Amyotrophic lateral sclerosis: quantitative autoradiography of [3H]MK-801/NMDA binding sites in spinal cord.
We have characterized a high-affinity binding site for [3H]MK-801, an NMDA receptor ion channel antagonist, in cervical spinal cords from patients who have died with amyotrophic lateral sclerosis (ALS) and from control subjects. In cervical spinal cord [3H]MK-801 labelled at least two binding sites, the highest affinity site having a Kd of between 9-16 nM. No significant differences in affinity were observed between spinal cords from ALS patients or controls. In spinal cords from ALS patients, large reductions in [3H]MK-801 receptor binding (between 30-40% reductions) were detected in both the dorsal and ventral horns. These data may reflect the death of receptor-bearing cells, or a form of receptor regulation.


Two cases of nivolumab plus ipilimumab therapy for dialysis patients with advanced bone metastasis from renal cell carcinoma.
Nivolumab and ipilimumab are immune checkpoint inhibitors. Combination therapy with these two drugs has been shown to improve the outcome of advanced renal cell carcinoma. However, data about the safety and the efficacy of combination therapy with these two drugs in hemodialysis patients are small. A 59-year-old male hemodialysis patient presented with bone metastasis from renal cell carcinoma, which was located at the right femur. He received nivolumab plus ipilimumab therapy. At 7 months after treatment, he was diagnosed with diabetes as an immune-related adverse event. He was managed with insulin therapy. At 11 months after treatment, CT revealed cytoreduction of metastasis. A 74-year-old male hemodialysis patient presented with bone metastasis of renal cell carcinoma located at the sacrum and left scapula. He received nivolumab plus ipilimumab therapy. At 6 months after treatment, CT showed no progression of metastasis. Nivolumab and ipilimumab therapy might be a viable treatment for hemodialysis patients with bone metastasis from renal cell carcinoma. However, close attention should be paid immune-related adverse events in such patients.


Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. We undertook the present work to perform the first genome-wide association study on individuals from the Americas who are enriched for Native American heritage. We analyzed 3,710 individuals from the US and 4 countries of Latin America who were diagnosed as having SLE, and healthy controls. Samples were genotyped with HumanOmni1 BeadChip. Data on out-of-study controls genotyped with HumanOmni2.5 were also included. Statistical analyses were performed using SNPtest and SNPGWA. Data were adjusted for genomic control and false discovery rate. Imputation was performed using Impute2 and, for classic HLA alleles, HiBag. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. The IRF5-TNPO3 region showed the strongest association and largest OR for SLE (rs10488631: genomic control-adjusted P [Pgcadj ] = 2.61 × 10(-29), OR 2.12 [95% CI 1.88-2.39]), followed by HLA class II on the DQA2-DQB1 loci (rs9275572: Pgcadj = 1.11 × 10(-16), OR 1.62 [95% CI 1.46-1.80] and rs9271366: Pgcadj = 6.46 × 10(-12), OR 2.06 [95% CI 1.71-2.50]). Other known SLE loci found to be associated in this population were ITGAM, STAT4, TNIP1, NCF2, and IRAK1. We identified a novel locus on 10q24.33 (rs4917385: Pgcadj = 1.39 × 10(-8)) with an expression quantitative trait locus (eQTL) effect (Peqtl = 8.0 × 10(-37) at USMG5/miR1307), and several new suggestive loci. SLE risk loci previously identified in Europeans and Asians were corroborated. Local ancestry estimation showed that the HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection against development of SLE. Our results demonstrate that studying admixed populations provides new insights in the delineation of the genetic architecture that underlies autoimmune and complex diseases.


CAR-T Cells and the Kidney: Insights from the WHO Safety Database.
Chimeric antigen receptor T (CAR-T) cells have proven to be a game changer for treating several hematologic malignancies. Randomized controlled trials have highlighted potential life-threatening adverse drug reactions (ADRs), including cytokine release syndrome (CRS). Acute renal failure (ARF) has also been reported in 20% of the patients treated. However, an analysis of renal safety supported by large-scale real-life data seems warranted. We queried VigiBase® for all reports of the Standardised MedDRA Query "acute renal failure" (ARF) involving a CAR-T cell, registered until 24 July 2022. Disproportionality for this ADR was analyzed through calculation of the Information Component [IC (95% confidence interval)]. A positive lower end of the 95% confidence interval of the IC is the threshold used in statistical signal detection in VigiBase®. The same analysis was carried out for various hydroelectrolytic disorders. We gathered 224 reports of ARF, and 125 reports of hydroelectrolytic disorders involving CAR-T cells. CAR-T cells were disproportionately reported with ARF [IC 1.5 (1.3-1.7)], even after excluding reports mentioning CRS. A significant disproportionate reporting was also found for hypernatremia [IC 3.1 (2.2-3.8)], hyperphosphatemia [IC 3.1 (1.8-3.9)], hypophosphatemia [IC 2.0 (0.6-2.9)], metabolic acidosis [IC 1.8 (1.2-2.2)], hyponatremia [IC 1.6 (1.1-2.0)], and hypercalcemia [IC 1.4 (0.5-2.1)]. There was no disproportionate reporting of dyskalemia. This study is limited by the inherent flaws of pharmacovigilance approaches. Nonetheless, our findings suggest that ARF and an array of hydroelectrolytic disorders are potential ADRs of CAR-T cell therapy, in real-life settings and in a nonselected population.


circWHSC1: A circular RNA piece in the human cancer puzzle.
Circular RNAs (circRNAs) are a group of non-coding RNAs with a closed loop shape, which are transcribed via non-canonical splicing. They are mainly formed by reverse splicing of a precursor mRNA. circWHSC1 (Hsa_circ_0001387), is a cancer-related circRNA that originated from the Wolf-Hirschhorn syndrome candidate 1 (WHSC1) gene on chromosome 4. circWHSC1 has been found to be overexpressed in different neoplastic conditions. circWHSC1 acts as a sponge for many different miRNAs, including miR-195-5p, miR-532-3p, miR-646, miR-142-3p, miR-7, miR-296-3p, miR-145, miR-1182, miR-212-5p, etc. It can also moderate several signaling pathways, including FASN/AMPK/mTOR, LTBP2, NPM1, HOXA1, TAB2, AKT3, hTERT, and MUC1. Studies have shown that circWHSC1 may leads to an increase in cell growth, tumor size, cell migration, invasion, and metastasis, but a reduction in apoptosis rates. Moreover, upregulation of CircWHSC1 has been associated with reduced patient's survival in different cancers, representing the function of this circRNA as a novel prognostic marker. Nevertheless, there are no reviews focusing on the relationship between circWHSC1 and cancers. Therefore, in the current review, we will first describe the oncogenic effect of circWHSC1 in various tissues according to the evidence from in vitro, in vivo, and human studies.


Rescue effects of intravenous immunoglobulin on optic nerve degeneration in a rat model of neuromyelitis optica.
Neuromyelitis optica (NMO) is an autoimmune inflammatory disease that predominantly attacks the optic nerve and spinal cord. This study evaluated the effect of administration of human IgG (hIgG) into the caudal vein on optic nerve degeneration in a rodent model of NMO. The optic nerves were exposed to AQP4-Ab-positive sera, and the administration of intravenous immunoglobulin (IVIG) was performed immediately, at 7 days (cohort A) or at 7 days and 10 days (cohort B) after exposure to the sera. A reference group, similarly exposed to the serum, was treated with saline. Retinal ganglion cells (RGCs) labeled by the injection of Fluoro-Gold into the superior colliculus were counted in whole-mounted retina. RGCs labeled by the injection of Fluoro-Gold into the superior colliculus were counted in the whole-mounted retina. The number of RGCs 14 days after optic nerve exposure to sera from patients with NMO was 1455 ± 192/mm(2) (n = 7) in cohort A, 1657 ± 192/mm(2) (n = 4) in cohort B, and 981 ± 182/mm(2) (n = 10) in the saline-treated reference group (p < 0.001). Western blotting revealed that the content of neurofilament in the optic nerve of the hIgG-treated group in cohort A was significantly greater than that in the reference group (p = 0.037). IVIG administration reduced optic nerve degeneration in a rat model of NMO-optic neuritis. IVIG could be used as a treatment in the acute phase of NMO.


Response to a commentary on "Food insecurity transitions and smoking behavior among older adults who smoke".
Thank you for the opportunity to respond to the commentary by Kim-Mozeleski and colleagues on "Food insecurity transitions and smoking behavior among older adults who smoke". This study examined the influence of food insecurity transitions on smoking cessation and daily cigarette consumption in 2014 within a sample of older U.S. adults from the Health and Retirement Study (HRS) who indicated that they smoked in 2012. In particular, Kim-Mozeleski and colleagues highlight that findings of Bergmans (2019) contrast with results of a previous publication by Kim-Mozeleski and colleagues. In sum, it is not readily apparent why findings contradict those of Kim-Mozeleski et al. (2018). Moderation or confounding due to macroeconomic factors that influence health and behavior is a possibility. Bergmans (2019) examined associations over a recent 2-year period of U.S. economic growth. In contrast, data from Kim-Mozeleski et al. (2018) spanned 12 years and overlapped the Great Recession. A detailed response to the commentary is provided.


