Pseudouridylic modification of a 6S RNA transcribed in vitro from highly repetitive and transcribable (Hirt) sequences of salmon total DNA.
Salmon total DNA was transcribed in a HeLa cell extract, and it was found that a distinct 6S RNA is transcribed by RNA polymerase III. By analogy with a 6S RNA transcribed from mouse total DNA in vitro, which we demonstrated to be the transcripts from type 2 Alu family (Sakamoto et al. (1984) Mol Gen Genet 194:1-6), the genes for the 6S RNA in the salmon genome are presumed to be reiterated in at least 10(4)-10(5) copies and to be dispersed among the genome. A fingerprint analysis showed that the nucleotide sequences of the genes for the 6S RNA are extensively conserved. Furthermore, we demonstrated that at least two positions in the 6S RNA are modified in vitro to pseudouridylic acid. The pseudouridylic acid residues are located in specific oligonucleotides and each of the modified nucleotides amounts to 0.5 to 1.0 mol per mol of RNA. The relationship between salmon highly repetitive and transcribable (Hirt) sequences and rodent type 2 Alu family, and the significance of the pseudouridylic modification in relation to the functional role of these sequences are discussed.


A conversion to flatter archwires.
Clinical and practical features are described for an operator changing fixed appliance technique from a standard edgewise system to one using pretorqued and preangulated brackets, with generally flat archwires.


Microstructural deformation observed by Mueller polarimetry during traction assay on myocardium samples.
Despite recent advances, the myocardial microstructure remains imperfectly understood. In particular, bundles of cardiomyocytes have been observed but their three-dimensional organisation remains debated and the associated mechanical consequences unknown. One of the major challenges remains to perform multiscale observations of the mechanical response of the heart wall. For this purpose, in this study, a full-field Mueller polarimetric imager (MPI) was combined, for the first time, with an in-situ traction device. The full-field MPI enables to obtain a macroscopic image of the explored tissue, while providing detailed information about its structure on a microscopic scale. Specifically it exploits the polarization of the light to determine various biophysical quantities related to the tissue scattering or anisotropy properties. Combined with a mechanical traction device, the full-field MPI allows to measure the evolution of such biophysical quantities during tissue stretch. We observe separation lines on the tissue, which are associated with a fast variation of the fiber orientation, and have the size of cardiomyocyte bundles. Thus, we hypothesize that these lines are the perimysium, the collagen layer surrounding these bundles. During the mechanical traction, we observe two mechanisms simultaneously. On one hand, the azimuth shows an affine behavior, meaning the orientation changes according to the tissue deformation, and showing coherence in the tissue. On the other hand, the separation lines appear to be resistant in shear and compression but weak against traction, with a forming of gaps in the tissue.


Microcephaly, jejunal atresia, aberrant right bronchus, ocular anomalies, and XY sex reversal.
We present a patient with microcephaly, jejunal atresia, aberrant right tracheobronchial tree, mild left blepharoptosis, and corectopia (irregular pupil), left sectoral iris stromal hypoplasia and peripheral anterior synechia, and 46,XY sex reversal. Testosterone and dihydrotestosterone (DHT) levels were within normal limits for a male infant at 3 weeks of age. Gonadectomy at age 18 months revealed immature testis tissue and no evidence of Müllerian structures. PCR amplification of the androgen receptor (AR) gene and flanking genomic regions revealed no evidence for deletion. Array-comparative genomic hybridization (array-CGH) for assessment of gene dosage in other regions of the genome was normal. This patient represents a multiple anomaly disorder similar to intestinal atresia-ocular anomalies-microcephaly syndrome (MIM#243605) but incorporating 46,XY sex reversal with testicular tissue, demonstrating a defect in the sexual differentiation pathway.


Interfacially-mediated oxygen inhibition for precise and continuous poly(ethylene glycol) diacrylate (PEGDA) particle fabrication.
Hydrogels based on poly(ethylene glycol) diacrylate (PEGDA) have been engineered for a variety of biomedical applications including drug delivery, cell delivery, and tissue engineering. The miniaturization of these materials to nanoscale and microscale particles has been a subject of intense activity, and promises to extend their range of applicability. In general, however, these efforts have been frustrated by the inhibition of chain growth polymerization by oxygen, an effect that is exacerbated as target length scales are reduced. Here, we report a method that exploits the undesirable oxygen-inhibited photopolymerization to produce size-controlled PEGDA hydrogel particles. The role of initial solution composition in determining the relative particle to droplet size ratio is reported, and is found to contribute through its influence on the polymerization rate, as well as the diffusivity of oxygen. Facile control of photopolymerization kinetics via UV light intensity and/or exposure time, allowed PEGDA particles to be produced with dimensions independent of the parent spherical droplets formed by conventional microfluidic emulsification.


Substance use in young adults with pediatric-onset spinal cord injury.
Cross-sectional survey. To assess the prevalence of substance use in young adults with pediatric-onset spinal cord injury (SCI) and its relationship with demographic factors, and medical and psychosocial outcomes. Young adults living in the United States who received pediatric SCI care at one of three SCI programs at the Shriners Hospitals for Children. Individuals aged 21-25 years who had sustained SCI before the age of 19 were interviewed with a structured questionnaire including standardized outcome measures: FIM, satisfaction with life scale (SWLS), short-form 12 health survey (SF-12), patient health questionnaire-9 (PHQ-9) depression scale, and Craig handicap assessment and recording technique (CHART). Sample included 215 individuals with a mean age at interview of 23.3 (s.d.=0.9) years and mean age at injury of 13.2 (s.d.=4.9) years. In all, 24% had a college degree, 36% were employed and 12% were married. Regular substance use was reported by 28% for tobacco, 55% for alcohol and 11% for marijuana. Tobacco use was associated with depressive symptoms and unemployment; alcohol use was associated with having a college degree, single status and independent mobility; and marijuana use was associated with not having a college degree. There were no significant associations between substance use and injury-related factors or life satisfaction. Substance use in young adults with pediatric-onset SCI was associated with factors such as education, employment, marital status and depressive symptoms. Clinicians caring for youth with SCI should counsel patients and caregivers regarding the use of substances and potential associations with outcomes in adulthood.


Computed tomography in a case of ophthalmoplegia syndrome.
Until now the radiological diagnosis of the Tolosa-Hunt syndrome has been made on orbital venography or arteriography. A case of Tolosa-Hunt syndrome, studied using computed tomography (CT), indicates that CT may be valuable in confirming the clinical diagnosis.


Antagonistic and plant-growth promoting novel Bacillus species from long-term organic farming soils from Sikkim, India.
Three bacteria namely Bacillus luciferensis K2, Bacillus amyloliquefaciens K12 and Bacillus subtilis BioCWB possessing plant growth promotion and biocontrol potential against phytopathogens and rice leaf folder were identified from organic soils of Sikkim, India. The results revealed significant higher production of phytohormones IAA (97.1 μg mL-1) and GA3 (10.6 μg mL-1) was found in K2, whereas BioCWB had higher phosphate solubilization (570.0 μg mL-1) efficacy and also possessed nitrogen fixation ability (5.34 log copy number mL-1 culture). All these bacteria had higher antagonistic activities against phytopathogens viz. Rhizoctonia solani, Fusarium proliferatum, Athelia rolfsii and Colletotrichum gloeosporioides and also had higher larvicidal activity against rice leaf folder Cnaphalocrocis medinalis (Guenne) under in vitro conditions. Molecular insights into the antagonistic mechanisms of Bacillus strains deciphered the presence of several antimicrobial peptides (ericin, subtilin, surfactin, iturin, bacilysin, subtilosin, fengycin and bacillomycin), volatiles (dimethyl disulphide, methyl-Furan, acetic acid, Z-1,3-pentadiene and 3-hexyn-2-ol) and soluble metabolites (9-octadecenamide, E-15-heptadecenal, E-3-eicosene and 5-octadecene). Furthermore, liquid microbial inoculum prepared using the bacterial strains (K2, K12 and BioCWB) were evaluated under glass house (rice) and field condition (capsicum), which significantly enhanced plant growth in rice and yield in capsicum compared to control. The present study revealed the combination of Bacillus spp. (K2, K12 and BioCWB) can be used as bio-inoculants for improving agricultural production in Sikkim. Moreover, for the first time, we demonstrated plant growth promoting (PGP) traits, antifungal and insecticidal properties of B. luciferensis.


Association between serum calcium level and in-hospital mortality in patients with acute myocardial infarction: a retrospective cohort study.
The association between serum calcium levels and the prognosis of patients with acute myocardial infarction (AMI) remains controversial. This study aimed to explore the association between serum calcium and in-hospital mortality in patients with AMI. The data of this study were extracted from the Philips eICU Collaborative Research Database. A total of 7284 patients were eventually enrolled in this study, of which 799 (10.97%) died during hospitalization. For each patient, serum calcium, corrected to albumin, was calculated and categorized into four groups: Q1 ≤ 8.5, Q2 8.5-9.5, Q3 9.5-10.5, and Q4 > 10.5 mg/dL. Multivariate analysis demonstrated that corrected sCa was an independent predictor of in-hospital death (Q2 vs. Q1, OR 0.5, 95% CI 0.4-0.7, P < 0.001; Q3 vs. Q1, OR 0.8, 95% CI 0.6-1.0, P = 0.035; Q4 vs. Q1, OR 1.6, 95% CI 1.1-2.3, P = 0.008). The association remained stable in the fully adjusted model. A significant U-shaped association between corrected serum calcium and in-hospital mortality was observed in piecewise linear regression model (Corrected sCa < 9.4 mg/dL, OR 0.8, 95% CI 0.7-0.9, P < 0.001; corrected sCa > 9.4 mg/dL, OR 1.5, 95% CI 1.3-1.8, P < 0.001). In conclusion, both decreased and increased corrected serum calcium is associated with increased in-hospital mortality in patients with AMI, and patients may have the lowest risk of in-hospital death when corrected serum calcium is 9.4 mg/dL (2.35 mmol/L).


