Maternal exposure to neonicotinoid insecticides and fetal growth restriction: A nested case-control study in the guangxi Zhuang birth cohort.
Fetal growth restriction (FGR) is a major determinant of perinatal morbidity and mortality, with adverse long-term neurocognitive effects in childhood and adulthood. Prenatal exposure to environmental pollutants has been reported to be associated with FGR. Neonicotinoids (NEOs) are extensively used insecticides worldwide and are suggested to have embryonic and developmental neurotoxicity. However, the effects of NEOs exposure on FGR is unknown. We aimed to quantify the single and combined associations of maternal exposure to NEOs and FGR. We conducted a nested case-control study based on the Guangxi Zhuang Birth Cohort, China. A total of 387 with FGR cases and 1096 without- FGR controls were included between 2015 and 2018. Ten NEOs were measured by UPLC-MS from the maternal blood samples were pre-collected in the first trimester. After adjusting for potential confounders, multivariable logistic regressions, weighted quantile sum regression and quantile g-computation were performed for individual and NEOs mixtures. In the individual exposure models, each 1-standard deviation increment of the natural-log in dinotefuran and acetamiprid concentrations were significantly associated with odds ratios of 1.93 (95% CI: 1.69, 2.20) and 1.31 (95% CI: 1.07, 1.59) higher odds of FGR, respectively. However, the FGR risk was negatively associated with thiacloprid, sulfoxaflor, and nitenpyram (OR = 0.23, 95%CI: 0.15, 0.34; OR = 0.48, 95%CI: 0.41, 0.56; OR = 0.86, 95%CI: 0.80, 0.93; respectively). Similar findings were found in the combined exposure analysis. Dinotefuran was the most strongly attributable to increase FGR, while sulfoxaflor and thiacloprid contributed the highest negative weighted on FGR. Furthermore, each quintile increase in all ten NEOs exposures was associated with FGR (OR = 0.21, 95% CI: 0.08, 0.54). Our findings suggest that maternal single and combined exposures to NEOs were associated with varying FGR risks. They contribute to the mounting evidence on serum NEOs exposure impact on FGR. However, a replication of these associations in other populations is warranted.


Tracking airborne CO2 mitigation and low cost transformation into valuable carbon nanotubes.
Primary evidence of the direct uptake of atmospheric CO2 and direct transformation into carbon nanotubes, CNTs, is demonstrated through isotopic labeling, and provides a new high yield route to mitigate this greenhouse gas. CO2 is converted directly to CNTs and does not require pre-concentration of the airbone CO2. This C2CNT (CO2 to carbon nanotube) synthesis transforms CO2-gas dissolved in a 750 °C molten Li2CO3, by electrolysis, into O2-gas at a nickel electrode, and at a steel cathode into CNTs or carbon or nanofibers, CNFs. CNTs are synthesized at a 100-fold price reduction compared to conventional chemical vapour deposition, CVD, synthesis. The low cost conversion to a stable, value-added commodity incentivizes CO2 removal to mitigate climate change. The synthesis allows morphology control at the liquid/solid interface that is not available through conventional CVD synthesis at the gas/solid interface. Natural abundance (12)CO2 forms hollow CNTs, while equivalent synthetic conditions with heavier (13)CO2 favours closed core CNFs, as characterized by Raman, SEM and TEM. Production ease is demonstrated by the first synthesis of a pure (13)C multiwalled carbon nanofiber.


Individuality of breathing patterns in adults assessed over time.
Sixteen healthy adult subjects underwent two studies separated by 4-5 years to test whether their resting pattern of breathing was reproducible over time. From breath-by-breath analysis of airflow, measured with a pneumotachometer, the pattern of breathing was quantified in terms of individual respiratory variables; inspiratory time (TI), expiratory time (TE), total breath duration (TTOT), tidal volume (VT), VT/TI, TI/TTOT, and by taking TI, TE and VT all together (TRIAD). Also, the shape of the entire airflow profile was quantified by harmonic analysis (ASTER). A statistical analysis was designed to compare differences between the 1st and the 2nd recording within individuals with those differences observed between random pairs of recordings from the two studies in the same 16 individuals. It was found that all variables were significantly more similar within-individuals than between-individuals; this is best demonstrated when considering the ASTER and/or the TRIAD. It was concluded that the individuality of breathing pattern is maintained over a long period despite changes in smoking habit, weight, mild respiratory diseases, and other changes which occurred between the two studies in our subjects.


Redox-sensitive micelles assembled from amphiphilic mPEG-PCL-SS-DTX conjugates for the delivery of docetaxel.
Docetaxel (DTX) can produce anti-tumor effects by inhibiting cell growth and inducing apoptosis. However, the poor solubility of DTX restricts its application and its clinical formulation has caused serious adverse reaction due to the use of Tween-80. In the present study, DTX was conjugated to an amphiphilic di-block polymer to solve these problems. Methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was selected as the polymer skeleton and a redox sensitive disulfide bond was used as the linker between DTX and mPEG-PCL. The synthesized mPEG-PCL-SS-DTX conjugates were characterized by (1)H-nuclear magnetic resonance ((1)H NMR) and Fourier transform infrared spectroscopy (FTIR). Interestingly, the mPEG-PCL-SS-DTX conjugates could self-assemble into micelles in aqueous solution. The critical micelle concentration (CMC) of mPEG-PCL-SS-DTX micelles was about 2.3mgL(-1) determined using pyrene molecule fluorescent probe method while the size of mPEG-PCL-SS-DTX micelles was determined to be ca. 17.6nm and 116.0nm with a bimodal distribution by dynamic light scattering (DLS). The in vitro release results indicated that the as-prepared micelles exhibited a sustained release profile with good redox sensitive properties. In particular, the hemolytic toxicity test indicated the as-prepared mPEG-PCL-SS-DTX micelles had negligible hemolytic activity, demonstrating their safety in drug delivery system. Cytotoxicity assay of the mPEG-PCL-SS-DTX micelles verified their highly enhanced cytotoxicity to MCF-7/A and A549 cells. These results thus demonstrated that the present redox-sensitive mPEG-PCL-SS-DTX micelle was an efficient and safe sustained drug delivery system in the biomedical area.


Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands.
The vitamin D receptor (VDR), the high affinity receptor for 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), is a member of the nuclear receptor superfamily. VDR preferentially forms a heterodimeric complex with the retinoid X receptor (RXR) and binds to 1alpha,25(OH)2D3 response elements (VDREs) that consist of two hexameric motifs in a directly repeated (DR) or inverted palindromic (IP) arrangement. DNA-complexed VDR acts as a molecular switch of nuclear 1alpha,25(OH)2D3 signaling by transmitting its activation status to different chromatin loci containing the 1alpha,25(OH)2D3 target genes. Approximately 0.5% of the human genome (about 200 genes) are estimated to be primary targets of 1alpha,25(OH)2D3, but via various mechanisms the VDR appears to interfere in the regulation of even more genes. The molecular basis of the regulatory actions of 1alpha,25(OH)2D3 and its synthetic analogs are ligand-triggered protein-protein interactions of the ligand-binding domain (LBD) of the VDR with coactivator (CoA), corepressor (CoR) and other nuclear proteins. Most analogs have been identified as agonists, a few as antagonists (ZK159222 and TEI-9647) and only Gemini and some of its variations as nonagonists. The positioning of helix 12 of the LBD is of critical importance for the agonistic, antagonistic and nonagonistic conformation of the VDR. In each of the three conformations, the VDR performs different protein-protein interactions, which then result in a characteristic functional profile. The functional profile of some 1alpha,25(OH)2D3 analogs, such as EB1089 and Gemini, can be modulated by protein and DNA interaction partners of the VDR. This provides them with some selectivity for DNA-dependent and -independent signaling pathways and VDRE structures.


Functionally modified gelatin microspheres impregnated collagen scaffold as novel wound dressing to attenuate the proteases and bacterial growth.
An attempt was made to develop a new therapeutic delivery system which would play a dual role of attenuating MMP activity in the wounds and also prevent infection by controlled delivery of antimicrobials. A catechol type MMP inhibitor 2,3-dihydroxybenzoic acid (DHBA) was conjugated to gelatin microspheres using EDC/NHS as coupling agents. The potential of the modified gelatin microspheres (DHB-MS) to attenuate the proteases such as MMP 2 and MMP 9 in the diabetic wound tissues was investigated by gelatin zymography. Further the modified microspheres were loaded with doxycycline and impregnated in a reconstituted collagen scaffold as novel wound dressing. The in vitro release behavior of doxycycline from both DHB-MS and DHB-MS impregnated collagen scaffold was investigated. DHB-MS when incubated with the tissue lysate for 6h displayed the complete inhibition of the MMPs in the tissue lysate. The in vitro drug release studies from the collagen scaffold exhibited the burst release of 44%, exerted immediate chemo prophylaxis and sustained delivery for 72 h. The MTT assay and fluorescent labeling with calcein AM indicated that the DHB-MS is biocompatible to human foreskin fibroblasts. Thus the system developed provides wider scope to control the pathogens involved in infection and also the excess matrix degradation.


Sonographic diagnosis of hydronephrosis in patients with spinal cord injury: influence of bladder fullness.
To investigate and compare the diagnostic accuracy of prevoid and postvoid renal sonography in detecting hydronephrosis in patients with spinal cord injury. A prospective, blind comparison of renal sonography and excretory urography in 67 spinal cord injury patients who underwent periodic urologic examinations. Renal sonography was performed twice, once when the patient's bladder was physiologically full (prevoid) and again when it was just emptied (postvoid). Of 140 kidneys, 24 from 16 patients were found to have hydronephrosis by excretory urography; 116 kidneys had normal urogram findings. Prevoid sonography missed the diagnosis of hydronephrosis in one kidney and showed hydronephrosis in 18 kidneys that had normal results on excretory urography (sensitivity, 95.8%; specificity, 84.5%; negative predictive value, 99.0%). The postvoid sonograms did not detect hydronephrosis in four kidneys and showed hydronephrosis in six kidneys that had normal results on excretory urography (sensitivity, 83.3%; specificity, 94.8%; negative predictive value, 96.5%). Compared to excretory urography, renal sonography detected eight more upper urinary tract abnormalities, which were confirmed by cystograms or radioisotopic renograms. Performing renal sonography while the bladder is full can increase the sensitivity in detecting hydronephrosis in asymptomatic spinal cord injured patients.


