Post-operative intensity-modulated radiotherapy for malignancies of the nasal cavity and paranasal sinuses.
To evaluate the clinical outcome and toxicity of post-operative intensity-modulated radiotherapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses. Twenty-five patients with histological proven cancer of the paranasal sinuses (n=21) or nasal cavity (n=4) were post-operatively treated with IMRT at the Leuven department to a total dose of 60 Gy (n=15) or 66 Gy (n=10). Both acute and chronic toxicity were prospectively scored in all patients. Median follow-up was 27 months (range: 12-47 months) among surviving patients. The actuarial 2-year local control (LC), overall survival (OS) and disease-free survival (DFS) rates were 81%, 88% and 77%, respectively. One patient developed isolated distant metastasis, while none of the patients developed regional failure. No grade 3 or 4 toxicity was reported, either acute or chronic. No radiation-induced blindness or brain necrosis was reported to date, although longer follow-up has to be awaited for definitive results. Post-operative IMRT for sinonasal cancer resulted in similar local control and survival rates as conventional or 3D-conformal radiotherapy techniques, and was associated with little acute toxicity. Longer follow-up is necessary to confirm the lack of late complications.


Pulsed Nd:YAG laser effect on eruption of rat mandibular incisors following disturbance of the enamel organ in the pulp.
We investigated the effects of pulsed neodymium:yttrium-aluminium-garnet (Nd:YAG) laser irradiation time on the eruption of 56 mandibular incisors in 28 rats. Clinically, some incisors erupted and the others did not. The incisors were irradiated at 2 W, 20 pulses/s for the period of 3 s, 5 s, 7 s, and 10 s, and the regeneration process was monitored at 20 days after laser treatment. Incisors irradiated for 3-5 s continued their eruption; five incisors irradiated for 7 s and all incisors irradiated for 10 s did not erupt. In the incisors that continued to erupt, the inner epithelial cells differentiated into ameloblast and a part of the pulp cavity was occupied by osteodentin. In the teeth in which eruption had ceased, the inner epithelium cells did not differentiate into ameloblast, and most of the pulp cavity was occupied by osteodentin. The results indicate that a relatively short time duration of pulsed Nd:YAG laser irradiation in the pulp induced the reparative process without disturbing the eruption.


Hepatic lipase mediates an increase in selective uptake of high-density lipoprotein-associated cholesteryl esters by human Hep 3B hepatoma cells in culture.
Selective uptake of high-density lipoprotein- (HDL-) associated cholesteryl esters (CE), i.e. lipid uptake independent from particle uptake, delivers CE to the liver and steroidogenic tissues in vivo. In vitro, besides hepatocytes and steroidogenic cells many other cell types selectively take up HDL CE. Hepatic lipase (HL) stimulates the internalisation of apoprotein (apo) B-containing lipoproteins by hepatocytes independent from lipolysis. In this study the role of HL in the hepatic metabolism of apo A-I-containing lipoproteins, i.e. HDL, was investigated. HDL3 (d = 1.125-1.21 g/ml) was radiolabeled in its protein (125I) and in its CE moiety ([3H]cholesteryl oleyl ether, ([3H]CEt)). HL originated from tissue culture media of hepatoma cells and from post-heparin plasma. Human Hep 3B hepatoma cells incubated in medium containing radiolabeled HDL3. In the absence of HL, the rate of apparent HDL3 particle uptake according to the lipid tracer ([3H]CEt) was in most cases in approximately 10-fold excess on that due to the protein label (125I), indicating selective CE uptake from HDL3. Addition of HL to these incubations increased the cellular uptake of [3H]CEt and of 125I from HDL3 and quantitatively the most prominent effect was an up to approximately 2.5-fold stimulation of apparent selective CE uptake ([3H]CEt-125I). This increase in selective CE uptake was observed in the presence of tetrahydrolipstatin, an inhibitor of the catalytically active site of HL, suggesting that this HL effect is independent from lipolysis. HL binds to cell surface heparan sulfate proteoglycans. To explore the role of these molecules for the HL effect on selective CE uptake, hepatoma cells were depleted of proteoglycans or Chinese hamster ovary (CHO) cells deficient in proteoglycan synthesis were used. Proteoglycan-deficiency reduced the HL-mediated increase in selective uptake by more than 80%. To investigate if low-density lipoprotein (LDL) receptors or the LDL receptor-related protein (LRP) are involved in the HL effect on selective CE uptake, murine embryonic fibroblasts (MEF) were used which are deficient in these receptors; alternatively, monensin, an inhibitor of endocytosis was present in the medium of Hep 3B cells during the uptake assay for labeled HDL3. These experiments yielded no evidence for a role of LDL receptors or LRP in the HL-mediated increase in selective CE uptake. In summary, HL mediates an increase in HDL3 selective CE uptake by human Hep 3B hepatoma cells. This HL effect is independent from lipolysis and independent from LRP and LDL receptors. However this HL effect is susceptible to cell surface proteoglycan deficiency. The potential physiologic implication is that HL modifies HDL selective CE uptake by the liver in vivo and such an effect could play a role in reverse cholesterol transport.


Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis.
Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptfgr) are implicated as a TGFβ1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER - SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER-SftpcI73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α/FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.


Mitral valve plasty in systemic lupus erythematosus in the setting of antiphospholipid syndrome.
The first case was of a 27-year-old female, who was diagnosed as having mitral valve stenosis with regurgitation, systemic lupus erythematosus and antiphospholipid syndrome at her previous pregnancy. We performed mitral valve plasty, which included open mitral commissurotomy and Kay's annulo plasty. The second case was of a 53-year-old female, who was diagnosed as old myocardial infarction, mitral regurgitation, systemic lupus erythematosus and antiphospholipid syndrome. She underwent mitral valve plasty and coronary artery bypass grafting. Both cases were treated by administration of methylpredonisolone and heparin perioperatively to avoid thrombosis and aggravation of systemic lupus erythematosus. Both patients showed good postoperative outcome without complications. We consider that it is important to perform the plasty as far as possible, and to administer effective anticoagulation treatment to prevent complications for patients in the setting of systemic lupus erythematosus and antiphospholipid syndrome.


Lysine 356 is a critical residue for binding the C-6 phospho group of fructose 2,6-bisphosphate to the fructose-2,6-bisphosphatase domain of rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.
Lysine 356 has been implicated by protein modification studies as a fructose-2,6-bisphosphate binding site residue in the 6-phosphofructo-2-kinase domain of rat liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (Kitajima, S., Thomas, H., and Uyeda, K. (1985) J. Biol. Chem. 260, 13995-14002). However, Lys-356 is found in the fructose-2,6-bisphosphatase domain (Bazan, F., Fletterick, R., and Pilkis, S. J. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 9642-9646). In order to ascertain whether Lys-356 is involved in fructose-2,6-bisphosphatase catalysis and/or domain/domain interactions of the bifunctional enzyme, Lys-356 was mutated to Ala, expressed in Escherichia coli, and then purified to homogeneity. Circular dichroism experiments indicated that the secondary structure of the Lys-356-Ala mutant was not significantly different from that of the wild-type enzyme. The Km for fructose 2,6-bisphosphate and the Ki for the noncompetitive inhibitor, fructose 6-phosphate, for the fructose-2,6-bisphosphatase of the Lys-356-Ala mutant were 2700- and 2200-fold higher, respectively, than those of the wild-type enzyme. However, the maximal velocity and the Ki for the competitive product inhibitor, inorganic phosphate, were unchanged compared to the corresponding values of the wild-type enzyme. Furthermore, in contrast to the wild-type enzyme, which exhibits substrate inhibition, there was no inhibition by substrate of the Lys-356-Ala mutant. In the presence of saturating substrate, inorganic phosphate, which acts by relieving fructose-6-phosphate and substrate inhibition, is an activator of the bisphosphatase. The Ka for inorganic phosphate of the Lys-356-Ala mutant was 1300-fold higher than that of the wild-type enzyme. The kinetic properties of the 6-phosphofructo-2-kinase of the Lys-356-Ala mutant were essentially identical with that of the wild-type enzyme. The results demonstrate that: 1) Lys-356 is a critical residue in fructose-2,6-bisphosphatase for binding the 6-phospho group of fructose 6-phosphate/fructose 2,6-bisphosphate; 2) the fructose 6-phosphate binding site is responsible for substrate inhibition; 3) Inorganic phosphate activates fructose-2,6-bisphosphatase by competing with fructose 6-phosphate for the same site; and 4) Lys-356 is not involved in 6-phosphofructo-2-kinase substrate/product binding or catalysis.


Phosphorylation of synthetic acidic peptides by casein kinase II: evidence for competition with phosphorylation of proteins involved in transcription.
Phosphorylation of several synthetic acidic peptides by biochemically isolated casein kinase II (CKII) and by cellular and nuclear extracts containing CKII-like activity has been investigated. Especially the synthetic peptide pyroGlu-Asp-Asp-Ser-Asp-Glu-Glu-Asn comprising the carboxy-terminal acidic hepta-peptide of the largest subunit of RNA polymerase II was found to serve as an excellent substrate for purified CKII. Moreover, this peptide reduces the rate of 'in vitro' ATP-dependent stimulation of DNA transcription induced by the proteins in the extracts. Since the peptide itself is also significantly phosphorylated in such assays, it is supposed that it serves as a competitive substrate for the phosphorylation of proteins in the extracts whose phosphorylation seems to be a prerequisite for their activity in the transcription process. This points to the involvement of CKII and substrate(s) of CKII in the process of transcription.


Identification of source of a marine oil-spill using geochemical and chemometric techniques.
The current work aimed to identify the source of an oil spill off the coast of Maranhão, Brazil, in September 2005 and effect a preliminary geochemical survey of this environment. A combination of bulk analytical parameters, such as carbon isotope (δ(13)C) and Ni/V ratios, and conventional fingerprinting methods (High Resolution Gas Chromatography and Mass Spectrometry) were used. The use of bulk methods greatly speeded source identification for this relatively unaltered spill: identification of the likely source was possible at this stage. Subsequent fingerprinting of biomarker distributions supported source assignment, pointing to a non-Brazilian oil. Steranes proved the most useful biomarkers for sample correlation in this work. Distribution patterns of environmentally more resilient compound types, such as certain aromatic structures, proved inconclusive for correlation, probably in view of their presence in the background.