Mother-child communication about possible cancer recurrence during childhood cancer survivorship.
Providing opportunities to communicate about possible cancer recurrence may be adaptive for youth in remission, yet parents may experience difficulty guiding discussions related to fears of cancer recurrence (FCR). This study aimed to characterize mother-child discussions about potential cancer recurrence during post-treatment survivorship and to determine predictors of maternal communication. Families (N = 67) were recruited after the child's initial cancer diagnosis (age 5-17 years) and mothers self-reported their distress (post-traumatic stress symptoms; PTSS). During survivorship 3-5 years later, mothers were video-recorded discussing cancer with their children. Presence and length of discussion about potential cancer recurrence, triggers for FCR, expressed affect, and conversational reciprocity were examined. Hierarchical regressions were used to assess maternal PTSS near the time of cancer diagnosis and child age as predictors of maternal communication. Three-quarters of dyads spontaneously discussed risk for or fears about cancer recurrence; mothers initiated the topic more frequently than their children. Dyads discussed internal (bodily symptoms) and external (medical, social) triggers of FCR. Higher maternal PTSS at diagnosis predicted significantly lower levels of maternal positive affect (β = -0.36, p = 0.02) and higher levels of maternal negative affect (β = 0.30, p = 0.04) during discussion of recurrence 3-5 years later. Older child age significantly predicted higher levels of maternal negative affect (β = 0.35, p = 0.02). Higher maternal PTSS at diagnosis predicted shorter discussions about recurrence for younger children (β = 0.27, p = 0.02). Understanding predictors and characteristics of mother-child discussions about recurrence can guide family-based FCR interventions, particularly those promoting communication as a supportive tool. Both maternal PTSS and child age are important to consider when developing these interventions.


Technological features of surface functionalization of nanosized particles of various nature.
The technological universality of the developed methods of surface functionalization was exemplified by carbon (160 nm) and ferrocarbon (4-6 nm) nanoparticles. Based on universal technological scheme, the study demonstrated the possibilities of methodical variants with due account for the intrinsic properties of the particles such as carbonic surface and magnetism. The basic analytic properties of the developed diagnostic systems were examined to assess their prospective use in detection of the stereospecific molecules and their interaction. The model systems have been developed, which demonstrated the analytic potencies of the reagents obtained.


Spontaneous, isolated, and gaze-evoked ocular flutter: A rare case report.
This case illustrates the need to correctly identify oscillopsia among cases of self-reported dizziness, and ocular flutter itself as a presenting sign of potentially serious underlying disease. The neurologist should approach these patients in a systematic manner, in order to exclude concurrent or impending comorbidities such as neoplastic disease.


Acetylcysteine for urinary tract mucolysis.
The use of acetylcysteine is described for the relief of mucinous obstruction of the distal ureter after a mid ureteral replacement with ileum. Acetylcysteine (300 cc of 1 per cent) was instilled at low pressure via a nephrostomy tube following documentation of the obstruction with a nephrostogram. Patency of the ureter was achieved within 5 minutes. Re-obstruction ensued but it resolved with repeat percutaneous instillation of acetylcysteine. Patency, confirmed by a followup nuclear renogram at 4 months, has been maintained with 700 mg. acetylcysteine orally 4 times a day.


Investigating the contacts and suspected contacts of tuberculous patients in New Orleans.
The New Orleans Health Department still investigates the contacts and suspected contacts of patients with tuberculosis, although it has stopped some tuberculosis control programs as unproductive. To determine whether contact investigation is worthwhile, in 1974 we sampled 1,110 men, women, infants, and children who had proved (391) or suspected (719) contact with a tuberculous patient. Nineteen percent (215 out of 1,110) of these contacts examined had tuberculous infections (reflected by positive skin tests). Seven (0.63%) also had pulmonary tuberculosis. We concluded that contact investigation effectively identified residents of New Orleans who were at risk of tuberculosis and the program should be continued.


Modulating the Charge-Transfer Step of a p-n Heterojunction with Nitrogen-Doped Carbon: A Promising Strategy To Improve Photocatalytic Performance.
Engineering p-n heterojunctions among metal oxide semiconductors to provide a built-in electric field is an efficient strategy to facilitate the separation of photogenerated electrons and holes and improve their photocatalytic activities. However, the inherent poor conductivity of p-n heterojunctions still limits the charge-transfer step and thus hampers their practical application in photocatalysis. In this work, a nitrogen-doped carbon-coated NiO/TiO2 p-n (NCNT) heterojunction with hierarchical mesoporous sphere morphology was synthesized by in situ pyrolytic decomposition of nickel-titanium complexes. The NiO/TiO2 p-n heterojunction in NCNT was fully characterized by several techniques, supported by theoretical calculations and Mott-Schottky plots. On coating with a thin nitrogen-doped carbon layer, the electron transfer of the obtained p-n heterojunction could be significantly enhanced. On account of the favorable structural features of the p-n heterojunction with nitrogen-doped carbon coating and hierarchical mesoporous structure, NCNT exhibited excellent photocatalytic activity toward various reaction systems, including the hydrogen evolution reaction and the visible-light-induced hydroxylation of phenylboronic acids.


The hormonal maintenance and restoration of guinea pig seminal vesicle fibromuscular stroma.
Using the separated epithelium and muscle preparation of the guinea pig seminal vesicle, we designed studies to investigate the hormonal control of epithelial collagen, muscle collagen and muscle cells. All hormone treatment regimens involved a comparison of the effects of hormone maintenance (homrone treatments initiated on the day of castration) versus hormone restoration (hormone treatments initiated after a castration-induced regression) on these 3 components of the fibromuscular stroma. In the epithelium, castration induced a 35 per cent decline in collagen content, which was either returned to normal by androgen restoration of prevented by androgen maintenance. In all androgen treatment regimens, changes in epithelial collagen correlated with changes in epithelial wet weight, cell number, RNA content and cell size. In contrast, growth of the epithelium was not stimulated by estrogen maintenance or restoration. Castration reduced muscle wet and dry weight, as well as cell size and RNA content, but there was no effect on cell number and collagen content. Androgen maintenance or restoration reversed the castration-induced regression in all parameters and also caused collagen content to increase 35 percent above normal. Estrogen maintenance of castrates sustained wet weight, dry weight and RNA content at normal and stimulated supranormal increases in both collagen content and cell number. Similarly, estrogen restoration induced supranormal increases in collagen content and returned RNA content to normal. However, estrogen's ability to stimulate supranormal increases in cell number and restore wet and dry weight to normal was lost after a castration-induced muscle regression. In summary, components of the guinea pig seminal vesicle fibromuscular stroma have been shown to be sensitive to androgens and/or estrogens. The action of androgen on these tissue components was independent of the state of tissue regression, whereas with the exception of RNA and collagen content all the effects of estrogen were significantly reduced with castration-induced regression of the tissue.


[Interstitial pneumonia with autoimmune features: monocentric prospective study].
To study demographic, clinical, serological and morphological features of interstitial pneumonia with autoimmune features (IPAF), compare survival in IPAF and interstitial lung disease in connective tissue diseases (CTD-ILD), and identify predictors of mortality and transformation to CTD in the IPAF group. The IPAF group included 48 patients (75.0% women, median age 57.5 years), CTD-ILD - 49 patients (79.6% women, median age 60.0 years). The analysis of demographic, clinical, laboratory and instrumental data was performed, as well as comparison of survival with the Kaplan-Meier method and the log-rank test in the IPAF and CTD-ILD groups. In the IPAF group, predictors of mortality and the development of CTD were studied with multivariate regression analysis. Duration of observation period did not differ significantly in the IPAF and CTD-ILD groups (40.0 and 37.0 months, respectively). Clinical criteria of IPAF were observed in 25 (52.1%) patients, serological - in 44 (91.7%), morphological - in 44 (91.7%). Mortality in the IPAF group was significantly higher than in the CTD-ILD group (29.2 and 6.1%, respectively; p=0.023). The presence of diabetes mellitus, CT-pattern of usual interstitial pneumonia, and an initial low forced vital capacity value were independent predictors of mortality in the IPAF group. During the observation period, the development of CTD was noted in 4 (8.3%) patients with IPAF. The independent predictor of the CTD development was the increased C-reactive protein level. IPAF is characterized by a lower survival rate compared to CTD-ILD, and a relatively low risk of CTD transformation.


Novel platinum(II) and palladium(II) complexes with cyclin-dependent kinase inhibitors: synthesis, characterization and antitumour activity.
The Pt(II) and Pd(II) complexes of the types cis-[Pt(L(1))(2)Cl(2)].H(2)O (1), cis-[Pt(L(2))(2)Cl(2)].3H(2)O (2), trans-[Pd(L(1))(2)Cl(2)].H(2)O (3), trans-[Pd(L(2))(2)Cl(2)].H(2)O (4), trans-[Pd(L(3))(2)Cl(2)].2DMF (5) and trans-[Pd(L(4))(2)Cl(2)].2DMF (6) (L(1)-L(4)=cyclin-dependent kinase inhibitors derived from 6-benzylamino-9-isopropylpurine) have been prepared and characterized. The complexes have been studied by elemental analyses, conductivity measurements, ES+ MS, FT-IR, (1)H, (13)C and (195)Pt NMR spectra, differential scanning calorimetry and thermogravimetric analysis. The molecular structures of L(1), trans-[Pd(L(3))(2)Cl(2)].2DMF (5) and trans-[Pd(L(4))(2)Cl(2)].2DMF (6) have been determined by single crystal X-ray analysis. The complexes have been tested in vitro due to their presumable anticancer activity against the following human cancer cell lines: K-562, MCF7, G-361 and HOS. Satisfying results were obtained for the complex 1 with IC(50) values of 6 microM acquired against G-361 as well as against HOS cell lines. The lowest values of IC(50) were achieved for the complexes 3 and 4 against MCF 7 cell line with IC(50) 3 microM(for 3) and also 3 microM (for 4).


Raman spectroscopic and ab initio studies on the molecular interactions in the binary liquid mixtures of 4'-fluoroacetophenone.
Raman spectral measurements were carried out for binary liquid mixtures 4'fluoroacetophenone (4F) in different volume concentration ranges at a regular intervals of 0.1 in different solvents. The asymmetric Raman peak observed at 1685 cm(-1) (carbonyl stretching mode) in pure 4F confirms the presence of self association in 4F. The optimization was performed for monomer and dimer structures of 4F as well as 4F dimer with solvents using Gaussian 03 W package. Vibrational wavenumber calculation was performed for monomer and dimer structures of 4F to explain the experimentally observed Raman spectra. The carbonyl stretching mode is the more polar group and its interaction with the solvent molecule plays a vital role in determining the physical and chemical properties of the solute. Hence the observed variation in the peak position and linewidth of carbonyl stretching mode was analysed as a result of intermolecular interactions between the solute and the solvent molecules. Also, interaction energies were calculated to support the results obtained from Raman spectra.


Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications.
Residual tissue androgens are consistently detected within the prostate tumors of castrate individuals and are thought to play a critical role in facilitating the androgen receptor-mediated signaling pathways leading to disease progression. The source of residual tumor androgens is attributed in part to the uptake and conversion of circulating adrenal androgens. Whether the de novo biosynthesis of androgens from cholesterol or earlier precursors occurs within prostatic tumors is not known, but it has significant implications for treatment strategies targeting sources of androgens exogenous to the prostate versus 'intracrine' sources within the prostatic tumor. Moreover, increased expression of androgen-metabolizing genes within castration-resistant metastases suggests that up-regulated activity of endogenous steroidogenic pathways may contribute to the outgrowth of 'castration-adapted' tumors. These observations suggest that a multi-targeted treatment approach designed to simultaneously ablate testicular, adrenal and intracrine contributions to the tumor androgen signaling axis will be required to achieve optimal therapeutic efficacy.


Selective spinal anesthesia for outpatient transurethral prostatectomy (TURP): randomized controlled comparison of chloroprocaine with lidocaine.
This is a study comparing two short-acting local anesthetics lidocaine and 2-chloroprocaine in combination with fentanyl, to provide selective spinal anesthesia for outpatient transurethral resection of the prostate (TURP). In this prospective, randomized double-blind study, selective spinal anesthesia was performed in 40 American Society of Anesthesiologists I-III outpatients undergoing TURP using either 40 mg of chloroprocaine mixed with 12.5 μg of fentanyl (n = 20) or 35 mg of lidocaine mixed with 12.5 μg of fentanyl (n = 20). The primary outcome was duration of spinal block. Secondary outcomes were time to reach T10 (onset), time to maximal level, duration above T10 and lidocaine 3, maximal level of block, and adverse effects. The median (minimum, maximum) onset time was 4 (1, 16) and 3 (2, 10) min for chloroprocaine and lidocaine, respectively. Time to maximal level was 20 (17, 29) and 22 (16, 26) min for chloroprocaine and lidocaine, respectively. Mean maximal level was T7-T8 for both agents. Duration of block above T10 was 54 (28, 88) and 63 (31, 87) min for chloroprocaine and lidocaine, respectively. Duration of block above lidocaine 3 was 93 (56, 218) and 98 (58, 151) min for chloroprocaine and lidocaine, respectively. There was no statistical difference between the two groups with respect to these clinical end points. Four patients in the lidocaine group developed transient neurological symptoms. One patient in the chloroprocaine group developed a cauda equina-like syndrome but recovered fully after several weeks. Selective spinal anesthesia with chloroprocaine and lidocaine for TURP yielded comparable results for clinical characteristics. Further research on transient neurological symptom and cauda equina risk with chloroprocaine is warranted.


Lung Ultrasound, Echocardiography, and Fluid Challenge for the Differential Diagnosis of Pulmonary Hypertension.
The differential diagnosis between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is sometimes difficult despite guidelines-derived standardized step-by-step diagnostic algorithms. We therefore explored the added value of lung ultrasound to a previously validated echocardiographic score of right heart catheterization measurements. Patients referred for PH underwent a right heart catheterization, echocardiography, and lung ultrasound before and after rapid infusion of 7 mL/kg of saline. A 7-point echocardiographic score based on cardiac chamber dimensions and estimates of filling pressures was implemented for the prediction of precapillary PH. Pulmonary congestion was identified by lung ultrasound B lines. The study enrolled 70 patients with PAH and 77 patients with HFpEF. The PAH patients had a higher echocardiographic score (3.5 ± 1.8 vs 1.6 ± 1.5; P < .001). The HFpEF patients had more B lines both before (8.1 ± 4.2 vs 5.1 ± 3.0; P < .001) and after fluid challenge (14.6 ± 5.4 vs 7.6 ± 3.5; P < .001) and a more important increase (Δ) of B lines after fluid challenge (6.5 ± 2.9 vs 2.5 ± 1.6; P < .001). The sensitivity and specificity of the echocardiographic score (cutoff ≥2) alone for PAH were 0.91 and 0.49, respectively (area under the curve of 0.78). The best diagnostic improvement was observed with addition of ΔB lines + E/e' post-fluid challenge to the echocardiographic score, with a significant increase of the area under the curve (0.98) and (with a cutoff given by the presence of echo score ≥2, ΔB lines <4 and E/e' post < 11) a sensitivity of 0.90 (95% CI, 0.83; 0.97) and specificity of 0.84 (95% CI, 0.76; 0.93). Lung ultrasound combined with echocardiography at baseline and after fluid challenge has an incremental value for the differential diagnosis between PAH and PH-HFpEF.


Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor alpha synthetic ligands in mouse liver.
Peroxisome proliferators activate nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and enhance the transcription of several genes in liver. We report here that synthetic PPARalpha ligands Wy-14,643, ciprofibrate, clofibrate, and others induce the nuclear translocation of constitutive androstane receptor (CAR) in mouse liver cells in vivo. Adenoviral-enhanced green fluorescent protein-CAR expression demonstrated that PPARalpha synthetic ligands drive CAR into the hepatocyte nucleus in a PPARalpha- and PPARbeta-independent manner. This translocation is dependent on the transcription coactivator PPAR-binding protein but independent of coactivators PRIP and SRC-1. PPARalpha ligand-induced nuclear translocation of CAR is not associated with induction of Cyp2b10 mRNA in mouse liver. PPARalpha ligands interfered with coactivator recruitment to the CAR ligand binding domain and reduced the constitutive transactivation of CAR. Both Wy-14,643 and ciprofibrate occupied the ligand binding pocket of CAR and adapted a binding mode similar to that of the CAR inverse agonist androstenol. These observations, therefore, provide information for the first time to indicate that PPARalpha ligands not only serve as PPARalpha agonists but possibly act as CAR antagonists.


[Intensity of the epidemic process of whooping cough under conditions of mass immunization over a period of many years].
On the basis of analysis of whooping cough incidence in 1959 to 1975 in Moscow the authors present characteristics of the epidemic process under conditions of planned many-year immunization of children against this infection. Whooping cough morbidity proved to undergo significant changes-from sharp falls the first 8 years of immunization to a relative stabilization with a gradual reduction the last 5 years. Marked seasonal and periodic elevations persist against the background of reduction of morbidity. Preschool- and schoolchildren are equally involved in the epidemic process; the most frequently involved are nonvaccinated children aged 1 year and 4 to 10 years, which lost postvaccinal immunity. Further reduction of the severity of whooping cough and increase in the number of unimanifested forms of the infection was noted. This was apparently connected not only with immunization, but also with the reduction of the virulence of H. pertusis detected in studying the cultures isolated in Moscow from 1967 to 1974. The intensity indices of the epidemic process in whooping cough pointed to the necessity of using a more effective vaccine for the protection of children from whooping cough, despite the noted reduction of morbidity, and diminished severity of the course of the disease, and of the causative agent virulence.


N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by site-, diastereo- and enantioselective vinylogous Mannich reactions.
A readily accessible small-molecule phosphine, derived from commercially available starting materials such as an enantiomerically pure amino acid, serves as the precursor to a Ag-based chiral complex that can be prepared and used in situ to promote a variety of enantioselective vinylogous Mannich (EVM) reactions that involve siloxypyrroles as reaction partners. Transformations with unsubstituted nucleophilic components proceed efficiently and with exceptional site- (γ vs α-addition), diastereo- and enantioselectivity [up to 98% yield, generally >98:2 γ/α and diastereomeric ratio (dr) and up to 99:1 enantiomeric ratio (er)]. The first examples of efficient, diastereo- and enantioselective vinylogous Mannich additions with 5-methyl-substituted siloxyfuran, resulting in the formation of O-substituted quaternary carbon stereogenic centers are presented as well. Appreciable efficiency and diastereo- and enantioselectivity (up to >98:2 dr and >99:1 er) is accompanied by formation of α-addition products that can be oxidatively removed.


The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4.
Catecholamines stimulate the first step of lipolysis by PKA-dependent release of the lipid droplet-associated protein ABHD5 from perilipin to co-activate the lipase ATGL. Here, we unmask a yet unrecognized proteolytic and cardioprotective function of ABHD5. ABHD5 acts in vivo and in vitro as a serine protease cleaving HDAC4. Through the production of an N-terminal polypeptide of HDAC4 (HDAC4-NT), ABHD5 inhibits MEF2-dependent gene expression and thereby controls glucose handling. ABHD5-deficiency leads to neutral lipid storage disease in mice. Cardiac-specific gene therapy of HDAC4-NT does not protect from intra-cardiomyocyte lipid accumulation but strikingly from heart failure, thereby challenging the concept of lipotoxicity-induced heart failure. ABHD5 levels are reduced in failing human hearts and murine transgenic ABHD5 expression protects from pressure-overload induced heart failure. These findings represent a conceptual advance by connecting lipid with glucose metabolism through HDAC4 proteolysis and enable new translational approaches to treat cardiometabolic disease.


Tumor control probability predictions for genetic radiotherapy.
Genetic radiotherapy, the combination of gene therapy and radiation therapy, for cancer treatment is evolving from laboratory studies to clinical trials. Genetic radiotherapy involves the viral infection of cells that change the sensitivity of transduced cells to radiation. Because there is no patient outcome data for genetic radiotherapy, prospective models are needed to determine the expected benefit of this new modality. Such a prospective model has been developed in this work. An existing tumor control probability (TCP) calculation model developed for external beam radiotherapy was modified for genetic radiotherapy. Specifically, the (1) transduced fraction and (2) enhancement factor of the transduced cells were included in the model. Parametric studies of the effects of these two variables on TCP for head-and-neck cancer were performed. Using reasonable transduction fraction and enhancement factor values (0.8 and 1.4, respectively), the model predicts an increase in the TCP for genetic radiotherapy over radiotherapy alone by up to 15% for the same radiotherapy dose. The theoretical limit of TCP increase was calculated to be near 70%, which may occur with improved techniques that increase the transduced fraction or because of a strong bystander effect. To maintain existing TCP, dose reductions from 5 Gy (reasonable values) to >30 Gy (ideal case) are predicted for genetic radiotherapy over radiotherapy alone. Our results indicate that genetic radiotherapy has the potential to significantly improve tumor control over radiotherapy alone.