Classical and novel retinoids: their targets in cancer therapy.
Retinoids are important mediators of cellular growth and differentiation. Retinoids modulate the growth of both normal and malignant cells through their binding to retinoid nuclear receptors and their subsequent activation. While retinoids have demonstrated therapeutic efficacy in the treatment of acute promyelocytic leukemia, their spectrum of activity remains limited. Other agents such as histone deacetylase inhibitors may significantly increase retinoid activity in a number of malignant cell types. The novel retinoids N-(4-hydroxyphenyl) retinamide (4-HPR) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437; AHPN) induce apoptosis in a wide variety of malignant cells. Their mechanism(s) of action remain unclear, although a number of potential targets have been identified. Whether the retinoid receptors are involved in 4-HPR and CD473/AHPN mediated apoptosis remains unclear. Both 4-HPR and CD437/AHPN display significant potential as therapeutic agents in the treatment of a number of premalignant and malignant conditions.


[Several surgical operations in animal husbandry for healthy birds required or implemented by animal welfare regulations].
Trimming of the comb, devocalisation, trimming of claws, pinioning and caponisation of birds are procedures, which are often requested or carried out by keepers of animals. Surgery of this kind, however, has far-reaching consequences for the affected animal. A well considered range of indications is a basic requirement for the performing of the mentioned surgical procedures by a veterinarian.


On-column solvent exchange for purified preparative fractions.
On-column solvent exchange, using many of the principles of solid-phase extraction, has been implemented to significantly reduce evaporation cycle time following reverse-phase preparative HPLC. Additional benefits, such as a reduced potential for salt formation, thermal decomposition, and residual solvent, are also described. Fractions obtained from preparative separations, typically in a large volume of acetonitrile:water, are injected into the preparative HPLC and then eluted in acetonitrile, creating a new fraction in a volatile organic solvent. Minimal modification to the instrument was required, and unattended operation is possible. Acetonitrile evaporation is achieved within 3 h, compared with 17 h for aqueous-based fractions; lower temperatures can be used during the evaporation step; mobile-phase additives, likely to form salts with the target compound if concentrated in the fraction, are removed before evaporation; sample recovery and purity are unaffected.


Retracted: Investigation of the Immunoprotective Effect of Zinc on Ovalbumin Induced BALB/C Male Mice Based on NF-KB Signaling Pathway.
[This retracts the article DOI: 10.1155/2022/8990629.].


Effects of estrogen/progestin agents on plasma retinoids and chylomicron remnant metabolism.
Women using estrogen-progestin oral contraceptive agents have a marked decrease in the activity of hepatic triglyceride lipase, an enzyme believed to be involved in the catabolism of lipoprotein remnants. The hypothesis that women receiving these agents have defective remnant processing resulting in elevated chylomicron remnant concentrations in plasma was tested. Retinyl esters, which in humans are transported by intestinally-derived lipoproteins, were used to estimate chylomicron and chylomicron remnant concentrations. Women on a variety of oral contraceptive agents had increased plasma triglyceride concentrations, but only minimally increased fasting retinyl ester concentrations. Retinol and retinyl binding protein were elevated to about 150% of controls (p less than 0.001). Retinyl ester concentrations during active fat absorption were then measured in a second group of women taking a single preparation. Three-hour retinyl ester levels were lower in the treated group than control (p less than 0.05), but the difference had disappeared at six hours. Postheparin plasma hepatic triglyceride lipase was reduced by 46% in the treated group (p less than 0.05). Thus despite reduction in hepatic lipase activity, there was no accumulation of retinyl esters in the contraceptive-treated women to suggest impaired remnant processing.


Spectroscopic studies on the interaction between CdTe nanoparticles and lysozyme.
Nanoparticles of cadmium telluride (CdTe) coated with thioglycolic acid (TGA) were prepared in the water phase. The interaction between CdTe nanoparticles (NPs) and lysozyme (Lyz) was investigated by fluorescence and circular dichroism (CD) spectroscopy at pH 7.40. It was proved that the fluorescence quenching of Lyz by CdTe NPs was mainly a result of the formation of CdTe-Lyz complex. By the fluorescence quenching results, the Stern-Volmer quenching constant (K(SV)), binding constant (Ka) and binding sites (n) were calculated. The binding distance (r) between Lyz (the donor) and CdTe NPs (the acceptor) was obtained according to fluorescence resonance energy transfer (FRET). Gradual addition of CdTe NPs to the solution of Lyz led to a marked increase in fluorescence polarization (P) of Lyz, which indicated that CdTe NPs were located in a restricted environment of Lyz. The effect of CdTe NPs on the conformation of Lyz has been analyzed by means of synchronous fluorescence spectra and CD spectra, which provided the evidence that the secondary structure of Lyz has been changed by the interaction of CdTe NPs with Lyz.


Potential of [11C]UCB-J as a PET tracer for islets of Langerhans.
Biomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [11C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system. Here, we evaluated whether [11C]UCB-J could be utilized as a PET tracer for the islets of Langerhans in the pancreas by targeting SV2A. The mRNA transcription of SV2A was evaluated in human isolated islets of Langerhans and exocrine tissue. In vitro autoradiography was performed on pancreas and brain sections from rats and pigs, and consecutive sections were immunostained for insulin. Sprague-Dawley rats were examined with PET-MRI and ex vivo autoradiography at baseline and with administration of levetiracetam (LEV). Similarly, pigs were examined with dynamic PET-CT over the pancreas and brain after administration of [11C]UCB-J at baseline and after pretreatment with LEV. In vivo radioligand binding was assessed using a one-compartment tissue model. The mRNA expression of SV2A was nearly 7 times higher in endocrine tissue than in exocrine tissue (p < 0.01). In vitro autoradiography displayed focal binding of [11C]UCB-J in the pancreas of rats and pigs, but the binding pattern did not overlap with the insulin-positive areas or with ex vivo autoradiography. In rats, pancreas binding was higher than that in negative control tissues but could not be blocked by LEV. In pigs, the pancreas and brain exhibited accumulation of [11C]UCB-J above the negative control tissue spleen. While brain binding could be blocked by pretreatment with LEV, a similar effect was not observed in the pancreas. Transcription data indicate SV2A to be a valid target for imaging islets of Langerhans, but [11C]UCB-J does not appear to have sufficient sensitivity for this application.


Metal oxide encapsulated by 3D graphene oxide creates a nanocomposite with enhanced organic adsorption in aqueous solution.
The presence of organic contaminants (OCs) in aquatic systems is a threat to ecological and human health. Adsorption by graphene-based adsorbent is a promising technique for OC removal and we previously fabricated crumpled graphene balls (CGBs), via a novel nano-spray drying technique, which show robust adsorptive performance. Yet, since CGBs contain non-accessible surface area due to 2D graphene stacking, the goal of this research was to investigate the efficacy of maximizing the accessible CGB surface by synthesizing a nanocomposite composed of metal oxide nanoparticles encapsulated by crumpled graphene oxide (MGC). The metal oxides reduce graphene oxide stacking, expand the internal adsorptive surface area, and boost the adsorptive capacity of the MGC. MGC (fumed SiO2 or SiO2) exhibit an enhanced Langmuir adsorption capacity (qm, normalized by the % carbon) for an OC model, methylene blue (MB), achieving improvements of 60-86% compared to CGB, 3-4 fold compared to powder activated carbon (PAC) and 6-7 fold compared to granular activated carbon (GAC). MGCs display rapid adsorption reaching equilibrium after 9-12 min of contact and remaining stable in wastewater effluent /surface water. A cost-efficiency comparison reveals MGCs achieve one ton of MB removal at similar or lower material costs than that of PAC/GAC.


Fabrication and properties of ITO films treated by excited atomic oxygen.
We consider the crystallization of ITO films induced by excited atomic oxygen. Owing to it, transmittance of these films in visible ranges increased by ~20% and surface impedance dropped from 36 down to 4.6Ω/□. The treatment temperature (127 °C) was significantly below that of conventional crystallization (320 °C). Application of elastic light scattering diagnostics shows that rms surface roughness increased from 2.65 nm up to 4.07 nm after film treatment. ITO treatment does not change isotropic azimuthal structure of the surface.


Myelin water imaging of multiple sclerosis at 7 T: correlations with histopathology.
Myelin water imaging (MWI) promises to be invaluable in understanding neurological diseases like MS. However, a limitation of MWI is signal to noise ratio. Recently, a number of investigators have performed MWI at field strengths higher than 1.5 T. Our goal was to determine if myelin water imaging at increased SNR, arising from the use of a small bore 7 T MR system with optimized coil geometry, enables the production of superior myelin water maps with increased spatial detail and enables better correlations with histology. Ten formalin-fixed MS brain samples underwent a 32-echo T(2) relaxation experiment which measured myelin water fraction (MWF) on a 7-T animal MRI scanner. MWF correlated strongly qualitatively and quantitatively with luxol fast blue staining for myelin [mean (range): R(2)=0.78 (0.56-0.95), p<0.0001]. The quality and detail of 7 T myelin water maps were far superior to that previously seen at 1.5 T, allowing for visualization of fine structures such as the normal prominent myelination of the deeper cortical layers, the alveus of the hippocampus and rings of preserved myelin in a concentric Balo's lesion. 7 T imaging will allow detailed assessment of myelin pathology to a degree not possible with lower field strengths.


Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase.
"Perinatal" hypophosphatasia is the most severe form of this inborn error of metabolism, which is characterized by deficient activity of the tissue-nonspecific (liver/bone/kidney) isoenzyme of alkaline phosphatase (ALP) (TNSALP). We report that autopsy tissue from three affected subjects, which was profoundly low in ALP activity, had essentially unremarkable levels of pyridoxal-5'-phosphate (PLP), pyridoxal, and total vitamin B6 content despite markedly elevated plasma PLP levels (5,800, 14,500, and 98,500 nM; adult norm, 5-109 nM). Our findings help to explain the general absence of symptoms of vitamin B6 excess or deficiency in hypophosphatasia, and provide evidence that TNSALP acts as an ectoenzyme to regulate extracellular rather than intracellular concentrations of PLP (the cofactor form of vitamin B6) and perhaps other phosphate compounds.


Oral terbutaline in the management of pharmacologically induced prolonged erection.
Prolonged erection and priapism are common complications following intracavernosal injection of vasoactive agents in the management of erectile dysfunction. It is usually treated by intracorporeal drainage and irrigation with sympathomimetic agents. There is no established oral therapy . To study the effect of oral terbutaline on prolonged erection following intracavernosal injection of vasoactive agent, a controlled randomized study was done in 68 patients. Detumescence was achieved in 42 and 15% of the cases with oral terbutaline and placebo, respectively. Results of this study suggest that an initial trial with oral terbutaline for pharmacologically induced prolonged erection may be successful.


