to manipulate the size and shape of nanocrystalline materials.


[Histostructural changes of rat cerebral cortex during hemorrhagic stroke modeling].
Pathological changes during modeling of primary and secondary acute hemorrhagic stroke were studied in rats. We revealed differences in the activity of pharmacological action of medications under condition of acute stroke. The action of medications increased viability of neurons in both hemispheres of rat cerebrum at a right-side primary and secondary hemorrhagic stroke. Following secondary stroke, the amount of degenerative neurons amounted 25.5 +/- 0.8 cells/mm2, following the action ofcerebrolysin this value was 17.6 +/- 1.7 cells/ mm2 and after the action of cortexine and cerebral this value amounted 18.0 +/- 0.9 cells/mm2 and 10.7 +/- 0.4 cells/ mm2, respectively. In control animals the number of degenerative neurons did not exceed 2% and averaged 1.5 +/- 0.1 cells/mm2. Analysis of the morphological and statistical data showed that the most effective remedies under the primary and secondary hemorrhagic insult are cortexine and cerebral. Cerebral was found to be more effective.


Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan.
Remyelination is a critical repair process that is initiated after a demyelinating insult. The failure to remyelinate contributes to neurological diseases such as multiple sclerosis. Here, we test the hypothesis that proteinase activity is required for the extensive remodeling of the extracellular matrix that occurs during remyelination. We show that mice lacking matrix metalloproteinase (MMP)-9 are impaired in myelin reformation after lysolecithin-induced demyelination. This deficiency may be explained at least in part by the failure to clear the accumulation of NG2, an inhibitory proteoglycan that retards the maturation and differentiation of oligodendrocytes that are needed for remyelination. These results emphasize for the first time that upregulation of MMP activity can be important for facilitating regeneration from some types of CNS injury.


The Impact of Light Physical Activity, Sedentary Behavior and Cardiorespiratory Fitness in Extending Lifespan and Healthspan Outcomes: How Little is Still Significant? A Narrative Review.
To describe the relationship between mortality and measures of low intensity physical activity (LIPA) as well as sedentary behavior (SB), and cardiorespiratory fitness (CRF). Study selection was performed through multiple database searches from January 1, 2000 until May 1, 2023. Seven LIPA studies, 9 SB studies, and 8 studies CRF studies were selected for primary analysis. LIPA and non-SB follow a reverse J shaped curve with mortality. The greatest benefits occur initially, and the rate of mortality reduction slows with increasing physical activity. Increasing CRF reduces mortality although the dose response curve is uncertain. For special populations such as individuals with, or at high risk of developing cardiovascular disease the benefit from exercise is heightened. LIPA, decreased SB and higher CRF lead to reductions in mortality and improved quality of life. Individualized counseling on the benefits of any amount of physical activity may increase compliance and serve as a starting point for lifestyle modifications.


Therapeutic effects of cetirizine in delayed pressure urticaria: clinicopathologic findings.
Cetirizine, a peripheral H1 antagonist, was administered to patients with delayed pressure urticaria in a double-blind, placebo-controlled, crossover study. Efficacy in reducing pressure-induced wheals and flares was evaluated. Histologic changes were also assessed with the skin window technique in weight-induced wheals. Results showed a statistically significant reduction in weight-induced wheal area (p less than 0.01) after cetirizine therapy; this improvement was accompanied by a concomitant reduction in eosinophil recruitment as demonstrated by the skin window technique (p = 0.0029). Subsequently, 14 patients with delayed pressure urticaria underwent biopsy before and after 3 weeks of cetirizine therapy to evaluate the drug's histologic effects. A blinded observer performed the histologic studies. Weight-induced lesions showed a mixed inflammatory infiltrate, primarily polymorphonuclear (neutrophils and eosinophils), whereas the unchallenged skin sites were normal. Cell counts from pressure-induced lesions showed a significant reduction in eosinophils after cetirizine treatment.


Design, Implementation, and Validation of a Piezoelectric Device to Study the Effects of Dynamic Mechanical Stimulation on Cell Proliferation, Migration and Morphology.
Cell functions and behavior are regulated not only by soluble (biochemical) signals but also by biophysical and mechanical cues within the cells' microenvironment. Thanks to the dynamical and complex cell machinery, cells are genuine and effective mechanotransducers translating mechanical stimuli into biochemical signals, which eventually alter multiple aspects of their own homeostasis. Given the dominant and classic biochemical-based views to explain biological processes, it could be challenging to elucidate the key role that mechanical parameters such as vibration, frequency, and force play in biology. Gaining a better understanding of how mechanical stimuli (and their mechanical parameters associated) affect biological outcomes relies partially on the availability of experimental tools that may allow researchers to alter mechanically the cell's microenvironment and observe cell responses. Here, we introduce a new device to study in vitro responses of cells to dynamic mechanical stimulation using a piezoelectric membrane. Using this device, we can flexibly change the parameters of the dynamic mechanical stimulation (frequency, amplitude, and duration of the stimuli), which increases the possibility to study the cell behavior under different mechanical excitations. We report on the design and implementation of such device and the characterization of its dynamic mechanical properties. By using this device, we have performed a preliminary study on the effect of dynamic mechanical stimulation in a cell monolayer of an epidermal cell line (HaCaT) studying the effects of 1 Hz and 80 Hz excitation frequencies (in the dynamic stimuli) on HaCaT cell migration, proliferation, and morphology. Our preliminary results indicate that the response of HaCaT is dependent on the frequency of stimulation. The device is economic, easily replicated in other laboratories and can support research for a better understanding of mechanisms mediating cellular mechanotransduction.