Intravoxel incoherent motion magnetic resonance imaging to predict vesicoureteral reflux in children with urinary tract infection.
To compare the diffusion parameters of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) between the "reflux" and the "non-reflux" kidneys, and to evaluate the feasibility of using IVIM DWI to predict vesicoureteral reflux (VUR) in children with a urinary tract infection (UTI). Eighty-three kidneys from 57 pediatric patients with a UTI were classified into "reflux" and "non-reflux" groups according to voiding cystourethrography (VCUG) results. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (PF) were measured and compared in the renal pelvis of both groups. Four indices (D*/ADC, PF/ADC, D*/D, and PF/D) were calculated and receiver operating characteristic (ROC) curve analyses were performed. VURs were detected on VCUG in 21 kidneys. PF and D* were significantly higher in the "reflux" group than in the "non-reflux" group. The indices were all significantly higher. The PF/D index showed the best diagnostic performance in predicting VUR in children with UTI (Az = 0.864). PF and D* were significantly higher in the "reflux" kidney than in the "non-reflux" kidney. Our new index (PF/D) could prove useful for predicting VUR. • IVIM DWI is both radiation-free and contrast media-free. • IVIM DWI index is easily calculated by combining diffusion parameters. • IVIM DWI may help predict VUR in children with UTI. • PF is significantly higher in the "reflux" than the "non-reflux" kidneys. • A new VUR index, PF/D could prove useful for predicting VUR.


Tumor microenvironment targeting and regulating iron-based metal-organic framework for magnetic resonance imaging guided synergetic therapy of doxorubicin and hydroxyl radicals.
Fe3+and 2-methylimidazole were selected to prepare tumor microenvironment targeted and regulated multifunctional drug carrier Fe-MOFs. The fact that Doxorubicin hydrochloride (DOX·HCl) release climbed 70% from 25% upon regulating the pH from 7.4 to 5.8 proved the pH responsive drug release of Fe-MOFs. Hydroxyl radicals (·OH) analysis proved that Fe-MOFs only generated hydroxyl radicals at pH 5.8, and dissolved oxygen performance showed the O2was produced during the process, which was expected to regulate hypoxia in tumor cells to increase anticancer effect. Cell viability experiments proved the selectivity of Fe-MOFs and the excellent performance of synergy therapy of DOX·HCl and hydroxyl radicals.In vivomagnetic resonance imaging experiments demonstrated excellent performance of positive images. All experiments showed that Fe-MOFs can be used for image-guided collaborative treatment to improve treatment efficiency and reduce side effects.


SAM, a cystathionine beta-synthase activator, promotes hydrogen sulfide to promote neural repair resulting from massive cerebral infarction induced by middle cerebral artery occlusion.
Neurologic deterioration after massive cerebral infarct should be identified at an early stage for medical and surgical treatments. We investigated the effect of hydrogen sulfide on the excitotoxity of PC12 cells exposed to oxygen-glucose deprivation (OGD) and its effect on the apoptosis of brain tissues in rats with middle cerebral artery occlusion (MCAO). Rats with MCAO were treated with SAM, a cystathionine beta-synthase (CBS) activator, or AOAA, a CBS inhibitor. Hydrogen sulfide content in the brain tissues of infarcted patients or rats with MCAO was decreased, whereas glutamate (GLU) content was increased. In addition, SAM reduced reactive oxygen species content, lactate dehydrogenase release, and apoptosis levels in the brain tissues of rats with MCAO. The PC12 cells that were exposed to OGD were also treated with 20 mM GLU and later treated with SAM or AOAA. In PC12 cells, SAM reduced the apoptosis caused by GLU after OGD. The protective effects of hydrogen sulfide was elicited through the sulfur-sulfhydrylation modification of NMDAR and the induction of ERK/MAPK signaling. Our results showed that hydrogen sulfide exerts a protective effect on the PC12 cells and the rats with MCAO, which might represent a possible therapeutic agent against massive cerebral infarct.


Kinetics of retroviral production from the amphotropic ΨCRIP murine producer cell line.
Rapidly expanding development and practice of gene therapy requires the availability of large quantities of high titer retroviral supernatants. One way to achieve high retroviral titers is through improved understanding of the kinetics of retroviral production and decay, and the subsequent development of improved cell culture methods. In the present study we investigated the effects of different operational modes on the retroviral production of the NIH 3T3 fibroblast derived amphotropic murine retroviral producing cell line pMFG/ΨCRIP. Semi-continuous culture (exchange of 50% of medium volume daily) was found to promote cell growth and enhance retroviral production. The rapid medium exchange resulted in significantly larger amounts of high titer supernatants and an extended production phase as compared to the batch control cultures. The specific viral productivity of the pMFG/ΨCRIP cells was in the range of 10 to 40 infectious viruses produced per thousand producer cells per day. The CV-1 African Green Monkey kidney cell line was used as the infection target. Lowering the serum level form 20% to 10% improved retroviral production slightly. However, at lower serum levels (1%, 5% and 10% (v/v)) growth of the producer cell line, and thus retroviral production, was directly proportional to the serum level. The half-life of the virus at 37°C was found to be 5.5 hours. Promoting the growth of producer cell lines can improve retroviral vectors titers and viral production. High cell density systems that allow for rapid cell growth and waste product removal are likely to be used to generate high-titer retroviral supernatants.


Posterior subtenon injection of triamcinolone acetonide after phacoemulsification in a patient with X-linked retinoschisis.
To describe a case of X-linked retinoschisis with pseudophakic cystoid macular edema treated by posterior subtenon injection of triamcinolone acetonide. The patient was a 60-year-old man. His best-corrected visual acuity (BCVA) was counting fingers in the right eye. Senile cataract was found with grade II nuclear sclerosis. Optical coherence tomography revealed foveoschisis with a central foveal thickness (CFT) of 545 μm. The patient underwent uneventful phacoemulsification and in-the-bag implantation of intraocular lens. Postoperative persistent cystoid macular edema was found, with CFT increased to 787 μm. The macular edema did not respond to topical corticosteroids and nonsteroidal anti-inflammatory drugs. Triamcinolone acetonide 20 mg was injected into the posterior subtenon space 10 weeks after the surgery. Macular cystic lesions dramatically disappeared 2 months after the injection, and CFT decreased to 171 μm, with accompanying inner/outer segment disruption. His BCVA also improved to 20/100. Macular edema or foveoschisis did not recur, and BCVA remained stable 1 year after the cataract operation. Foveoschisis and pseudophakic cystoid macular edema disappeared after posterior subtenon injection of triamcinolone acetonide without recurrence during the 15-month follow-up period.


Sonoelectrochemical synthesis of spike-like gold-silver alloy nanoparticles from bulk substrates and the application on surface-enhanced Raman scattering.
The synthesis of non-spherical spike-like gold-silver alloy nanoparticles on platinum substrates was first developed by sonoelectrochemical methods in this study. First, a silver substrate was roughened by a triangular-wave oxidation-reduction cycle (ORC) in an aqueous solution containing 0.1 M HCl. Silver-containing complexes were found in the solution after the ORC treatment. Then a gold substrate was subsequently roughened by the similar ORC treatment in the same silver complexes-containing solution. After this procedure, Au- and Ag-containing complexes were left in the solution. Subsequently, the Au working electrode was immediately replaced by a Pt electrode. A cathodic overpotential was applied under controlled sonication and slight stirring to synthesize Au-Ag alloy nanoparticles on the Pt substrate. Encouragingly, the surface-enhanced Raman scattering (SERS) of Rhodamine 6G on the Au-Ag alloy nanoparticles-deposited Pt substrate exhibits a higher intensity by eight-fold of magnitude and a better resolution, as compared to that obtained on the Au nanoparticles-deposited Pt substrate.


Acanthamoeba castellanii: in vitro UAH-T17c3 trophozoite growth study in different culture media.
Acanthamoeba is one of the most common free-living amoebae. It is widespread in the environment and can infect humans, causing diseases such as keratitis and encephalitis. In this study, we used a strain of Acanthamoeba castellanii (UAH-T17c3) isolated from cooling towers, and we evaluated the efficiency of three different culture media in its growth, with the aim of selecting one which allowed better growth, was easier to prepare, and was able to keep the trophozoites by long periods of time. We compared the growth of A. castellanii in peptone-yeast extract-glucose (PYG, the most commonly used medium to grow this strain) to the growth in PYG-Bactocasitone (PYG with 2% Bactocasitone) and brain-heart infusion broth (BHI is a standard microbiological medium rarely used in the culture of amoebae). Flow cytometry and cell count results showed all three media allowed the growth of trophozoites. PYG-Bactocasitone was shown to be the best for long-term culture. The BHI and PYG-Bactocasitone media have not been used for Acanthamoeba spp. trophozoite growth. In view of the results, we can affirm that these media are adequate to grow the above-mentioned strain for in vitro screening assays.


Lip reduction cheiloplasty for Miescher's granulomatous macrocheilitis (Cheilitis granulomatosa) in childhood.
Miescher's granulomatous macrocheilitis (cheilitis granulomatosa) is a mono- symptomatic presentation of Melkersson-Rosenthal Syndrome which is characterized by granulomatous swelling of the lips, and can affect both children and adults. We report the successful outcome following lip reduction surgery on an 11-year-old boy. We suggest that surgery may have a role in the management of those patients who have failed to respond to medical treatment.


Correlation between GP-170 expression, prognosis, and chemoresistance of superficial bladder carcinoma.
To study GP-170 in superficial bladder cancer at initial diagnosis and at recurrence and to evaluate if intravesical chemoprophylaxis modifies the expression of GP-170 in tumor recurrences. GP-170 was retrospectively assessed in 160 patients affected by primary superficial transitional cell carcinoma of the bladder and followed for up to 10 years. Eighty-four patients (52.5%) recurred after transurethral resection (TUR). Adjuvant intravesical chemotherapy after TUR was adopted in 52 patients. The correlations between GP-170 and G-grade, T-category, risk of recurrence and of progression, and adoption of adjuvant intravesical chemotherapy were investigated. The correlations between variations in grade and stage at recurrence and modifications in GP-170 expression were also studied. No significant correlation between GP-170 expression and G-grade and T-category was found. A significant correlation was detected between GP-170 expression and recurrence ( P=0.0383). It showed a biphasic pattern, i.e., tumors that did not express GP-170 had a higher recurrence rate, but high GP-170 levels were also associated with an increasing risk of recurrence. Intravesical chemotherapy did not induce significative variations in GP-170 expression. No correlation was found between progression and GP-170. GP-170 seems to be an independent prognostic factor for recurrence in superficial bladder tumors. A negative GP-170 pattern and high levels of GP-170 are associated with an increasing risk of recurrence but have no impact upon progression. In our experience, GP-170 is neither induced nor modified by intravesical chemotherapy, although it might represent a factor of chemoresistance when strongly expressed.