Pseudocirrhosis and portal hypertension in patients with metastatic cancers: a systematic review and meta-analysis.
Pseudocirrhosis is a clinical and radiological entity mimicking liver cirrhosis in patients without a history of chronic liver disease. We performed a systematic review and meta-analysis of the current literature to evaluate the state-of-the-art and investigate the epidemiology and clinical features of pseudocirrhosis. We searched PubMed, Web of Science and Scopus for literature published until February 28, 2022. We included in the final analysis 62 articles (N = 389 patients): 51 case reports (N = 64 patients), 5 case series (N = 35 patients) and 6 observational studies (N = 290 patients). About 80% of patients included in the case reports and case series had breast cancer. Most patients had at least one clinical sign of portal hypertension and ascites was the most common clinical manifestation of portal hypertension. The median time from pseudocirrhosis to death was 2 months (IQR 1-7 months). Alkylating agents and antimitotics were the most common classes of anticancer drugs reported in our study population. Notably, about 70% of patients received three or more anticancer drugs. Finally, pseudocirrhosis is a condition that occurs in patients with hepatic metastases and may have a negative impact on survival and clinical management of patients because of the potential development of portal hypertension and its complications.


Tick species from Africa by migratory birds: a 3-year study in Italy.
The role of resident or migratory birds in dispersal of tick species and tick-borne pathogens is still poorly known in Italy. We report here the results of a 3-year project based on sampling ticks from migratory birds, as well as from the vegetation at three stop-over sites for migrants, namely the islands of Ventotene (Latium), Asinara (Sardinia) and Ustica (Sicily). During the spring seasons from 2017-2019, in total 2681 ticks were collected, 2344 of which were sampled from migratory birds and 337 from the vegetation. Ticks were identified by morphology or by molecular tools when necessary. In total, 16 tick species were identified among which the following were exclusively found on birds: Hyalomma rufipes (43.3%), Hy. truncatum (0.1%), Ixodes frontalis (11.8%), Ix. inopinatus (0.2%), Ix. ricinus (3%), Haemaphysalis punctata (0.08%), Hae. erinacei (0.1%), Amblyomma variegatum (0.08%) and Argas vulgaris 0.1%), whereas five species were exclusively collected from the vegetation: Rhipicephalus bursa (10.5%), Rh. turanicus (5.9%), Rh. sanguineus sensu lato (2%), Rh. pusillus (2.4%), Hae. sulcata (0.08%). Hy. marginatum (10.3%) and Ix. ventalloi (9.3%) were found both on birds and on the vegetation on the island Ustica. It is worth noting that the search for ticks on the vegetation did not detect allochthonous tick species. Although we found several interesting local species and allochthonous ticks like Hy. rufipes, Am. variegatum and Ar. vulgaris on birds, further investigations are needed to better define the possible role of migratory birds in the introduction of ticks and tick-borne diseases in Italy, above all after the evidence of imported ticks positive to Crimean Congo hemorrhagic fever (CCHF) virus in several European countries.


Isolation of a genomic clone containing the promoter region of the human ATP binding cassette (ABC) transporter, ABCB6.
We previously reported on the isolation of a new rat ATP binding cassette (ABC) transporter, ABCB6. We now report the isolation of the full-length cDNA and genomic clones containing the human ABCB6 gene. ABCB6 is 100% identical to the cloned MTABC3 human ABC transporter and contains the typical ABC signature, Walker A and B motifs. We found that HuABCB6 is expressed at low levels in normal human liver. We found that ABCB6 was overexpressed in human hepatocellular carcinomas compared to paired surrounding non-malignant tissue. We found that there was no difference in ABCB6 gene copy between human liver cancer and its paired non-malignant tissue. Because HuABCB6 was overexpressed in human cancers compared to peri-tumoral tissue in the absence of gene amplification, transcriptional regulation may play an important role in its expression. Therefore, we isolated a 14 kb genomic DNA clone containing the HuABCB6 promoter and 5'-flanking region. The 5'-flanking region contains a CpG island, lacks an appropriately positioned TATA element and contains a number of putative transcription factor binding sites. Two transcription start sites were identified by S1 nuclease mapping at -274 and -296 bp from the start codon. Transient transfection of the HuABCB6 promoter constructs (HuABCB6/1.68, 1.39, 1.13, 0.90, 0.52) containing the luciferase reporter gene resulted in a 1100-2300-fold increase in luciferase activity compared to the empty vector control whereas HuABCB6/1.68 subcloned in the reverse orientation resulted in no activity. We observed a significant decrease in luciferase activity with the promoter constructs, HuABCB6/0.25, 0.15 and 0.06, which indicates that an orientation-dependent functional promoter is contained within our previously predicted promoter region of -315 bp to -565 bp as deletion of this 250 bp sequence resulted in a loss of promoter activity.


When genotype prevails: sexual female-to-male transformation in classical antiquity, recorded by Gaius Plinius Secundus and Phlegon.
Cases of sexual reassignment in classical antiquity, namely a female-to-male gender change occurring after childhood, are described in the literature. Textual evidence concerning these cases of androgynism and their symbolism as well as a comprehensive scholar analysis is provided in the present study. Μedical interpretation of these cases covers the entire spectrum of differential diagnosis of heterosexual puberty in pseudohermaphrodites characterized by genital ambiguity.


Influence of Regional Nerve Block in Addition to General Anesthesia on Postoperative Delirium, Pain, and In-hospital Stay in Patients Undergoing Cardiothoracic Surgery: A Meta-analysis.
This study aims to investigate whether venous injection of sedative agent or regional nerve block in alliance with major anesthesia could decrease the risk of postoperative delirium occurrence in patients receiving cardiothoracic surgery. Electronic academic databases were retrieved for related publications, and statistical software was used for data pooling and analysis. Forest plot was used to show the pooled sensitivity, specificity, and diagnostic odds ratio. Combined receiver operating characteristic curve was used to show the area under the curve of complex data. Seven studies were included for analysis. The risk of occurrence of delirium still showed no difference (risk rate = 0.93, 95% CI, 0.85-1.03) between the intervention group and placebo group. Postoperative pain feeling was more alleviated in patients with prophylactic application of regional nerve block. In addition, prophylactic application of regional nerve block could decrease the risk of postoperative in-hospital stay (risk rate = 0.28, 95% CI, 0.02-0.54). Our study demonstrated that, in elderly patients or pediatric patients undergoing cardiac surgery, prophylactic application of regional nerve block failed to decrease the incidence of postoperative delirium. However, the option of regional nerve block could decrease the duration of in-hospitalization stay and alleviate the acute pain during the postoperative period after open-heart surgery.


Mixed micelles of monomeric and dimeric cationic surfactants with phospholipids: effect of hydrophobic interactions.
Surface tension (gamma) and time resolved fluorescence quenching (TRFQ) measurements have been performed on the binary mixtures of monomeric as well as dimeric alkylammonium bromides with l-alpha-dimyristoylphosphatidycholine (DMPC) and L-alpha-dipalmitoylphosphatidycholine (DPPC). The critical micelle concentration (cmc) has been evaluated from the gamma measurements. The gamma plots show two breaks in the gamma versus [total surfactant] curves in most of the cases. The first break (C1) has been attributed to the mixed vesicle formation process. The break down of the vesicles leads to the mixed micellization between the surfactant and phospholipid monomers at the second break (C2). The amount of surfactant used in the vesicle breakdown process (DeltaC) increases linearly with the increase in the amount of phospholipid and depends significantly on the hydrophobicities of the cationic components. The surface area per molecule (a) evaluated from the gamma plots indicates compact monolayer formation in the case of monomeric surfactants with lower hydrophobicities and reverse is observed for dimeric surfactants. The pyrene life time (tau) of the solubilized pyrene in the hydrophobic environment of mixed micelles, fully supports the conclusion that derived from a.


Primary bone tumours of the hand. Report of 21 cases.
Twenty-one primary bone tumours of the hand in children from 8 paediatric hospitals are reported. Osteochondromas and enchondromas were not included. Our material consisted of 16 patients with common tumours (3 Ewing's sarcoma, 5 aneurysmal bone cyst, 6 osteoid osteoma and 2 epidermoid cyst) and 5 patients with uncommon tumours (osteoma, simple bone cyst, haemangiopericytoma, capillary angiomatous tumour and benign ossifying fibroma or osteoblastoma). The X-ray diagnosis of the common tumours should have high concordance with histology, whereas that of uncommon tumours is much more difficult and uncertain. The characteristic features of Ewing's sarcoma are stressed as all our children with this tumour had a delayed diagnosis and a fatal outcome. Differential diagnosis with other short tubular bone lesions of the hand - specifically osteomyelitis - is discussed and the possibilities of microscopic diagnosis are stressed.


Variable-column bubble oxygenator. A new system for bubble oxygenation.
A new bubble oxygenator has been developed. Its main advantage is that the dimensions of the oxygenating chamber can be varied. Thus, the capacity for oxygenation may be adapted to different patients. It was used in 2,700 open-heart operations performed at the Institut do Coracão, Faculdade de Medicina, Universidade de São Paulo, between January, 1971, and December, 1973. A group of 50 patients were subjected to more detailed studies. We found that the average hemolysis was 38.67 mg. per cent with a mean perfusion duration of 69 minutes, 38 seconds. Fibrinogen and platelet concentrations decreased by 14 and 25 per cent, respectively. The pH, PcO2, PO2, and base excess before and after cardiopulmonary bypass ranged within normal levels, and oxygenation (PO2) was always satisfactory.


The effect of sympathectomy on calcitonin gene-related peptide levels in the rat trigeminovascular system.
The effect of sympathectomy on the calcitonin gene-related peptide (CGRP) level in the rat primary trigeminal sensory neurone was investigated. Six weeks after bilateral removal of the superior cervical ganglion there was a 70% rise in the CGRP content of the iris and the pial arteries, a 34% rise in the concentration in the trigeminal ganglion but no change in the brainstem. The CGRP rise in both end organs suggests that this phenomenon may be common to all peripheral organs receiving combined sensory and sympathetic innervations. The lack of any rise in the brainstem CGRP content raises the possibility that this process spares central terminations. In contrast, the level of neuropeptide Y, a peptide mainly contained in sympathetic terminals, fell to 35% of control values in the iris and pial arteries whilst the trigeminal ganglion and brainstem concentrations remained unchanged. The possible relevance of these observations to the clinical syndrome of postsympathectomy pain (sympathalgia) is discussed. There are similarities between the delayed onset of the human pain state and the delayed rise in sensory peptides after sympathectomy.