Expression of bacterial beta-galactosidase in animal cells.
A recombinant plasmid containing the gene for bacterial beta-galactosidase, situated close to the simian virus 40 early promoter, has been constructed. Transfection of CHO, L, and COS-1 cells with this plasmid led to the expression and appearance of the enzyme. Using this system, we have developed a series of promoter cloning vehicles capable of accepting promoter signals for animal genes.


A quality assessment of systematic reviews on telerehabilitation: what does the evidence tell us?
To evaluate the quality of systematic reviews on telerehabilitation. The AMSTAR--Assessment of Multiple Systematic Reviews--checklist was used to appraise the evidence related to the systematic reviews. Among the 477 records initially identified, 10 systematic reviews matched the inclusion criteria. Fifty percent were of high quality; anyway the majority of them did not report the following aspects: i) analysis of the grey literature; ii) a list of the excluded studies and their characteristics; iii) the identification of possible source of bias and the assessment of its likehood; iv) an appropriate method to combine the findings of the included studies addressing the heterogeneity as well. From the main findings of the high-scored systematic reviews telerehabilitation resulted at least as effective as usual care: 1) in the short term treatment of mental health related to people affected by spinal cord injury; 2) in rural communities for treating patients affected by chronic conditions; 3) in treating common pathologies (mainly asthma) affecting children and adolescents. As for stroke, evidence is currently insufficient to reach conclusions about its effectiveness. As for costs, there is insufficient evidence to confirm that telerehabilitation is a cost-saving or cost-effective solution. In the authors' knowledge this is the first attempt to evaluate the quality of systematic reviews on telerehabilitation. This work also identified the main findings related to the high-scored systematic reviews; the analysis confirms that there is a mounting evidence concerning the effectiveness of telerehabilitation, at least for some pathologies.


BMP4 rescues a non-cell-autonomous function of Msx1 in tooth development.
The development of many organs depends on sequential epithelial-mesenchymal interactions, and the developing tooth germ provides a powerful model for elucidating the nature of these inductive tissue interactions. In Msx1-deficient mice, tooth development arrests at the bud stage when Msx1 is required for the expression of Bmp4 and Fgf3 in the dental mesenchyme (Bei, M. and Maas, R. (1998) Development 125, 4325-4333). To define the tissue requirements for Msx1 function, we performed tissue recombinations between wild-type and Msx1 mutant dental epithelium and mesenchyme. We show that through the E14.5 cap stage of tooth development, Msx1 is required in the dental mesenchyme for tooth formation. After the cap stage, however, tooth development becomes Msx1 independent, although our experiments identify a further late function of Msx1 in odontoblast and dental pulp survival. These results suggest that prior to the cap stage, the dental epithelium receives an Msx1-dependent signal from the dental mesenchyme that is necessary for tooth formation. To further test this hypothesis, Msx1 mutant tooth germs were first cultured with either BMP4 or with various FGFs for two days in vitro and then grown under the kidney capsule of syngeneic mice to permit completion of organogenesis and terminal differentiation. Previously, using an in vitro culture system, we showed that BMP4 stimulated the growth of Msx1 mutant dental epithelium (Chen, Y., Bei, M. Woo, I., Satokata, I. and Maas, R. (1996). Development 122, 3035-3044). Using the more powerful kidney capsule grafting procedure, we now show that when added to explanted Msx1-deficient tooth germs prior to grafting, BMP4 rescues Msx1 mutant tooth germs all the way to definitive stages of enamel and dentin formation. Collectively, these results establish a transient functional requirement for Msx1 in the dental mesenchyme that is almost fully supplied by BMP4 alone, and not by FGFs. In addition, they formally prove the postulated downstream relationship of BMP4 with respect to Msx1, establish the non-cell-autonomous nature of Msx1 during odontogenesis, and disclose an additional late survival function for Msx1 in odontoblasts and dental pulp.