Changes of Plasma Fatty Acids in Four Lipid Classes to Understand Energy Metabolism at Different Levels of Non-Esterified Fatty Acid (NEFA) in Dairy Cows.
The transition period is a central moment in dairy cows breeding because metabolic disorders may occur in relation to a dramatic increase in energy demand. This research aimed to identify new biomarkers for the diagnosis of hyperketonemia in bovine in early lactation phase with different value of plasmatic non-esterified fatty acid (NEFA). The profile of plasma fatty acids (FAs) divided into four lipid classes was evaluated using thin layer chromatography and gas chromatographic techniques (TLC-GC). A group of 60 multiparous Holstein-Friesian dairy cows were recruited in the present study. Blood samples were collected from the coccygeal vein and NEFA and the β-hydroxybutyrate (BHB) were evaluated. All animals were divided in 2 groups based on NEFA, NEFA0 group had as mean value 0.24 ± 0.12 mEq/L and NEFA1 group had as mean value 0.87 ± 0.23 mEq/L. Plasma FA concentrations were analyzed separately in free fatty acids, cholesterol esters, phospholipids and triglycerides. Six FAs demonstrated a predictive value in the hyperketonemic dairy cows. In the free fatty acid class, the predictive FAs were C14:0 (AUC = 0.77), C18:1 ω 9 (AUC = 0.72), C18:1 ω 7 (AUC = 0.70) and C18:3 ω 3 (AUC = 0.68). In the phospholipids class the predictive parameters were C12:0 (AUC = 0.78) and C8:0 (AUC = 0.73). In cholesterol, esters and triglycerides lipidic classes no FA had a predictive function.


Investigation into the impact of tyrosine on the product formation and quality attributes of mAbs in rCHO cell cultures.
Tyrosine (Tyr) is crucial to the maintenance of the monoclonal antibody (mAb) titers and quality attributes in fed-batch cultures of recombinant Chinese hamster ovary (rCHO) cells. However, the relation between tyrosine and these aspects is not yet fully defined. In order to further elucidate such a relation, two groups of fed-batch experiments with high tyrosine (H-T) or low tyrosine (L-T) additions producing an IgG1 monoclonal antibody against CD20 were implemented to investigate the intracellular and extracellular effects of tyrosine on the culture performance. It was found that the scarcity of tyrosine led to the distinctive reduction in both viable cell density and antibody specific production rate, hence the sharply reduced titer, possibly related to the impaired translation efficiency caused by the substrate limitation of tyrosine. In addition, alterations to the critical quality attributes were detected in the L-T group, compared to those in the H-T condition. Notable decrease in the contents of intact antibody was found under the L-T condition because of the elevated reductive level in the supernatant. Moreover, the aggregate content in the L-T condition was also reduced, probably resulting from the accumulation of extracellular cystine. In particular, the lysine variant content noticeably increased with tyrosine limitation owing to the downregulation of two carboxypeptidases, i.e., CpB and CpH. Overall, understanding the role of tyrosine in these aspects is fundamental to the increase of product titers and control of critical quality attributes in the monoclonal antibody production of rCHO cell fed-batch cultures. KEY POINTS: • Tyrosine is essential in the maintenance of product titers and the control of product qualities in high cell density cultivations in rCHO cell. • This study revealed the bottleneck of decreased qmAbupon the deficiency of tyrosine. • The impact of tyrosine on the critical product qualities and the underlying mechanisms were also thoroughly assessed.


Tumour-infiltrating lymphocytes and melanoma tumorigenesis: an insight.
The presence of tumour-infiltrating lymphocytes (TILs) amid the tumour cells in the stroma and overlying epidermis is a constant feature of melanoma, the deadliest skin cancer. These lymphocytes are mostly cytotoxic T cells (CTLs) that can be propagated in vitro by specific cytokines. Also, they can kill melanoma cells. This specific killing can be abrogated by monoclonal antibodies against CD3, CD8, T-cell receptors (TCRs) and against class I human leucocyte antigens (HLAs). This indicates that these CTLs can recognize the melanoma cells through the TCRs, in an HLA class I-restricted manner. Therefore, these cells and their products both are critical players in T cell-induced melanoma regression and are powerful predictors of survival. This review seeks to examine the characteristics, activation and role of TILs and their associated molecules in melanomas.


Biochemical and histological impact of Vernonia amygdalina supplemented diet in obese rats.
This study was carried out to evaluate the anti-obesity effect of Vernonia amygdalina Del. (VA) supplemented diet. VA leaf powder was fed at 5% and 15% to diet-induced obese rats for 4 weeks and its effect compared with orlistat (5.14 mg/kg p.o.), an anti-obesity drug. Food intake, body and organ weights, total body fat, some lipid components and amino transaminase activities in serum, hepatocytes and brain; as well as serum glucose, were measured during or at end of the study. Result showed respective decrease of 12.78% and 38.51% in body weight gain, of VA fed rats against 17.45% of orlistat at end of study (P < 0.05); but with no effect on food intake. Total body fat was lowered by 28.04% and 30.02% vs. obese control rats (CDC) (P < 0.05). Furthermore, serum triacylglycerol (TG), serum and brain total cholesterol (TCHOL), were down regulated at 15% VA supplementation (P < 0.05). Serum glucose which increased in obese rats by 46.26% (P < 0.05) vs. NC, indicating intolerance, was restored by VA (38.75% and 34.65%) and orlistat (31.80%) vs. CDC (P < 0.05). VA diet also exerted hepato-protection, via lowering serum alanine amino transaminase (ALT) (41.35% and 27.13%) and aspartate amino transaminase (AST) (17.09% and 43.21%) activities (P < 0.05). Orlistat had no effect on these enzymes. Histology of adipose tissue corroborated the changes on total body fat. We concluded that, diet supplemented with VA can attenuate dietary obesity as well as ameliorates the potential risks of hepato-toxicity and glucose intolerance associated with obesity.


Assignment of the somatic A/B compartments to chromatin domains in giant transcriptionally active lampbrush chromosomes.
The three-dimensional configuration of the eukaryotic genome is an emerging area of research. Chromosome conformation capture outlined genome segregation into large scale A and B compartments corresponding mainly to transcriptionally active and repressive chromatin. It remains unknown how the compartmentalization of the genome changes in growing oocytes of animals with hypertranscriptional type of oogenesis. Such oocytes are characterized by highly elongated chromosomes, called lampbrush chromosomes, which acquire a typical chromomere-loop appearance, representing one of the classical model systems for exploring the structural and functional organization of chromatin domains. Here, we compared the distribution of A/B compartments in chicken somatic cells with chromatin domains in lampbrush chromosomes. We found that in lampbrush chromosomes, the extended chromatin domains, restricted by compartment boundaries in somatic cells, disintegrate into individual chromomeres. Next, we performed FISH-mapping of the genomic loci, which belong to A or B chromatin compartments as well as to A/B compartment transition regions in embryonic fibroblasts on isolated lampbrush chromosomes. We found, that in chicken lampbrush chromosomes, clusters of dense compact chromomeres bearing short lateral loops and enriched with repressive epigenetic modifications generally correspond to constitutive B compartments in somatic cells. A compartments align with lampbrush chromosome segments with smaller, less compact chromomeres, longer lateral loops, and a higher transcriptional status. Clusters of small loose chromomeres with relatively long lateral loops show no obvious correspondence with either A or B compartment identity. Some genes belonging to facultative B (sub-) compartments can be tissue-specifically transcribed during oogenesis, forming distinct lateral loops. Here, we established a correspondence between the A/B compartments in somatic interphase nucleus and chromatin segments in giant lampbrush chromosomes from diplotene stage oocytes. The chromomere-loop structure of the genomic regions corresponding to interphase A and B compartments reveals the difference in how they are organized at the level of chromatin domains. The results obtained also suggest that gene-poor regions tend to be packed into chromomeres.


Colloidal mobilization of arsenic from mining-affected soils by surface runoff.
Scorodite-rich wastes left as a legacy of mining and smelting operations pose a threat to environmental health. Colloids formed by the weathering of processing wastes may control the release of arsenic (As) into surface waters. At a former mine site in Madrid (Spain), we investigated the mobilization of colloidal As by surface runoff from weathered processing wastes and from sediments in the bed of a draining creek and a downstream sedimentation-pond. Colloids mobilized by surface runoff during simulated rain events were characterized for their composition, structure and mode of As uptake using asymmetric flow field-flow fractionation coupled to inductively plasma mass spectrometry (AF4-ICP-MS) and X-ray absorption spectroscopy (XAS) at the As and Fe K-edges. Colloidal scorodite mobilized in surface runoff from the waste pile is acting as a mobile As carrier. In surface runoff from the river bed and the sedimentation pond, ferrihydrite was identified as the dominant As-bearing colloidal phase. The results from this study suggest that mobilization of As-bearing colloids by surface runoff may play an important role in the dispersion of As from metallurgical wastes deposited above ground and needs to be considered in risk assessment.


Pyomyoma after abortion: Uterus conserving surgery is possible to maintain fertility. Case report.
Pyomyoma is a rare complication associated with high rates of morbidity and mortality. We report the case of a 28-year-old nulligravida patient presenting pyomyoma following a spontaneous abortion at fourteen weeks and four days. Fourteen days following spontaneous miscarriage she was referred to the hospital with abdominal pain and fever. An antibiotic treatment was initiated. However, after ten days, the patient's condition deteriorated and a decision for an emergency laparotomy made. The pyomyoma was successfully resected and the patient's postoperative recovery was uneventful. A new pregnancy was confirmed two years later. The diagnosis of pyomyoma can be difficult but surgical treatment is often indicated. Performing a prompt myomectomy avoids the need for hysterectomy, preserving future fertility. Pregnancy is possible following uterine sparing treatment of pyomyoma.