Regional circulatory distribution of novel cardiac bio-markers and their relationships with haemodynamic measurements.
Regional sampling may identify sites of production or removal of novel biomarkers in the circulation; their relationship to haemodynamic measurements may clarify their association with the pathophysiology of heart failure. Samples were obtained from up to eight circulatory sites from 22 patients with left ventricular dysfunction undergoing elective cardiac catheterisation. The plasma concentrations (PC) of six biomarkers [mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adreno-medullin (MR-proADM), high sensitivity pro-calcitonin (hsPCT), copeptin and galectin-3 (Gal-3)] were measured. Plasma concentrations of MR-proANP were highest in the pulmonary artery (PA) and left ventricle, suggesting myocardial production. Lower concentrations of copeptin, CT-proET-1, MR-proADM and hsPCT were found in the supra-renal inferior vena cava (SRIVC) sample suggesting renal extraction. Plasma concentrations of Galectin-3 varied little by sampling site. Plasma concentrations of MR-proANP (R=0.69, P=0.002), MR-proADM (R=0.51, P=0.03), CT-proET-1 (R=0.60, P=0.009) and Copeptin (R=0.47, P<0.05) measured from PA samples correlated with PA systolic pressure. There was no relation between any measured marker and cardiac index. Regional sampling shows variation in the plasma concentration of various novel peptides that provides clues to sites of net production and removal. Plasma concentrations of several biomarkers were positively correlated with pulmonary artery pressure.


Pharmacokinetic and bioequivalence studies of trospium chloride after a single-dose administration in healthy Chinese volunteers.
The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t1/2 was (15.11 ± 3.24) h and (16.00 ± 3.96) h; Tmax was (4.0 ± 1.2) h and (4.1 ± 0.9) h; Cmax was (3.76 ± 1.87) ng·mL - 1 and (3.70 ± 1.89) ng·mL - 1; AUC0-t was (33.51 ± 14.39) ng·mL - 1·h and (33.33 ± 14.88) ng·mL - 1·h, and the AUC0-∞ was (35.20 ± 14.88) ng·mL - 1·h and (35.16±15.17) ng·mL - 1·h. The ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods (p>0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.


A new approach in artificial neuron theory for use in computer aided diagnosis.
An artificial neuron, which has an original training process, has been developed as part of a project in the field of computer aided diagnosis. The aim of this work is to analyse medical images to recognise an abnormal region of an organ. In contrast to other methods, generating information of the abnormality's level is part of the recognition stage. Moreover, the whole process is independent of the particular disease. The neuron was tested using lung images taken by a gamma camera.


Responses of neurons in the lamb nucleus tractus solitarius to stimulation of the caudal oral cavity and epiglottis with different stimulus modalities.
Receptors located in the posterior oral cavity and on the epiglottis play an important role in the initiation of upper airway reflexes such as swallowing, gagging, coughing and apnea. Peripheral nerves which innervate these receptor areas terminate in the nucleus tractus solitarius (NTS). We have recorded the responses of 61 neurons in the lamb NTS to stimulation of the caudal tongue, palate and epiglottis with mechanical, chemical and thermal stimuli and mapped receptive field location. Although there was some overlap in the areas of the NTS from which neurons with oral cavity and epiglottal receptive fields could be recorded, a significant difference was observed in the mean recording sites of the two groups of neurons. Neurons with oral cavity receptive fields were located more rostral, lateral and ventral in the NTS than neurons with receptive fields on the epiglottis. Little convergence of sensory input onto single cells in the NTS was observed between the oral cavity and the epiglottis. Only one NTS neuron had a receptive field in both of these receptor areas. In contrast, a large number of neurons with oral cavity receptive fields received input from two receptor areas. These neurons had a receptive field on the tongue which was located directly beneath the receptive field on the palate. Mechanical stimuli were the most effective for neurons with either oral cavity or epiglottal receptive fields and thermal stimuli were the least effective. Neurons which responded to mechanical stimuli responded better to a moving stimulus than to a punctate one, and large increases in the strength of a punctate stimulus were required to elicit significant increases in response frequency. Most NTS neurons responded to more than one of the stimulus modalities. However, a significant difference in the mean number of stimulus modalities which elicited responses was observed between neurons with oral cavity and epiglottal receptive fields. The number of multimodal neurons with epiglottal receptive fields was higher than those with oral cavity receptive fields. The multimodal nature of neurons which responded to epiglottal or oral cavity stimulation combined with their location in reflexogenic areas of the NTS suggests that these neurons could be important in the integration of afferent input from the oral cavity and upper airway. If these NTS neurons are involved in the control of oral and upper airway reflexes it would be important for them to respond to as many of the stimulus cues as possible and the majority of these neurons do just that.


Analysis of supra-nucleosome particles from unfertilized eggs of sea urchins.
Two discrete supranucleosomal particles that differ in their electrophoretic migration on 1% agarose gels were isolated from unfertilized sea urchin eggs. Both particles contain the same complement of cleavage stage (CS) chromosomal proteins, which is identical to the complete set of basic proteins isolated directly from chromatin by extraction with 0.25 N HCl. DNA fragments between 210 and 1500 bp were found in both particles, and the basic unit of DNA repeat length determined by micrococcal nuclease digestion was 126 +/- 3 bp. The isolated nucleoparticles are electrophoretically stable over a wide range of DNA sizes (126-1500 bp) indicating that their structure is maintained by internal interactions among the CS chromosomal proteins, previously designated CS A through CS G. Based on these results we conclude that the CS chromosomal proteins are functionally equivalent to classical histones in their ability to direct higher ordered structures of chromatin.


A mitochondrial long-chain fatty acid oxidation defect leads to transfer RNA uncharging and activation of the integrated stress response in the mouse heart.
Cardiomyopathy and arrhythmias can be severe presentations in patients with inherited defects of mitochondrial long-chain fatty acid β-oxidation (FAO). The pathophysiological mechanisms that underlie these cardiac abnormalities remain largely unknown. We investigated the molecular adaptations to a FAO deficiency in the heart using the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse model. We observed enrichment of amino acid metabolic pathways and of ATF4 target genes among the upregulated genes in the LCAD KO heart transcriptome. We also found a prominent activation of the eIF2α/ATF4 axis at the protein level that was independent of the feeding status, in addition to a reduction of cardiac protein synthesis during a short period of food withdrawal. These findings are consistent with an activation of the integrated stress response (ISR) in the LCAD KO mouse heart. Notably, charging of several transfer RNAs (tRNAs), such as tRNAGln was decreased in LCAD KO hearts, reflecting a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the ISR in the hearts of mice with muscle-specific deletion of carnitine palmitoyltransferase 2. Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signalling, in particular the ISR. These results may serve as a foundation for investigating the role of the ISR in the cardiac pathology associated with long-chain FAO defects.Translational Perspective: The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. The heart disease observed in patients with a genetic defect in this pathway highlights the importance of FAO for cardiac health. We show that the consequences of a FAO defect extend beyond cardiac energy homeostasis and include amino acid metabolism and associated signalling pathways such as the integrated stress response.


Microvascular free tissue transfer for tongue reconstruction after hemiglossectomy: a functional assessment of radial forearm versus anterolateral thigh flap.
The purpose of this study was to evaluate tongue function and donor site morbidity in patients with oral cancer surgically treated and reconstructed with radial or anterolateral thigh free flaps. Twenty patients underwent primary reconstruction after hemiglossectomy between January 2002 and June 2004. Ten patients were reconstructed using a free forearm flap and the remaining with an anterolateral thigh flap. Eight patients on each group underwent postoperative radiotherapy (average, 60 Gy). All of them were followed postoperatively to determine after 6 months their functional outcome as it related to speech, deglutition, tongue mobility, and donor site morbidity. The intelligibility, deglutition, and tongue mobility were each scored on a scale ranging from 1 to 7 by an independent investigator. Data were analyzed by the 2-tail Mann-Whitney U test. No differences in mean speech intelligibility, tongue mobility, or deglutition mean scores were seen between radial forearm flap and anterolateral thigh flap (P > .05). In all anterolateral thigh flap-treated cases, the donor site was closed directly and no complications were seen. However, in all forearm flaps donor site closure was carried out with skin grafts and dorsal forearm splinting was applied for 1 week postoperatively. In 4 cases a partial skin graft failure was observed and donor sites healed for second intention. Anterolateral thigh flap, with its versatility in design, long pedicle with a suitable vessel diameter, and low donor site morbidity, could be the ideal flap for hemiglossectomy defect reconstruction.


Clinical study of six cases showing late relapse of germ cell tumors.
Late relapse of germ cell tumors has been considered rare. We report six patients treated at our institution with relapses of germ cell tumors more than 2 years after first successful management. Median time to late relapse for pure seminomas and non-seminomatous germ cell tumors was 30.0 and 75.5 months, respectively. The sites of the late relapses in two cases of pure seminoma were located out of the fields of irradiation. After systematic chemotherapy, both these patients remain disease free. Two patients with non-seminomatous germ cell tumors received salvage chemotherapy at the time of late relapse, but tumor markers did not normalize in either case. A complete resection of relapsed masses was performed in three cases of non-seminomatous germ cell tumors. All three patients are without evidence of disease. The incidence of late relapse in patients with pure seminomas and non-seminomas was 2.4% and 3.3%, respectively, which suggests the necessity for long-term follow up.


[Operative standardization in randomized controlled surgical trials. Meeting of the INSECT trial].
INSECT is an internationally registered, three-armed, multicentre, intraoperatively randomised model trial of the Study Centre of the German Surgical Society. The interventions being compared are running suture technique with slowly absorbable monofilament suture material (PDS vs MonoPlus) and interrupted technique with a braided, rapidly absorbable suture material (Vicryl). The primary endpoint is the rate of incisional hernias 1 year postoperatively. A total of 25 surgeons from 24 different institutions at all levels of care evaluated the theoretical and practical sessions of the surgical investigator meeting using 25 criteria, including course organisation, content, and speaker evaluation, and a categorical grading system from 1 (very good) to 6 (insufficient). Distribution of the 625 grades was: very good (1) n=367, good (2) n=207, satisfactory (3) n=39, adequate (4) n=2, and "No statement" n=10. The average score for the investigator meeting was 1.5. The participants felt they were successfully prepared theoretically and practically for trial interventions and conduct by attending the meeting. Clear explanation of the measures for treatment equivalence before and during trials is mandatory in randomised controlled surgical trials.