Fantasies about stem cell therapy in chronic ischemic stroke patients.
Stem cell therapy (SCT) has been proposed for the treatment of neurological disorders. Although there is insufficient clinical evidence to support its efficacy, unproven SCTs are being performed worldwide. In this study, we investigated the perspectives and expectations of chronic ischemic stroke patients and physicians about SCTs. A total of 250 chronic ischemic stroke patients were interviewed at 4 hospitals. Structured open and closed questions about SCT for chronic stroke were asked by trained interviewers using the conventional in-person method. In addition, 250 stroke-related physicians were randomly interviewed via an e-mail questionnaire. Of the 250 patients (mean 63 years, 70% male), 121 (46%) responded that they wanted to receive SCT in spite of its unknown side effects. Around 60% of the patients anticipated physical, emotional, and psychological improvement after SCT, and 158 (63%) believed that SCT might prevent strokes. However, physicians had much lower expectations about the effectiveness of SCTs, which was not in line with patient expectations. Multivariate analysis revealed that the male gender [odds ratio (OR): 2.00, 95% confidence interval (CI): 1.10-3.64], longer disease duration (OR: 1.01, 95% CI: 1.00-1.02), higher modified Rankin Scale score (OR: 1.30, 95% CI: 1.06-1.60), and familiarity with stem cells (OR: 1.86, 95% CI: 1.10-3.15) were independently associated with wanting SCT. The major source of information about SCT was television (68%), and the most reliable source was physicians (49%). Patients have unfounded expectations that SCT will improve their functioning. Considering our finding that the major source of information on stem cells is media channels, but not the physician, to decrease patients' inappropriate exposure, doctors should make more effort to educate patients using mass media with accurate information.


An information-processing model of the BOLD response in symbol manipulation tasks.
Two imaging experiments were performed--one involving an algebraic transformation task studied by Anderson, Reder, and Lebiere (1996) and the other an abstraction symbol manipulation task studied by Blessing and Anderson (1996). ACT-R models exist that predict the latency patterns in these tasks. These models require activity in an imaginal buffer to represent changes to the problem representation, in a retrieval buffer to hold information from declarative memory, and in a manual buffer to hold information about motor behavior. A general theory is described about how to map activity in these buffers onto the fMRI blood oxygen level dependent (BOLD) response. This theory claims that the BOLD response is integrated over the duration that a buffer is active and can be used to predict the observed BOLD function. Activity in the imaginal buffer is shown to predict the BOLD response in a left posterior parietal region; activity in the retrieval buffer is shown to predict the BOLD response in a left prefrontal region; and activity in the manual buffer is shown to predict activity in a motor region. More generally, this article shows how to map a large class of information-processing theories (not just ACT-R) onto the BOLD response and provides a precise interpretation of the cognitive significance of the BOLD response.


Functional Outcomes and Urological Complications after Genital Gender Affirming Surgery with Urethral Lengthening in Transgender Men.
We determined the urological complications and lower urinary tract function after genital gender affirming surgery with urethral lengthening in transgender men. A single center, retrospective cohort study was performed from January 2013 to January 2018. Patient demographics, medical history, perioperative data, surgical and urological complications, and preoperative and postoperative urological outcomes were obtained. Of the 63 patients included in the study 8 (13%) underwent metoidioplasty and 55 (87%) phalloplasty, comprised of 27 (43%) free radial forearm flap, 19 (30%) anterolateral thigh flap and 9 (14%) superficial circumflex iliac artery perforator flap surgeries. In phalloplasty the types of urethral lengthening were tube-in-tube free radial forearm flap in 27 (49%), free radial forearm flap (second fasciocutaneous flap) in 18 (33%), superficial circumflex iliac artery perforator flap in 5 (9%) or labial in 5 (9%). Mean followup was 23 months (range 12 to 71). Stricture formation occurred in 35 (63%) phalloplasty and 5 (63%) metoidioplasty cases. Urethral fistula formation occurred in 15 (27%) phalloplasty and 4 (50%) metoidioplasty cases. Mean time to strictures and fistulas was approximately 3 months. Overall 46 (73%) patients needed revision surgery because of fistulas/strictures. After treatment 44 (70%) patients were able to void from the tip of the phallus. No clinically relevant differences in International Prostate Symptom Scores, frequency volume charts and uroflowmetry were found preoperatively vs postoperatively. Genital gender affirming surgery with urethral lengthening is a complex procedure with a high complication rate. After treating complications no clinically relevant differences in urological functioning were recorded. The majority of transgender men could void from the tip of the penis and showed favorable urological outcomes.