Novel 2-(substituted benzyl)quinuclidines inhibit human α7 and α4β2 nicotinic receptors by different mechanisms.
This work presents the design and synthesis of a series of novel 2-benzylquinuclidine derivatives, comprising 12 methiodide and 11 hydrochloride salts, and their structural and pharmacological characterization at the human (h) α7 and α4β2 nicotinic receptors (nAChRs). The antagonistic potency of these compounds was tested by Ca(2+) influx assays on cells expressing the hα7 or hα4β2 nAChR subtype. To determine the inhibitory mechanisms, additional radioligand binding experiments were performed. The results indicate that the methiodides present the highest affinities for the hα7 nAChR agonist sites, while the same compounds bind preferably to the hα4β2 nAChR ion channel domain. These results indicate that the methiodides are competitive antagonists of the hα7 nAChR but noncompetitive antagonists of the hα4β2 subtype. Docking and molecular dynamics simulations showed that the methiodide derivative 8d binds to the hα7 orthosteric binding sites by forming stable cation-π interactions between the quaternized quinulinuim moiety and the aromatic box in the receptor, whereas compounds 7j and 8j block the hα4β2 AChR ion channel by interacting with a luminal domain formed between the serine (position 6') and valine (position 13') rings that overlaps the imipramine binding site.


Grey scale ultrasonography and arthrography in evaluation of popliteal cysts.
Ultrasonography will reliably detect popliteal cysts of clinically significant size and improvements in ultrasound imaging have enhanced the value of ultrasound in relation to arthrography in the assessment of cyst rupture. Forty-eight knees in 25 patients suspected of having a popliteal cyst were examined by ultrasonography followed immediately by arthrography. Popliteal cysts were demonstrated in 40% (19/48) by ultrasound and in 46% (22/48) by arthrogram. Arthrography detected small cysts not seen with ultrasound, but altrasonic scanning showed cysts which did not fill on arthrography. A ruptured cyst or deep venous thrombosis was suspected in 10 patients. Rupture was confirmed in two patients by arthrography, in both of whom soft tissue changes and attenuation of the distal margin of the cysts were shown by ultrasound.


Uptake blockade of endocannabinoids in the NTS modulates baroreflex-evoked sympathoinhibition.
Previous studies supporting a possible physiological role for an endogenous cannabinoid, arachidonylethanolamide (AEA, anandamide), showed a significant increase in AEA content in the nucleus tractus solitarius (NTS) after an increase in blood pressure (BP) and prolonged baroreflex inhibition of renal sympathetic nerve activity (RSNA) after exogenous AEA microinjections into the NTS. These results, along with other studies, support the hypothesis that endogenous AEA can modulate the baroreflex through cannabinoid CB(1) receptor activation within the NTS. This study was performed to characterize the physiological role of endogenously released cannabinoids (endocannabinoids) in regulating baroreflex control of RSNA through actions in the NTS. Endocannabinoid effects were assessed by measuring the RSNA baroreflex response to increased pressure after bilateral microinjections of AM404, an endocannabinoid transport inhibitor, into the NTS of adult male Sprague Dawley rats. AM404 blocks uptake of endocannabinoids and enhances the effects of any endocannabinoids released [M. Beltramo, et al., Functional role of high-affinity anandamide transport, as revealed by selective inhibition, Science 277 (5329) (1997) 1094-1097.] into the NTS. Therefore, it was hypothesized that microinjections of AM404 should exhibit effects similar to microinjections of exogenous AEA. In this study, AM404 microinjections into the NTS were found to significantly prolong baroreflex inhibition of RSNA compared to control, similar to effects of exogenous AEA. This effect is thought to result from an increased endocannabinoid presence in the NTS, leading to prolonged CB(1) receptor activation. These results indicate that endocannabinoids released in the NTS have the potential to modulate baroreflex control at this site in the central baroreflex pathway.


Regularity of SLE in ( t , κ ) and refined GRR estimates.
Schramm-Loewner evolution ( SLE κ ) is classically studied via Loewner evolution with half-plane capacity parametrization, driven by κ times Brownian motion. This yields a (half-plane) valued random field γ = γ ( t , κ ; ω ) . (Hölder) regularity of in γ ( · , κ ; ω ), a.k.a. SLE trace, has been considered by many authors, starting with Rohde and Schramm (Ann Math (2) 161(2):883-924, 2005). Subsequently, Johansson Viklund et al. (Probab Theory Relat Fields 159(3-4):413-433, 2014) showed a.s. Hölder continuity of this random field for κ < 8 ( 2 - 3 ) . In this paper, we improve their result to joint Hölder continuity up to κ < 8 / 3 . Moreover, we show that the SLE κ trace γ ( · , κ ) (as a continuous path) is stochastically continuous in κ at all κ ≠ 8 . Our proofs rely on a novel variation of the Garsia-Rodemich-Rumsey inequality, which is of independent interest.


Biofidelic child head FE model to simulate real world trauma.
Biomechanics of human head has been widely studied since several decades. At a mechanical level, the use of engineering allowed investigating injury mechanisms developing numerical models of adult head. For children, the problem is more difficult and evaluating child injury mechanisms using data obtained from scaling adult injury criteria does not account for differences in morphology and structure between adults and children. During growth, child head undergoes different modifications in morphology and structure. The present paper compares the anthropometry and numerical simulations of a child head model based on medical CT scans to a child head model developed by scaling an adult head model using the method proposed by Mertz [H.J. Mertz, A procedure for normalizing impact response data, SAE paper 840884, 1984]. These analysis point out significant differences showing that scaling down an adult head to obtain a child head does not appear relevant. Biofidelic and specific child geometry is needed to investigate child injury mechanisms.


Quantitative bacterial tissue cultures from 209 prostatectomy specimens: findings and implications.
To define the prevalence of prostatic bacterial infection or colonization, tissue from 209 patients undergoing prostatectomy (204 transurethral and 5 suprapubic) was submitted for quantitative bacterial tissue cultures. Tissue from 44 patients (21 per cent) yielded positive, single organism bacterial growth. In an attempt to identify preoperatively this patient subgroup, multiple preoperative and intraoperative variables were examined. Although the presence of a preoperative indwelling catheter was associated with positive prostate cultures, only 34 per cent (24 of 70) of the patients with preoperative catheters had positive prostate cultures. Of the 44 patients with positive prostate cultures 36 (82 per cent) had sterile urine cultures documented preoperatively, all urine specimens having been obtained in the absence of antibiotics. The data support a significant prevalence (21 per cent or more) of prostatic infection in patients undergoing prostatic surgery for obstructive symptoms and an apparent paucity of reliable indicators by which to identify preoperatively this patient population.


Effectiveness and safety of glucocorticoids to treat COVID-19: a rapid review and meta-analysis.
Glucocorticoids are widely used in the treatment of various pulmonary inflammatory diseases, but they are also often accompanied by significant adverse reactions. Published guidelines point out that low dose and short duration systemic glucocorticoid therapy may be considered for patients with rapidly progressing coronavirus disease 2019 (COVID-19) while the evidence is still limited. We comprehensively searched electronic databases and supplemented the screening by conducting a manual search. We included randomized controlled trials (RCTs) and cohort studies evaluating the effectiveness and safety of glucocorticoids in children and adults with COVID-19, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and conducted meta-analyses of the main indicators that were identified in the studies. Our search retrieved 23 studies, including one RCT and 22 cohort studies, with a total of 13,815 patients. In adults with COVID-19, the use of systemic glucocorticoid did not reduce mortality [risk ratio (RR) =2.00, 95% confidence interval (CI): 0.69 to 5.75, I2=90.9%] or the duration of lung inflammation [weighted mean difference (WMD) =-1 days, 95% CI: -2.91 to 0.91], while a significant reduction was found in the duration of fever (WMD =-3.23 days, 95% CI: -3.56 to -2.90). In patients with SARS, glucocorticoids also did not reduce the mortality (RR =1.52, 95% CI: 0.89 to 2.60, I2=84.6%), duration of fever (WMD =0.82 days, 95% CI: -2.88 to 4.52, I2=97.9%) or duration of lung inflammation absorption (WMD =0.95 days, 95% CI: -7.57 to 9.48, I2=94.6%). The use of systemic glucocorticoid therapy prolonged the duration of hospital stay in all patients (COVID-19, SARS and MERS). Glucocorticoid therapy was found to reduce the duration of fever, but not mortality, duration of hospitalization or lung inflammation absorption. Long-term use of high-dose glucocorticoids increased the risk of adverse reactions such as coinfections, so routine use of systemic glucocorticoids for patients with COVID-19 cannot be recommend.


Single-cell sequencing analysis reveals gastric cancer microenvironment cells respond vastly different to oxidative stress.
Gastric cancer is a common type of gastrointestinal malignant tumor in China. The mechanism of the development and progression of gastric cancer remains the continuing research focus. The tumor microenvironment plays an important role in the development and progression of tumors. The present study used single-cell sequencing data to characterize the microenvironment of gastric cancer, investigate the effects of oxidative stress on gastric cancer microenvironmental cells through the comparison between cancer tissue and normal tissue, and identify the key genes associated with gastric cancer patients' survival. The results showed that compared with normal gastric tissue, gastric cancer tissue had a decreased oxidative stress response, weaker oxidative detoxification ability, and increased oxidative stress-induced cell death. In the different types of single cells of gastric cancer microenvironment, the oxidative stress response of T cell was increased, the ability of oxidative detoxification was enhanced, and the oxidative stress-induced cell death was exacerbate. Mucous cell showed the same trend as gastric cancer cells: decreased oxidative stress response, weak oxidative detoxification ability, and weakened oxidative stress-induced cell death. Moreover, TRIM62, MET, and HBA1, which were significantly associated with oxidative stress, may be biomarkers for the prognosis of gastric cancer. High expression of TRIM62 indicated a good prognosis, while MET and HBA1 indicated a poor prognosis, which will be confirmed by further clinical studies.