Correlation between peripheral CA-125 levels and ovarian activity.
Serum CA-125 concentrations were measured at three different times in normal cycles, pill-suppressed cycles, and cycles stimulated for intrauterine insemination (IUI) or oocyte retrieval, i.e., (1) during the first half of the cycle, (2) at midcycle or at the moment of oocyte retrieval, and (3) the second half of the cycle. Significant variations of serum CA-125 concentrations were not seen during the cycle in normally cycling women or in women taking oral contraceptives: mean +/- SD 28.9 +/- 13.3 U/mL and 26.9 +/- 11.3 U/mL, respectively. In patients stimulated for in vitro fertilization, luteal phase CA-125 levels (60.6 +/- 38 U/mL) were significantly higher than during stimulation (21.5 +/- 5.9 U/mL) or at oocyte retrieval (19.6 +/- 6.4 U/mL). In stimulated cycles for IUI, without laparoscopy or follicular puncture, a comparable rise of CA-125 was observed in the luteal phase (49.6 +/- 37.8 U/mL). However, in patients undergoing laparoscopic sterilization, serum CA-125 concentrations before and after laparoscopy were not significantly different (22.8 +/- 6.3 U/mL and 25 +/- 4.2 U/mL, respectively).


InterCellDB: A User-Defined Database for Inferring Intercellular Networks.
Recent advances in single cell RNA sequencing (scRNA-seq) empower insights into cell-cell crosstalk within specific tissues. However, customizable data analysis tools that decipher intercellular communication from gene expression in association with biological functions are lacking. The authors have developed InterCellDB, a platform that allows a user-defined analysis of intercellular communication using scRNA-seq datasets in combination with protein annotation information, including cellular localization and functional classification, and protein interaction properties. The application of InterCellDB in tumor microenvironment research is exemplified using two independent scRNA-seq datasets from human and mouse and it is demonstrated that InterCellDB-inferred cell-cell interactions and ligand-receptor pairs are experimentally valid.


Application of integrated CRITIC and GRA-based Taguchi method for multiple quality characteristics optimization in laser-welded blanks.
There is a need to study the multi-objective optimization technique as the appropriate method to enhance welding qualities under optimal process conditions. Therefore, this study investigated the application of the integrated Criteria Importance Through Intercriteria Correlation (CRITIC), which is an objective weighting technique, and the Grey Relational Analysis (GRA)-based Taguchi method to solve multiple criteria optimization problem in the Nd:YAG laser welding process. The Taguchi-based L36 orthogonal array table was employed in this study to optimize six process parameters, including the beam diameter, laser power, flow rate, welding speed, laser offset, and pulse shape, with the aim to simultaneously achieve maximum weld strength and minimum weld width. The base metal JIS G3141 SPCC steel with 0.5 and 1.0 mm thicknesses was used in the present experiment. Following the welding process and optimization, the weld strength was measured using a Cometech QC-506M1 universal testing machine, while the weld width was determined under a Nikon SMZ25 stereomicroscope. Based on the results, the weight fractions of the weld strength and weld width from the applied CRITIC method were equal to 0.4157 and 0.5843, respectively. Meanwhile, the GRA revealed that the process parameters recorded an optimal setting for beam diameter of 0.8 mm, flow rate of 8 L/min, laser power of 0.6 kW, welding speed of 2.5 mm/s, laser offset of 0.2 mm, and pulse shape I. Furthermore, the weld strength and the weld width were enhanced from 236 to 328 MPa and from 1.13 to 1.04 mm, respectively. Additionally, the Analysis of Variance (ANOVA) indicated that the laser power and welding speed were the most influential parameters on the welding qualities. Most importantly, the findings of the confirmation experiment showed that the proposed approach was able to effectively identify the optimal laser welding parameters, which ultimately improved the multiple quality characteristics.


Validity and ease of use of a computerized Hess chart.
To investigate agreement between computerized and conventional methods for obtaining Hess charts and to compare relative ease of use of both methods. Hess charts of 65 patients were obtained by the use of the computerized Assaf Ocular Motility Analyzer (OMA) and the conventional Lees screen method. The Hess charts produced by each method were compared with a previously described scoring system. Patients compared the ease of testing by using a 5-point Likert scale. For horizontal deviations of the right eye, the OMA provided a significantly larger (P = 0.0001) deviation (301° ± 267°) than the Lees screen (204° ± 306°). The Lees screen gave a significantly larger score for vertical deviations of the left eye (117° ± 158° vs 96° ± 129°; P = 0.003). Vertical deviations of the right eye and horizontal deviations of the left eye did not differ significantly between tests. Patients required the same amount of time to complete both tests, but the OMA was slightly easier to perform than the Lees screen (Likert score, 1.2 ± 0.5 vs 1.3 ± 0.4; P = 0.046). The scores measured were larger with OMA in the horizontal and smaller in the vertical direction than with the Lees screen in some directions. Although the OMA did not save time, patients found it easier to perform than the Lees screen. The OMA may be considered a useful alternative to the Lees screen.


Dermal Allograft Augmentation for Rotator Cuff Tears.
Large and massive rotator cuff tears continue to be challenging for shoulder surgeons. Given the high percentage of retears after repair of these tears, several surgical technical advancements have been proposed. The use of grafts (xenograft, synthetic, and allograft) as an augmentation of the repair has been growing over the last several years in an attempt to improve structural integrity and postoperative outcomes. Patch augmentation with dermal allografts is the most commonly used, showing promising biomechanical, structural, and functional outcomes. Several factors have been associated with healing outcomes, including age, tear size, and fatty degeneration. The rotator cuff healing index can be used to assess for patients with Hamada grades 1 and 2 with elevated retear risk and potential indications for repair with graft augmentation. A score of 7 points represents a reasonable threshold for the addition of a dermal allograft due to a significant reduction in healing rates when comparing patients with a score of 6 points (66%) to 7 points (only 38%) without augmentation of the repair. Biomechanical studies have demonstrated a greater maximum failure load compared with standard repair. The healing rates of rotator cuff repairs using scaffolds range between 60% and 85%, compared with 40% with nonaugmented repairs. Moreover, the use of repair augmentation has been associated with improved range of motion and functional scores compared with nonaugmented repairs, with allografts showing the best visual analog scale pain score and postoperative external rotation results. Given these favorable healing rates, functional outcomes, and low complication rates, augmenting rotator cuff repairs with a dermal allograft may be a suitable option in active patients with a diminished chance of postoperative healing.


Assessment of non-tuberculosis abnormalities on digital chest x-rays with high CAD4TB scores from a tuberculosis prevalence survey in Zambia and South Africa.
Chest X-rays (CXRs) have traditionally been used to aid the diagnosis of TB-suggestive abnormalities. Using Computer-Aided Detection (CAD) algorithms, TB risk is quantified to assist with diagnostics. However, CXRs capture all other structural abnormalities. Identification of non-TB abnormalities in individuals with CXRs that have high CAD scores but don't have bacteriologically confirmed TB is unknown. This presents a missed opportunity of extending novel CAD systems' potential to simultaneously provide information on other non-TB abnormalities alongside TB. This study aimed to characterize and estimate the prevalence of non-TB abnormalities on digital CXRs with high CAD4TB scores from a TB prevalence survey in Zambia and South Africa. This was a cross-sectional analysis of clinical data of participants from the TREATS TB prevalence survey conducted in 21 communities in Zambia and South Africa. The study included individuals aged ≥ 15 years who had high CAD4TB scores (score ≥ 70), but had no bacteriologically confirmed TB in any of the samples submitted, were not on TB treatment, and had no history of TB. Two consultant radiologists reviewed the images for non-TB abnormalities. Of the 525 CXRs reviewed, 46.7% (245/525) images were reported to have non-TB abnormalities. About 11.43% (28/245) images had multiple non-TB abnormalities, while 88.67% (217/245) had a single non-TB abnormality. The readers had a fair inter-rater agreement (r = 0.40). Based on anatomical location, non-TB abnormalities in the lung parenchyma (19%) were the most prevalent, followed by Pleura (15.4%), then heart & great vessels (6.1%) abnormalities. Pleural effusion/thickening/calcification (8.8%) and cardiomegaly (5%) were the most prevalent non-TB abnormalities. Prevalence of (2.7%) for pneumonia not typical of pulmonary TB and (2.1%) mass/nodules (benign/ malignant) were also reported. A wide range of non-TB abnormalities can be identified on digital CXRs among individuals with high CAD4TB scores but don't have bacteriologically confirmed TB. Adaptation of AI systems like CAD4TB as a tool to simultaneously identify other causes of abnormal CXRs alongside TB can be interesting and useful in non-faculty-based screening programs to better link cases to appropriate care.


Guidelines to Home Exercises and Lifestyle Modifications for Common Small Animal Orthopedic Conditions.
Patients with osteoarthritis and other orthopedic conditions may benefit from a home exercise program, as well as lifestyle modifications based on their condition. Home exercises can be performed to improve a pet's range of motion, weight-bearing, strength, and overall mobility. A home exercise program should be designed to improve the patient's impairments, and progression of exercises should occur depending on the patient's response and ability to master each exercise. Modifications to the pet's home environment should be considered so the pet can maneuver around the house and perform its daily tasks.


Esthetic orthodontic appliances for the adult.
There is no malocclusion in the adult that cannot be treated as well with esthetic appliances as with the conventional metal brackets. In a study about adult orthodontic patients. Breece and Nieberg found that most people wait until they are adults to start treatment because no one recommended it previously. It is essential that the dental practitioner understand the positive psychological impact of esthetic appliances upon the attitude of the adult and recommend that the adult needing orthodontic treatment enjoy the benefits of these technologic advances in esthetics and comfort.