Self-Oxygenation of Tissues Orchestrates Full-Thickness Vascularization of Living Implants.
Bioengineering of tissues and organs has the potential to generate functional replacement organs. However, achieving the full-thickness vascularization that is required for long-term survival of living implants has remained a grand challenge, especially for clinically sized implants. During the pre-vascular phase, implanted engineered tissues are forced to metabolically rely on the diffusion of nutrients from adjacent host-tissue, which for larger living implants results in anoxia, cell death, and ultimately implant failure. Here it is reported that this challenge can be addressed by engineering self-oxygenating tissues, which is achieved via the incorporation of hydrophobic oxygen-generating micromaterials into engineered tissues. Self-oxygenation of tissues transforms anoxic stresses into hypoxic stimulation in a homogenous and tissue size-independent manner. The in situ elevation of oxygen tension enables the sustained production of high quantities of angiogenic factors by implanted cells, which are offered a metabolically protected pro-angiogenic microenvironment. Numerical simulations predict that self-oxygenation of living tissues will effectively orchestrate rapid full-thickness vascularization of implanted tissues, which is empirically confirmed via in vivo experimentation. Self-oxygenation of tissues thus represents a novel, effective, and widely applicable strategy to enable the vascularization living implants, which is expected to advance organ transplantation and regenerative medicine applications.


Discrimination between alkali metal cations by yeast. II. Cation interactions in transport.
K(+) is a competitive inhibitor of the uptake of the other alkali metal cations by yeast. Rb(+) is a competitive inhibitor of K(+) uptake, but Li(+), Na(+), and Cs(+) act like H(+). At relatively low concentrations they behave as apparent noncompetitive inhibitors of K(+) transport, but the inhibition is incomplete. At higher concentrations they inhibit the remaining K(+) transport competitively. Ca(++) and Mg(++) in relatively low concentrations partially inhibit K(+) transport in an apparently noncompetitive manner although their affinity for the transport site is very low. In each case, in concentrations that produce "noncompetitive" inhibition, very little of the inhibiting cation is transported into the cell. Competitive inhibition is accompanied by appreciable uptake of the inhibiting cation. The apparently noncompetitive effect of other cations is reversed by K(+) concentrations much higher than those necessary to essentially "saturate" the transport system. A model is proposed which can account for the inhibition kinetics. This model is based on two cation-binding sites for which cations compete, a carrier or transporting site, and a second nontransporting (modifier) site with a different array of affinities for cations. The association of certain cations with the modifier site leads to a reduction in the turnover of the carrier, the degree of reduction depending on the cation bound to the modifier site and on the cation being transported.


Proton-assisted air oxidation mechanisms of iron(ii) bis-thiosemicarbazone complexes at physiological pH: a kinetico-mechanistic study.
The kinetics of oxidation of different biologically-active FeII bis-thiosemicarbazone complexes in water has been monitored at varying dioxygen concentration, temperature, pressure, and pH. The oxidation reactions observed can be resolved as a single-step process, producing the expected ferric complex, with rates increasing with decreasing pH. From the pH-dependence of the observed rate constants, a rate law with two terms can be derived, one of them being independent of the acid concentration and the other term showing a saturation behaviour with respect to [H+]. These results indicate the existence of two parallel pathways for oxidation: the acid-independent pathway is only operative for the complexes with ligands bearing terminal, non-coordinated, unsubstituted amines, whereas the term with a [H+]-limiting kinetic behaviour is observed for all the complexes and indicates that the reacting species has to be protonated prior to the oxidation step. From the data collected, the rate law and the thermal and pressure activation parameters have been used to interpret the operating reaction mechanisms. Given the fact that the empirical trends rule out an outer-sphere oxidation process, DFT calculations have been carried out to explain the results and suggest the likely formation, under steady-state very low concentration conditions, of FeIII superoxo and hydroperoxo intermediates.


Photophysical properties and application in live cell imaging of B,B-fluoro-perfluoroalkyl BODIPYs.
The photophysical properties of newly identified B,B-fluoro-perfluoroalkyl BODIPYs (2 and 3), which possess a fluoro group and a trifluoromethyl or pentafluoroethyl group at the boron center, were investigated. B,B-Fluoro-perfluoroalkyl BODIPYs 2 and 3 exhibited better photophysical/chemical properties than B,B-difluoro-BODIPY 1, as follows: (1) higher photostability both in methanol solvent and in a live cell environment, (2) higher stability against acid degradation, and (3) improved fluorescence signal-to-noise ratios in a cell system. These favorable properties of B,B-fluoro-perfluoroalkyl BODIPYs are likely due to the highly electron-withdrawing nature of the perfluoroalkyl groups on the boron atom, which reduces the reactivity to 1O2 and strengthens the complexation of the dipyrromethene ligands to the boron atom. Thus, B,B-fluoro perfluoroalkyl BODIPYs may be useful functional molecules for various applications.