Is there a difference in clinical efficacy of bright light therapy for different types of depression? A pilot study.
There is growing interest in the possible applications of Bright Light Therapy (BLT). BLT might be a valid alternative or add-on treatment for many other psychiatric disorders beyond seasonal affective disorder. This pilot study aims to examine whether the efficacy of Bright Light Therapy (BLT) is similar for different subtypes of mood disorders. Participants were 48 newly admitted outpatients with major depressive disorder with either melancholic features (n=20) or atypical features (n=28). Morning BLT was administered daily for 30 min at 5.000-10.000 lx on working days for up to 3 consecutive weeks. Participants' depressive symptoms improved significantly after BLT (p<.05, d=-.53). The effects of BLT remained stable across a 4 week follow-up. There were no significant differences in efficacy of BLT between groups (p>.05). No effect of seasonality on the improvement in depressive symptoms after BLT was found, (p=.781). The study had a small sample size and lacked a control condition. This pilot study provides preliminary evidence that BLT could be a promising treatment for depression, regardless of the melancholic or atypical character of the depressive symptoms.


Studies of the heterogeneity of antithrombin III concentrates.
The biological activities of antithrombin III (At III) concentrates, prepared by several manufacturers for clinical use, have been compared by three assay methods, and their heparin-binding properties studied by crossed immunoelectrophoresis and heparin affinity chromatography. Concentrates from two of the four manufacturers showed discrepancies between assay methods, with concentrations by heparin co-factor assays significantly lower than those by immunological and progressive antithrombin methods. Heterogeneity was also found by heparin binding studies, with about half the total At III antigen in these concentrates being unable to bind to heparin. These results confirm previous findings of heterogeneity in At III concentrates and show that some concentrates contain substantial amounts of altered At III molecules in which the heparin-binding site has been denatured but the thrombin-neutralizing site left largely intact.


Use of Social Media as a Platform for Education and Support for People With Diabetes During a Global Pandemic.
Patient education is a fundamental aspect of self-management of diabetes. The aim of this study was to understand whether a social media platform is a viable method to deliver education to people with diabetes and understand if people would engage and interact with it. Education sessions were provided via 3 platforms in a variety of formats. "Tweetorials" and quizzes were delivered on the diabetes101 Twitter account, a virtual conference via Zoom and video presentations uploaded to YouTube. Audience engagement during and after the sessions were analyzed using social media metrics including impressions and engagement rate using Twitter analytics, Tweepsmap, and YouTube Studio. A total of 22 "tweetorial" sessions and 5 quizzes with a total of 151 polls (both in tweetorial and quiz sessions) receiving a total of 21,269 votes took place. Overall, the 1-h tweetorial sessions gained 1,821,088 impressions with an engagement rate of 6.3%. The sessions received a total of 2,341 retweets, 2,467 replies and 10,060 likes. The quiz days included 113 polls receiving 16,069 votes. The conference covered 8 topics and was attended live by over 100 people on the day. The video presentations on YouTube have received a total of 2,916 views with a watch time of 281 h and 8,847 impressions. Despite the limitations of social media, it can be harnessed to provide relevant reliable information and education about diabetes allowing people the time and space to learn at their own pace.


Transpyloric extension of gastric carcinoma.
Transpyloric extension of gastric carcinoma occurred in 17 (20%) of 88 patients with gastric carcinoma. In the majority of cases, this was a microscopic phenomenon, but in 7 patients with gastric carcinoma there were gross changes in the duodenum which were reflected in the upper-gastrointestinal series. Contrary to general opinion, transpyloric extension of gastric carcinoma is not a rare finding.


Brivaracetam substituting other antiepileptic treatments: Results of a retrospective study in German epilepsy centers.
To evaluate the success of initiation of adjunctive brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam. In this retrospective noninterventional study conducted in specialized epilepsy centers across Germany, patients initiated adjunctive brivaracetam between February 15, 2016, and August 31, 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months, and withdrew at least one AED either before or within 6 months after brivaracetam initiation. Five hundred and six patients had at least one brivaracetam dose and were included in the safety set (SS). Four hundred and seventy patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation, and were included in the full analysis set (FAS) for effectiveness analyses. At baseline, patients had a median of seven lifetime AEDs and a median of 3.8 seizures/28 days. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (49.4%). 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure-free. In the SS, 34.6% of patients reported treatment-emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug-related. Incidences of behavioral AEs before (3-month baseline) and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs). Brivaracetam was effective and well-tolerated in patients who required a change in AED drug regimen and initiated adjunctive brivaracetam in German clinical practice.


Inflammation high-field magnetic resonance imaging.
Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). MS has been subject to high-field magnetic resonance (MR) imaging research to a great extent during the past years, and much data has been collected that might be helpful in the investigation of other inflammatory CNS disorders. This article reviews the value of high-field MR imaging in examining inflammatory MS abnormalities. Furthermore, possibilities and challenges for the future of high-field MR imaging in MS are discussed.


Cell surface enzyme attachment is mediated by family 37 carbohydrate-binding modules, unique to Ruminococcus albus.
The rumen bacterium Ruminococcus albus binds to and degrades crystalline cellulosic substrates via a unique cellulose degradation system. A unique family of carbohydrate-binding modules (CBM37), located at the C terminus of different glycoside hydrolases, appears to be responsible both for anchoring these enzymes to the bacterial cell surface and for substrate binding.


Lobeline inhibits Ca2+ current in cultured neurones from rat sympathetic ganglia.
The effect of lobeline was studied on the voltage-activated Ca2+ current in sympathetic neurones from the rat superior cervical ganglia using the whole-cell variant of the patch-clamp technique. Lobeline (10-300 microM) inhibited the Ca2+ current evoked by voltage steps from -80 mV (holding potential) to 0 mV (test potential) in a dose dependent manner. The inhibitory effects of noradrenaline (10 microM) and lobeline (100 microM) were compared using a prepulse protocol with high (+80 mV) depolarization. Within the same cell depolarizing prepulses decreased the inhibitory effect of noradrenaline but did not change the extent of lobeline inhibition. Addition of GTPgammaS (300 microM) to the pipette solution did not prevent the inhibitory effect of lobeline (100 microM) but greatly reduced that of noradrenaline (100 microM). Our experiments suggest, that the weak nicotinic agonist lobeline exerts a direct blocking effect on Ca2+ channels at concentrations commonly used to release transmitters.


Editorial Commentary: Treating Hidden Lesions Using Hidden Data: Isolated Lesions of the Shoulder Biceps Pulley.
In a study evaluating a rare condition (isolated lesions of the shoulder biceps pulley), retrospective analysis of a comprehensive, prospective surgical database allows authors to determine the results for the surgical management of this uncommon pathology. The creation and use of a comprehensive surgical database can help surgeons evaluate their own data to help improve patient outcomes. The authors present favorable data on the effectiveness of open subpectoral biceps tenodesis to treat isolated biceps reflection pulley lesions. By maintaining a comprehensive surgical database the authors were able to evaluate their results for the surgical management of this uncommon pathology. The creation and maintenance of a surgical database can help monitor and improve patient outcomes in any practice.


The Neurological Examination Improves Cranial Accelerometry Large Vessel Occlusion Prediction Accuracy.
We combined cranial accelerometry, a device-based approach to large vessel occlusion (LVO) prediction, with neurological examination findings to determine if this improves diagnostic accuracy compared to either alone. Cranial accelerometry recordings and NIHSS scores were obtained during stroke codes and thrombectomy transfers at an academic medical center using convenience sampling. The reference standard was discharge diagnosis of LVO stroke. We compared accuracy statistics between machine learning models trained using cranial accelerometry alone, with asymmetric arm weakness added, with NIHSS scores added, and retrospective examination only LVO prediction scales. An exploratory analysis required asymmetric arm weakness prior to model training or scale testing. Of 68 patients, there were 23 LVO strokes. Cranial accelerometry was 65% sensitive (95% CI 43-84%) and 87% specific (95% CI 73-95%). Adding asymmetric arm weakness increased specificity to 91% (95% CI 79-98%). Adding asymmetric arm weakness and the NIHSS increased sensitivity to 74% (95% CI 52-90%) and decreased specificity to 89% (95% CI 76-96%). LVO prediction scales had wide sensitivity and specificity ranges. The exploratory analysis improved sensitivity to 91% (95% CI 72-99%) and specificity to 93% (95% CI 92-99%) with only three false positives and two false negatives. Cranial accelerometry models are improved by various additions of asymmetric arm weakness and the NIHSS. An exploratory analysis requiring asymmetric arm weakness prior to cranial accelerometry model training minimized false positives and negatives.


Incidence of sedation-related adverse events during ERCP with anesthesia assistance: a multicenter observational study.
Anesthesia assistance is commonly used for ERCP. General anesthesia (GA) may provide greater airway protection but may lead to hypotension. We aimed to compare GA versus sedation without planned intubation (SWPI) on the incidence of hypoxemia and hypotension. We also explored risk factors for conversion from SWPI to GA. This observational study used data from the Multicenter Perioperative Outcomes Group. Adults with American Society of Anesthesiologists physical status class I to IV undergoing ERCP between 2006 and 2019 were included. We compared GA and SWPI on incidence of hypoxemia (oxygen saturation <90% for ≥3 minutes) and hypotension (mean arterial pressure <65 mm Hg for ≥5 minutes) using joint hypothesis testing. The association between anesthetic approach and outcomes was assessed using logistic regression. The noninferiority delta for hypoxemia and hypotension was an odds ratio of 1.20. One approach was deemed better if it was noninferior on both outcomes and superior on at least 1 outcome. To explore risk factors associated with conversion from SWPI to GA, we constructed a logistic regression model. Among 61,735 cases from 42 institutions, 38,830 (63%) received GA and 22,905 (37%) received SWPI. The GA group had 1.27 times (97.5% confidence interval, 1.19-1.35) higher odds of hypotension but .71 times (97.5% confidence interval, .63-.80) lower odds of hypoxemia. Neither group was noninferior to the other on both outcomes. Conversion from SWPI to GA occurred in 6.5% of cases and was associated with baseline comorbidities and higher institutional procedure volume. GA for ERCP was associated with less hypoxemia, whereas SWPI was associated with less hypotension. Neither approach was better on the combined incidence of hypotension and hypoxemia.