RGD-IL-24, a novel tumor-targeted fusion cytokine: expression, purification and functional evaluation.
Targeting drugs to tumor cells is a central challenge for improving existing cancer therapies. ACDCRGDCFCG peptide (RGD-4C) binds to alphavbeta3 integrin, which is selectively expressed in tumor blood vessels and on the surface of some tumor cells. Interleukin 24 (IL-24) is a novel cancer growth-suppressing and apoptosis-inducing cytokine. To enhance the antitumor effect, we coupled RGD-4C to the N-terminus of IL-24 and expressed RGD-IL-24 in Escherichia coli. Cell proliferation and adhesion experiments revealed that RGD-IL-24 specifically binds to MCF-7 cancer cells, and induces apoptosis of MCF-7 cancer cells. These studies support the use of the RGD-IL-24 protein in tumor-targeting therapy.


Lung growth in rats subsequent to administration of intraperitoneal elastase during the first 4 weeks of life.
Male rats received intraperitoneal injections of porcine pancreatic elastase twice weekly during the first 4 weeks of life. Saline-injected male rats served as controls. After a 4-week recovery period, the rats were sacrificed, and the excised lungs were studied using saline- and air-filled volume-pressure curves, morphology, and biochemistry. Both air- and saline-filled volume-pressure curves showed loss of elastic recoil in the elastase-treated animals. In elastase-treated animals the mean linear intercept was increased, the numbers of alveoli per unit area, per unit volume, and per lung decreased, and alveolar surface area decreased. These animals also showed a disproportionate increase of alveolar duct air at the expense of the proportion of alveolar air. Morphometric differences between the elastase-treated animals and the controls were somewhat smaller in this experiment than in a previous one in which the animals were sacrificed immediately after 4 weeks of intraperitoneal elastase. We attribute this difference to alveolar multiplication between 4 and 8 weeks of age. However, evidence is presented that these alveoli were abnormal. Loss of recoil properties was more evident after the 4-week recovery period than at the termination of elastase administration, suggesting that the newly formed alveoli were functionally abnormal. Collagen content was increased in the elastase group, but elastin was significantly decreased. This may be a good elastase model for assessing the hypothesis that lungs minimally damaged in infancy may have an increased susceptibility to environmental damage in later life.


[Reuse of angiography catheters. Results and discussion of the present state of knowledge].
The re-use of angiographic catheters after cleansing and sterilization with ethylene oxide has received increasing attention, primarily because of cost considerations. However, there are various risks in this common practice, mainly because the principles of maintenance are neglected. Experimental findings on cleansing, sterilization, and mechanical safety are discussed, leading to the conclusion that re-use of disposable catheters is possible only under certain circumstances.


The C-terminal regions of the envelope glycoprotein gp2 of equine herpesviruses 1 and 4 are antigenically distinct.
The unusual mucin-like high molecular mass (Mr) glycoprotein 2 (gp2) has only been described in the equid alphaherpesviruses, among which there is considerable antigenic cross-reactivity. Equine herpesvirus 1 (EHV-1) gp2 is cleaved into a highly glycosylated N-terminal subunit and a 42 kDa C-terminal cleavage product. In order to investigate their antigenic recognition by horses naturally infected with EHV-1 and/or equine herpesvirus 4 (EHV-4), the C-terminal cleavage product and high Mr gp2 were affinity purified. Cross-reactivity between EHV-1 and EHV-4 was observed for the high Mr gp2 using Western blotting. In contrast only horses with antibodies to EHV-1 detected the 42 kDa EHV-1 gp2 C-terminal cleavage product. This phenomenon was evident in pooled sera from adult horses and also in foals that had demonstrated seroconversion due to EHV-1 infection. The results indicate that the C-terminal region of EHV-1 gp2 is antigenically distinct from that of EHV-4 gp2 and can be detected only after an EHV-1-specific immune response.


Updates and advances on pharmacological properties of Taraxacum mongolicum Hand.-Mazz and its potential applications.
As a well-recognized dietary and medicinal plant, Taraxacum mongolicum Hand.-Mazz (TMHM) has been used for making wines, candies, energy drinks, and other functional foods. The TMHM contains a diverse range of active phytoconstituents, including flavonoids, triterpenoids, phenolic acids, sesquiterpene lactones, pigments, coumarins and sterols. Recent pharmacological evidence has revealed multiple biological effects of TMHM, including anti-inflammatory, antioxidant, antibacterial, and gastric-protective effects, which contribute to the ameliorative effects of TMHM on inflammation-associated diseases, constipation, gastric disorders, empyrosis, hyperlipidemia, and swollen carbuncles. Although recent advances have highlighted the potential of TMHM to be applied in the clinical practice, food, and nutraceutical industry, the mechanistic understanding and systematic information on TMHM are still scarce. Here, in this timeline review, we have attempted to compile literary documents on pharmacological potential of TMHM concerning its chemical composition, biological activities, toxicity, and pharmacokinetics to promote further researches on clinical and therapeutic potential of TMHM and its food/nutraceutical applications.


Massive thymic hyperplasia in an adolescent.
Massive thymic hyperplasia (weight, greater than 100 gm) is a rare lesion in adolescents, and most of the anterior mediastinal masses are true neoplasms. We present a case of massive thymic hyperplasia, in which a 680-gm thymus was resected from a 15-year-old boy. We also present the computed tomographic scan appearance of this lesion, which differed from that previously described, and correlate the histological and radiological findings.


In vivo differential diagnosis of prostate cancer and benign prostatic hyperplasia: localized proton magnetic resonance spectroscopy using external-body surface coil.
Localized proton-stimulated echo acquisition mode (STEAM) spectroscopy was performed in seven patients with benign prostatic hyperplasia (BPH), six patients with prostate cancer, and seven healthy volunteers to determine whether citrate levels detected using a saddle-type external-body surface coil (two loops of 13 cm x 17 cm) could reliably discriminate BPH from prostatic cancer. Relative area ratios of citrate level to choline plus creatine or citrate to lipid signal were compared with postoperative pathologic histology findings. The metabolic signals were well detectable as much as the line width of water resonance was ranging from 5 to 9 hz. Average SNRs of citrate in BPH and prostate cancer were 11.4 and 1.9, respectively. The major finding was consistently lower citrate levels in prostate cancer compared with BPH and normal prostate central gland. This was significantly (p < 0.01) reflected by lower mean citrate/[creatine+choline] peak area ratio and citrate/lipid peak area ratio observed for region of cancer (0.446 +/- 0.063, 0.097 +/- 0.030) compared with BPH (1.458 +/- 0.107, 0.786 +/- 0.162) and normal central gland (1.418 +/- 0.129, 0.175 +/- 0.011), respectively. These studies demonstrate the potential of citrate spectrum detected by an external-body surface coil as an in vivo marker for discriminating prostate cancer from BPH.


Postoperative Complications After Thyroidectomy: Time Course and Incidence Before Discharge.
Although complication rates after thyroidectomy are well described in the literature, the timing of these events is less understood. This study delineates the timeline and risk factors for early adverse events after thyroidectomy. This study included a retrospective review of 161,534 patients who underwent thyroidectomy between 2005 and 2018 using the American College of Surgeons National Surgical Quality Improvement Program database. Time to specific complications was analyzed for all patients undergoing thyroidectomy, with further stratification of hemithyroidectomy and total thyroidectomy cohorts. Univariate analyses were conducted to analyze demographics, preoperative comorbidities, and complications. A multivariate logistic regression model was generated to identify significant risk factors for 7-day postoperative complications. The overall complication rate was 3.28%. A majority of complications arose before discharge including the following: blood transfusion (96%), hematoma formation (68%), pneumonia (53%), and cardiac arrest (67%). Approximately 37% of unplanned reoperations occurred before discharge in the hemithyroidectomy versus 63% in the total thyroidectomy cohort. Greater than 65% of mortalities occurred after discharge in both groups. Complications generally occurring within 7 d for the entire cohort included the following: pneumonia (3; 2-8 [median postoperative day; interquartile range]), pulmonary embolism (6; 2-12), cardiac arrest (1; 0-5), myocardial infarction (2; 1-6), blood transfusions (0; 0-1), and hematoma formation (0; 0-2). Superficial surgical site infection (9; 6-16) occurred later. Patients who underwent outpatient surgery had a decreased risk of complications (odds ratio 0.41) in the 7-day postoperative period. Although early complications after thyroidectomy are rare, they have a distinct time course, many of which occur after discharge. However, in selected patients undergoing outpatient thyroidectomy, overall risk of complications is decreased. Understanding timing helps establish better preoperative communication and education to improve postoperative expectations for the provider and patient.


An essential role for Gα(i2) in Smoothened-stimulated epithelial cell proliferation in the mammary gland.
Hedgehog (Hh) signaling is critical for organogenesis, tissue homeostasis, and stem cell maintenance. The gene encoding Smoothened (SMO), the primary effector of Hh signaling, is expressed aberrantly in human breast cancer, as well as in other cancers. In mice that express a constitutively active form of SMO that does not require Hh stimulation in mammary glands, the cells near the transgenic cells proliferate and participate in hyperplasia formation. Although SMO is a seven-transmembrane receptor like G protein-coupled receptors (GPCRs), SMO-mediated activation of the Gli family of transcription factors is not known to involve G proteins. However, data from Drosophila and mammalian cell lines indicate that SMO functions as a GPCR that couples to heterotrimeric G proteins of the pertussis toxin (PTX)-sensitive Gαi class. Using genetically modified mice, we demonstrated that SMO signaling through G proteins occurred in the mammary gland in vivo. SMO-induced stimulation of proliferation was PTX-sensitive and required Gαi2, but not Gαi1, Gαi3, or activation of Gli1 or Gli2. Our findings show that activated SMO functions as a GPCR to stimulate proliferation in vivo, a finding that may have clinical importance because most SMO-targeted agents have been selected based largely on their ability to block Gli-mediated transcription.


[Acute stroke imaging before IV thrombolysis: what modality of imaging for France in 2007?].
To report the results of a radiological survey of the management of acute stroke prior to intravenous thrombolysis. A questionnaire on imaging as used in the management of stroke was sent to 80 stroke units across France at the beginning of 2007 and included the first imaging modality used (CT or MRI), the imaging protocol before treatment and the exclusion criteria followed for thrombolysis. CT was most often used as the first modality for the management of acute stroke (by 70% of the 53 responding centers) and 26 centers (49%) used both CT and MRI. Only 12 centers (22%) routinely performed MRI to screen for acute stroke. However, more than half the patients who had received thrombolysis in 2006 had been examined using MRI. In fact, after three-hour poststroke, intravenous thrombolysis was predominantly decided upon from MRI data. The survey showed that imaging criteria are well standardized for CT, whereas they are more variable for MRI. Furthermore, the majority (28 of 38) of the centers considered that thrombolysis could be applied despite a clinical contraindication (such as unknown time of onset or convulsions) if MRI categorically diagnosed an acute stroke. This survey showed that CT-based screening of acute stroke before thrombolysis remains the standard modality in France, with a consensus on decision-making criteria. The survey also revealed a change in imaging management, with a growing role for MRI as the first examination.