Diabetic neuropathy.
The incidence and prevalence of diabetic neuropathies in Insulin Dependent (IDDM) and Non-Insulin Dependent (NIDDM) Diabetes Mellitus is not known because in previous studies the heterogeneity of diabetes and of the neuropathies was not taken into account, criteria for diagnosis and surveillance for neuropathy were variable, and studies were not prospective or population based. We have begun such prospective epidemiologic studies using a uniform algorithm for the classification of the diabetic disorders and uniform and validated approaches for the assessment of symptoms, neurologic deficits and various quantitative end-points of neural dysfunction. As regards cause, a key question which we are trying to answer is whether hyperglycemia and associated metabolic alterations affect neural tissue directly or whether there is an intervening tissue alteration between metabolic derangement and tissue change. Improved control of hyperglycemia does not appear to be associated with rapid neurologic improvement, possibly arguing for an intervening tissue alteration. The recently observed decrease in nerve oxygen tension and blood flow in streptozotocin diabetes suggests that an alteration of the nerve microenvironment may relate importantly to the cause of diabetic neuropathy.


Iranian Emergency Medical Service Response in Disaster; Report of three Earthquakes.
The earthquake is one of the most natural catastrophic crises that can cause a lot of casualties. Considering an earthquake-prone country, Iran is ranked as one of the world's most dangerous countries. In this article, we describe the actions taken by emergency medical service (EMS) after the earthquake in Kermanshah, Varzaghan, and Bam and compared the strengths and weaknesses of the emergency response program and the limitations and challenges of this system in dealing with these major crises. This study is a cross-sectional study that compares some of the information and findings related to three earthquakes that occurred in Iran, including Bam, Varzaghan and Sarpol-e-Zahab earthquakes. The data reported in the present article is descriptive and is based on various independent sources such as National Emergency Operation Center, Local Emergency Operations Center (EOC), the EMS of the country, the World Health Organization, the United Nations, the statistics website, the Forensic Data website, the International Institute of Seismology and Earthquake Engineering, conferences and personal interviews. To ensure the credibility of the information, the authors reported data that had been verified by two or more sources. The characteristics of the geographic area of the 3 earthquakes has been described. Post-earthquake response activities were described in details in subheadings including rapid warning and response, surge capacity plan, rapid response teams, emergency medical teams, increasing the capacity of health facilities, increasing transfer capacity, and handling, transportation and distribution of injuries. In the recent earthquake, had been occurred in Sarpol-e-Zahab, the health response of the country was largely satisfactory. The existence of structures such as EOC at various levels, the unified incident command system, emergency operations plan, and Medical Care Monitoring Center are among the most important reasons for satisfactory performance.


Red cell distribution width as a predictor of prostate cancer progression.
The aims of this study were to investigate the utility of red blood cell distribution width (RDW) as a simple and readily available marker in prostate cancer, as well as to evaluate RDW as a predictor of progression in prostate cancer patients. We evaluated 62 newly diagnosed prostate cancer patients who underwent transrectal ultrasound (TRUS)-guided biopsy and 62 healthy controls of mean age 64 (range, 45-75) years at the Urology Clinic of Bozok University Hospital. Data collection was performed using our laboratory information system database to retrieve findings regarding RDW, hemoglobin, prostate- specific antigen (PSA), and age. The RDW values were compared between the healthy control group and prostate cancer patients. A high risk of progression as defined as a Gleason score (GS) >6, total number of cores positive for cancer >33%, each core containing >50% cancer cells, and a prostate-specific antigen (PSA) level >10 ng/ mL. Patients were classified according to risk of progression, as well as divided into subgroups according to the RDW quartile. The mean RDW value of prostate cancer patients was 14.6, compared with 13.7 in the healthy control group (p=0.001). A higher RDW was associated with an increased risk of progression, whereas a lower RDW value was correlated with a low risk of progression. RDW is an easily derived measure that might, in combination with other markers, help predict prostate cancer risk and progression. We suggest that RDW may be used in combination with other parameters in the assessment of prostate cancer.


Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy.
Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.


Exosome-like Nanoparticles from Ginger Rhizomes Inhibited NLRP3 Inflammasome Activation.
The nucleotide-binding domain and leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome is a key regulator of innate immune responses, and its aberrant activation is implicated in the pathogenesis of many diseases such as Alzheimer's disease and type 2 diabetes. Targeting the NLRP3 inflammasome could hold promise to combat these complex diseases, but therapies specifically inhibiting the NLRP3 inflammasome have not been developed for patient treatment. The current study aimed to identify food-borne exosome-like nanoparticles (ELNs) that inhibit NLRP3 inflammasome activity. Nine vegetables or fruits were selected to extract ELNs, which were examined for their inhibitory effects on activation of the NLRP3 inflammasome in primary macrophages. Although most of the tested ELNs posed minimal impacts, the ELNs from ginger rhizomes (G-ELNs) strongly inhibited NLRP3 inflammasome activation. The G-ELNs contained lipids, proteins, and RNAs and were easily taken up by macrophages. G-ELN treatment suppressed pathways downstream of inflammasome activation including caspase1 autocleavage, interleukin (IL)-1β and IL-18 secretion, and pyroptotic cell death. Apoptotic speck protein containing a caspase recruitment domain (ASC) oligomerization and speck formation assays indicated that G-ELNs blocked assembly of the NLRP3 inflammasome. The lipids in G-ELNs, rather than the RNAs or proteins, were responsible for the inhibitory activity observed. Together, the data suggested G-ELNs as new potent agents that block NLRP3 inflammasome assembly and activation. The unique features of G-ELNs including biomolecule protection and tissue bioavailability should facilitate the development of G-ELN-based therapy to target the NLRP3 inflammasome in the disease settings.