Impact of disease-modifying therapies on MRI outcomes in patients with relapsing -remitting multiple sclerosis: A systematic review and network meta-analysis.
Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disorder of the central nervous system. The clinical presentation supported by characteristic findings on MRI forms the backbone of the current diagnostic criteria. This study was aimed to investigate the efficacy based on MRI outcomes of FDA approved disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS). We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs) of DMTs. The outcome measures were the mean number of T2 [new/enlarging lesions], new T1 [gadolinium-enhancing (Gd+) T1 and hypointense T1] lesions in brain MRI performed at 12 months or 24 months. We performed a network meta-analysis using the frequentist approach in STATA version 16.0. We identified 26 RCTs for final analysis. Interferon β-1a and placebo were the most common comparison treatment. Ocrelizumab was more effective in reducing the number of Gd+T1 lesions. Dimethyl fumarate 480 mg was relatively better in reducing the number of new T2 lesions. The treatment ranking showed that ocrelizumab and dimethyl fumarate 480 mg were more efficacious (1 and 0.9 in SUCRA, respectively) for reducing the number of new Gd+T1/hypointense lesions; dimethyl fumarate 480 mg/720 mg and natalizumab were more efficacious (1.0, 0.9 and 0.8 in SUCRA, respectively) to reduce the number of new T2 lesions. Ocrelizumab, dimethyl fumarate 480/720 mg and natalizumab demonstrated favourable MRI outcomes in patients with the RRMS.


The impact of upper and lower motor neuron burden on diagnostic certainty, and clinical course of spinal-onset amyotrophic lateral sclerosis: a cluster-based approach.
Upper motor neuron (UMN) and lower motor neuron (LMN) involvement represent the core clinical features of amyotrophic lateral sclerosis (ALS). Several studies divided patients into prevalent UMN and LMN impairment phenotypes to investigate the association between motor systems impairments and ALS clinical course. However, this distinction was somehow heterogeneous and significantly affected the comparability across studies. This study aimed to investigate whether patients spontaneously segregate based on the extent of UMN and LMN involvement without a-priori categorization and to identify potential clinical and prognostic features of different clusters. Eighty-eight consecutive spinal-onset ALS patients were referred to an ALS tertiary center between 2015 and 2022. UMN and LMN burden was assessed with the Penn Upper Motor Neuron scale (PUMNS) and the Devine score, respectively. PUMNS and LMN scores were normalized into 0-1 and analyzed using a two-step cluster analysis and the Euclidean distance measure. The Bayesian Information Criterion was used to determine the cluster number. Demographic and clinical variables were tested for differences among the clusters. Three distinct clusters emerged at cluster analysis. Patients in "cluster-1" showed moderate UMN and severe LMN involvement, corresponding to the typical ALS phenotype. Patients in "cluster-2" showed mild LMN and severe UMN damage, corresponding to a predominant UMN phenotype, while "cluster-3" patients showed mild UMN and moderate LMN damage, corresponding to a predominant LMN phenotype. Patients in "cluster-1" and "cluster-2" showed a higher prevalence of definite ALS than those in "cluster-3" (61% and 46 vs 9%, p < 0.001). "Cluster-1" patients had a lower median ALSFRS-r score compared to both "cluster-2" and 3 patients (27 vs 40 and 35, < 0.001). "Cluster-1" (HR: 8.5; 95% CI 2.1-35.1 and p = 0.003) and 3 (HR: 3.2; 95% CI 1.1-9.1; p = 0.03) were associated with shorter survival than those in "cluster-2". Spinal-onset ALS can be categorized into three groups according to LMN and UMN burden. The UMN burden is related to higher diagnostic certainty and broader disease spread, while LMN involvement is associated with higher disease severity and shorter survival.


The solution structure of a B-DNA undecamer comprising a portion of the specific target site for the cAMP receptor protein in the gal operon. Refinement on the basis of interproton distance data.
A restrained least squares refinement of the solution structure of the double-stranded DNA undecamer 5'd(AAGTGT-GACAT).5'd(ATGTCACACTT) comprising a portion of the specific target site of the cAMP receptor protein in the gal operon is presented. The structure is refined on the basis of both distance and planarity restraints, 2331 in all. The distance restraints comprise 150 interproton distances determined from pre-steady state nuclear Overhauser enhancement measurements and 2159 other interatomic distances derived from idealized geometry (i.e., distances between covalently bonded atoms, between atoms defining fixed bond angles, and between atoms defining hydrogen bonding in AT and GC base pairs). Two refinements were carried out and in both cases the final RMS difference between the experimental and calculated interproton distances was 0.2 A. The difference between the two refined structures is small (overall RMS difference of 0.23 A) and represents the error in the refined coordinates. Although the refined structures have an overall B-type conformation there are large variations in many of the local conformational parameters including backbone and glycosidic bond torsion angles, helical twist and propellor twist, base roll and base tilt angles.


Three-dimensional structure of (1-36)bacterioopsin in methanol-chloroform mixture and SDS micelles determined by 2D 1H-NMR spectroscopy.
Spatial structures of proteolytic segment A (sA) of bacterioopsin of H. halobium (residues 1-36) solubilized in a mixture of methanol-chloroform (1:1), 0.1 M LiClO4 organic mixture, or in perdeuterated sodium dodecyl sulfate (SDS) micelles, were determined by 2D 1H-NMR techniques. 324 and 400 NOESY cross-peak volumes were measured in NOESY spectra of sA in organic mixture and SDS micelles, respectively. The sA spatial structures were determined by local structure analysis, distance geometry calculation with program DIANA and systematic search for energetically allowed side chain rotamers consistent with NOESY cross-peak volumes. The structures of sA are similar in both milieus and have the right-handed alpha-helical region from Pro8 to Met32 with root mean square deviation (RMSD) of 0.25 A between backbone heavy atoms and fit well with Pro8 to Met32 alpha-helical region in electron cryo-microscopy model of bacteriorhodopsin. The N-terminal region Ala2-Gly6 of sA in organic mixture has a fixed structure of two consecutive gamma-turns as 2 * 2(7)-helix (RMSD of 0.25 A) stabilized by the Thr5 NH...O = C Gln3 and Ile4 NH...O = C Ala2 hydrogen bonds while this region in SDS micelles has disordered structure with RMSD of 1.44 A for backbone heavy atoms. The C-terminal region Gly33-Asp36 of sA is disordered in both milieus. Torsion angles chi 1 of sA were unequivocally determined for 13 (SDS) and 11 (organic mixture) of alpha-helical residues and are identical in both milieus.


Further investigations of the relation between polymorphisms in sex steroid related genes and autistic-like traits.
Autism spectrum disorders (ASDs) are more prevalent in boys than in girls, indicating that high levels of testosterone during early development may be a risk factor. Evidence for this hypothesis comes from studies showing associations between fetal testosterone levels, as well as indirect measures of prenatal androgenization, and ASDs and autistic-like traits (ALTs). In a recent study we reported associations between ALTs and single nucleotide polymorphisms (SNPs) in the genes encoding estrogen receptor 1 (ESR1), steroid-5-alpha-reductase, type 2 (SRD5A2) and sex hormone-binding globulin (SHBG) in a subset (n=1771) from the Child and Adolescent Twin Study in Sweden (CATSS). The aim of the present study was to try to replicate these findings in an additional, larger, sample of individuals from the CATSS (n=10,654), as well as to analyze additional SNPs of functional importance in SHBG and SRD5A2. No associations between the previously associated SNPs in the genes ESR1 and SRD5A2 and ALTs could be seen in the large replication sample. Still, our results show that two non-linked SNPs (rs6259 and rs9901675) at the SHBG gene locus might be of importance for language impairment problems in boys. The results of the present study do not point toward a major role for the investigated SNPs in the genes ESR1 and SRD5A2 in ALTs, but a possible influence of genetic variation in SHBG, especially for language impairment problems in boys, cannot be ruled out.


Tuberoplasty: minimally invasive osteosynthesis technique for tibial plateau fractures.
Fractures of the tibial plateau are in constant progression. They affect an elderly population suffering from a number of comorbidities, but also a young population increasingly practicing high-risk sports and using two-wheeled vehicles. The objective of this study was therefore to propose a new technique for the treatment of this type of fracture. There are a variety of classical pitfalls of conservative treatment such as defective reduction resulting in early osteoarthritis and alignment defects. Conventional treatments lead to joint stiffness and amyotrophy of the quadriceps, caused by the open technique and late loading. We propose an osteosynthesis technique for tibial plateau fractures with minimally invasive surgery. A minimally invasive technique would be more appropriate to remedy all of the surgical drawbacks resulting from current practices. The surgical technique that we propose uses a balloon allowing progressive and total reduction, associated with percutaneous screw fixation and filling with polymethylmethacrylate (PMMA) cement. The advantages are optimal reduction, minimal devascularization, soft tissues kept intact, as well as early loading and mobilization. This simple technique seems to be a good alternative to conventional treatment. The most comminuted fractures as well as the most posterior compressions can be treated, while causing the least impairment possible. Arthroscopy can be used to verify fracture reduction and cement leakage. At the same time, it can be used to assess the associated meniscal lesions and to repair them if necessary.


Nasal regurgitation as the presenting symptom of rhinolithiasis.
Rhinoliths are not common but like other rare conditions have an attraction and therefore will be familiar. This case report has been presented as a reminder that perforation of the hard palate by a rhinolith does occur occasionally, and in this instance was a pleasant surprise to all concerned.


Successful pregnancy and vaginal delivery after heart transplantation.
Successful pregnancy and delivery in women with serious cardiovascular diseases have been reported. We describe here a patient with a transplanted heart, treated with cyclosporine and prednisone, who underwent pregnancy and vaginal delivery with good outcomes for mother and infant.


Anorexia nervosa and the Val158Met polymorphism of the COMT gene: meta-analysis and new data.
This study aimed to test the association between the Val158Met polymorphism (rs4680) of the catechol-O-methyl transferase gene and anorexia nervosa (AN). First, an association study on two cohorts (306 cases and 1009 controls from Utrecht, and 174 cases and 466 controls from Leiden/NTR) was performed. Subsequently, the results were integrated into a meta-analysis, together with all the case-control and family-based studies, which were testing the same hypothesis and were available in the literature. Altogether, eight studies (11 datasets) were included in this meta-analysis, with a total of 2021 cases, 2848 controls, and 89 informative (heterozygous) trios. The present association studies found no association between AN and rs4680 when testing the allelic contrast [Utrecht odds ratio (OR)=1.14, P=0.14; Leiden OR=1.02, P=0.85]. There was an indication of an association under the dominant model of genetic effect in the Utrecht cohort (for the Met allele, OR=1.42, P=0.03). Nevertheless, the meta-analyses of both the allelic contrast and the dominant effect were nonsignificant (the allelic pooled OR=1.03, P=0.42 and the dominant pooled OR=1.1, P=0.18). The meta-analyses were performed under the fixed-effect model and there was no significant heterogeneity among the effect sizes. Meta-analytically combined evidence from the present genotypings and the literature search shows that the effect sizes are homogeneous across studies and that rs4680 is not associated with AN.