Nectar guides and floral nectary in Lamium album L. subsp. album: structure and histochemistry in light, fluorescence, and electron microscopy.
Lamium album is a native common plant growing in Eurasia. It is used in medicine and cosmetics and is highly valued in apiculture. The aim of the study was to investigate the structure of the floral nectary in three stages of flower development. Additionally, histochemical studies of the nectary and nectar guides present on the lower corolla lobe were carried out. No detailed analyses of nectary tissues in this species have been conducted to date. The present analyses were performed with the use of light, fluorescence, and scanning electron microscopy. The nectary gland in the flowers of Lamium album subsp. album formed an incomplete ring at the ovary base. The nectarostomata were arranged in clusters only in the adaxial epidermis of the anterior part of the nectary. During the secretory activity of the nectary (1st day of flowering), numerous small vacuoles and cells with large lobulate nuclei with surrounding plastid clusters were observed in the epidermis and glandular parenchyma cells. The vascular bundles contained xylem and phloem elements. Corolla wilting (3rd day of flowering) was accompanied by destructive changes in the nectary parenchyma, leading to the formation of empty spaces and appearance of cell remnants on the nectary surface. The histochemical analyses revealed the presence of starch and phenolic compounds as well as acidic and neutral lipids, which are characteristic of essential oils, in the nectary tissues. The nectar guides were composed of large yellow papillae containing phenolic compounds and acidic and neutral lipids, which were also present in glandular trichomes and abaxial parenchyma cells. The present study has demonstrated that the scent of Lamium album subsp. album flowers is produced with the involvement of essential oils contained in adaxial and abaxial epidermis cells, glandular trichomes, and nectary tissues.


New insights into the regulation and functions of Tec family tyrosine kinases in the immune system.
The Tec family of protein tyrosine kinases play an important role in signaling through antigen-receptors such as the TCR, BCR and Fcepsilon receptor. Recent studies have generated new insights into the domains in Tec kinases that take part in intramolecular and intermolecular binding. Furthermore, the consequences of these domain interactions for Tec activation and downregulation have been better defined. Genetic studies of kinase-knockout mice have emphasized the importance of Tec kinases in lymphocyte development, differentiation and apoptosis.


Reversal of midazolam sedation with flumazenil following conservative dentistry.
The purpose of this double-blind randomized study was to assess recovery of mental function following reversal of midazolam-induced sedation with the specific antagonist flumazenil (R015-1788) or placebo following conservative dental procedures. Recovery was assessed using choice reaction time and critical flicker fusion threshold, both objective tests of psychomotor function; linear analogue sedation scores and simple memory tests. Assessments were repeated up to 3 h after administration of flumazenil or placebo to discover whether recovery was sustained or whether resedation occurred due to the short duration of action of flumazenil. Flumazenil in doses from 0.5 to 1.0 mg rapidly reversed the sedative and amnesic effects of a mean dose of 8.2 mg of midazolam without apparent evidence of subsequent resedation. Since recovery of mental function in the control group had ordinarily occurred 45 min after administration of placebo, routine reversal of midazolam sedation with flumazenil cannot be justified. Nevertheless, in cases of undue sedation persisting after dental treatment, flumazenil may be used with minimal risk of resedation occurring.


Staining Toxoplasma gondii with fluorescein-labelled antibody. I. The reaction in smears of peritoneal exudate.
Antitoxoplasma globulin was labelled with fluorescein and was used to stain Toxoplasma gondii organisms in smears of peritoneal exudate. The evidence indicates that this staining was due to an antigen-antibody reaction at the cellular level. Methods are presented for handling the organisms so that they can be stained over a period of several months. Some general characteristics of the antigen system involved are described.


[Hemoglobin, hematocrit, lactates and glucose in blood of fattening pigs in the course of slaughering and snout loop fixation].
Blood was sampled from fattening pigs fixed with the snout loop in the pen as well as during slaughter after control or container transport. Assays were made of haemoglobin (Hb), haematocrit (Hk), glucose concentration (PG), and lactic acid (MS) in the plasma. The mean values and standard deviations of Hb and Hk were 13.97 +/- 1.14 g/100 ml, 48.36 +/- 3.67 per cent, 15.24 +/- 1.12 g/100 ml, 49.83 +/- 4.04 per cent, 15.32 +/- 1.23 g of 100 ml, and 51.08 +/- 3.73 per cent. The means values of PG were between 51 and 101 mg of 100 ml and those of MS between 8 and 16 mMol/l.


Sub-lethal viral exposure and growth on drought stressed host plants changes resource allocation patterns and life history costs in the Speckled Wood butterfly, Pararge aegeria.
This study investigated the interactive effects of growth on drought stressed host plants and pathogen challenge with the baculovirus Autographa californica nucleopolyhedrovirus (AcMNPV) on survival and fitness-related traits using the Speckled Wood butterfly, Pararge aegeria (L.). Exposure to AcMNPV significantly reduced survival to pupation. For surviving larvae, sub-lethal infection significantly decreased daily mass acquisition rates and pupal mass. Growth on drought stressed plants increased daily mass acquisition rates resulting in heavier pupae, and increased resource allocation to adult reproduction. The interaction between host plant drought and viral exposure resulted in different resource allocation strategies, and thus different growth trajectories, between larvae. This in turn resulted in significantly different allometric relationships between larval mass (at inoculation) and both development time and investment in flight muscles. For larvae with relatively lighter masses there was a cost of resisting infection when growth occurred on drought stressed host plants, both within the larval stage (i.e. longer larval development times) and in the adult stage (i.e. lower investment in flight muscle mass). This multi-factor study highlights several potential mechanisms by which the complex interplay between low host plant nutritional quality due to drought, and pathogen exposure, may differentially influence the performance of P. aegeria individuals across multiple life stages.


Controversies of fetal cardiac intervention.
Remarkable advances in ultrasound imaging technology have made it possible to diagnose fetal cardiovascular lesions as early as 12-14 weeks of gestation and to assess their physiological relevance by echocardiography. Moreover, invasive techniques have been developed and refined to relieve significant congenital heart disease (CHD), such as critical aortic and pulmonary stenoses in the pediatric population including neonates. Recognition of the fact that certain CHDs can evolve in utero, and early intervention may improve the outcome by altering the natural history of such conditions has led to the evolution of a new fetal therapy, i.e. fetal cardiac intervention. Two entities, pulmonary valvar atresia and intact ventricular septum (PA/IVS) and hypoplastic left heart syndrome (HLHS), are associated with significant morbidity and mortality even with postnatal surgical therapy. These cases are believed to occur due to restricted blood flow, leading to impaired growth and function of the right or left ventricle. Therefore, several centers started the approach of antenatal intervention with the primary goal of improving the blood flow through the stenotic/atretic valve orifices to allow growth of cardiac structures. Even though centers with a reasonable number of cases seem to have improved the technique and the immediate outcome of fetal interventions, the field is challenged by ethical issues as the intervention puts both the mother and the fetus at risk. Moreover, the perceived benefits of prenatal treatment have to be weighed against steadily improving postnatal surgical and hybrid procedures, which have been shown to reduce morbidity and mortality for these complex heart defects. This review is an attempt to provide a balanced opinion and an update on fetal cardiac intervention.


Monitoring of residues of ochratoxin A in blood and kidney of chicken using HPLC-FLD.
Detoxification of ochratoxin A can be achieved by chemical or enzymatic hydrolyzation, the products of such reactions are ochratoxin α and phenylalanine. Ochratoxin α like ochratoxin A, is a fluorescing molecule, therefore sensitive analysis is possible at very low concentration levels. Methods have been established that make it possible to look for residues of ochratoxin A and its main metabolite ochratoxin α in blood and tissues at very low concentration levels. Plasma is extracted by the use of small amounts of chloroform; the extract is cleaned with water and afterwards evaporated to dryness]. The residue is re-dissolved and analysed by HPLC-FLD. Using this method a limit of detection of 0.5μg/l for both ochratoxin A and ochratoxin α can be reached.


A morphometric analysis of the superior cervical ganglion and its surrounding structures.
The aim of this cadaveric study was to detect the superior cervical ganglion (SCG) in a topographic manner according to vertebrae and to determine the relationship between the vertebrae, mandibular angle and longus colli muscle through morphometric analysis. The present study was performed on 40 SCG of 20 human cadavers (16 males, 4 females). The level of the SCG was determined based on the vertebrae. Ganglion length, width and thickness were detected. Distance to the adjacent vertebra, the mandibular angle and medial side of the longus colli muscle were measured. The results were evaluated statistically. The SCG existing in all cadavers was detected at the C2 vertebra level in 34 cadavers and at the C3 vertebra level in 6 cadavers. The average length, width and thickness of the SCG were 15.18 ± 1.12, 4.62 ± 0.25, and 1.83 ± 0.10 mm, respectively. No statistically significant difference was detected in terms of the distances between the ganglion and anterior tubercle of transverse processes of the vertebrae as well as the mandibular angle on either side. The distance between the SCG and the medial edge of the longus colli muscle was significantly greater on the left side in both men (p < 0.001) and women (p < 0.01). Recognition of morphometric characteristics of the SCG and detection of its location according to adjacent formations may serve as a guide for nerve blockage studies and help surgeons to preserve the ganglion in both anterior and anterolateral cervical approaches.


Current status and future prospects of protein vaccine candidates against Schistosoma mansoni infection.
Schistosomiasis is an acute and chronic tropical parasitic disease caused by blood dwelling worm of the genus Schistosoma. It is the most destructive disease globally and is a major cause of morbidity and mortality for developing countries. Three main species of schistosomes infect human beings from which S. mansoni is the most common and widespread. Over the last several decades, chemotherapy using praziquantel has been a commonly used strategy for the treatment and control of schistosomiasis. However, control programs focused exclusively on chemotherapy have been challenging because of the frequency and rapidity of reinfection and these programs were expensive. Thus, new schistosomiasis control strategies will be needed. Vaccination strategy would be an ideal tool for a significant and sustainable reduction in the transmission and disease burden of schistosomiasis. An effective anti schistosome vaccine would greatly contribute to decreasing schistosomiasis-associated morbidity via protective immune responses leading to reduced worm burdens and decreased egg production. Vaccine development is a long process that can take decades. There have been three candidate vaccines that have been produced by Good Manufacturing Procedure and entered human clinical trials for S. mansoni are Sm14, SmTSP-2, and Sm-p80. Other candidates that are in pre-clinical trials at various stages include paramyosin, Sm29, SmKI-1, and Sm23. Since the growth of several new technologies, including genomics, transcriptomics, microarrays, immunomic profiling, and proteomics, have helped in the identification of promising new target schistosome antigens. Therefore, this review considers the present status of protein vaccine candidates against Schistosoma mansoni and provides some insight on prospects vaccine design and discovery.