Evaluation of tumor hypoxia prior to radiotherapy in intermediate-risk prostate cancer using 18F-fluoromisonidazole PET/CT: a pilot study.
Hypoxia is a major factor in prostate cancer aggressiveness and radioresistance. Predicting which patients might be bad candidates for radiotherapy may help better personalize treatment decisions in intermediate-risk prostate cancer patients. We assessed spatial distribution of 18F-Misonidazole (FMISO) PET/CT uptake in the prostate prior to radiotherapy treatment. Intermediate-risk prostate cancer patients about to receive high-dose (>74 Gy) radiotherapy to the prostate without hormonal treatment were prospectively recruited between 9/2012 and 10/2014. Prior to radiotherapy, all patients underwent a FMISO PET/CT as well as a MRI and 18F-choline-PET. 18F-choline and FMISO-positive volumes were semi-automatically determined using the fuzzy locally adaptive Bayesian (FLAB) method. In FMISO-positive patients, a dynamic analysis of early tumor uptake was performed. Group differences were assessed using the Wilcoxon signed rank test. Parameters were correlated using Spearman rank correlation. Of 27 patients (median age 76) recruited to the study, 7 and 9 patients were considered positive at 2.5h and 3.5h FMISO PET/CT respectively. Median SUVmax and SUVmax tumor to muscle (T/M) ratio were respectively 3.4 and 3.6 at 2.5h, and 3.2 and 4.4 at 3.5h. The median FMISO-positive volume was 1.1 ml. This is the first study regarding hypoxia imaging using FMISO in prostate cancer showing that a small FMISO-positive volume was detected in one third of intermediate-risk prostate cancer patients.


A healthy way of learning.
Nurse consultant Aileen Fraser is working to improve the co-ordination and delivery of healthcare services for older people, in part by developing staff awareness and skills. She has introduced a training programme for assistant practitioners and a system where all nurses observe and supervise a colleague three times a year. Observing others is a good way to learn about your own practice or change your approach, she believes.


Use of media for recruiting clinical research volunteers in Ecuador.
Up to this date, there are no reports made about the use of media for recruiting research volunteers in Latin American populations. Given the emergence of clinical research in Ecuador, a study of this kind in the local population will be beneficial for future research, and is probably applicable to other countries in the region. Two public calls were made for a cross-sectional study on cognitive function and diabetes. We only included people between 55 and 65 years of age without previous neurocognitive conditions. We invited individuals through interviews on the radio, television broadcasts and local newspapers, along with social media ads. Each individual was asked about the method by which they learned of the project. We calculated the frequency in which each method was reported and a chi-square test was used to assess gender differences in the results. A total of 274 patients were enrolled in the study, 64.2% are women and 35.8% men. We found that 29.93% learned of it from third persons, 20.8% through radio, 8.76% through social media, 8.39% by newspaper, and 5.11% by television, while a remaining 27.01% had not previously heard of the recruitment call. Methods reported varied significantly between men and women (p = 0.03). Traditional media were the most common method of recruitment, with radio interviews being the most frequently reported. Individually, none of them surpassed the frequency of people learning of the project from other people (snowball effect). Social networks play an important role, exceeding certain traditional media. We have described for the first time in Latin America the use of media as methods to recruit volunteers for research, and the importance of project dissemination by the participants to reach more people.


R&D investment and financial performance in EU countries: The role of shareholder protection and creditor rights in renewable energy firms.
Renewable energy sources have become a priority for countries' energy agendas due to climate change. Accordingly, the financial performance of renewable energy firms should be enhanced through research and development (R&D) investment to achieve the energy transition. The positive effect of R&D investment on financial performance is well documented in the literature. However, it is not clear whether this positive effect varies or not depending on the institutional characteristics of countries, such as shareholder protection and creditor rights. This study examines whether shareholder protection, on the one hand, and creditor rights, on the other, have any moderating effect on the R&D-financial performance nexus by using firm-level data from 912 renewable energy firms in 21 European Union countries from 2011 to 2020. The results show that shareholder protection strengthens the positive effect of R&D investment on the financial performance of renewable energy firms, while creditor rights negatively moderate this relationship. Thus, firms operating in countries with strong shareholder protection (creditor rights) invest more (less) in R&D activities, which leads to an increase (decrease) in financial performance. Consequently, policymakers may consider policy changes that encourage shareholders and discourage creditors from maximizing their R&D investments, which increase financial performance.