MicroRNA-183 and microRNA-96 are associated with autoimmune responses by regulating T cell activation.
MircoRNAs (miRs) are small molecules that regulate gene expression at the posttranscriptional level. They have been proposed to be involved in the regulation of several immune responses including autoimmunity. Here, we identified miR-183 and miR-96 to be highly expressed in CD4+ T cells from peripheral blood of Graves' orbitopathy (GO) patients as well as in human and murine T cells upon activation in vitro. By using Luciferase-based binding assays, we identified EGR-1 as target for miR-183 and miR-96. Overexpression of miR-183 and miR-96 in murine CD4+ T cells by retroviral gene transfer resulted in decreased EGR-1 and PTEN expression, elevated Akt phosphorylation and enhanced proliferation. In contrast, treatment of murine CD4+ T cells with specific antagomiRs increased EGR-1 and PTEN expression and interfered with the proliferative activity upon stimulation in vitro. Strikingly, adoptive transfer of miR-183 and miR-96 overexpressing antigen-specific T cells into INS-HA/Rag2KO mice accelerated the development of autoimmune diabetes, whereas transfer of antagomiR-treated cells delayed the disease onset. These results indicate that miR-183 and miR-96 have the ability to regulate the strength of T cell activation and thereby the development and severity of T cell-dependent autoimmune diseases.


Different genetic alterations underlie dual hypersensitivity of CHO mutant UV-1 to DNA methylating and cross-linking agents.
CHO mutant UV-1, isolated on the basis of hypersensitivity to UV radiation (254 nm), was further characterized with respect to sensitivity to classes of DNA damaging agents in a differential cytotoxicity (DC) assay. Compared to its parental strain, Gly- A, UV-1 was dramatically (10- to 100-fold) hypersensitive to both DNA methylating and cross-linking agents. In addition, UV-1 was moderately (two- to fourfold) hypersensitive to several other classes of mutagens. DNA isolated from UV-1 or Gly- A after exposure to 14C-labeled methylnitrosourea (MNU) contained similar amounts of label, thus ruling out differences in uptake or binding. Three phenotypic revertants of UV-1 were resistant to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and other methylating agents but retained hypersensitivity to cross-linking agents. Moreover, fusion of UV-1 with two different UV-sensitive CHO mutants also having hypersensitivity to cross-link and methylation damage produced hybrids resistant to mitomycin C (MMC) but not to methyl methane sulfonate (MMS). Since the methylation and cross-link sensitivities were uncoupled in both genetic tests, the complex phenotype of UV-1 is likely due to more than one genetic alteration.


Effect of sample freezing on the isolation of Mycoplasma spp. from the clitoral fossa of the mare.
The growth of Mycoplasma equigenitalium and Mycoplasma subdolum from specimens collected from the clitoral fossa of each of four Standardbred mares was not diminished by freezing of the specimens in liquid nitrogen (-196 degrees C) for up to 30 days when compared to samples cultured immediately.


Sequential hormonal supplementation with vaginal estradiol and progesterone gel corrects the effect of clomiphene on the endometrium in oligo-ovulatory women.
We investigated the possibility of correcting the endometrial alterations induced with clomiphene citrate (CC) by vaginal hormonal supplementation (HS) with estradiol (E2) and progesterone gel. Oligo-ovulatory women were prospectively randomized into four groups receiving either 50 mg (groups 1 and 2) or 100 mg (groups 3 and 4) of CC from cycle day 3-8. Groups 2 and 4 also received vaginal E2 cream 0.1 mg twice daily from day 8 until the LH surge and vaginal progesterone gel, starting 3 days after ovulation. All participants had an endometrial biopsy performed 10 +/- 1 days after ovulation. All biopsies in the HS groups (2 and 4) showed complete predecidual changes, and were 'in-phase' with findings normally made 10 days post-ovulation (+/- 2 days of clinical dating). However, without HS (groups 1 and 3), only 4/6 and 3/6 biopsies showed predecidual changes in women receiving 50 and 100 mg of CC. The addition of vaginal E2 and progesterone to CC ovulation induction regimens normalizes the alterations in endometrial morphology. Hormonal treatment combining vaginal E2 and progesterone may improve endometrial receptivity in CC cycles and ultimately yield higher pregnancy rates.


Cost analysis of open radical cystectomy versus robot-assisted radical cystectomy.
To perform a cost analysis comparing the cost of robot-assisted radical cystectomy (RARC) with open RC (ORC) in a UK tertiary referral centre and to identify the key cost drivers. Data on hospital length of stay (LOS), operative time (OT), transfusion rate, and volume and complication rate were obtained from a prospectively updated institutional database for patients undergoing RARC or ORC. A cost decision tree model was created. Sensitivity analysis was performed to find key drivers of overall cost and to find breakeven points with ORC. Monte Carlo analysis was performed to quantify the variability in the dataset. One RARC procedure costs £12 449.87, or £12 106.12 if the robot was donated via charitable funds. In comparison, one ORC procedure costs £10 474.54. RARC is 18.9% more expensive than ORC. The key cost drivers were OT, LOS, and the number of cases performed per annum. High ongoing equipment costs remain a large barrier to the cost of RARC falling. However, minimal improvements in patient quality of life would be required to offset this difference.


Direct observation of ultrafast collective motions in CO myoglobin upon ligand dissociation.
The hemoprotein myoglobin is a model system for the study of protein dynamics. We used time-resolved serial femtosecond crystallography at an x-ray free-electron laser to resolve the ultrafast structural changes in the carbonmonoxy myoglobin complex upon photolysis of the Fe-CO bond. Structural changes appear throughout the protein within 500 femtoseconds, with the C, F, and H helices moving away from the heme cofactor and the E and A helices moving toward it. These collective movements are predicted by hybrid quantum mechanics/molecular mechanics simulations. Together with the observed oscillations of residues contacting the heme, our calculations support the prediction that an immediate collective response of the protein occurs upon ligand dissociation, as a result of heme vibrational modes coupling to global modes of the protein.


Endoscopic management of rare congenital malformations of the male urethra.
Partial duplication of the urethra and dilatation of Cowper's duct are very rare congenital anomalies of the lower urinary tract which can be diagnosed and located by endoscopy. Treatment consists in transurethral resection of the septum between the urethra and the accessory channel.


1,1'-(Ethane-1,2-di-yl)bis-(4-{(E)-2-[4-(di-methyl-amino)-phen-yl]ethen-yl}pyridin-1-ium) dibromide ethanol 0.67-solvate.
The asymmetric unit of the title solvated mol-ecular salt, 3C32H36Br2N4 2+·6Br-·2C2H5OH, consists of 1.5 cations, three bromide anions and one ethanol solvent mol-ecule of crystallization. The half-cation is completed by crystallographic inversion symmetry. In the crystal, O-H⋯Br hydrogen bonds and weak C-H⋯Br inter-actions link the components.


An aminopeptidase N-activatable chemiluminescence probe for image-guided surgery and metastasis tracking of tumor.
Malignant tumors are a severe threat to human health. Surgical removal is still the preferred method in clinical practice among the many treatment strategies. Nevertheless, tiny residual tumor lesions and distant metastases are always missed during surgery, resulting in tumor recurrence. Therefore, it is important for doctors to distinguish residual tumor tissues and distant metastases from normal tissues but remains challenging. Herein, we rationally designed an aminopeptidase-activatable chemiluminescence (CL) probe Ala-PD to distinguish cancer tissues from normal tissues through a spraying manner. In vitro studies revealed that Ala-PD could specifically respond to APN with a ∼26-fold CL signal turn-on ratio and a limit of detection of 0.531 ng/mL. Moreover, Ala-PD exhibited an ultrahigh tumor-to-normal tissue CL ratio of above 1.2 × 106. Furthermore, the ability of Ala-PD to image metastatic tumor tissues was also achieved in tumor-bearing mouse, highlighting the potential of Ala-PD to be applied in image-guided surgery clinically.


Ion-acoustic waves in weakly ionized plasmas with charge-exchange collisions.
Ion-neutral charge-exchange collisions in plasmas of laboratory, space, and astrophysical origins are fundamental to understanding wave dissipation and wave generation phenomena. This paper implements a charge-exchange collision operator in the Boltzmann-Poisson system equations for a weakly ionized plasma. When considering an electric field perturbation, the governing kinetic equations provide significant results concerning the plasma conductivity and the dielectric function, appearing in simple, sensible forms. The present analysis reveals a backward wave propagation phenomenon at maximum conductivity when the wavenumber of the plasma wave is smaller than the reciprocal of the ion-neutral collisions mean free path. In addition, it is shown that ion-neutral coupling resulting from charge-exchange collisions enhances ion-acoustic waves below and beyond the ion plasma frequency and leads to the onset of a fundamental instability that overcomes Landau damping under certain circumstances. The collisionless model is recovered as a limiting case, i.e., in the asymptotic limit of a long mean free path.


Corrigendum: Regional health differences - developing a socioeconomic deprivation index for Germany.
[This corrects the article on p. 98-114 in vol. 2.].


PET imaging of αvβ₃ integrin expression in tumours with ⁶⁸Ga-labelled mono-, di- and tetrameric RGD peptides.
Due to the restricted expression of α(v)β(3) in tumours, α(v)β(3) is considered a suitable receptor for tumour targeting. In this study the α(v)β(3)-binding characteristics of (68)Ga-labelled monomeric, dimeric and tetrameric RGD peptides were determined and compared with their (111)In-labelled counterparts. A monomeric (E-c(RGDfK)), a dimeric (E-[c(RGDfK)](2)) and a tetrameric (E{E[c(RGDfK)](2)}(2)) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with (68)Ga. In vitro α(v)β(3)-binding characteristics were determined in a competitive binding assay. In vivo α(v)β(3)-targeting characteristics of the compounds were assessed in mice with subcutaneously growing SK-RC-52 xenografts. In addition, microPET images were acquired using a microPET/CT scanner. The IC(50) values for the Ga(III)-labelled DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2) and DOTA-E{E[c(RGDfK)](2)}(2) were 23.9 ± 1.22, 8.99 ± 1.20 and 1.74 ± 1.18 nM, respectively, and were similar to those of the In(III)-labelled mono-, di- and tetrameric RGD peptides (26.6 ± 1.15, 3.34 ± 1.16 and 1.80 ± 1.37 nM, respectively). At 2 h post-injection, tumour uptake of the (68)Ga-labelled mono-, di- and tetrameric RGD peptides (3.30 ± 0.30, 5.24 ± 0.27 and 7.11 ± 0.67%ID/g, respectively) was comparable to that of their (111)In-labelled counterparts (2.70 ± 0.29, 5.61 ± 0.85 and 7.32 ± 2.45%ID/g, respectively). PET scans were in line with the biodistribution data. On all PET scans, the tumour could be clearly visualised. The integrin affinity and the tumour uptake followed the order of DOTA-tetramer > DOTA-dimer > DOTA-monomer. The (68)Ga-labelled tetrameric RGD peptide has excellent characteristics for imaging of α(v)β(3) expression with PET.