Increased neural motor activation and functional reorganization in patients with idiopathic rapid eye movement sleep behavior disorder.
Altered brain activity and functional reorganization patterns during self-initiated movements have been reported in early pre-motor and motor stages of Parkinson's disease. The aim of this study was to investigate whether similar alterations can be observed in patients with idiopathic REM-sleep behavior disorder (RBD). 13 polysomnography-confirmed male and right-handed RBD patients and 13 healthy controls underwent a bilateral hand-movement fMRI task including internally selected (INT) and externally-guided (EXT) movement conditions for each hand. We examined functional activity and connectivity differences between groups and task-conditions, structural differences using voxel-based morphometry, as well as associations between functional activity and clinical variables. No group differences were observed in fMRI-task performance or in voxel-based morphometry. Both groups showed faster reaction times and exhibited greater neural activation when movements were internally selected compared to externally-guided tasks. Compared to controls, RBD patients displayed stronger activation in the dorsolateral prefrontal cortex and primary somatosensory cortex during INT-tasks, and in the right fronto-insular cortex during EXT-tasks performed with the non-dominant hand. Stronger activation in RBD patients was associated with cognitive and olfactory impairment. Connectivity analysis demonstrated overall less interregional coupling in patients compared to controls. In particular, patients showed reduced temporo-cerebellar, occipito-cerebellar and intra-cerebellar connectivity, but stronger connectivity in fronto-cerebellar and fronto-occipital pathways. The observed stronger activation during hand-movement tasks and connectivity changes in RBD may reflect early compensatory and reorganization patterns in order to preserve motor functioning. Our findings may contribute to a better understanding and prognosis of prodromal stages of α-synucleinopathies.


Long-Term Opioid Use and Dementia Risk in Patients With Chronic Pain.
This study aimed to investigate the association between long-term opioid use and the risk of dementia in patients with chronic pain. A head-to-head propensity score-matched (PSM) comparative cohort study was conducted to examine the effect of long-term opioid use on dementia risk. A time-varying Cox regression analysis was performed to calculate adjusted hazard ratios (aHRs) with 95% CIs to identify independent predictors of dementia risk. The study included 41,636 patients after PSM, with 20,968 in the opioid use group (≥180 defined daily doses per year) and 20,968 in the non-opioid use group. Multivariate Cox regression analysis was conducted to compare the dementia risk between the opioid use and non-opioid use groups. The incidence of dementia was calculated as the number of cases per 10,000 person-years for each group. Adjusted incidence ratios were determined to assess the dementia risk associated with opioid use. The multivariate Cox regression analysis showed that the aHR for dementia risk in the opioid use group, compared with the non-opioid use group, was 1.86 (95% CI 1.25-2.09; P < .001). The incidence of dementia was higher among opioid users (44.09 per 10,000 person-years) compared with nonusers (38.85 per 10,000 person-years). The adjusted incidence ratio for dementia risk in the opioid use group, compared with the nonuse group, was 1.13 (95% CI: 1.07-1.21, P < .001). Long-term opioid use may be associated with an increased risk of dementia in patients with chronic pain. These findings highlight the need for cautious prescribing and monitoring of opioid use in this population, considering the potential long-term cognitive implications.


Focused Library Generator: case of Mdmx inhibitors.
We present a Focused Library Generator that is able to create from scratch new molecules with desired properties. After training the Generator on the ChEMBL database, transfer learning was used to switch the generator to producing new Mdmx inhibitors that are a promising class of anticancer drugs. Lilly medicinal chemistry filters, molecular docking, and a QSAR IC50 model were used to refine the output of the Generator. Pharmacophore screening and molecular dynamics (MD) simulations were then used to further select putative ligands. Finally, we identified five promising hits with equivalent or even better predicted binding free energies and IC50 values than known Mdmx inhibitors. The source code of the project is available on https://github.com/bigchem/online-chem.


Lesional cerebellar epilepsy: a review of the evidence.
Classical teaching in epileptology localizes the origins of focal seizures solely in the cerebral cortex, with only inhibitory effects attributed to subcortical structures. However, electrophysiological and neuroimaging studies over the last decades now provide evidence for an initiation of epileptic seizures within subcortical structures. Intrinsic epileptogenicity of hypothalamic hamartoma has already been established in recognition of subcortical epilepsy, whereas a seizure-generating impact of dysplastic cerebellar lesions remains to be clarified. Herein, we examine the supportive evidence and clinical presentation of cerebellar seizures and review therapy options.


Radiosurgery for vestibular schwannomas.
Radiosurgery has been established as an important alternative to microsurgery. We report our experience with radiosurgery for tumor control and the complications of unilateral vestibular schwannomas. We reviewed our early experience regarding clinical presentation, management and outcomes in 45 patients with acoustic schwannomas who underwent gamma knife stereotactic radiosurgery. The median follow-up period was 25 months (range, 6-48 months). Thirteen patients had undergone 1 or more previous resections before radiosurgery; 32 underwent radiosurgery as the first procedure. Median tumor volume was 4.5 mL (range, 0.5-30.0), and median radiotherapy dose was 11.5 Gy (range, 10.5-14.0 Gy). Tumor control was achieved in 43 patients (95.6%). Loss of central contrast enhancement was a characteristic change and was noted in 29 patients (64.4%). Reduction in tumor size was shown in 15 patients (33.3%). Thirteen patients (28.9%) had good or serviceable hearing preoperatively, and in all of these, the preoperative status was retained immediately after radiosurgery. At follow-up, however, 10 patients (76.9%) had preserved hearing and 3 (23.1%) had reduced hearing on the treated side. Hearing in 1 patient that was not serviceable preoperatively later improved to a serviceable level. No patients had delayed facial palsy or lower cranial nerve dysfunction, but one had delayed trigeminal sensory loss. Radiosurgery achieved a high tumor control rate and a relatively low post-radiosurgical complication rate for acoustic neuromas.


Rhytidectomy.
The understanding of cervicofacial anatomy, and of the physiologic and anatomic changes that occur with the aging process, has vastly increased over the past three to four decades. This knowledge has led to more logical approaches to face-lift surgery. Vastly different than most other surgical domains, cervicofacial rhytidectomy is a cosmetic procedure. Face-lift surgery is driven not just by the ultimate result, but also by patient-driven economic factors of cost and recovery time. General resistance by patients to what they perceive as more invasive procedures often also plays a significant role in planning procedures.


Ways and means of coping with uncertainties of the relationship of the genetic blue print to protein structure and function in the cell.
As one of the disciplines of systems biology, proteomics is central to enabling the elucidation of protein function within the cell; furthermore, the question of how to deduce protein structure and function from the genetic readout has gained new significance. This problem is of particular relevance for proteins engaged in cell signalling. In dealing with this question, I shall critically comment on the reliability and predictability of transmission and translation of the genetic blue print into the phenotype, the protein. Based on this information, I will then evaluate the intentions and goals of today's proteomics and gene-networking and appraise their chances of success. Some of the themes commented on in this publication are explored in greater detail with particular emphasis on the historical roots of concepts and techniques in my forthcoming book, published in German: Von Molekülen zu Zellen. 100 Jahre experimentelle Biologie. Betrachtungen eines Biochemikers.


Mysteries of HIV: challenges for therapy and prevention.
A number of problems still surround infection by the human immunodeficiency virus and the pathogenesis of AIDS. Solutions to the problems would provide valuable information for the development of antiviral therapy and a vaccine.


Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.
In striated muscle, X-ROS is the mechanotransduction pathway by which mechanical stress transduced by the microtubule network elicits reactive oxygen species. X-ROS tunes Ca(2+) signalling in healthy muscle, but in diseases such as Duchenne muscular dystrophy (DMD), microtubule alterations drive elevated X-ROS, disrupting Ca(2+) homeostasis and impairing function. Here we show that detyrosination, a post-translational modification of α-tubulin, influences X-ROS signalling, contraction speed and cytoskeletal mechanics. In the mdx mouse model of DMD, the pharmacological reduction of detyrosination in vitro ablates aberrant X-ROS and Ca(2+) signalling, and in vivo it protects against hallmarks of DMD, including workload-induced arrhythmias and contraction-induced injury in skeletal muscle. We conclude that detyrosinated microtubules increase cytoskeletal stiffness and mechanotransduction in striated muscle and that targeting this post-translational modification may have broad therapeutic potential in muscular dystrophies.


Dynamical criticality of spin-shear coupling in van der Waals antiferromagnets.
The interplay between a multitude of electronic, spin, and lattice degrees of freedom underlies the complex phase diagrams of quantum materials. Layer stacking in van der Waals (vdW) heterostructures is responsible for exotic electronic and magnetic properties, which inspires stacking control of two-dimensional magnetism. Beyond the interplay between stacking order and interlayer magnetism, we discover a spin-shear coupling mechanism in which a subtle shear of the atomic layers can have a profound effect on the intralayer magnetic order in a family of vdW antiferromagnets. Using time-resolved X-ray diffraction and optical linear dichroism measurements, interlayer shear is identified as the primary structural degree of freedom that couples with magnetic order. The recovery times of both shear and magnetic order upon optical excitation diverge at the magnetic ordering temperature with the same critical exponent. The time-dependent Ginzburg-Landau theory shows that this concurrent critical slowing down arises from a linear coupling of the interlayer shear to the magnetic order, which is dictated by the broken mirror symmetry intrinsic to the monoclinic stacking. Our results highlight the importance of interlayer shear in ultrafast control of magnetic order via spin-mechanical coupling.