Oxygenated Cyclopentenones via the Pauson-Khand Reaction of Silyl Enol Ether Substrates.
We report here the application of silyl enol ether moieties as efficient alkene coupling partners within cobalt-mediated intramolecular Pauson-Khand reactions. This cyclization strategy delivers synthetically valuable oxygenated cyclopentenone products in yields of ≤93% from both ketone- and aldehyde-derived silyl enol ethers, incorporates both terminal and internal alkyne partners, and delivers a variety of decorated systems, including more complex tricyclic structures. Facile removal of the silyl protecting group reveals oxygenated sites for potential further elaboration.


Evaluation of ω-alkynyl-labeled linoleic and arachidonic acids as substrates for recombinant lipoxygenase pathway enzymes.
ω-Alkynyl-fatty acids can be used as probes for covalent binding to intracellular macromolecules. To inform future in vivo studies, we determined the rates of reaction of ω-alkynyl-labeled linoleate with recombinant enzymes of the skin 12R-lipoxygenase (12R-LOX) pathway involved in epidermal barrier formation (12R-LOX, epidermal lipoxygenase-3 (eLOX3), and SDR9C7). We also examined the reactivity of ω-alkynyl-arachidonic acid with representative lipoxygenase enzymes employing either "carboxyl end-first" substrate binding (5S-LOX) or "tail-first" (platelet-type 12S-LOX). ω-Alkynyl-linoleic acid was oxygenated by 12R-LOX at 62 ± 9 % of the rate compared to linoleic acid, the alkynyl-9R-HPODE product was isomerized by eLOX3 at only 43 ± 1 % of the natural substrate, whereas its epoxy alcohol product was converted to epoxy ketone linoleic by an NADH-dependent dehydrogenase (SDR9C7) with 91 ± 1 % efficiency. The results suggest the optimal approach will be application of the 12R-LOX/eLOX3-derived epoxyalcohol, which should be most efficiently incorporated into the pathway and allow subsequent analysis of covalent binding to epidermal proteins. Regarding the orientation of substrate binding in LOX catalysis, our results and previous reports suggest the ω-alkynyl group has a stronger inhibitory effect on tail-first binding, as might be expected. Beyond slowing the reaction, however, we found that the tail-first binding and transformation of ω-alkynyl-arachidonic acid by platelet-type 12S-LOX results in almost complete enzyme inactivation, possibly due to reactive intermediates blocking the enzyme active site. Overall, the results reinforce the conclusion that ω-alkynyl-fatty acids are suitable for selected applications after appropriate reactivity is established.


Comparison of the Effectiveness of Water-Based Extraction of Substances from Dry Tea Leaves with the Use of Magnetic Field Assisted Extraction Techniques.
This article presents the findings of a study investigating the feasibility of using a magnetic field assisted technique for the water-based extraction of mineral components, polyphenols, and caffeine from dry black and green tea leaves. The authors present a concept of applying constant and variable magnetic fields in the process of producing water-based infusions from selected types of tea. Analyses investigating the effectiveness of the proposed technique in comparison with conventional infusion methods assessed the contents of selected mineral components-i.e., Al, Ca, Cu, K, Mg, P, S, and Zn-which were examined with the use of ICP-OES. The contents of caffeine and polyphenolic compounds were assessed using the HPLC. A changing magnetic field permitted an increased effectiveness of extraction of the mineral components, caffeine, and polyphenols. The findings support the conclusion that a changing magnetic field assisted extraction method is useful for obtaining biologically valuable components from tea infusions.


MRSA with progression from otitis media and sphenoid sinusitis to clival osteomyelitis, pachymeningitis and abducens nerve palsy in an immunocompetent 10-year-old patient.
A previously healthy 10-year-old patient with headache, otalgia, and hearing loss was diagnosed with pachymeningitis and methicillin-resistant Staphylococcus aureus otitis media and bacteremia. Despite antimicrobial therapy, intracranial extension progressed, including clival osteomyelitis, sphenoid sinusitis, cavernous sinus inflammation and cranial nerve palsies, until the sphenoid sinus was drained. This case exemplifies an aggressive MRSA intracranial infection that advanced despite antibiotic therapy.


Lingual thyroid: a review of 12 cases.
Twelve patients with lingual thyroid are reviewed. Two of these patients had a follicular carcinoma in the ectopic gland and both are well 5 and 16 years after treatment. The diagnosis is essentially clinical but confirmation may be made with a thyroid scan. Six patients were treated conservatively with thyroxine with good results. Six patients were treated by surgical excision, 2 undergoing autotransplantation of the excised gland into the anterior abdominal wall.


Jejunoileal diverticulosis, a rare cause of ileal perforation - Case report.
Jejunoileal diverticulosis (JID) is a rare condition associated with nonspecific symptoms, consisting of acquired false diverticula. It frequently co-exists with colonic diverticulosis. Diagnosis is usually made incidentally or after complications. These include hemorrhage, obstruction and diverticulitis, with or without perforation. 81-year-old man presented with a painful abdominal mass in the right lower quadrant (RLQ), diffuse abdominal discomfort and fever. Abdominal examination confirmed a well-defined mass in the RLQ without rebound tenderness. Laboratory analysis revealed elevated inflammatory markers and CT scan showed a cavitated lesion with an air-fluid level in the RLQ, without evidence of intraperitoneal free air or fluid. Admitted for conservative treatment, failure to improve led to laparotomy on the 6th day of hospitalization, with identification of jejunoileal diverticulosis complicated with diverticulitis and walled-off perforation. We performed segmental enterectomy. The incidence of JID is estimated at 0.2-7% and it is usually diagnosed in the sixth/seventh decade of life. From a diagnostic perspective, JID is a challenging disorder, without reliable diagnostic tests. Diverticulitis is the most common complication. Perforation generally causes only localized peritonitis, as involved diverticula are often walled off by the surrounding mesentery. In selected cases, medical therapy may suffice. For all other patients prompt laparotomy with segmental intestinal resection is the treatment of choice. JID remains under diagnosed. When it presents as an acute complication it may require immediate surgical intervention. In an elderly person, especially with known gastrointestinal diverticulosis, one must have a high index of suspicion for perforation.


Deep pelvic infiltrating endometriosis: MRI consensus lexicon and compartment-based approach from the ENDOVALIRM group.
The purpose of this consensus article was to develop guidelines by a focused panel of experts to elaborate a lexicon of image interpretation, and a standardized region-based reporting of deep infiltrating endometriosis (DIE) with magnetic resonance imaging (MRI). Evidence-based data and expert opinion were combined using the RAND-UCLA Appropriateness Method to attain consensus guidelines. Experts scoring of pelvic compartment delineation and reporting template were collected; responses were analyzed and classified as "RECOMMENDED" versus "NOT RECOMMENDED" (when ≥ 80% consensus among experts) or uncertain (when < 80% consensus among experts). Consensus regarding pelvic compartment delineation and DIE reporting was attained using the RAND-UCLA Appropriateness Method. The pelvis was divided in nine compartments and extrapelvic lesions were assigned to an additional (tenth) compartment. A consensus was also reached for each structure attributed to a compartment and each reporting template item among the experts. No consensus was reached for a normal aspect of uterosacral ligament, but a consensus was reached for an unequivocal involvement leading to a positive diagnosis and an equivocal involvement leading to uncertain diagnosis. Tailored MRI lexicon and standardized region-based report were proposed. These consensus recommendations should be used as a guide for DIE reporting and staging with MRI. Standardized MRI compartment-based structured reporting is recommended to enable consistent accuracy and help select the best therapeutic approach.


Kinetic analysis of L-lactate transport in human erythrocytes via the monocarboxylate-specific carrier system.
Three parallel pathways of L-lactate transport across the membrane of human red blood cells can be discriminated: (a) by nonionic diffusion; (b) via the band 3 anion exchange protein; and (c) via a specific monocarboxylate carrier system. Influx of lactate via the latter system leads to alkalinization of the medium, suggesting lactate-proton symport. Kinetic analysis of initial lactate influx via the monocarboxylate carrier indicates a symport system with ordered binding of the two ligands, in the sense that a proton binds first to the translocator, followed by lactate binding to the protonated carrier. The influence of varying trans-pH under conditions of net (zero-trans) flux with constant cis-pH indicates that the monocarboxylate translocator should be considered as a mobile carrier, with the ligand-binding sites exposed alternatively to the outside and the inside of the membrane.


Comparison of the analgesic effects of various opioid peptides by a newly devised intracisternal injection technique in conscious mice.
To determine accurately the central analgesic effects of opioid peptides, we devised a special technique for intracisternal administration of drugs to conscious mice. When this method was utilized we found that a series of endogenous opioid peptides and enkephalin analogues, (D-Ala2,Met5)-enkephalinamide and (D-Met2,Pro5)-enkephalinamide produced dose-related analgesic effects, as determined by the tail pinch test. These effects were antagonized by pretreatment with naloxone 0.5 mg/kg s.c. This technique should be a most accurate one for the determination of central analgesic effects of various drugs in conscious mice.