Transferrin: common and rare variants in italy. Evidence for the existence of the rare TfC6 among Caucasians.
The results of a large screening for the transferrin polymorphism in five different areas of Italy (3099 cases) are given. Frequencies of common types were similar to those of already known Caucasian populations. Among rare types TfB were more frequently observed than TfD. Evidence is given for the existence of the TfC6 allele in Caucasians. A family group analysis of some rare types was done.


[Guidelines for diagnosis, treatment and monitoring of primary immune thrombocytopenia].
The consensus document on the diagnosis, treatment and monitoring of primary immune thrombocytopenia was developed in 2010 by specialists with recognized expertise in this disease under the auspices of the Spanish Society of Hematology and Hemotherapy and the Spanish Society of Pediatric Hematology and Oncology, with the aim to adapt to Spain the recommendations of the recently published international consensus documents. The decision to start treatment is based on bleeding manifestations and platelet count (<20×10(9)/L). The first-line treatment is corticosteroids, albeit for a limited period of 4-6 weeks. The addition of intravenous immunoglobulin is reserved to patients with severe bleeding. Splenectomy is the most effective second-line treatment. For patients refractory to splenectomy and those with contraindications or patient refusal, the new thrombopoietic agents are the drugs of choice due to their efficacy and excellent safety profile. The other treatment options have highly variable response rates, and the absence of controlled studies does not allow to establish clear recommendations. Monitoring should be individualized. In patients without active treatment, blood counts are recommended every 3-6 months, and the patient should be instructed to consult in case of bleeding, surgery or invasive procedure and pregnancy. In most of the pediatric population, the disease tends to spontaneous remission. High-dose corticosteroids in short course and intravenous immunoglobulin are the treatment of choice. Second- and further-line treatments should be monitored in specialized centers.


TH5487, a small molecule inhibitor of OGG1, attenuates pulmonary fibrosis by NEDD4L-mediated OGG1 degradation.
Pulmonary fibrosis is a highly aggressive and lethal disease that currently lacks effective targeting therapies. Herein, we established a mouse model of pulmonary fibrosis induced by intratracheal instillation of bleomycin (BLM) in wild-type (WT) and 8-oxoguanine DNA glycosylase-1 (OGG1) knockout (Ogg1-/-) mice. TH5487, a specific small-molecule inhibitor of OGG1, was found to ameliorate BLM-induced pulmonary fibrosis in WT mice. Concomitantly, TH5487 treatment markedly suppressed the BLM-mediated alveolar epithelial-mesenchymal transition (EMT) and increase in OGG1 protein level in the lungs of WT mice. However, administration of TH5487 did not further improve this fibrotic transformation in Ogg1-/- mice. More importantly, adeno-associated virus-mediated lung-specific OGG1 overexpression accelerated alveolar EMT and the resultant fibrosis progression antagonized by TH5487 in the fibrotic lungs of WT mice, suggesting that the down-regulation of OGG1 protein level could be essential for TH5487 to exert its anti-fibrogenic function. Mechanism study in alveolar epithelial cells demonstrated that TH5487 treatment canceled TGF-β1-mediated suppression of NEDD4-like E3 ubiquitin ligase (NEDD4L), which ubiquitinated OGG1 and targeted it for proteasomal degradation. Furthermore, TH5487-mediated suppression of alveolar EMT and the fibrotic processes was counteracted by silencing NEDD4L in TGF-β1-induced alveolar epithelial cells. Collectively, these data underline the potential of TH5487 as an effective anti-fibrotic agent for pulmonary fibrosis.


Functional outcome of patients with benign meningioma treated by 3D conformal irradiation with a combination of photons and protons.
To evaluate efficacy and tolerance of external fractionated combination of photon and proton radiation therapy (RT) for intracranial benign meningiomas. Between 1994 and 2002, 51 patients with intracranial meningiomas of the base of the skull were treated with a combination of photon and proton RT. Median total dose was 60.6 cobalt Gy equivalent (54-64). One hundred eight eye-related symptoms were collected; 80 other symptoms were noted and followed up. Mean follow-up was 25.4 months. Acute tolerance was excellent. Out of the 108 eye-related symptoms, 106 (96%) were evaluated. Improvements were reported for 73 (68.8%) of them. Out of the 88 other miscellaneous symptoms, 81 (92%) were evaluated. Improvements were reported in 54 cases (67%). Median time to improvement ranged from 1 to 24 months after completion of the radiotherapy, depending on the symptom. We did not observe any worsening of primary clinical signs. Radiologically, 1 patient relapsed 4 months after the end of irradiation. Pathology revealed a malignant (Grade 3) transformation of the initial Grade 1 meningioma. Four-year local control and overall survival rates were, respectively, 98% and 100%. Stabilization of the tumor was observed in 38 cases (72%), volume reduction in 10 cases (20%), and intratumor necrosis in 3 cases. Two patients complained of Grade 3 side effects: 1 unilateral hearing loss requiring aid and 1 case of complete pituitary deficiency. These results stressed the clinical efficacy of fractionated-associated photon-proton RT in the treatment of meningiomas, especially on cranial nerve palsies, without severe toxicity in almost all patients.


Early intervention in obsessive-compulsive disorder: From theory to practice.
Obsessive-compulsive disorder (OCD) is frequent and often disabling. Yet, correct diagnosis and appropriate treatment implementation are usually delayed, with undesirable consequences. In this paper we review the rationale for early intervention in OCD and provide recommendations for early intervention services. Two scenarios are discussed, i.e., subclinical (prodromal) obsessive-compulsive symptoms (OCS) and full-blown OCD. Although the typical patient with OCD reports a long history of subclinical OCS, longitudinal studies suggest most individuals with OCS in the community do not convert to full-blown OCD. Thus, research on "at risk" phenotypes for OCD and how they should incorporate different risk factors (e.g., polygenic risk scores) are badly needed. For this specific scenario, preventative treatments that are cheap, well tolerated and highly scalable (e.g., lifestyle interventions) are of major interest. On the other hand, increasing evidence suggests OCD to be a progressive disorder and the severity and duration of illness to be associated with both biological changes and increased clinical complexity, including greater number of physical and psychiatric comorbidities, increased family accommodation and worse treatment response. Therefore, prompt identification and early treatment implementation for full-blown OCD are also critical for ethical, clinical and therapeutic reasons. Based on the existing findings, we argue that, regardless of focusing on subclinical OCS or clinical OCD, early intervention services need to target a childhood age group. In addition to delivering well established treatments to people with full-blown OCD early on their illness, early intervention services also need to provide psychoeducation for patients, families and teachers.


Lack of significant effect of L(+)-glutamate on serum gamma-glutamyltransferase activity determined in the presence of glycylglycine.
No increase in gamma-glutamyltransferase activity determined in human sera at 25, 30, or 37 degrees C could be demonstrated when L(+)-glutamate, 10 to 5000 mumol/liter, was incorporated into reaction media containing glycylglycine, 40 mmol/liter.


Lymphocyte induced macrophage cytotoxicity: characterization of the macrophage cytotoxicity-inducing lymphocyte.
The phenotype of lymphocytes, obtained from mice immunized with allogeneic tumor cells, with the capacity to induce macrophage cytotoxicity was determined. Macrophage cytotoxicity was induced, either by incubating the macrophages with Macrophage Arming Factor (MAF) containing supernatants of cultures of sensitized lymphocytes and tumor cells (arming) or by incubating the macrophages directly with sensitized lymphocytes and tumor cells (activation). The MAF producing or activating capacity of the lymphocytes was not only "triggered" by the sensitizing tumor cells but also by normal cells and other tumor cells bearing the H-2 determinants of the sensitizing tumor cell. The capacity to render macrophages cytotoxic was not reduced after treatment of the lymphocytes with mitomycin-C or treatment with anti-murine Ig and complement. This capacity of the lymphocytes was abrogated after treatment with anti-T-cell serum or anti-Thy 1.2 serum and complement. After treatment with anti-Lyt 1 or anti-Lyt 2 serum and complement, the activating capacity was significantly reduced and the MAF producing capacity of the lymphocytes abrogated. Mixing the Lyt 1 depleted and Lyt 2 depleted lymphocytes or addition of normal lymphocytes to the Lyt 1 depleted or Lyt 2 depleted populations did not restore the MAF producing and activating capacities. This indicated that the lymphocytes inducing macrophage cytotoxicity in this allogeneic system are Lyt-1+2+ T-lymphocytes, which do not need to divide prior to perform their action.


Prevalence of Paediatric Surgical Conditions in Eastern Uganda: A Cross-Sectional Study.
The role of surgery in global health has gained greater attention in recent years. Approximately 1.8 billion children below 15 years live in low- and middle-income countries (LMIC). Many surgical conditions affect children. Therefore, paediatric surgery requires specific emphasis. Left unattended, the consequences can be dire. Despite this, there is a paucity of data regarding prevalence of surgical conditions in children in LMIC. The present objective was to investigate the prevalence of paediatric surgical conditions in children in a defined geographical area in Eastern Uganda. A cross-sectional study was carried out in the Iganga-Mayuge Health and Demographic Surveillance Site located in Eastern Uganda. Through a two-stage, cluster-based sampling process, 490 households from 49 villages were randomly selected, generating a study population of 1581 children. The children's caregivers were interviewed, and the children were physically examined by two medical doctors to identify any surgical conditions. The interview was performed with 1581 children, and 1054 were physically examined. Among these, the overall prevalence of any surgical condition was 16.0 per cent (n = 169). Of these, 39 per cent had an unmet surgical need (66 of 169). This is equivalent to a 6.3 per cent prevalence of current unmet surgical need. The most common groups of surgical condition were congenital anomalies and trauma-related conditions. Surgical conditions in children are common in eastern Uganda. The unmet need for surgery is high. With a growing population, the need for paediatric surgical capacity will increase even further. The health care system must be reinforced to provide services for children with surgical conditions if United Nations Sustainability Development Goal 3 is to be achieved by 2030.