Basement membrane changes in atrophic tubules in the human kidney.
Changes in the basement membrane (BM) in atrophic tubules in human kidney biopsies were studied by electron microscopy and by immunohistochemistry on cryostat sections with antibodies against collagen type I, type III, type IV, laminin, EMA, keratin and vimentin. The BM showed different degrees of thickening with formation of reduplications which contained fibrocytes. Remnants of cytoplasm of epithelial cells and fibrocytes were incorporated in the thickened BM. This showed signs of lysis and disintegration, indicating that the redundant BM formed by the epithelial cells is removed, although imperfectly, by interstitial cells. Thinning of the BM was another frequent finding. Immunohistochemistry showed a clear reactivity for collagen type IV and laminin in all BM material. The epithelial cells showed multilayering and a peculiar type of dark cells extending underneath adjacent cells and separating them from their BM attachment.


Health consequences of improving the content of ergothioneine in the food supply.
Ergothioneine (ERGO) is a potent antioxidant and anti-inflammatory amino acid that is highly bioavailable to humans from the diet. ERGO is now regarded by some as a 'longevity vitamin' that has the potential to mitigate some chronic diseases of ageing and thereby increase life expectancy when present in adequate amounts. However, only limited knowledge exists regarding ERGO content in the human diet. Since ERGO is produced primarily by fungi, mushrooms are known to be the leading dietary source, but ERGO is found in relatively low amounts throughout the food chain as a result of soil-borne fungi or bacteria passing it on to plants through their roots. Some conventional agricultural practices that negatively impact soil fungi, such as excessive soil disturbance (ploughing), can significantly reduce ERGO content of food crops when compared to regenerative practices such as eliminating tillage of the soil (no-till). This has led us to the concept that ERGO may be a definitive connection between soil health and human health.


The effect of L-deprenyl on behavior, cognitive function, and biogenic amines in the dog.
Behavioral and pharmacological effects of oral administration of L-deprenyl in the dog are described. Spontaneous behavior is unaffected at doses below 3 mg/kg while at higher doses there was stereotypical responding. There was evidence of improved cognitive function in animals chronically treated with a 1 mg/kg dose but the effectiveness varied considerably between subjects. Chronic administration produced a dose dependent inhibition in brain, kidney and liver monoamine oxidase B, and had no effect on monoamine oxidase A. There were also dose dependent increases in brain phenylethylamine and in plasma levels of amphetamine. Dog platelets did not have significant levels of MAO-B. Brain dopamine and serotonin metabolism were unaffected by L-deprenyl at doses up to 1 mg/kg. It appears that for the dog, deamination of catecholamines is controlled by MAO-A. Nevertheless, it is suggested that L-deprenyl serves as a dopaminergic agonist, and there is also evidence that it affects adrenergic transmission. These catecholaminergic actions may account for the effects of L-deprenyl on behavior and cognitive function.


Application of blood brain barrier models in pre-clinical assessment of glioblastoma-targeting CAR-T based immunotherapies.
Human blood brain barrier (BBB) models derived from induced pluripotent stem cells (iPSCs) have become an important tool for the discovery and preclinical evaluation of central nervous system (CNS) targeting cell and gene-based therapies. Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary form of gene-modified cell-based immunotherapy with potential for targeting solid tumors, such as glioblastomas. Crossing the BBB is an important step in the systemic application of CAR-T therapy for the treatment of glioblastomas and other CNS malignancies. In addition, even CAR-T therapies targeting non-CNS antigens, such as the well-known CD19-CAR-T therapies, are known to trigger CNS side-effects including brain swelling due to BBB disruption. In this study, we used iPSC-derived brain endothelial-like cell (iBEC) transwell co-culture model to assess BBB extravasation of CAR-T based immunotherapies targeting U87MG human glioblastoma (GBM) cells overexpressing the tumor-specific mutated protein EGFRvIII (U87vIII). Two types of anti-EGFRvIII targeting CAR-T cells, with varying tonic signaling profiles (CAR-F263 and CAR-F269), and control Mock T cells were applied on the luminal side of BBB model in vitro. CAR-F263 and CAR-F269 T cells triggered a decrease in transendothelial electrical resistance (TEER) and an increase in BBB permeability. CAR-T cell extravasation and U87vIII cytotoxicity were assessed from the abluminal compartment using flow cytometry and Incucyte real-time viability imaging, respectively. A significant decrease in U87vIII cell viability was observed over 48 h, with the most robust cytotoxicity response observed for the constitutively activated CAR-F263. CAR-F269 T cells showed a similar cytotoxic profile but were approximately four fold less efficient at killing the U87vIII cells compared to CAR-F263, despite similar transmigration rates. Visualization of CAR-T cell extravasation across the BBB was further confirmed using BBTB-on-CHIP models. The described BBB assay was able to discriminate the cytotoxic efficacies of different EGFRvIII-CARs and provide a measure of potential alterations to BBB integrity. Collectively, we illustrate how BBB models in vitro can be a valuable tool in deciphering the mechanisms of CAR-T-induced BBB disruption, accompanying toxicity and effector function on post-barrier target cells.


Hypervalent iodine-mediated β-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution.
β-Difluoroalkylborons, featuring functionally important CF2 moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.


Phosphorus nuclear magnetic resonance studies on the calcium-dependent energy metabolism of rat cerebrum under conditions of increased potassium in vitro.
Using phosphorus nuclear magnetic resonance (31P NMR) we studied the biochemical changes that accompany high-K+ depolarization in cerebral tissue in vitro. Rat brain slices (wet weight 4-6 g) were placed in a glass NMR sample tube which was superfused with well-oxygenated Krebs solution at 25 degrees C. The broad signal seen in the spectrum of brain slices almost disappeared after phospholipids were extracted by using chloroform and methanol. Phospholipids in the extracts were identified as phosphatidylcholine and phosphatidylethanolamine. In high-K+ Krebs solution tissue phosphocreatine (PCr) was decreased while inorganic phosphate (Pi) was increased, and in normal solution PCr and Pi recovered to control levels within about 20 min. The extent of changes in PCr and Pi depended on the concentrations of K+. Ouabain or tetrodotoxin did not influence these changes significantly. In calcium-free solution, where Ca2+ was replaced by Mg2+, the changes caused by high K+ were decreased to 40% of that in normal high-K+ solution. When ouabain was further added to the calcium-free solution, the changes were decreased to 10%. This suggested that the increased metabolism in high K+ was caused mainly by calcium-dependent mechanisms and partly by the Na(+)-K+ pump.


Concomitant mitral regurgitation in patients with low-gradient aortic stenosis: an analysis from the German Aortic Valve Registry.
Patients with severe aortic stenosis (AS) frequently presented mitral regurgitation (MR), which may interfere with the standard echocardiographic measurements of mean pressure gradient (MPG), flow velocity, and aortic valve area (AVA). Herein we investigated the prevalence and severity of MR in patients with severe AS and its role on the accuracy of the standard echocardiographic parameters of AS quantification. Of all patients with severe AS undergoing transcatheter or surgical aortic valve replacement enrolled in the German Aortic Registry from 2011 to 2017, 119,641 were included in this study. The population was divided based on the values of left ventricular ejection fraction ([LVEF] > 50%, LVEF 31-50%, and LVEF ≤ 30%] and AVA (0.80 to ≤ 1.00 cm2, 0.60 to < 0.80 cm2, 0.40 to < 0.60 cm2, and 0.20 to < 0.40 cm2). Overall, 77,890 (65%) patients with mild to-moderate and 4262 (4%) with severe MR were compared with 37,489 (31%) patients without MR. Patients with mild-to-moderate and severe MR presented significantly lower mPG (ΔmPG [95%CI] - 1.694 mmHg [- 2.123 to - 1.265], p < 0.0001 and - 6.954 mmHg [- 7.725 to - 6.183], p < 0.0001, respectively), that increased with LVEF impairment. Conversely, AVA did not differ (severe versus no MR: ΔAVA [95%CI]: - 0.007cm2 [- 0.023 to 0.009], p = 0.973). Increasing MR severity was associated with significant mPG reduction throughout all AVA strata, causing a low-gradient pattern, that manifested since the early stages of severe AS (LVEF > 50%: AVA 0.80 to 1.00 cm2; LVEF 31-50%: AVA 0.60 to 0.80 cm2). In patients with severe AS, concomitant MR is common, contributes to the onset of a low-gradient AS pattern, and affects the diagnostic accuracy of flow-dependent AVA measurements. In this setting, a multimodality, AVA-centric approach should be implemented. In patients with severe aortic stenosis, concomitant mitral regurgitation contributes to the onset of a low-gradient pattern, warranting a multimodality, and AVA-centric diagnostic approach.


Cervical spine geometry correlated to cervical degenerative disease in a symptomatic group.
To investigate whether a statistical correlation exists between lateral cervical geometry and cervical pathology, as identified on neutral anteroposterior (AP) and lateral radiographs within a symptomatic group; describe the cervical pathology and determine its location and frequency; and identify the subject's age, sex, and chief complaint. Department of radiology at a chiropractic college. One hundred eighty-six consecutive pairs of AP and lateral cervical radiographs were reviewed for pathology. A 5-category severity scale was used to describe degenerative joint disease, the most common pathological finding. The subject's age, sex, and symptoms were recorded. Geometric analysis was focused on vertebral position, alignment, and gravitational loading acquired from the neutral lateral cervical radiograph. Regression and discriminant analysis identified 5 geometric variables that correctly classified pathology subjects from nonpathology subjects 79% of the time. Those variables were: (1) forward flexion angle of the lower cervical curve; (2) gravitational loading on the C5 superior vertebral end plate; (3) horizontal angle of C2 measured from its inferior vertebral end plate; (4) disk angle of C3; and (5) posterior disk height of C5. Degenerative joint disease was the most common pathological finding identified within discrete age, sex, and symptom groups. We identified 5 geometric variables from the lateral cervical spine that were predictive 79% of the time for cervical degenerative joint disease. There were discrete age, sex, and symptom groups, which demonstrated an increased incidence of degenerative joint disease.


Preliminary X-ray crystallographic study of lysozyme produced by Streptomyces globisporus.
Lysozyme from Streptomyces globisporus has been crystallized in a form suitable for X-ray structure analysis using ammonium sulfate as a precipitant. The crystals are hexagonal, space group P6(1)22 (P6(5)22) with unit cell dimensions: a = b = 129 A, c = 143 A. There are three or four molecules per asymmetric unit. The crystals diffract X-rays to at least 3.0 A resolution.