[Method of protecting of sutures in the stomach and intestines].
The authors have developed and described the method for intraoperative prophylaxis of complications caused by incompetence of the sutures on the stomach and bowels. It consists in closure of the sutures along the line of contiguity by two-layers of compact-porous collagenous explants, which possess antibacterial properties, the period of resorption in abdominal cavity being 15-20 days. The characteristics of the explants are presented and their advantages compared to commonly used methods covering by pellicle or glue film peritonization by sero-muscular sutures. Application of collagenous explants from "Sanguicol" preparation in surgical treatment of 155 patients with external intestinal fistulas, compared to peritonization by sero-muscular sutures (66 patients), has demonstrated a high effectiveness of proposed explants in prevention of postoperative intraabdominal complications.


Local multifocal oscillatory potential abnormalities in diabetes and early diabetic retinopathy.
To study retinal dysfunction in diabetes and early nonproliferative diabetic retinopathy (NPDR) using a new method to analyze local multifocal electroretinogram oscillatory potentials (mfOPs). One eye of each of 26 normal subjects, 16 diabetic subjects without retinopathy (NoR), and 16 diabetic subjects with early NPDR was examined. Slow-flash multifocal electroretinograms (sf-mfERGs) were recorded from the central 45 degrees, and stereo fundus photographs of the diabetic eyes were taken. The first-order (K1), induced first-order (K1i), and second-order (K2) response components were extracted from each retinal location, and K1i and K2 were added to create Ks2. Responses from 35 contiguous areas were digitally filtered 90 to 225 Hz to isolate the mfOPs. The signal-to-noise ratio (SNR) of the mfOPs was calculated, and abnormality was defined as SNR below the fifth percentile of the normal subjects. Combining the K1i and K2 components to form Ks2 before isolation of the mfOPs by digital filtering increased the SNR. Mean Ks2 and K1 mfOP SNRs were abnormal in 25% and 19% of the NoR eyes, respectively, and both were abnormal in 62% of the NPDR eyes. The retinal distributions of the local Ks2 and K1 mfOP abnormalities overlapped, but they differed. Furthermore, local Ks2 mfOP abnormalities were preferentially associated with retinal sites containing NPDR but K1 mfOP abnormalities were not. The cells that contribute to the generation of local mfOPs are affected by diabetes and, to a greater degree, by early NPDR. The results suggest that fast adaptive mechanisms influencing the mfOPs are most abnormal at retinal sites containing NPDR.


An unusual CD56(bright) CD16(low) NK cell subset dominates the early posttransplant period following HLA-matched hematopoietic stem cell transplantation.
The expansion of the cytokine-producing CD56(bright) NK cell subset is a main feature of lymphocyte reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT). We investigated phenotypes and functions of CD56(bright) and CD56(dim) NK subsets from 43 HLA-matched non-T cell-depleted HSCT donor-recipient pairs. The early expansion of CD56(bright) NK cells gradually declined in the posttransplant period but still persisted for at least 1 year and was characterized by the emergence of an unusual CD56(bright)CD16(low) subset with an intermediate maturation profile. The activating receptors NKG2D and NKp46, but also the inhibitory receptor NKG2A, were overexpressed compared with donor CD56(bright) populations. Recipient CD56(bright) NK cells produced higher amounts of IFN-gamma than did their respective donors and were competent for degranulation. Intracellular perforin content was increased in CD56(bright) NK cells as well as in T cells compared with donors. IL-15, the levels of which were increased in the posttransplant period, is a major candidate to mediate these changes. IL-15 serum levels and intracellular T cell perforin were significantly higher in recipients with acute graft-vs-host disease. Altogether, CD56(bright) NK cells postallogeneic HSCT exhibit peculiar phenotypic and functional properties. Functional interactions between this subset and T cells may be important in shaping the immune response after HSCT.


[TMJ pathology in hemophilia patients].
Hemarthrosis is one of the leading symptoms in congenital blood-clotting disorders. This condition leads to significant pain syndrome, joint deformation impaired function and diminished life quality. TMJ pathology showing all signs of hemophilic arthropathy is common in hemophilia patients.