Effect of adenosine, adenosine triphosphate, adenosine deaminase, dipyridamole and aminophylline on acetylcholine release from electrically-stimulated brain slices.
The effect of adenosine on release of acetylcholine (ACh) was investigated in slices of rat cortex perfused with Krebs solution, at rest and during electrical stimulation at frequencies between 0.2 and 20 Hz. Electrical stimulation brought about a linear increase in release of ACh. Adenosine, in concentrations ranging from 1 to 100 microM, reduced in a dose-dependent manner the release of ACh and was more active on the stimulated than on the resting release. However, the fractional reduction by adenosine of stimulated release of ACh did not vary with increasing stimulation rate. Adenosine triphosphate was less active than adenosine in reducing release of ACh. The inhibitory effect of adenosine was antagonized by aminophylline (0.5 mM) and did not occur when the stimulated release of ACh was enhanced by blocking muscarinic autoreceptors with atropine (15 nM). Aminophylline (0.1 and 0.5 mM) itself exerted a biphasic effect on release of ACh, increasing it at rest and during stimulation at low frequencies, and decreasing it at higher stimulation rates. The manipulation of endogenous adenosine concentrations by adding adenosine deaminase or diphyridamole, an inhibitor of adenosine uptake, had little effect on release of ACh. Dipyridamole, (4 microM), only significantly decreased release of ACh at the 20 Hz stimulation rate.


A new benzylisoquinoline alkaloid from Leontice altaica.
A new benzylisoquinoline alkaloid, lincangenine-4-β-D-glucopyranoside (1), has been isolated from the roots of Leontice altaica, together with 5 known alkaloids. Its structure was elucidated on the basis of 1D and 2D NMR data, and chemical means.


Isobolographic profile of interactions between tiagabine and gabapentin: a preclinical study.
Combining the use of some antiepileptic drugs (AEDs) in patients with epilepsy can result in interactions of a pharmacodynamic or pharmacokinetic character. To quantify the profile of interactions between tiagabine (TGB) and gabapentin (GBP), two novel AEDs influencing the GABAergic neurotransmitter system, an isobolographic analysis was performed in the maximal electroshock seizure threshold (MEST), pentylenetetrazole (PTZ)-induced seizure and chimney tests in mice. TGB and GBP injected alone dose-dependently raised the electroconvulsive threshold in mice, which allowed the evaluation of TID(20) (the dose increasing the threshold by 20% compared with controls) in the MEST-test. TID(20) values for TGB and GBP alone were 4.3 mg/kg and 70 mg/kg, respectively. On the basis of isobolographic calculations, TGB was also co-administered with GBP at three fixed ratios (1:3, 1:1 and 3:1) of their respective TID(20) doses. The isobolographic analysis showed that all three combinations of TGB with GBP exerted supra-additive (synergistic) interactions in the MEST-test in mice. Likewise, TGB and GBP injected alone suppressed the clonic phase of PTZ-induced seizures, with (effective) doses protecting 50% of the animals tested against clonic convulsions (ED(50)) for TGB and GBP of 0.9 and 199.3 mg/kg, respectively. Moreover, the two-drug combinations at the same fixed ratios of 1:3, 1:1 and 3:1 in PTZ-induced seizures also showed a tendency towards supra-additive (synergistic) interactions. The adverse (neurotoxic) effects produced by TGB and GBP alone or in combinations at the same fixed ratios of 1:3, 1:1 and 3:1 were evaluated in the chimney test. The (toxic) doses evoking motor impairment in 50% of animals tested (TD(50)) for TGB and GBP alone were 13.6 and 979.6 mg/kg, respectively. The isobolographic analysis showed the interactions between the AEDs to be additive in this test. From a preclinical point of view, the interactions observed experimentally showed that the combination of TGB and GBP, due to a synergistic anti-seizure activity of the drugs, might provide adequate seizure control in patients with refractory epilepsy.


Organization and regional distribution of centers for the management of children and adolescents with diabetes in Italy.
The incidence of type 1 diabetes in childhood is increasing by 3 % per year, placing growing demands on healthcare professionals and medical expenditures. Aim of this study wars to assess the organization of care to children with diabetes in Italy. During 2012 a structured questionnaire was sent to all of the members of Italian Society of Paediatric Endocrinology and Diabetology (ISPED). Questions examined organizational structure of Centers, personnel dedicated to the care of children with diabetes, number of subjects followed, local legal legislation supporting centres. A total of 68 centers taking care to 15,563 children and adolescents with diabetes under 18 years of age were identified with a prevalence of 1.4 per 1,000 people. A wide variation in the organizational background was also reported. Fourty-four centers were organized as outpatient departments, 17 as simple units, 5 as complex units and 2 as simple departmental structures. Most centers had a multidisciplinary team. Ten out of twenty Italian regions had introduced supportive regional legislation, but it was fully applied only in six of them. Great differences between regions were found in organizational structures, staffing levels and supportive legislation. The national legislation on diabetes was broadly implemented throughout the country regions. Further efforts are needed to improve standards and consistency of pediatric diabetes care in Italy.


Spontaneous regression of pulmonary involvement after smoking reduction and removal of and radiation therapy for Langerhans cell histiocytosis of the sphenoid bone: which comes first, the chicken or the egg?
Isolated pulmonary Langerhans cell histiocytosis (LCH) in adults is known to regress spontaneously after smoking cessation alone, but little is known about whether this rationale could also apply in cases of multisystem pulmonary LCH. In particular, pediatric patients with multisystem LCH including involvement in "risk organs" such as lungs often benefit from systemic chemotherapy. Here, we present a 37-year-old man with spontaneous regression of pulmonary lesions in multisystem LCH, achieved solely by smoking reduction following local treatment of bone lesions.


CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.
Alternative splicing of pre-messenger RNA is a key feature of transcriptome expansion in eukaryotic cells, yet its regulation is poorly understood. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. Supporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns. Moreover, the rate of transcription elongation has been linked to alternative splicing. Here we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide. We further show that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. These findings provide a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks.


Structural, functional, and mechanistic insights uncover the fundamental role of orphan connexin-62 in platelets.
Connexins oligomerise to form hexameric hemichannels in the plasma membrane that can further dock together on adjacent cells to form gap junctions and facilitate intercellular trafficking of molecules. In this study, we report the expression and function of an orphan connexin, connexin-62 (Cx62), in human and mouse (Cx57, mouse homolog) platelets. A novel mimetic peptide (62Gap27) was developed to target the second extracellular loop of Cx62, and 3-dimensional structural models predicted its interference with gap junction and hemichannel function. The ability of 62Gap27 to regulate both gap junction and hemichannel-mediated intercellular communication was observed using fluorescence recovery after photobleaching analysis and flow cytometry. Cx62 inhibition by 62Gap27 suppressed a range of agonist-stimulated platelet functions and impaired thrombosis and hemostasis. This was associated with elevated protein kinase A-dependent signaling in a cyclic adenosine monophosphate-independent manner and was not observed in Cx57-deficient mouse platelets (in which the selectivity of 62Gap27 for this connexin was also confirmed). Notably, Cx62 hemichannels were observed to function independently of Cx37 and Cx40 hemichannels. Together, our data reveal a fundamental role for a hitherto uncharacterized connexin in regulating the function of circulating cells.


Immunoprophylaxis of dermatophytosis in animals.
Dermatophytosis is a relatively common disease in many countries occurring endemically both in companion and food animals. Fungi belonging to the genera Trichophyton and Microsporum are most often isolated from clinical cases. Measures to control and prevent dermatophytosis include sanitation, hygienic measures and treatment. In some countries, successful control and eradication have been achieved by mass vaccination of cattle and fur-bearing animals. Vaccines containing live attenuated cells of the fungus stimulate a cell-mediated immune response conferring long-lasting protection against subsequent challenge by the homologous fungus. A delayed type hypersensitivity (DTH) skin test using appropriate dermatophyte antigens is suitable to assess the response. Inactivated dermatophyte vaccines are available for use in cattle, horse, dog, and cat in some countries. However, the scientific literature is scarce making it difficult to conclude on efficacy and appropriate use. Current vaccines are all first generation vaccines. Attempts have been made to prepare subunit vaccines based on new knowledge about virulence factors like the keratinases, so far with limited success. Candidate antigens must be able to stimulate a strong T helper 1 cell response and future research should focus on identification of major T-cell epitopes that specifically elicit a DTH reaction. Dermatophytosis is a zoonotic disease. In Norway and a few other countries, systematic vaccination against cattle ringworm has almost eliminated the disease, and ringworm in man caused by T. verrucosum is almost nonexistent. A similar benefit could be expected if a safe and efficacious vaccine was available for Microsporum canis infection in cats and dogs.


Backbone dynamics of the oligomerization domain of p53 determined from 15N NMR relaxation measurements.
The backbone dynamics of the tetrameric p53 oligomerization domain (residues 319-360) have been investigated by two-dimensional inverse detected heteronuclear 1H-15N NMR spectroscopy at 500 and 600 MHz. 15N T1, T2, and heteronuclear NOEs were measured for 39 of 40 non-proline backbone NH vectors at both field strengths. The overall correlation time for the tetramer, calculated from the T1/T2 ratios, was found to be 14.8 ns at 35 degrees C. The correlation times and amplitudes of the internal motions were extracted from the relaxation data using the model-free formalism (Lipari G, Szabo A, 1982, J Am Chem Soc 104:4546-4559). The internal dynamics of the structural core of the p53 oligomerization domain are uniform and fairly rigid, with residues 327-354 exhibiting an average generalized order parameter (S2) of 0.88 +/- 0.08. The N- and C-termini exhibit substantial mobility and are unstructured in the solution structure of p53. Residues located at the N- and C-termini, in the beta-sheet, in the turn between the alpha-helix and beta-sheet, and at the C-terminal end of the alpha-helix display two distinct internal motions that are faster than the overall correlation time. Fast internal motions (< or = 20 ps) are within the extreme narrowing limit and are of uniform amplitude. The slower motions (0.6-2.2 ns) are outside the extreme narrowing limit and vary in amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)


Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy.
The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (V(c)/F), peripheral distribution volume (V(p)/F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 297 +/- 28.5 [corrected] liters, 848 +/- 209 [corrected] liters, 80 +/- 15 [corrected] liters/h and 50.5 +/- 3.1 [corrected] liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/S(CR)) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC(0-24)). In patients without tubular dysfunction, AUC(0-24) values markedly decreased from 6.7 to 1.4 mg . h/liter for BW/S(CR) increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/S(CR) should be further evaluated.