The psychological impact of Covid-19 pandemic on people with Multiple Sclerosis: A meta-analysis.
Covid-19 pandemic caused relevant psychological consequences in the general population. Since people with Multiple Sclerosis (pwMS) are usually at higher risk of psychological distress than age-matched healthy controls (HC), a meta-analytic study was conducted, aimed at evaluating i) differences between pwMS and HC in the psychological variables during the pandemic, ii) differences in the levels of anxiety, depression, stress, sleep disturbances and quality of life before and during the Covid-19 pandemic in pwMS. The literature search on three electronic databases yielded 196 studies (113 after the duplicates removal). Seven studies compared psychological variables between pwMS and HC during the pandemic, while seven studies evaluated the pre- vs during the pandemic differences in pwMS. The following outcomes were selected: depression, anxiety, physical QoL, mental QoL, stress, sleep quality/disturbances. Mean weighted effect sizes (ES) were calculated using Hedges'g, via Prometa3 software. During the pandemic, pwMS showed higher levels of depression (g = 0.51, p=.001), anxiety (g = 0.41, p=.032), and stress (g = 0.51, p=.016) compared to HC. The comparison on psychological outcomes before and during the pandemic in pwMS revealed no significant increase during the pandemic on levels of anxiety (g = 0.08, p=.380), depression (g = 0.02, p=.772), mental QoL (g= -0.14, p=.060), physical QoL (g = 0.00, p=.986), whereas sleep quality deteriorated during the pandemic (g = 0.52, p<.001). In agreement with pre-pandemic literature, pwMS showed higher levels of psychological distress than HC also during the Covid-19 pandemic. Contrariwise, longitudinal studies revealed that, in pwMS, the only psychological-associated variable that worsened significantly was the sleep quality, but this outcome was evaluated only in two studies. Future studies will have to assess/evaluate the long-term psychological consequences of the pandemic on pwMS.


Nanoparticle release from nano-silver antimicrobial food containers.
Polymer nanocomposites incorporating metal or metal oxide nanoparticles have been developed to improve their characteristics (flexibility, gas barrier properties, antimicrobial or antioxidant properties, etc.). Among them silver nanoparticles are used because of their antimicrobial effect in many daily life materials, i.e. food packaging. However, there is not any reference to the migration of nanoparticles to the food. In this paper the results of migration studies (with different simulant solutions and times) in three commercial nanosilver plastic food containers are shown. Migration solutions were evaluated by ICP-MS and SEM-EDX analysis and silver in dissolved form and silver as nanoparticles were analyzed, a key aspect for the toxicity. Silver migration was observed for all samples studied, with the total silver migration values ranging between 1.66 and 31.46 ng/cm(2) (lower than the permissible limits). Size and morphology of the silver nanoparticles changed for the different samples (ranging between 10 and 60 nm) and migration of other nanosized materials was also confirmed.


Biochemical evidence for the 5-HT agonist properties of PAT (8-hydroxy-2-(di-n-propylamino)tetralin) in the rat brain.
In vitro investigations revealed that PAT (8-hydroxy-2-(n-dipropylamino)tetralin) interacted with postsynaptic 5-HT receptors in the rat brain: the drug stimulated 5-HT-sensitive adenylate cyclase in homogenates of colliculi from new-born rats (KAapp 8.6 microM) and inhibited the specific binding of [3H]5-HT to 5-HT1 sites. The PAT-induced inhibition of [3H]5-HT binding showed marked regional differences compatible with a preferential interaction of PAT (IC50 2 nM) with the 5-HT1A subclass. As previously seen with 5-HT agonists, the efficacy of PAT for displacing [3H]5-HT bound to hippocampal membranes was markedly increased by Mn2+ (1 mM) and reduced by GTP (0.1 mM). PAT also affected presynaptic 5-HT metabolism since it inhibited competitively (Ki 1.4 microM) [3H]5-HT uptake into cortical synaptosomes and reduced (in the presence of the 5-HT uptake inhibitor fluoxetine) the K+-evoked release of [3H]5-HT previously taken up or newly synthesized from [3H]tryptophan in cortical or striatal slices. This latter effect was prevented by 5-HT antagonists (methiothepin, metergoline) suggesting that it was mediated by the stimulation of presynaptic 5-HT autoreceptors by PAT. Like 5-HT, PAT counteracted the stimulatory effect of K+-induced depolarization on the synthesis of [3H]5-HT from [3H]tryptophan in cortical slices. It is concluded that PAT is a potent 5-HT agonist acting on both post- and presynaptic 5-HT receptors in the rat brain.


Basilar artery disease--clinical outcome and Doppler sonographical follow-up.
In the past 5 years we have investigated 29 patients with symptomatic basilar artery stenoses (14 cases) and occlusions (14) and a patent primitive trigeminal artery with thin-calibered basilar and vertebral arteries (1) using directional continuous-wave Doppler sonography of the vertebral arteries. A total of 19 patients survived, and 17 of them were clinically and sonographically reexamined after 40.4 +/- 15.8 months (mean +/- SD). Among the 8 patients with basilar stenoses, 6--with no further transient ischemic attacks (TIAs) in the interval--exhibited an increase in the summed modified Pourcelot indices (relative end-diastolic flow velocities) of the vertebrals by 0.18 +/- 0.16; the other 2 showed a decrease by 0.26 each, in 1 case temporally related to a TIA, in the 2nd case without further clinical deterioration. In the 8 survivors with basilar occlusions, 5 remained--by sonographic criteria--unchanged with summed modified Pourcelot indices of the vertebrals of 0.00, while 3 patients exhibited a slight increase in the summed modified Pourcelot indices of 0.13 +/- 0.03. While the difference between the outcome of subsets of patients treated with regimens of 30,000-40,000 units heparin/day or phenprocoumon and less radical drugs were statistically not significant, the former regimen appeared clinically more efficacious in preventing further deterioration in approximately two-thirds of the patients affected. Due to the potential recurrence of neurological symptoms, a treatment period with phenprocoumon of 6 months after discharge from hospital appears justified. Due to these therapeutic efforts, approximately half of the patients initially affected survived with no or only a mild neurological deficit.(ABSTRACT TRUNCATED AT 250 WORDS)


CircRNAs in tumor immunity and immunotherapy: Perspectives from innate and adaptive immunity.
Tumor immunotherapy is a new therapeutic approach that has been evolving in the last decade and has dramatically changed the treatment options for cancer. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) with high stability, tissue-specific and cell-specific expression. There is growing evidence that circRNAs are involved in the regulation of both adaptive and innate immunity. They play important roles in tumor immunotherapy by affecting macrophage, NK and T cell function. The high stability and tissue specificity make them ideal candidate biomarkers for therapeutic effects. CircRNAs also represent one of promising targets or adjuvant for immunotherapy. Investigations in this field progress rapidly and provide essential support for the diagnosis, prognosis and treatment guidance of cancers in the future. In this review, we summarize the role of circRNAs on tumor immunity from the viewpoint of innate and adaptive immunity, and explore the role of circRNAs in tumor immunotherapy.


Leiomyoma of digit of hand: Report of three cases with literature review.
Leiomyoma is a benign tumor of smooth muscle origin most common in areas of the body with abundant smooth muscle including the gynecologic, genitourinary, and gastrointestinal system. Leiomyoma outside of these locations is believed to arise from vascular smooth muscle and arrector pili muscles. Leiomyoma of an extremity is a rare diagnosis, especially when present in a digit of the hand due to the paucity of smooth muscle in this location. We report three cases of leiomyoma of a digit of the hand.


Preparation of raf-oncogene-specific antiserum with raf protein produced in E. coli.
In this report we describe the expression of v-raf protein in E. coli using a tryptophan-promoter-driven expression vector and its immunological characterization by anti-peptide sera. The purified recombinant protein was used to produce raf-specific antibodies which are suitable for studying v-raf and c-raf proteins in vitro and in vivo in a variety of species ranging from mouse to man.


Ochratoxin A blood concentration in healthy subjects and bladder cancer cases from Pakistan.
ASTRACT: The mycotoxin ochratoxin A (OTA) is a public health issue in many countries. Data on OTA concentrations in foods and in blood are available for several European countries including the Balkan area, as well as for Canada and Japan. Yet, for developing countries such data are scarce. In this study we determined OTA blood levels as biomarker of exposure in bladder cancer patients and in healthy controls from Pakistan. OTA in blood was analyzed after extraction by HPLC with fluorescence detection (limit of detection: <0.03 ng/mL) in 96 patients and in 31 controls. Over 92% of all blood samples (87 patients, 30 controls) contained quantifiable amounts of OTA: The mean OTA concentrations were 0.33 ng/mL (SD 0.42; range: 0.03 to 3.41 ng/mL) in bladder cancer patients, and 0.31 ng/mL (SD 0.29; range: 0.04 to 1.25 ng/mL) in healthy controls. These OTA concentrations are comparable to those reported for the general population in the European Union.


Raman and Infrared spectroscopies and X-ray diffraction data on bupivacaine and ropivacaine complexed with 2-hydroxypropyl-β-cyclodextrin.
The data presented in this article are related to the research article entitled "Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations (http://dx.doi.org/10.1016/j.ijpharm.2017.03.051)" (Martins et al., 2017) [1]. This work shows the molecular and structural behavior of the local anesthetics (LAs) bupivacaine (BVC, C18H28N2O) and ropivacaine (RVC, C17H26N2O) before and after complexation with the water-soluble oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HP-β-CD).


What magnetic resonance imaging has told us about the pathogenesis of rheumatoid arthritis--the first 50 years.
Modern imaging modalities, including magnetic resonance imaging (MRI), are valuable diagnostic and therapy monitoring tools in rheumatoid arthritis (RA). This article reviewed how these imaging modalities have greatly improved our understanding of pathogenic mechanisms in RA, namely the link between inflammation and damage. For example, traditional paradigms regarding the mechanisms of joint destruction, including the idea that synovitis and damage are uncoupled, have been challenged. As the power of MRI increases, there is a need to define normality since apparently normal joints occasionally exhibit MRI evidence of synovitis in the absence of symptoms.