Echoscopy in scanning abdominal diseases in a critical care setting.
Targeted ultrasound examinations with portable ultrasound device (handheld ultrasound system [HHUS]) have been defined as "echoscopy" by the European Federation of Societies of Ultrasound in Medicine and Biology (EFSUMB). For abdominal diseases it has been shown that echoscopy is sensitive and specific. The aim of this study is to show that the use of HHUS for abdominal ultrasonography is possible under the conditions prevailing in emergency and intensive care medicine and that it is not inferior to high-end devices (high-end ultrasound systems [HEUS]). Examinations were carried out with a first-generation Vscan™ (GE Medical Systems, Solingen, Germany) and HEUS device (Siemens Acuson X‑300 or X‑700, Siemens Healthcare, Erlangen, Germany). The HEUS device was seen as standard. The examinations were randomized and blinded and carried out by two examiners within 30 min in order to avoid falsifications due to time delay. They took place in the intensive care unit, the emergency room and the emergency medical service. The results had to be recorded in an examination sheet. In all, 86 patients (54 men and 32 women, aged 73 ± 14.58 [28-95] years) were included. In 45.35% (39/86) of the ultrasound examinations using HEUS and in 41.86% (36/89) of the cases using HHUS the examination conditions were optimal. Furthermore, 76.19% of the examinations were carried out by both examiners in the same scanning position. For the detection of liver tumours, HHUS shows a sensitivity of 70% and specificity of 100%. With regard to identifying signs of cholecystitis, i.e., evidence of surrounding inflammation (a) or hydrops (b), HHUS shows a sensitivity of 66.67% (a) and 60% (b) and a specificity of 97.06% (a) and 96.86% (b). The diagnosis of an ileus is successful with a sensitivity of 87.5% and a specificity of 60%. The respiratory variability of the inferior vena cava has a sensitivity of 100% and a specificity of 40% using HHUS. Ascites and pleural effusions can be diagnosed with a sensitivity of 89% and a specificity of 93.1%. When using the FAST (Focused Assessment with Sonography for Trauma) protocol, HHUS has a sensitivity of 80% and a specificity of 90.9%. With the exception of kidney cysts and inferior vena cava, the measurement of the diameter has a positive correlation. Echoscopy of the abdomen in emergency and intensive care medicine is possible despite restrictive circumstances. The inferior vena cava can only be assessed to a limited extent with the first generation of Vscan™. In order to use sonography in emergency and intensive care medicine, a standardized procedure is to be aimed for and training in emergency sonography is necessary.


Energy landscape in protein folding and unfolding.
We use (1)H NMR to probe the energy landscape in the protein folding and unfolding process. Using the scheme ⇄ reversible unfolded (intermediate) → irreversible unfolded (denatured) state, we study the thermal denaturation of hydrated lysozyme that occurs when the temperature is increased. Using thermal cycles in the range 295 < T < 365 K and following different trajectories along the protein energy surface, we observe that the hydrophilic (the amide NH) and hydrophobic (methyl CH3 and methine CH) peptide groups evolve and exhibit different behaviors. We also discuss the role of water and hydrogen bonding in the protein configurational stability.


Treatment of non-toxic multinodular goiter with radioactive iodine.
Fourteen patients with large non-toxic multinodular goiters were treated with 20 to 100 mCi (740 to 3,700 MBq) of radioactive iodine (iodine-131). In seven, the goiter had recurred after a partial thyroidectomy and four of these had had two operations. Eight had symptoms of respiratory obstruction, two had dysphagia, and the others sought treatment for cosmetic reasons. After administration of iodine-131, there was a significant decrease in goiter size in 11 of the 14 patients, and all those with obstructive symptoms showed improvement. No significant local side effects occurred, but hypothyroidism and Graves' disease each occurred once during follow-up from one to 13 years. Radioactive iodine in doses of 20 to 100 mCi is an effective, safe therapeutic alternative in patients with large non-toxic multinodular goiter, particularly when there is recurrence following surgery or when there are contraindications to surgery.


Reversible cholestatic hepatitis due to carbamazepine in an adolescent.
We report a 13-year-old boy who developed fever, rash and hepatitis with cholestasis (on biochemistry and liver histology) after 10 weeks' use of carbamazepine. Recovery of liver biochemistry occurred 4 months after discontinuing the drug.


Deep anterior lamellar Keratoplasty.
Keratoconus is a disease causing increased steepening of the cornea resulted in irregular astigmatism. Treatment options are Glasses, Hard contact lenses, Cross linking, Intracorneal Segments insertion, Refractive surgery (Gilda et al., 2008), or Keratoplasty. Lamellar Keratoplasty (LKP) can be a better choice to manage cases of moderate and some cases of severe Keratoconus without deep scarring and severe thinning, also in cases of corneal scarring not involving the deeper layers of the cornea. LKP is a corneal graft technique consisting of transplantation of partial-thickness donor tissue, devoid of endothelium, Descemet membrane (DM), and rear stroma into a recipient healthy stromal bed after dissection of pathologic anterior stroma. However, deep lamellar Keratoplasty (DLKP) is a surgical method that completely removes pathologic corneal stroma tissue down to the DM, followed by transplantation of donor cornea without endothelium over the host bed. DLKP has a number of advantages over penetrating Keratoplasty (PKP). Because it does not violate the intraocular structures of the eye, it diminishes or eliminates the chance of postoperative glaucoma, cataract formation, retinal detachment, cystoids macular edema, expulsive choroidal hemorrhage and epithelial ingrowths. Furthermore, this procedure avoids the replacement of host endothelium with donor endothelium and thus precludes endothelial graft rejection, with comparable visual outcomes and low rate of chronic endothelial cell loss compared to PKP.


Impact on In- and Out-of-Hospital Drug Prescriptions of Including a More Expensive Me-Too Antidepressant in a Hospital Drug Formulary: a Controlled Longitudinal Study.
The effect of the inclusion of a more expensive me-too medicine in a hospital drug formulary (HDF) on both in- and out-of-hospital utilization, and the contextual factors which influence this type of induction is rarely studied. Accordingly, this work aimed to quantify the effect of the decision of a hospital of including a more expensive me-too antidepressant in its HDF. A controlled longitudinal study was carried out in a Regional Health Service of Spain. We performed a segmented regression analysis with control group. We used the following dependent variables: defined daily doses (DDD) per 1000 inhabitants per day, DDD per 100 bed days, and cost per DDD. At a hospital level, the modification in the formulary led to utilization changes: (1) an increase in immediate consumption of the newly included me-too drug; and, (2) an annual 25.96% [95% CI: 2.96%-48.95%] decrease in the adjusted trend of the already existing parent antidepressant. The adjusted trend of the cost per DDD of the sum of all medications in the therapeutic group increased by 20.03% annually [95% CI: 3.24%-36.82%]. In the out-of-hospital setting utilization changes were: (1) the adjusted trend of the newly included me-too drug rose by 12.14% annually [95% CI: 4.97%-19.30%]; and, (2) that of the parent drug underwent a negative change in trend of 4.18% annually [95% CI: 0.00%-8.36%]. The inclusion of a more expensive me-too drug in the HDF led to increased consumption of this more expensive me-too drug both in- and out-of-hospital.


Determining Protein Phosphorylation Status Using Antibody Arrays and Phos-Tag Biotin.
We describe here a standard protocol for determining the phosphorylation status of protein multiplexes using antibody arrays and a biotinylated Phos-tag with a dodeca(ethylene glycol) spacer (Phos-tag Biotin). The procedure is based on an antibody microarray technique used in conjunction with an enhanced chemiluminescence system, and it permits the simultaneous and highly sensitive detection of multiple phosphoproteins in a cell lysate. By using this procedure, we have demonstrated the quantitative detection of the entire phosphorylation status of a target protein involved in intracellular signaling.


Healthcare Use Among Black and White Congenital Heart Disease Medicaid Enrollees.
Congenital heart disease (CHD) is the most common birth anomaly in the US. Research shows lost-to-follow-up trends and racial disparities in healthcare use. This study examines racial differences in healthcare use among Medicaid-covered children with CHD. Using 2010-2019 claims data from a pediatric Medicaid Accountable Care Organization, 960 Black and White children with complex CHD and ≥ 3 years of continuous Medicaid coverage were identified. Three cohorts were constructed (starting age: < 1-year-olds, 1-5-year-olds, 6-15-year-olds) and followed for 3 years. Multivariate analysis assessed annual healthcare use (cardiology, primary care, emergency department) by race, adjusting for patient and provider covariates. Overall, 51% of patients had an annual cardiology visit, and 54% had an annual primary care visit. Among the 1-5-year-old cohort, Black children were predicted to be 13% less likely to have an annual cardiology visit compared to their White counterparts (p = 0.001). Older Black children were predicted to be more likely to have a primary care visit compared to their White counterparts. Nearly half of Medicaid-enrolled children with complex CHD did not receive recommended cardiology care. Young Black children were less likely to receive an annual cardiac visit, while older Black children were more likely to receive primary care. While the percentage with an annual cardiac visit was low, the majority had seen a cardiologist within the 3-year window, suggesting these children are still receiving cardiology care, if less frequently than recommended. Opportunities exist for cardiology and primary care to collaborate to ensure patients receive timely recommended care.


Evaluation of purinergic mechanism for the treatment of voiding dysfunction: a study in conscious spinal cord-injured rats.
To investigate the effect of a selective P2X(3-)P2X(2/3) purinergic receptor antagonist (a-317491) on detrusor hyperreflexia in conscious chronic spinal cord-injured female rats. Six chronic spinal cord-transected female Sprague-Dawley rats (290-336 g) were used in this study. Spinal transection at the T8-T9 segmental level was performed using aseptic techniques under halothane anesthesia. Fourteen to 16 weeks after spinal transection, A-317491, a selective P2X(3-)P2X(2/3) purinergic receptor antagonist, was administered intravenously in cystometry studies at increasing doses of 0.03, 0.1, 0.3, 1, 3, 10 and 30 micromol/kg at 40-50 minute intervals. Cystometrograms (CMGs) were performed before and after the administration of each dose of the drug. The continuous filling of CMGs revealed a large number of small-amplitude (> 8 cmH(2)O), non-voiding contractions (NVCs) (average, 9.7 per voiding cycle) preceding voiding contractions (mean amplitude, 31 cmH(2)O; duration, 2.5 minutes), which occurred at an interval of 539 seconds and at a pressure threshold of 5.7 cmH(2)O. When tested in a range of doses (0.03-30 micromol/kg, intravenous), A-317491 in doses between 1 and 30 micromol/kg significantly (p < 0.05) increased the interval between voids by 25%, reduced the number of NVCs by 42-62%, and increased the pressure threshold for voiding by 53-73%, but did not change the amplitude of the duration of the voiding contractions. The effects of the drug were apparent within 10 minutes following administration. These results indicate that purinergic mechanisms, presumably involving P2X(3) or P2X(2/3) receptors on bladder C-fiber afferent nerves, play an important role in the detrusor hyperreflexia that occurs after spinal cord injury in rats.