Clinical profile and associated factors of pulmonary involvement in primary Sjögren's syndrome.
The aim of this study is to identify the clinical characteristics of primary Sjögren's syndrome (PSS) patients with pulmonary involvement and the associated factors for pulmonary involvement in PSS. We retrospectively reviewed clinical features, laboratory examinations, imaging tests, pathological results and therapeutic strategy of 367 PSS patients. Comparisons were made between two subgroups: PSS with pulmonary involvement and those without. Correlation between the pathology of minor salivary gland biopsy (MSGB) and diverse features with pulmonary involvement were detected by Pearson correlation analysis and associated factors were selected by multivariate logistic regression analysis. The lung involved PSS patients had significantly higher level of inflammatory associated indexes (p<0.05). There is no significant correlation between pathology of MSGB and lung involvements. Age, elevated neutrophils level and hypoproteinemia are significantly associated with lung disease with in PSS cohort (p<0.05). As for therapeutic strategy, moderate dose prednisone (15-40mg/d) and cyclophosphamide (CTX) are mainly different between two subgroups. PSS patients with pulmonary involvements show enhanced inflammation. Age, elevated neutrophils level and hypoproteinemia are independent associated with pulmonary involvements in PSS patients. For those PSS with pulmonary involvement moderate dose of prednisone and CTX were still the mainstream.


Romanian psychiatric residents' opinions on factors that influence their decision to emigrate: A 5-year follow-up study.
To evaluate the situation of migration of psychiatrists from Romania and a prioritization exercise of main factors related with psychiatric residents' decision to emigrate could be a starting point of elaboration of a strategy of reforms. Important changes have been done in economic status of residents in 2018. The impact of these measures in changing opinions was checked. This is a cross sectional evaluation study on a randomized selected sample of Romanian psychiatric residents' opinions on factors that influence decision of migration in EU countries in two time points, 2015 and 2020. Thirty-eight percent of residents intend to work abroad comparing with 78% before the economic changes (25.8% vs. 71.7% for a limited period of time and 15.7% vs. 28.3% intend to emigrate) and 2% vs. 5% intend to leave the specialty. The important factors for decision to emigrate changed from "Better working conditions" (15.7% vs. 37.3% residents) to "Better training"; the factor "respect and appreciation by colleagues" remained important for 19.1% versus 17.9%. "Lack of working place for partner" was considered by 26.7% of responders as an important disadvantage of working abroad. "Being far from family members", which was considered 5 years ago by 64.2% of responders as an important disadvantage of working abroad, nowadays concerns only 6.7%, probably because it seems easier to go abroad together with the family members. The factors (better training in psychiatry and psychotherapy, better supervision, more involvement in research) that influence the residents' decision to emigrate represent the starting points for future reforms in educational and medical system in psychiatry.


Lateral double magnetic tunnel junction device with orthogonal polarizer for high-performance magnetoresistive memory.
Magnetic tunnel junction (MTJ)-based memory devices have larger switching delay and energy consumption, compared to cache or dynamic random access memory. In order to broaden the applications of the magnetoresistive random access memory, reducing the switching time and energy consumption of the MTJ is required. Here, a novel lateral double MTJ with an orthogonal polarizer is proposed. The proposed device consists of three ferromagnetic regions: the first pinned region (PR1) with perpendicular magnetic anisotropy (PMA), a free region (FR) with PMA, and the second pinned region (PR2) with in-plane magnetic anisotropy (IMA). PR1 and PR2 are placed on top of the oxide barrier, which separates them from the FR, comprising a lateral double MTJ structure. The current pulse through PR2 helps to perturb the magnetization of the FR. Since the angle between PR2 and FR is 90°, the initial torque increases significantly, decreasing switching delay by 4.02 times and energy-delay product by 7.23 times. It is also shown, that the area of the access transistor can be reduced by approximately 10%, while maintaining the same energy-delay product and reducing gate RC delay.


Long non‑coding RNA HCP5 promotes prostate cancer cell proliferation by acting as the sponge of miR‑4656 to modulate CEMIP expression.
Aberrant expression of long noncoding RNAs (lncRNAs) has been demonstrated in human cancers and regulates the malignant behavior of cancer cells. Previous studies demonstrated the critical involvement of lncRNA histocompatibility leukocyte antigen (HLA) complex P5 (HCP5) in the development of cancers, however, the function of HCP5 in prostate cancer has not been reported. In the present study, we found the overexpressed expression of HCP5 in prostate cancer tissues and cell lines via RT‑qPCR analysis. High expression of HCP5 was positively correlated with the metastasis of prostate cancer. Downregulation of HCP5 inhibited the proliferation, colony formation and induced apoptosis of prostate cancer cells. Functional experiments demonstrated that HCP5 acted as a competing endogenous RNA (ceRNA) to sponge miR‑4656. Ectopic expression of HCP5 decreased the expression of miR‑4656 in prostate cancer cells. MiR‑4656 was found to be decreased in prostate cancer tissues and was negatively correlated with the expression of HCP5. Further luciferase reporter assay revealed that miR‑4656 was able to bind the 3'‑untranslated region (3'‑UTR) of the cell migration inducing hyaluronidase 1 (CEMIP) and suppressed the expression of CEMIP. Consistent with the negative regulation of miR‑4656 by HCP5, western blot analysis uncovered that overexpression of HCP5 upregulated the abundance of CEMIP in prostate cancer cells. The CCK‑8 assay showed that depletion of CEMIP significantly inhibited the HCP5‑promoted proliferation of prostate cancer cells. Collectively, our data provide a novel mechanism by which HCP5 regulates the progression of prostate cancer.


Development of workplace-based assessments of non-technical skills in anaesthesia.
Non-technical skills are recognised as crucial to good anaesthetic practice. We designed and evaluated a specialty-specific tool to assess non-technical aspects of trainee performance in theatre, based on a system previously found reliable in a recruitment setting. We compared inter-rater agreement (multir-ater kappa) for live assessments in theatre with that in a selection centre and a video-based rater training exercise. Twenty-seven trainees participated in the first in-theatre assessment round and 40 in the second. Round- 1 scores had poor inter-rater agreement (mean kappa = 0.20) and low reliability (generalisability coefficient G = 0.50). A subsequent assessor training exercise showed good inter-rater agreement, (mean kappa = 0.79) but did not improve performance of the assessment tool when used in round 2 (mean kappa = 0.14, G = 0.42). Inter-rater agreement in two selection centres (mean kappa = 0.61 and 0.69) exceeded that found in theatre. Assessment tools that perform reliably in controlled settings may not do so in the workplace.


m7G regulator-mediated methylation modification patterns define immune cell infiltration and patient survival.
Numerous studies have demonstrated the important roles of epigenetic modifications in tumorigenesis, progression and prognosis. However, in hepatocellular carcinoma, the potential link between N7-methylguanosine (m7G) modification and molecular heterogeneity and tumor microenvironment (TME) remains unclear. We performed a comprehensive evaluation of m7G modification patterns in 816 hepatocellular carcinoma samples based on 24 m7G regulatory factors, identified different m7G modification patterns, and made a systematic correlation of these modification patterns with the infiltration characteristics of immunocytes. Then, we built and validated a scoring tool called m7G score. In this study, we revealed the presence of three distinct m7G modification patterns in liver cancer, with remarkable differences in the immunocyte infiltration characteristics of these three subtypes. The m7G scoring system of this study could assess m7G modification patterns in individual hepatocellular carcinoma patients, could predict TME infiltration characteristics, genetic variants and patient prognosis. We also found that the m7G scoring system may be useful in guiding patients' clinical use of medications. This study revealed that m7G methylation modifications exerted a significant role in formation of TME in hepatocellular carcinoma. Assessing the m7G modification patterns of single patients would help enhance our perception of TME infiltration characteristics and give significant insights into immunotherapy efficacy.


Toxicity of Fusarium metabolites to brine shrimps (Artemia salina).
Extracts of the followingFusaria cultures, isolated from cereals were examined for toxicity to Artemia salina:F. avenaceum (6 isolates),F. crookwellense (7),F. graminearum (11),F. nivale (5) andF. Sporotrichioides (2). The same cultures, growing on wheat grain, were assayed also mycotoxins presence using TLC method. Most toxic were found cultures ofF. Sporotrichioides and results of bioassay was similar to results of their TLC analysis. We found cultures of newly described speciesF. Crookwellense to be more toxic than cultures ofF. Graminearum.


Intra-marrow penetrations and root coverage outcomes: a systematic review.
Intra-marrow penetrations (IMPs) have been performed during guided tissue regeneration (GTR) procedures with reported clinical benefits. The aim of this systematic review was to investigate the use and effect of IMPs during root coverage procedures. A broad search for human and animal studies was performed on PubMed, Cochrane Database of Systematic Reviews and Cochrane Central Registry of Controlled Trials and Web of Science, following a registered review protocol (PROSPERO). All prospective study designs, case series and case reports on gingival recession treatment (follow-up ≥ 6 months) that employed IMPs were included. Root coverage, complete root coverage prevalence, and adverse effects were recorded, and risk of bias was assessed. Of 16,181 screened titles, 5 articles (all of them human studies) met inclusion criteria. All studies (including two randomized clinical trials) treated Miller class I and II recession defects, using coronally advanced flap with IMPs alone or in conjunction with GTR protocols. Therefore, all treated defects received IMPs and no studies compared protocols with and without IMPs. Outcomes were indirectly compared with existing root coverage literature. Mean root coverage was 2.7 mm and 68.5% at 6.8 months (median: 6 months, range 6-15 months) for sites treated with IMPs. IMPs are rarely used during root coverage procedures, have not been associated with intra-surgical or wound healing adverse effects and have not been investigated as independent factor. Future clinical studies are needed to directly compare treatment protocols with and without IMPs and investigate the potential benefits of IMPs for root coverage.


Engineering protein thermal stability. Sequence statistics point to residue substitutions in alpha-helices.
Amino acid sequences have been compared for thermophilic and mesophilic molecules from six different protein families, which include lactate and glyceraldehyde-3-phosphate dehydrogenases, triose phosphate isomerases, superoxide dismutases, thermolysins and subtilisins. Since a three-dimensional structure was known for at least one of the sequences in each family, analysis of preferred residue substitutions, presumably to achieve thermal stability, could be examined from a structural context. The overall results, which are generally consistent across all the families, suggested decreased flexibility and increased hydrophobicity in alpha-helical regions as the main stabilizing principles. The most favoured residual exchanges, hopefully useful in engineering stability into proteins, are discussed.