Return to Intended Oncologic Treatment (RIOT) in Resected Gastric Cancer Patients.
Postoperative chemotherapy (CMT) or chemoradiotherapy (CRT) is commonly recommended for gastric cancer (GC) patients in order to improve survival. However, some factors that prevent patients from return to intended oncologic treatment (RIOT) may increase the risk of recurrence and decrease the survival benefits achieved with curative resection. The aim of this study was to determine the frequency and factors associated with inability to RIOT and their impact on survival. This retrospective study included stage II/III GC patients treated with potentially curative gastrectomy. Patients who could return to intended oncologic treatment (RIOT group) and those who could not (inability to RIOT group) were analyzed. Of the 313 eligible GC patients, 89 (28.4%) and 85 (27.2%) patients receive CRT and CMT, respectively, representing a RIOT rate of 55.6%. The main reason was attributed to general poor performance status (30.2%), followed by surgical postoperative complications (POC) (20.1%). Older age, higher ASA, D1 lymphadenectomy, and major POC were related to inability to RIOT. Older age, neutrophil-lymphocyte ratio (NLR), and major POC were independent risk factors for inability to RIOT. Five-year DFS and OS were worse for the inability to RIOT group than for the RIOT group (p = 0.008 and p = 0.004, respectively). In multivariate analyses, absence of neoadjuvant therapy, total gastrectomy, pT3/T4, pN+, and inability to RIOT were associated with worse DFS. Type of gastrectomy, lymphadenectomy, pN status, Rx resection, and RIOT group were associated with OS. Older age, high NLR, and major POC were risk factors for inability to RIOT. RIOT was an independent predictor of survival.


The IDDM13 region containing the insulin-like growth factor binding protein-5 (IGFBP5) gene on chromosome 2q33-q36 and the genetic susceptibility to rheumatoid arthritis.
We considered that the constitutive over-expression by cultured rheumatoid arthritis (RA) fibroblast-lineage synoviocytes of genes like IGFBP5 could indicate new candidate susceptibility genes. IGFBP5 is located in a region where an insulin-dependent diabetes mellitus (IDDM) susceptibility locus, IDDM13 (2q33-q36), has been mapped. Previous evidence that non-MHC IDDM loci overlap RA susceptibility loci made IGFBP5 and its region an interesting candidate locus which was tested for linkage. Forty-nine sibships (2-4 affected siblings per sibship) with RA were genotyped with microsatellite markers covering an 11.2 cM interval in the IGFBP5/IDDM13 region. Both the two-point LOD scores and a 'nonparametric' allele-sharing analysis revealed no evidence for linkage (max LOD = 0.54, P = 0.5, respectively). Adjustments for the presence of 'shared-epitope' alleles did not significantly change the LOD scores. These results suggest that, despite the involvement of the 2q33-q36 chromosomal region in another organ-specific autoimmune disease, it is unlikely that this region harbors a RA susceptibility locus.


Arbuscular mycorrhizal fungus regulates cadmium accumulation, migration, transport, and tolerance in Medicago sativa.
Cadmium (Cd) pollution in croplands is a global environmental problem. Measures to improve the tolerance of sensitive crops and reduce pollutant absorption and accumulation are needed in contaminated agricultural areas, and inoculation with rhizosphere microorganisms to regulate plant resistance and heavy metal transport can provide an effective solution. A pot experiment was conducted to analyse the impact of arbuscular mycorrhizal fungi (AMF) on alfalfa oxidase activity, heavy metal resistance genes and transport proteins, metabolism, and other biochemical regulation mechanisms that lead to complexation, compartmentalisation, efflux, enrichment, and antioxidant detoxification pathways. The AMF reduced shoot and protoplasm Cd inflow, and promoted organic compound production (e.g., by upregulating HM-Res4 for 1.2 times), to complex with Cd, reducing its biological toxicity. The AMF increased the ROS scavenging efficiency and osmotic regulatory substance content of the alfalfa plants, reduced oxidative stress (ROS dereased), and maintained homeostasis. It also alleviated Cd inhibition of photosynthetic electron transport, tricarboxylic acid circulation, and nitrogen assimilation. These AMF effects improved leaf and root biomass by 43.87% and 59.71% and facilitated recovery of a conservative root economic strategy. It is speculated that AMF induces the resistance signal switch by regulating the negative feedback regulation mode of indole acetic acid upward transport and methyl jasmonate downward transmission in plants.


Gardnerella vaginalis-associated bacterial vaginosis in Bulgarian women.
Bacterial vaginosis (BV) is the most common cause of vaginal discharge in women of reproductive age. The purpose of this study was to determine the frequency of BV in Bulgarian pregnant and nonpregnant women from several age ranges and to compare three different laboratory methods for Gardnerella vaginalis detection in patents suffering from BV. Between September 2011 and June 2012, 809 women of 16-40 years of age separated in two major groups: nonpregnant - 469 (355 with and 114 without symptoms) and pregnant - 340 (213 and 127 respectively) were enrolled for the study. The women underwent three different laboratory tests simultaneously: scoring of Gram staining of vaginal smear, culture, and polymerase chain reaction (PCR) assay for G. vaginalis. The microscopic method detected high frequency of BV in symptomatic (57%) whereas only a minority of asymptomatic subjects (14%) were detected. G. vaginalis-associated BV was diagnosed in approximately equal proportions when evaluated with PCR and microscopic method for both pregnant and nonpregnant women. The comparative analysis of microscopic evaluation, culture and PCR assays demonstrated greater concurrence (about 90%) between Gram staining and PCR detection for BV, than both methods compared to culture. The combination of microscopy and PCR turned out to be very reliable and repeatable for detecting G. vaginalis-associated BV. This is the first comparative investigation on the epidemiology of G. vaginalis-associated BV in Bulgaria. The established highest frequency in the young Bulgarian women (21-30 years) is alarming and should be considered in prophylaxis and reproductive programmes.


Human myoblast transplantation in mice infarcted heart alters the expression profile of cardiac genes associated with left ventricle remodeling.
Myocardial infarction (MI) and left ventricle remodeling (LVR) are two of the most challenging disease entities in developed societies. Since conventional treatment cannot fully restore heart function new approaches were attempted to develop new strategies and technologies that could be used for myocardial regeneration. One of these strategies pursued was a cell therapy--particularly applying skeletal muscle stem cells (SkMCs). Using NOD-SCID murine model of MI and human skeletal myoblast transplantation we were able to show that SkMC administration significantly affected gene expression profile (p<0.05) (NPPB, CTGF, GATA4, SERCA2a, PLB) of the heart ventricular tissue and this change was beneficial for the heart function. We have also shown, that the level of heart biomarker, NT-proBNP, decreased in animals receiving implanted cells and that the NT-proBNP level negatively correlated with left ventricle area fraction change (LVFAC) index which makes NT-proBNP an attractive tool in assessing the efficacy of cell therapy both in the animal model and prospectively in clinical trials. The results obtained suggest that transplanted SkMCs exerted beneficial effect on heart regeneration and were able to inhibit LVR which was confirmed on the molecular level, giving hope for new ways of monitoring novel cellular therapies for MI.


Esophagobronchial fistula in a patient with Behçet's disease: report of a case.
Esophageal involvement in Behçet's disease is generally considered to be very uncommon. So far, six cases of esophageal ulcers associated with perforation, penetration, or fistula in Behçet's disease have been described in the English literature. This report describes esophagobronchial fistula in a patient with intestinal Behçet's disease. A 62-year-old man was transferred to our hospital for peritonitis due to a small intestinal perforation after an appendectomy. At the age of 14 years he had had recurrent oral ulcers. Ulcerations of the ileum and epididymitis were found, and a pathological examination revealed nonspecific inflammation. Furthermore, an esophageal ulcer with esophagobronchial fistula was diagnosed. The fistula required not only endoscopic treatment but also surgical intervention. The patient's clinical features were consistent with the active phase of intestinal Behçet's disease. The symptoms gradually resolved without any treatment. Four years after remission, however, the symptoms recurred with gastrointestinal hemorrhage and polyarthritis. In the ileocolic region, punch-out ulcerations were noted. The clinical history and features led to a diagnosis of Behçet's disease associated with recurrent gastrointestinal ulcerations. Steroid therapy (prednisolone, 20 mg daily) was started, and led to a rapid resolution of the symptoms. The patient is now being followed up as an outpatient while receiving prednisolone (10 mg per day), without complaint of any gastrointestinal symptoms.


Treatment of Homozygous Familial Hypercholesterolemia With Evinacumab.
Patients with homozygous familial hypercholesterolemia (HoFH) have extremely elevated levels of low-density lipoprotein cholesterol (LDL-C), with premature atherosclerosis and aortic valve disease. Available drug treatments are inadequate, and even with serial apheresis, HoFH patients rarely achieve acceptable LDL-C levels. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 that lowers LDL-C via a novel receptor-independent mechanism. We describe an Ontario patient with HoFH who for 17 months has been treated with monthly infusions of evinacumab added to pre-existing statin, ezetimibe, and evolocumab therapy. Evinacumab in this HoFH patient was associated with markedly improved LDL-C levels and decreased frequency of apheresis.