Pediatric pain treatment and prevention for hospitalized children.
Prevention and treatment of pain in pediatric patients compared with adults is often not only inadequate but also less often implemented the younger the children are. Children 0 to 17 years are a vulnerable population. To address the prevention and treatment of acute and chronic pain in children, including pain caused by needles, with recommended analgesic starting doses. This Clinical Update elaborates on the 2019 IASP Global Year Against Pain in the Vulnerable "Factsheet Pain in Children: Management" and reviews best evidence and practice. Multimodal analgesia may include pharmacology (eg, basic analgesics, opioids, and adjuvant analgesia), regional anesthesia, rehabilitation, psychological approaches, spirituality, and integrative modalities, which act synergistically for more effective acute pediatric pain control with fewer side effects than any single analgesic or modality. For chronic pain, an interdisciplinary rehabilitative approach, including physical therapy, psychological treatment, integrative mind-body techniques, and normalizing life, has been shown most effective. For elective needle procedures, such as blood draws, intravenous access, injections, or vaccination, overwhelming evidence now mandates that a bundle of 4 modalities to eliminate or decrease pain should be offered to every child every time: (1) topical anesthesia, eg, lidocaine 4% cream, (2) comfort positioning, eg, skin-to-skin contact for infants, not restraining children, (3) sucrose or breastfeeding for infants, and (4) age-appropriate distraction. A deferral process (Plan B) may include nitrous gas analgesia and sedation. Failure to implement evidence-based pain prevention and treatment for children in medical facilities is now considered inadmissible and poor standard of care.


Analysis of cytomegalovirus and Epstein-Barr virus antibody responses in treated hemophiliacs. Implications for the study of acquired immune deficiency syndrome.
One hundred hemophiliacs were studied for serological evidence of infection with cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B virus. Ninety-eight percent had markers of hepatitis B infection, while 69% had antibody to EBV and only 42% had antibody to CMV, suggesting that factor VIII preparations do not transmit EBV and CMV efficiently. Seventy-one percent of those seropositive to EBV had an antibody pattern suggestive of active infection, as compared with 23% of healthy young adult blood donors. These findings make the patients with hemophilia an unusually favorable population for the study of the role of persistent viral infection in the immunodeficiency now found to be widespread in groups at high risk for acquired immune deficiency syndrome (AIDS) and for the contribution of CMV and EBV to AIDS itself.


[The study of cancer pain and its correlates].
From August 1989 to December 1990, we collected 1523 cases of malignancy at Tri-service General Hospital (TSGH), and 470 cases (30.9%) of these malignancy had pain complaint. Moreover, we found that 68.1% (79/116 cases) of malignancy with bony metastasis had pain complaint. These informations were obtained from medical records. By counting the site of these 1523 cases, the leading sites in sequence were lung (207 cases), stomach (164 cases), cervix uteri (132 cases), breast (117 cases) and colon (91 cases). Regarding the incidence of cancer pain among these malignancy, bone cancer had the highest incidence (75.0%), followed by tongue (66.7%), brain (65.7%), liver (62.3%) and pancreas (60.0%). There was no difference of the incidence of cancer pain between male and female. The incidences of cancer pain in different age groups were different; the young patients had higher incidence than elderly patients. The analgesics for cancer pain used most frequently by physicians at TSGH were nonsteroid anti-inflammatory drugs and meperidine. Although the therapeutic management of cancer pain has been advancedly developed, we found that the treatments of cancer pain by physicians at TSGH were not aggressive enough. Therefore, promotion of the concept in advanced pain control and techniques is our important task in the near future.


'Snapping hip' and sacroiliac sprain: example of a cause-effect relationship.
A case history demonstrating a cause-effect relationship between sacroiliac sprain and a 'snapping hip' is presented. Periodic iliac manipulation is shown to eliminate crepitus elicited by simultaneous active or passive extension of the knee and hip. The significance of this case history as evidence of the efficacy of iliac manipulation in the management of sacroiliac syndrome is discussed.


Pathway-specific connections between peptide-containing preganglionic and postganglionic neurons in the vagus nerve of the toad (Bufo marinus).
We have examined immunohistochemically the distribution of postganglionic nerve cell bodies and their preganglionic inputs in the vagus nerve of the toad, Bufo marinus. Nerve cell bodies containing immunoreactivity (IR) to somatostatin (SOM) were found at the origin of the oesophago-gastric ramus; these neurons projected to the lung. Cell bodies with SOM-IR also occurred in the intracardiac branches of the vagus, but were absent from the distal segments of the pulmonary and oesophageal rami of the vagus. Cell bodies with IR to vasoactive intestinal peptide (VIP) also occurred at the origin of the oesophago-gastric ramus, but most of these neurons projected to the oesophagus. Most neurons in the distal pulmonary and oesophageal rami were VIP-IR. Some nerve cell bodies in the vagosympathetic trunk and in the intracardiac rami contained both SOM-IR and VIP-IR. Vagal preganglionic nerve fibres with IR both to a somatostatin-like peptide and to substance P were associated exclusively with those postganglionic VIP-IR neurons that projected to the oesophagus. These results provide evidence for highly specific connections between immunohistochemically defined populations of preganglionic and postganglionic neurons in the vagus nerve.