Guessing and misinformation about pregnancy risk among urban mothers.
Only one-third of urban mothers interviewed twice, a year apart, answered correctly both times about when during the menstrual cycle a woman is most likely to become pregnant. Classroom discussions about contraception, attendance at family planning clinics, and discussions with one's mother about contraception are not positively associated with knowledge about pregnancy risk. Those using methods other than the pill or IUD are more knowledgeable about pregnancy risk--perhaps because they have a greater need to know.


[The application of in vivo multi-channel recording methods in the studies of the affective pain in rats].
To record the electrical activities of Antirior cingulate cortex (ACC) neurons by in vivo multi-channel recording methods using the model of complete freund's adjuvant (CFA) induced conditioned place avoidance (C-CPA), which has been set up in our previous studies. The electrode was self-made and the CPA responses were recorded by in vivo multi-channel recording method. (1) The electrical activities of ACC neurons could be successfully recorded by the self-made electrode. (2) Before or after the injection of CFA, rats were respectively conditioned to the different place. The firing rates of ACC neurons in the CFA-paired place vs that in the non-CFA-paired place was (0.853 ± 1.377) imp/s vs (0.221 ± 0.971) imp/s (P < 0.05, n = 26). (3) The CPA responses in the CFA-paired place vs that in the non-CFA-paired place were (303.55 ± 61.77)s vs (140.32 ± 33.52)s(P < 0.05, n = 6). The firing rates of rACC (rostral Anterior Cingulate Cortex) neurons were involved in the occurrence of the affective pain.


An information theoretic approach to pedigree reconstruction.
Network structure is a dominant feature of many biological systems, both at the cellular level and within natural populations. Advances in genotype and gene expression screening made over the last few decades have permitted the reconstruction of these networks. However, resolution to a single model estimate will generally not be possible, leaving open the question of the appropriate method of formal statistical inference. The nonstandard structure of the problem precludes most traditional statistical methodologies. Alternatively, a Bayesian approach provides a natural methodology for formal inference. Construction of a posterior density on the space of network structures allows formal inference regarding features of network structure using specific marginal posterior distributions. An information theoretic approach to this problem will be described, based on the Minimum Description Length principle. This leads to a Bayesian inference model based on the information content of data rather than on more commonly used probabilistic models. The approach is applied to the problem of pedigree reconstruction based on genotypic data. Using this application, it is shown how the MDL approach is able to provide a truly objective control for model complexity. A two-cohort model is used for a simulation study. The MDL approach is compared to COLONY-2, a well known pedigree reconstruction application. The study highlights the problem of genotyping error modeling. COLONY-2 requires prior error rate estimates, and its accuracy proves to be highly sensitive to these estimates. In contrast, the MDL approach does not require prior error rate estimates, and is able to accurately adjust for genotyping error across the range of models considered.


Short-term benefits of catch-up growth for small-for-gestational-age infants.
Recent studies suggest that small newborns who present rapid postnatal growth may have an increased risk of chronic diseases in adulthood. On the other hand, it is widely assumed that catch-up growth is desirable for low birthweight children, but the literature on this subject is limited. Population-based cohort study in southern Brazil, with 3582 children examined at birth, 20 and 42 months of age. Catch-up growth from 0 to 20 months was related to subsequent risks of hospital admissions and mortality. Children who were small-for-gestational-age (SGA) but presented substantial weight gain (> or =0.66 z-score) up to the age of 20 months had 65% fewer subsequent hospital admissions than other SGA children (5.6% versus 16.0%; P < 0.001). Mortality to age 5 years was 75% lower (3 versus 13 per 1000, a non-significant difference based on a small number of deaths) for rapid-growing SGA children compared to the remaining SGA children. Their admission and mortality rates were similar to those observed for children born with an appropriate birthweight for their gestational age (AGA). Similar positive effects of rapid growth were found for AGA children. There appear to be definite benefits associated with catch-up growth. Growth promotion efforts for infants who are born small should take into account their possible short- and long-term consequences.


Surgical treatment for thyroid cancer.
Thyroid cancer, although a rare disease, may cause significant disability and even death. Its proper surgical management is based on an understanding of the different biolgoic behavior of the four subtypes. Papillary and follicular cancers are best managed by total lobectomy on the side of the lesion and subtotal lobectomy on the contralateral side, unless there is gross disease bilaterally or distant metastasis (in which circumstances total thyroidectomy is performed). Cervical lymph node metastasis, when present, is handled satisfactorily by modified neck dissection. Because of its high incidence of multicentricity and its more serious prognosis, medullary thyroid carcinoma is managed by total thyroidectomy and--usually--radical neck dissection for involved nodes. For anaplastic carcinoma, there is no effective treatment at present. Postoperatively, all patients should be given suppressive doses of thyroid hormone to prevent myxedema and to prevent cancer from recurring. Radioiodine therapy may be of value in suppressing metastasis of some papillary and follicular cancers that exhibit a high degree of follicular differentiation.


Production of DON-related trichothecenes byFusarium graminearum Schw from Krasnodarski krai of the USSR.
34Fusarium graminearum Schw isolates produced 4-deoxynivalenol to form significant amounts of 4, 7 - dideoxynivalenol and lesser amounts of 4 - deoxynivalenol monoacetates on grain substratesin vitro. This is the first report on the capability a large group of naturally occurring isolates to produce 4,7-dideoxynivalenol. The average levels of 4,7-dideoxynivalenol on rice, corn, barley, and wheat as a substrate were respectively 26.8, 14.0, 12.8, and 10.5% of the level of 4-deoxynivalenol. 4, 7 - dideoxynivalenol was present in all examined naturally contaminated wheat kernel samples at levels of 1.7 to 7.9% of the level of 4-deoxynivalenol. These findings suggest that more attention should be given to the occurrence of 4,7-dideoxynivalenol in cereals.


The state-of-the-art system dynamics application in integrated water resources modeling.
In recent years, water resources management has become more complicated and controversial due to the impacts of various factors affecting hydrological systems. System Dynamics (SD) has in turn become increasingly popular due to its advantages as a tool for dealing with such complex systems. However, SD also has some limitations. This review contains a comprehensive survey of the existing literature on SD as a potential method to deal with the complexity of system integrated modeling, with a particular focus on the application of SD to the integrated modeling of water resources systems. It discusses the limitations of SD in these contexts, and highlights a number of studies which have applied a combination of SD and other methods to overcome these limitations. Finally, our study makes a number of recommendations for future modifications in the application of SD methods in order to enhance their performance.


Assessing the performance of three resveratrol in binding with SIRT1 by molecular dynamics simulation and MM/GBSA methods: the weakest binding of resveratrol 3 to SIRT1 triggers a possibility of dissociation from its binding site.
SIRT1 is an NAD+-dependent deacetylase, whose activators have potential therapeutic applications in the age-related, metabolic, neurode-generative and cardiovascular diseases. Resveratrol (RSV) has been regarded as potent SIRT1 activator in the treatment of atherosclerosis and cardiovascular diseases. Moreover, the previous crystal structure of SIRT1 complex with RSV indicated that three RSV participated in the SIRT1 activation, namely RSV1 and RSV2 strengthened the interaction of SIRT1 to its substrate peptide and promoted the stimulation of SIRT1 activity, while RSV3 exhibited an auxiliary function. Whereas the molecular mechanism of the insignificant role of RSV3 has not been reported. Moreover, the dynamics properties of three RSV in the binding site of SIRT1 are still unknown. In this study, to evaluate the role of RSV3 systematically, five SIRT1_RSV system (SIRT1_RSV1-3, SIRT1_RSV1-2, SIRT1_RSV1, 3, SIRT1_RSV2-3 and SIRT13) were constructed and subjected to 20 ns molecular dynamics simulation. Our simulations showed that the binding of RSV1 was extremely stable in any system and might be independent to the existence of RSV2 and RSV3. The stability of RSV2 was slightly weaker than that of RSV1. More interestingly, RSV3 could completely dissociate from its binding site in SIRT1_RSV1-3 system at 7 ns, which might be an important factor for its auxiliary role in activating SIRT1. Actually, some preliminary signs of RSV3 dissociation already appeared around 1 ns. In detail, the innate weakness between RSV3 and Lys444 would trigger frequent formation and breakage of the RSV3-Lys444 hydrogen bond. Residue Asp298 preferred to form hydrogen bond with RSV2 rather than RSV3 once the RSV3-Lys444 hydrogen bond became stronger. Without the RSV3-Asp298 interaction, the remaining RSV3-Lys444 and RSV3-Asp292 hydrogen bonds hardly preserved the RSV3's binding, which resulted in the dissociation of RSV3. Our work elucidated the inequable contributions of three RSV on their binding interaction with SIRT1 and indicated that the binding sites of RSV1 and RSV2 should be enough to design more potent SIRT1 activator.


Fenofibrate attenuates ischemia reperfusion-induced acute kidney injury and associated liver dysfunction in rats.
Ischemia/reperfusion (I/R) is one of the common reasons for acute kidney injury (AKI) and we need to develop effective therapies for treating AKI. We investigated the role of fenofibrate against I/R-induced AKI and associated hepatic dysfunction in rats. In male wistar albino rats, renal pedicle occlusion for 40 min and 24 h reperfusion resulted in AKI. I/R-induced AKI was demonstrated by measuring serum creatinine, creatinine clearance, urea, uric acid, potassium, fractional excretion of sodium and urinary microproteins. Oxidative stress in rat kidneys was quantified by assaying superoxide anion generation, thiobarbituric acid reactive substances, and reduced glutathione levels. AKI-induced hepatic damage was quantified by assaying serum aminotransferases, alkaline phosphatase and bilirubin levels. Moreover, serum cholesterol, high density lipoprotein and triglycerides were quantified. Hematoxylin-eosin staining of renal and hepatic tissues was done and the kidney and liver injury scores were determined. Immunohistology of endothelial nitric oxide synthase (eNOS) was done in rat kidneys. Fenofibrate was administered for 1 week before subjecting rats to AKI. In separate group, the nitric oxide synthase inhibitor, L-nitroarginine methyl ester (L-NAME) was administered prior to fenofibrate treatment. In I/R group, significant alteration in the serum/urine parameters indicated AKI and hepatic dysfunction along with marked increase in kidney and liver injury scores. Treatment with fenofibrate attenuated AKI and associated hepatic dysfunction. Moreover, I/R-induced decrease in renal eNOS expression was abrogated by fenofibrate. Pre-treatment with L-NAME abolished fenofibrate mediated reno- and hepato-protective effects. In conclusion, fenofibrate attenuates I/R-induced AKI and associated hepatic dysfunction putatively through modulation of eNOS expression.