Early outcome of tetralogy of Fallot repair in the current era of management.
Traditional use of trans-annular patch (TAP) to release right ventricular outflow tract (RVOT) obstruction during tetralogy of Fallot (TOF) repair may lead to a harmful pulmonary regurgitation. Different approaches have been used to release RVOT obstruction and spare the pulmonary valve (PV) function. In this study, we aim to evaluate the post-operative course of patients who had TOF repair in the current era that emphasizes on protective strategy of releasing RVOT obstruction and preserving PV function. A retrospective study of all TOF cases repaired in our institute between March 2002 and December 2007 was conducted. Cases were classified into two groups; group I included patients that had a TAP, while group II included cases that had simple TOF repair without TAP. Group I was subdivided into two groups, group (A) which include patients who had TAP without a valve. Group (B) includes those who had TAP with a monocuspid valve (Contegra). We compared post-operative care and outcome of all groups. Eighty-three patients fulfilled the study criteria. There were 64 cases (77%) in group I, and 19 cases (23%) in group II. All children tolerated surgical repair and did well. We observed no statistically significant difference in the post-operative ICU care, complications rates and morbidity between all groups. There was no surgical mortality in all groups. Children undergoing TOF repair had excellent short-term outcome with the current protective strategy aiming to spare valvular function, and conserving myocardial function. Applying a monocuspid patch technique did not show clear short-term benefits. Long term follow up is needed to evaluate future difference in different techniques.


Optimal temperature in targeted temperature management without automated devices using a feedback system: A multicenter study.
Targeted temperature management (TTM) at 32 °C-36 °C improves patient outcomes following out-of-hospital cardiac arrest (OHCA). TTM using automated temperature management devices with feedback systems (TFDs) is recommended, but the equipment is often unavailable. This study aimed to investigate therapeutic relations between targeted temperatures and TFDs on the outcomes of OHCA patients with TTM. This multicenter study analyzed nontraumatic OHCA registry data between October 2015 and June 2020 from 29 institutions. Patients were classified into four groups based on targeted temperatures and TFD implementation: TTM at 33 °C with TFD (33TFD), TTM at 36 °C with TFD (36TFD), TTM at 33 °C without TFD (33NTFD), and TTM at 36 °C without TFD (36NTFD). Clinical outcomes were survival till hospital discharge and neurological status at discharge. A total of 938 patients were included in the analysis. There was an independent association between the 33NTFD patients with the least survival and the worst neurological outcomes among the four groups after adjustment for covariates. However, no significant differences were observed in survival and neurological outcomes among the 33TFD, 36TFD, and 36NTFD groups after adjusting for covariates. Compared to 33NTFD, 36NTFD patients exhibited significantly higher adjusted ORs for survival and favorable neurological status at hospital discharge. In OHCA patients receiving TTM without TFDs, the adjusted predicted probability of survival and good neurological outcomes at hospital discharge was greater for TTM at 36 °C than that at 33 °C. This suggests that a TTM of 36 °C rather than 33 °C is associated with more favorable clinical outcomes if TFDs are unavailable.


A unique case of light chain (AL) amyloidosis masquerading as hypophosphatemic osteomalacia.
Light chain (AL) amyloidosis is the result of a clonal plasma cell disorder which causes organ damage by deposition of misfolded light chains. Kidney is a common site of amyloid deposition. Proteinuria, usually in nephrotic range and unexplained renal insufficiency are the main manifestations of renal injury. We report a unique case of renal involvement by AL amyloidosis masquerading as metabolic bone disease. 38 year old male patient presented with progressively increasing diffuse bony pains, low backache and proximal weakness of both lower limbs since two years. On investigation, he was detected to have hypophosphatemic osteomalacia due to renal phosphate loss which was fibroblast growth factor 23 (FGF23)- independent. He also had nephrotic range low molecular weight proteinuria. Renal biopsy to ascertain the aetiology revealed deposition of amyloid fibrils in the glomerular mesangium on electron microscopy. Its characterization by immunofluorescence (IF) was consistent with immunoglobulin light chain (AL) amyloidosis. In the absence of a demonstrable plasma cell clone on bone marrow biopsy, we made a diagnosis of monoclonal gammopathy of renal significance (MGRS). He was treated with chemotherapy following which there was symptomatic improvement and reduction in phosphaturia. This case describes a unique presentation of renal injury due to AL amyloidosis masquerading as hypophosphatemic osteomalacia. The aim of this report is to highlight that hypophosphatemia in adults is usually acquired and treatment of underlying etiology results in cure, unlike in children where genetic counseling and phosphate replacement is the mainstay of treatment.


Running the numbers on plant synthetic biology solutions to global problems.
Synthetic biology and metabolic engineering promise to deliver sustainable solutions to global problems such as phasing out fossil fuels and replacing industrial nitrogen fixation. While this promise is real, scale matters, and so do knock-on effects of implementing solutions. Both scale and knock-on effects can be estimated by 'Fermi calculations' (aka 'back-of-envelope calculations') that use uncontroversial input data plus simple arithmetic to reach rough but reliable conclusions. Here, we illustrate how this is done and how informative it can be using two cases: oilcane (sugarcane engineered to accumulate triglycerides instead of sugar) as a source of bio-jet fuel, and nitrogen fixation by bacteria in mucilage secreted by maize aerial roots. We estimate that oilcane could meet no more than about 1% of today's U.S. jet fuel demand if grown on all current U.S. sugarcane land and that, if cane land were expanded to meet two-thirds of this demand, the fertilizer and refinery requirements would create a large carbon footprint. Conversely, we estimate that nitrogen fixation in aerial-root mucilage could replace up to 10% of the fertilizer nitrogen applied to U.S. maize, that 2% of plant carbon income used for growth would suffice to fuel the fixation, and that this extra carbon consumption would likely reduce grain yield only slightly.


Exposure of neonatal rats to the endocrine disrupter Bisphenol A affects ontogenic expression pattern of testicular steroid receptors and their coregulators.
In light of the adverse reports of Bisphenol A (BPA) on reproduction and considering the pivotal role played by the steroid receptors (SRs) and their coregulators in male reproduction, it was of interest to decipher the influence that BPA may have on their expression pattern during critical 'windows' of development. Male rats were injected with 2.4 µg per pup per day of BPA from postnatal days (PND) 1-5 and controls received vehicle. During development, the testicular expression pattern of SRs (AR, ERβ and ERα), coactivators (SRC-1, SRC-2 and SRC-3) and corepressors (NCoR and SMRT) in BPA-exposed rats were compared. A significant decrease in the expression of SRs was seen in the BPA group. SRC-1 showed a significant decrease, whereas SRC-2 and SRC-3 showed a significant increase in the protein expression whereas corepressor expression remained unaltered in the BPA-exposed groups. Such impairments in the expression pattern can be a putative mechanism of adversities on fertility as a result of BPA exposure.


Benzoquinones from millipedes deter mosquitoes and elicit self-anointing in capuchin monkeys (Cebus spp.).
Neotropical monkeys of the genus Cebus anoint themselves by rubbing arthropods and plants against their pelage. A recent study has shown that free-ranging wedge-capped capuchin monkeys (C. olivaceus) in Venezuela self-anoint with a benzoquinone-secreting millipede, an activity by which they are hypothesized to appropriate chemical deterrents of mosquitoes. To evaluate the plausibility of this hypothesis, female yellow fever mosquitoes (Aedes aegypti) were presented with two millipede secretory compounds, 2-methyl-1,4-benzoquinone and 2-methoxy-3-methyl-1,4-benzoquinone, on nylon-reinforced silicone membranes placed over wells filled with human blood, a highly preferred food. Mosquitoes exhibited fewer landings, fed less frequently, and flew more frequently (a possible indication of repellency) in the presence of membranes treated with benzoquinones than with controls. These compounds also elicit self-anointing in captive male and female tufted (C. apella) and white-faced (C. capucinus) capuchin monkeys.


Chemical modification of the neutral amino acid transport system L of Chinese hamster ovary cells with p-chloromercuribenzene sulfonate.
Branched-chain and aromatic neutral amino acids enter mammalian cells predominantly through a Na(+)-independent transport agency called System L. The sulfhydryl specific reagent p-chloromercuribenzene sulfonate (pCMBS) has been shown to be a potent inactivator of System L transport activity in Chinese hamster ovary cells, however, inactivation by pCMBS can be prevented by the presence of System L-specific substrate amino acids during the inactivation reaction. In addition, the presence of amino acids that are not substrates for System L have no effect on pCMBS inactivation of System L. Inactivation of System L activity by pCMBS was sensitive to pH and reversible by incubation with dithiothreitol. These findings suggest that there is a sulfhydryl group in, or very near, the amino acid-binding site of the System L transporter of CHO cells. Substrate protection, however, could be explained by conformational changes in the transporter associated with substrate binding. The presence of a substrate protectable sulfhydryl group on the System L transporter would aid in the attempt to identify this transporter using the technique of differential labeling.


A root penetration model of Arabidopsis thaliana in phytagel medium with different strength.
Phytagel media were evaluated as systems to mechanically impede roots of A. thaliana. Studying mechanical properties of Phytagel and exploring the root response to mechanical stimulation can facilitate plant culture and plant development. Breaking strengths of 0.5-2.0% phytagel media were tested by uniaxial compression test. Different phytagel concentrations were set to alter the strength of layers in growth medium. Negative correlations were observed between root length, straightness and medium strength. When roots elongated through soft upper-layer (0.6%), penetration ratio decreased with the increase of lower-layer strength (0.6-1.2%) and all roots couldn't penetrate into lower-layer with concentration ≥1.2%. Roots could grow into soft lower-layer (0.6%) from hard upper-layer (0.6-1.2%), with decreased penetration ratio. When roots grew in soft lower-layer, the growth rate linked with upper-layer strength increased to peak. Roots penetration capability into 1.2% lower-layer was improved by growing plants through moderate layer inserted between soft and hard layer, and roots in 0.8% moderate medium have a significant higher penetration ratio than that in 1.0%. It was concluded that the Phytagel systems studied were suitable for studying the effect of mechanical impedance on the elongation of A. thaliana roots. The medium strength affected root penetration significantly and acclimation can improve root penetration capability.