Albumin Utilization Evaluation in a Major Teaching Hospital in Iran: Recommendations for Guideline Development.
Human albumin solution is an expensive colloidal preparation which is commonly used in clinical practice. Due to high cost of albumin, increased rate of the inappropriate use worldwide, and many other reasons, it is imperative to establish a practical protocol to use albumin products and limit its usage. The aim of this study was to identify albumin utilization patterns in a teaching hospital and to demonstrate the importance of the need to reconsider prescribing strategies for albumin administration. This retrospective cross-sectional study was performed between August 2016 and December 2016 at Firoozgar Hospital affiliated to Iran University of Medical Sciences, Tehran, Iran. All albumin prescriptions for adult patients during the study period were enrolled for appropriateness evaluation according to the latest evidence-based studies and guidelines. Among 320 albumin prescriptions, 168 (52.5%) were inappropriate according to the current evidence. The most common irrational causes for the albumin usage were hypoalbuminemia (23.4%), nutritional support (13.7%), neuroprotection in subarachnoid hemorrhage (3%), pretreatment for cancer surgery (2.8%), edema (1.6%), hepatic failure (1.6%), and paracentesis (3%). The total amount of albumin used for 320 patients was 52,050 g, from which 28,470 g was inappropriate resulting in $97,398 wastage. These findings, along with aforementioned guidelines, support the requirement for physicians' educational programs and proper strategies for appropriate prescriptions and could also be important in modifying the available guidelines concerning expensive drugs such as albumin.


Technology-based cognitive training and rehabilitation interventions for individuals with mild cognitive impairment: a systematic review.
Individuals with mild cognitive impairment (MCI) are at heightened risk of developing dementia. Rapid advances in computing technology have enabled researchers to conduct cognitive training and rehabilitation interventions with the assistance of technology. This systematic review aims to evaluate the effects of technology-based cognitive training or rehabilitation interventions to improve cognitive function among individuals with MCI. We conducted a systematic review using the following criteria: individuals with MCI, empirical studies, and evaluated a technology-based cognitive training or rehabilitation intervention. Twenty-six articles met the criteria. Studies were characterized by considerable variation in study design, intervention content, and technologies applied. The major types of technologies applied included computerized software, tablets, gaming consoles, and virtual reality. Use of technology to adjust the difficulties of tasks based on participants' performance was an important feature. Technology-based cognitive training and rehabilitation interventions had significant effect on global cognitive function in 8 out of 22 studies; 8 out of 18 studies found positive effects on attention, 9 out of 16 studies on executive function, and 16 out of 19 studies on memory. Some cognitive interventions improved non-cognitive symptoms such as anxiety, depression, and ADLs. Technology-based cognitive training and rehabilitation interventions show promise, but the findings were inconsistent due to the variations in study design. Future studies should consider using more consistent methodologies. Appropriate control groups should be designed to understand the additional benefits of cognitive training and rehabilitation delivered with the assistance of technology.


Use of expectant management based on prostate cancer risk and health status: How far are we from a risk-adapted approach?
While active surveillance, a form of expectant management (EM), is preferred for patients with low-risk prostate cancer (PCa), some favor a more risk-adapted approach that recognizes patient preferences and condition-specific factors. However, previous research has shown non-patient-related factors often drive PCa treatment. In this context, we characterized trends in AS with respect to disease risk and health status. Using SEER-Medicare data, we identified men 66 years and older diagnosed with localized low- and intermediate-risk PCa from 2008 to 2017 and examined receipt of EM, defined as the absence of treatment (i.e., surgery, cryotherapy, radiation, chemotherapy, and androgen deprivation therapies) within 1 year of diagnosis. We performed bivariable analysis to compare trends in use for EM vs. treatment, stratified by disease risk (i.e., Gleason 3+3, 3+4, 4+3; PSA<10, 10-20) and health status (i.e., NCI Comorbidity Index (NCI), frailty, life expectancy). We then ran a multivariable logistic regression model to examine determinants of EM. Within this cohort, 26,364 (38%) were categorized as low-risk (i.e., Gleason 3+3 and PSA<10) and 43,520 (62%) as intermediate-risk (i.e., all others). Over the study period, use of EM significantly increased across all risk groups, except for Gleason 4+3 (P = 0.662), as well across all health status groups. However, linear trends did not differ significantly between frail vs. nonfrail patients for both those categorized as low-risk (P = 0.446) and intermediate-risk (P = 0.208). Trends also did not differ between NCI 0 vs. 1 vs. >1 for low-risk PCa (P = 0.395). In the multivariable models, EM was associated with increasing age and being frail for men with both low- and intermediate risk disease. Conversely, EM selection was negatively associated with higher comorbidity score. EM increased significantly over time for patients with low- and favorable intermediate-risk disease, with the most notable differences based on age and Gleason score. In contrast, trends in uptake of EM did not differ substantively by health status, suggesting that physicians may not be effectively incorporating patient health into PCa treatment decisions. Additional work is needed to develop interventions that recognize health status as an essential component of a risk-adapted approach.


Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells.
FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, is a synthetic compound produced by the modification of a metabolite from I. sinclairii. Here, we found that FTY720 induced non-apoptotic cell death in human glioma cells (U251MG, U87MG, and U118MG). FTY720 (10 µM) dramatically induced cytoplasmic vacuolation in glioma cells. However, FTY720-mediated vacuolation and cell death are not associated with autophagy. Genetic or pharmacological inhibition of autophagy did not inhibit FTY720-induced cell death. Herein, we detected that FTY720-induced cytoplasmic vacuoles were stained with lysotracker red, and FTY720 induced lysosomal membrane permeabilization (LMP). Interestingly, cathepsin inhibitors (E64D and pepstatin A) and ectopic expression of heat shock protein 70 (HSP70), which is an endogenous inhibitor of LMP, markedly inhibited FTY720-induced cell death. Our results demonstrated that FTY720 induced non-apoptotic cell death via the induction of LMP in human glioma cells.


Trade policy governance: What health policymakers and advocates need to know.
Trade policies affect determinants of health as well as the options and resources available to health policymakers. There is therefore a need for health policymakers and related stakeholders in all contexts to understand and connect with the trade policymaking process. This paper uses the TAPIC (transparency, accountability, participation, integrity, capacity) governance framework to analyze how trade policy is commonly governed. I conclude that the health sector is likely to benefit when transparency in trade policymaking is increased, since trade negotiations to date have often left out health advocates and policymakers. Trade policymakers and negotiators also tend to be accountable to economic and trade ministries, which are in turn accountable to economic and business interests. Neither tend to appreciate the health consequences of trade and trade policies. Greater accountability to health ministries and interests, and greater participation by them, could improve the health effects of trade negotiations. Trade policies are complex, requiring considerable policy capacity to understand and influence. Nevertheless, investing in understanding trade can pay off in terms of managing future legal risks.


Bronchobiliary fistulae as a complication of untreated pulmonary hydatid cyst presenting with bilioptysis: A report of two cases.
We reported two patients, a 45-year-old lady and a 48-year-old man, known cases of untreated liver and lung hydatid cysts complicated with bronchobiliary fistulae. Surgery was performed, and bronchobiliary fistulae were diagnosed intraoperatively. Lobectomy was done on the lobe, which was chronically infected. Symptoms resolved after surgery in both cases. Green-colored sputum in a patient with a history of echinococcosis should raise the physician's attention to the probability of a connection between the bronchial tree and the biliary tract. Surgery in advanced cases is a suitable therapeutic option.


Potential food safety problems in genetic engineering.
The rapid development of gene technology, exemplified by the recombinant DNA technique and the hybridoma technique, will heavily influence our food supply in the years to come. Fermentation products from genetic-engineered microbials, the microbials themselves and new plant products will create a number of questions concerning the possible pathogenicity, toxicity, and changed nutritional values of such foodstuffs. This is a great challenge not only to the development of new approaches in nutritional toxicology but also to international cooperation in the field because genetic-modified organisms are not expected to recognize human-made trade barriers or borders. Therefore the initiative of OECD establishing an ad hoc group on safety and regulations in biotechnology is greatly acknowledged.


Synthesis and structure-activity relationships of 4,5-fused pyridazinones as histamine H₃ receptor antagonists.
Three series of novel 4,5-fused pyridazinones were synthesized as histamine H(3) receptor antagonists. The 2,5,6,7-tetrahydrocyclopenta[d]pyridazin-1-one 5q and 5,6,7,8-tetrahydro-2H-phthalazin-1-one 5u displayed high affinity at both rat and human H(3) receptors, and showed potent antagonist and full inverse agonist activity in functional assays.


Chest Wall and Abdominal Blocks for Thoracic and Abdominal Surgeries: A Review.
The purpose of this review is to provide an up-to-date description and overview of the rapidly growing literature pertaining to techniques and clinical applications of chest wall and abdominal fascial plane blocks in managing perioperative pain. Clinical evidence suggests that regional anesthesia blocks, including fascial plane blocks, such as pectoralis, serratus, erector spinae, transversus abdominis, and quadratus lumborum blocks, are effective in providing analgesia for various surgical procedures and have more desirable side effect profile when compared to traditional neuraxial techniques. They offer advantages such as reduced opioid consumption, improved pain control, and decreased opioid-related side effects. Further research is needed to establish optimal techniques and indications for these blocks. Presently, they are a vital instrument in a gamut of multimodal analgesia options, especially when there are contraindications to neuraxial or para-neuraxial procedures. Ultimately, clinical judgment and provider skill set determine which blocks-alone or in combination-should be offered to any patient.


Intermolecular Heck-type coupling of aryl iodides and allylic acetates.
[reaction: see text] A palladium-catalyzed arylation of allylic acetates followed by beta-acetoxy elimination was shown to produce Heck-type coupling products. Optimal reaction conditions employed ligand-free palladium on carbon in the presence of tetrabutylammonium chloride, a trialkylamine base, and water.


Nephroureterectomy after radical cystectomy.
We report 6 cases of upper tract transitional cell carcinoma that developed after total cystectomy with ileal loop diversion. We conclude that if nephroureterectomy is to be used as treatment, excision of the ureteroileal anastomoses should be done.