Immunoscintigraphy for detecting acute myocardial infarction without electrocardiographic changes.
To establish whether immunoscintigraphy with antibody to myosin may detect acute myocardial infarction without electrocardiographic changes. Prospective study of patients with suspected acute myocardial infarction or unstable angina with cardiac imaging with 111indium myosin antibody, estimation of cardiac enzyme concentrations, electrocardiography, 201thallium imaging, and radionuclide ventriculography. Coronary care unit in a district general hospital. 119 Consecutive patients with suspected acute myocardial infarction or unstable angina. Patients with cardiomyopathy, myocarditis, valvular heart disease, myocardial infarction or cardiac surgery in the previous two weeks or with left bundle branch block and women of childbearing age were excluded. Of 75 patients with suspected acute myocardial infarction, seven had no diagnostic electrocardiographic changes despite normal conduction patterns. Immunoscintigraphy with myosin antibody disclosed necrosis in all seven patients, which was localised in regions supplied by diseased coronary arteries in all but one. Six patients had abnormal images on 201thallium imaging, and all seven had abnormal wall motion at the site of antibody uptake. One patient with minimal left main stem and right coronary artery atheroma had uptake of antibody at two discrete sites. Immunoscintigraphy with antibody to myosin confirms myocardial infarction in the absence of electrocardiographic changes and discloses the site of infarction.


Exploratory study of a screening measure for polycystic ovarian syndrome, quality of life assessment, and neuropsychological evaluation.
The universally adopted 2018 PCOS medical diagnostic and treatment guidelines for Polycystic Ovarian Syndrome (PCOS) cites the need for a brief screening measure that can be easily administered in the clinical care setting. We evaluate a 12-item questionnaire emphasizing the medical symptoms of PCOS with a group of women with PCOS as well as comparison samples of college women not diagnosed with PCOS. Of 120 undergraduate psychology women 18 to 41 years of age, 86 screened negative on a 12-item PCOS symptoms inventory. They were compared to a group of PCOS patients diagnosed medically in a manner consistent with the Teede et al. (2018) evidence-based diagnostic guidelines. The screen-positive, screen-negative, and PCOS-confirmed groups were compared on the PCOS Quality-of-Life (QoL) questionnaire, Zung Self-Rating Depression Scale (ZDS), Spielberg State-Trait Anxiety Inventory (STAI), Fatigue Symptom Inventory (FSI), Spiritual well-being and Spiritual Beliefs Inventories, the computerized Automated Neuropsychological Assessment Metric (ANAM) battery, and an experimental tachistoscopic Bilateral Perceptual Asymmetries Letter and Dots Matching Bilateral Field Advantage (BFA) test (to evaluate the effects of early brain androgenization possible from PCOS). For each questionnaire and neuropsychological performance principal outcome, the Linear Mixed Effects (LME) model was employed to evaluate the predictive significance of demographic characteristics and group membership (confirmed cases, screen negative and screen positive cases) for these outcomes. The PCOS-confirmed women scored more poorly than the screen-negative (reference) and screen-positive groups on all the measures of physical, emotional, social, and spiritual well-being measures. On the ANAM neuropsychological battery, PCOS-confirmed women did more poorly on Sternberg Memory and Stimulus Response throughput measures. They also had slower correct response speed for both the unilateral and bilateral dot- and letter-matching tachistoscopic stimulus presentations. However, the bilateral field advantage throughput performance ratio did not differ among groups, which is a global measure of bilateral versus unilateral brain/behavior asymmetries. PCOS screening can be a feasible and important part of women's healthcare. PCOS-confirmed women should receive not only the medical standard of care from the 2018 guidelines, but also comprehensive psychosocial and neurocognitive support to enhance their quality of life.


A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use.
Data regarding the effects of oral contraceptive use on women's risk of melanoma have been difficult to resolve. We undertook a pooled analysis of all case-control studies of melanoma in women completed as of July 1994 for which electronic data were available on oral contraceptive use along with other melanoma risk factors such as hair colour, sun sensitivity, family history of melanoma and sun exposure. Using the original data from each investigation (a total of 2391 cases and 3199 controls), we combined the study-specific odds ratios and standard errors to obtain a pooled estimate that incorporates inter-study heterogeneity. Overall, we observed no excess risk associated with oral contraceptive use for 1 year or longer compared to never use or use for less than 1 year (pooled odds ratio (pOR)=0.86; 95% CI=0.74-1.01), and there was no evidence of heterogeneity between studies. We found no relation between melanoma incidence and duration of oral contraceptive use, age began, year of use, years since first use or last use, or specifically current oral contraceptive use. In aggregate, our findings do not suggest a major role of oral contraceptive use on women's risk of melanoma.


H2-O influence on antigen presentation in H2-E-expressing mice.
MHC class II molecules sample peptides generated in the endosomal/lysosomal system for cell surface presentation to CD4+ T cells. Peptide loading requires the endosomal/lysosomal resident HLA-DM (DM; H2-DM, mouse), but in B cells, DM is tightly associated with HLA-DO (DO; H2-O, mouse). We have previously shown that H2-O differentially modulates the processing and presentation of different antigenic epitopes on H2-Ab molecules. Using H2-Ead-transgenic mice, we here show that presentation of different epitopes by H2-Ed/b molecules is similarly influenced by H2-O after membrane immunoglobulin-mediated uptake of antigen. In addition, B cells from H2-Ead-transgenic mice (which co-express H2-Ab and H2-Ed/b molecules) show an altered pattern of presentation of H2-Ab-restricted epitopes. In H2-Ead-transgenic, H2-O-deficient mice, further changes in the peptide repertoire were observed. Thus, H2-Ed/b expression influences the epitopes presented by H2-Ab, and this effect is further altered by expression of H2-O.


Neuroprotective effects of aqueous extracts of Uncaria tomentosa: Insights from 6-OHDA induced cell damage and transgenic Caenorhabditis elegans model.
Previous pharmacological studies have indicated that AC11 (a standardized aqueous extract of Uncaria tomentosa) has beneficial effects on DNA repair and immune function. However, its benefits go beyond this. The present study utilized electron spin resonance (ESR) and spin trapping technique, as well as the 6-OHDA-induced cell damage and transgenic Caenorhabditis elegans models, towards exploring the antioxidant and neuroprotective ability of AC11. Our results showed that AC11 could scavenge several types of free radicals, especially hydroxyl radicals (60% of hydroxyl radicals were scavenged by 30 μg/ml of AC11). In SH-SY5Y cells, we found that AC11 could dose dependently protect 6-OHDA induced cell damage by increase cell viability and mitochondrial membrane potential. AC11 pretreatment also significantly decreased the level of lipid peroxidation, intracellular reactive oxygen species and nitric oxide in 6-OHDA treated cells. In NL5901 C. elegans, 10 μg/ml AC11 could reduce the aggregation of α-synuclein by 40%. These findings encourage further investigation on AC11 and its active constituent compounds, as possible therapeutic intervention against Parkinson's disease.


Treatment of Large and Giant Middle Cerebral Artery Aneurysms: Risk Factors for Unfavorable Outcomes.
This study aimed to assess the clinical and radiologic outcomes after neurosurgical treatment of large and giant aneurysms of the middle cerebral artery (MCA). In addition, we aimed to identify risk factors for unfavorable outcomes. This retrospective study included 105 patients with 106 large or giant MCA aneurysms treated with neurosurgical methods, including microsurgery and endovascular treatment, over a 15-year period. The mean aneurysm size was 15.3 ± 7.1 mm. Ten (9.4%) were giant aneurysms. The MCA bifurcation was the most common aneurysm site, followed by the MCA trunk and distal MCA. Aneurysm clipping was the most common treatment method, followed by clipping or trapping with bypass surgery and endovascular treatment. However, acute cerebral infarction was the most common complication (16.0%), poor outcomes (modified Rankin Scale score, 3-6) developed in 12.3% of aneurysms after treatment, and 6.6% of treated aneurysms needed retreatment. Multivariate analysis showed that independent risk factors for acute cerebral infarction after treatment were aneurysms located on the MCA trunk and 2 or more underlying diseases. Initial presentation with subarachnoid hemorrhage and complications during treatment were independent risk factors for poor outcomes. In addition, endosaccular coiling was an independent risk factor for retreatment. Neurosurgical management should be considered a priority for large and giant MCA aneurysms because of the high rupture rate and clinical symptoms. However, treatment outcomes remain unsatisfactory. Therefore, tailored management with consideration of risk factors for unfavorable outcomes should be implemented.


Impaired activity of daily living is a risk factor for high medical cost in patients of non-variceal upper gastrointestinal bleeding.
Non-variceal upper gastrointestinal bleeding (NVUGIB) is still a common and life-threatening disease, thus it would have a big impact on medical care cost. However, little is known about risk factors for increased medical care cost in NVUGIB patients. The purpose of the study was to clarify predictor of requiring high medical care cost in NVUGIB patients. Patients who underwent endoscopic hemostasis due to NVUGIB between April 2012 and March 2015 were included in this retrospective study. We analyzed the association between patients' background including activity of daily livings (ADL) and high medical care cost using logistic regression model. Medical care cost was calculated in reference to the "Diagnosis Procedure Combination" which is diagnosis-dominant case-mix system in Japan. The cutoff value of high medical care cost was defined as its first quartile. ADL was assessed according to Katz-6 score. We defined impaired ADL patient who revealed Katz-6 score more than 1. A total of 128 consecutive patients were included in this study. Median medical care cost was 5323 USD (IQR 3661-8172 USD). There were 13 patients (10%) in impaired ADL group. In univariate analysis, age and impaired ADL before admission revealed significant association with high cost. Of these, impaired ADL was an only independent risk factor [odds ratio 15.3 (95% CI 2.49-183)] in multivariate analysis. Impairment in ADL before admission was an independent predictor for high medical care cost with NVUGIB patients.