Removal of microbial biofilm on Water Hyacinth plants roots by ultrasonic treatment.
The capacity of floating aquatic plants to purify sewage effluents drops rapidly as a result of biofouling processes that occur on the plant roots. This is due to the high concentration of microorganisms (MO) present in the wastewater. The possibility to apply low frequency (20 kHz) in sonification was examined under laboratory conditions. The ability of US to remove MO from the roots was studied using commercially available sonicators at intensity levels ranging from 2.7 W/cm(2) to 81.4 W/cm(2), (corresponding power levels ranging from 75 W to 500 W) while varying application periods between 5 and 60 min. The results show that MO can be removed effectively (up to 98%) by exposing the Eichhornia crassipes roots to US for 5 min at the intensity level of 64.5 W/cm(2). The efficiency of the wastewater treatment increased with exposure time and power input. The study proved that the US treatment is effective in removing MO that otherwise adhere to the roots, by more then two orders of magnitude.


Myricetin Inhibits α-Synuclein Amyloid Aggregation by Delaying the Liquid-to-Solid Phase Transition.
The aggregation of α-synuclein (α-Syn) is a critical pathological hallmark of Parkinson's disease (PD). Prevention of α-Syn aggregation has become a key strategy for treating PD. Recent studies have suggested that α-Syn undergoes liquid-liquid phase separation (LLPS) to facilitate nucleation and amyloid formation. Here, we examined the modulation of α-Syn aggregation by myricetin, a polyhydroxyflavonol compound, under the conditions of LLPS. Unexpectedly, neither the initial morphology nor the phase-separated fraction of α-Syn was altered by myricetin. However, the dynamics of α-Syn condensates decreased upon myricetin binding. Further studies showed that myricetin dose-dependently inhibits amyloid aggregation in the condensates by delaying the liquid-to-solid phase transition. In addition, myricetin could disassemble the preformed α-Syn amyloid aggregates matured from the condensates. Together, our study shows that myricetin inhibits α-Syn amyloid aggregation in the condensates by retarding the liquid-to-solid phase transition and reveals that α-Syn phase transition can be targeted to inhibit amyloid aggregation.


Effects of radiotherapy on plasma energy metabolites in patients with breast cancer who received neoadjuvant chemotherapy.
Neoadjuvant chemotherapy (NACT) is employed in patients with breast cancer (BC) with the aim of reducing tumor burden and improving surgical outcomes. We evaluated the levels of energy metabolites pre- and post-radiotherapy (RT) in breast cancer (BC) patients who previously received NACT and investigated the alterations of these metabolites in relation to the patient achieving a pathologic complete response to NACT. We included 37 BC patients who were treated with NACT following surgery and analyzed the concentrations of energy balance-related metabolites using targeted metabolomics before and one month after the end of RT. The control group was composed of 44 healthy women. Pre-radiotherapy, patients had significant decreases in the plasma levels of 12 metabolites. RT corrected these alterations and the improvement was superior in patients with a pathologic complete response. Our results highlight the importance of metabolism in the outcomes of patients with BC.


Comparison of data-driven identified hypertension-protective dietary patterns among Chinese adults: based on a nationwide study.
Diet pattern (DP) is a key modifiable and cost-effective factor in hypertension (HTN) management. The current study aimed to identify and compare the hypertension-protective DPs among Chinese adults. 52,648 participants aged over 18 years were included from China Nutrition and Health Surveillance (CNHS) 2015-2017. Reduced rank regression (RRR) and partial least square regression (PLS) was applied to identify the DPs. Multivariable-adjusted logistic regression was used to assess the association between the DPs and HTN. DPs derived by RRR and PLS were both featured by higher consumption of fresh vegetables and fruits, mushrooms and edible fungi, seaweeds, soybeans and related products, mixed legumes, dairy products, fresh eggs, and lower of refined grain consumption. Compared to the lowest quintile, participants in the highest quintile had lower odds of HTN (RRR-DP: OR = 0.77, 95% CI = 0.72-0.83; PLS-DP: OR = 0.76, 95% CI = 0.71-0.82; all p < 0.0001). Simplified DP scores were observed the same protective tendencies (Simplified RRR-DP: OR = 0.81, 95% CI = 0.75-0.87; Simplified PLS-DP: OR = 0.79, 95% CI = 0.74-0.85; all p < 0.0001) and showed effective extrapolation in subgroups defined by gender, age, location, lifestyle, and different metabolic conditions. The identified DPs had high conformity with East Asian dietary habits, and significantly negative associations with HTN among Chinese adults. The simplified DP technique also indicated the potential for improving the extrapolation of the results of DP analysis related to HTN.


Direct analysis of Al2O3 powders by total reflection X-ray fluorescence spectrometry.
A direct analysis procedure for the determination of trace impurities of Ca, V, Cr, Mn, Fe, Ni, Cu, Zn and Ga in Al2O3 ceramic powders by total reflection X-ray fluorescence spectrometry (TXRF) is described. The powders were analysed in the form of slurries containing 1-10 mg mL(-1) of powder. The use of the procedure in the case of powders with differing grain size and for different slurry concentrations was investigated. Three different quantification possibilities were compared, namely the use of Al as a matrix component, the use of Fe as a trace element contained in the sample or of Co added in concentrations of 200 microg g(-1) as internal standard. The homogeneity of elemental distributions in sample layers deposited on the TXRF quartz carriers by evaporating 5 microL of the 10 mg mL(-1) slurries was studied by scanning the 4- to 5-mm-diameter spots of two samples by synchrotron radiation TXRF at Hasylab. For powders with differing graininess but mainly finer than about a few 10 microm, no systematic influence of the grain size on the accuracy of the determinations of Ca, V, Fe, Ni, Cu and Zn could be observed. The measurement precision, however, seemed to be limited by inhomogeneous distributions of the trace elements in the samples as testified by the synchrotron radiation TXRF scans. Detection limits of the developed TXRF procedure for Ca, V, Cr, Mn, Fe, Ni, Cu, Zn and Ga were found to be in the 0.3-7 microg g(-1) range and were shown to increase slightly with the grain size of the samples. Quantification using Al (matrix) as internal standard led to systematically higher values out of the accuracy required, whereas the other two approaches in all cases led to reliable results.


Modeling the differences in the time-series profiles of new COVID-19 daily confirmed cases in 3,108 contiguous U.S. counties: A retrospective analysis.
The COVID-19 pandemic in the U.S. has exhibited a distinct multiwave pattern beginning in March 2020. Paradoxically, most counties do not exhibit this same multiwave pattern. We aim to answer three research questions: (1) How many distinct clusters of counties exhibit similar COVID-19 patterns in the time-series of daily confirmed cases? (2) What is the geographic distribution of the counties within each cluster? and (3) Are county-level demographic, socioeconomic and political variables associated with the COVID-19 case patterns? We analyzed data from counties in the U.S. from March 1, 2020 to January 2, 2021. Time series clustering identified clusters in the daily confirmed cases of COVID-19. An explanatory model was used to identify demographic, socioeconomic and political variables associated with the outbreak patterns. Three patterns were identified from the cluster solution including counties in which cases are still increasing, those that peaked in the late fall, and those with low case counts to date. Several county-level demographic, socioeconomic, and political variables showed significant associations with the identified clusters. The pattern of the outbreak is related both to the geographic location within the U.S. and several variables including population density and government response. The reported pattern of cases in the U.S. is observed through aggregation of the daily confirmed COVID-19 cases, suggesting that local trends may be more informative. The pattern of the outbreak varies by county, and is associated with important demographic, socioeconomic, political and geographic factors.


Ionic Accumulation as a Diagnostic Tool in Perovskite Solar Cells: Characterizing Band Alignment with Rapid Voltage Pulses.
Despite record-breaking devices, interfaces in perovskite solar cells are still poorly understood, inhibiting further progress. Their mixed ionic-electronic nature results in compositional variations at the interfaces, depending on the history of externally applied biases. This makes it difficult to measure the band energy alignment of charge extraction layers accurately. As a result, the field often resorts to a trial-and-error process to optimize these interfaces. Current approaches are typically carried out in a vacuum and on incomplete cells, hence values may not reflect those found in working devices. To address this, a pulsed measurement technique characterizing the electrostatic potential energy drop across the perovskite layer in a functioning device is developed. This method reconstructs the current-voltage (JV) curve for a range of stabilization biases, holding the ion distribution "static" during subsequent rapid voltage pulses. Two different regimes are observed: at low biases, the reconstructed JV curve is "s-shaped", whereas, at high biases, typical diode-shaped curves are returned. Using drift-diffusion simulations, it is demonstrated that the intersection of the two regimes reflects the band offsets at the interfaces. This approach effectively allows measurements of interfacial energy level alignment in a complete device under illumination and without the need for expensive vacuum equipment.


Computed tomography to operating room in less than 3 hours minimizes complications from appendicitis.
The aim of our study is to select patients with nonperforated appendicitis verified by computed tomography (CT) scan and to determine if there is a temporal component to perforation. A retrospective cohort study of patients with CT scan evidence of nonperforated appendicitis from 2007 to 2012. 411 patients, aged 39.7 ± 16.25 years (47.5% male) were included in the study. 330 patients (80.3%) were nonperforated at surgery. Analysis of 3-hour intervals from CT scan to operating room (OR) revealed an absolute reduction in the rate of perforation from 27% at the 6- to 9-hour interval, to 17% and 10% at the 3- to 6-hour and 0- to 3-hour intervals, respectively, (P < .04). All organ space infections occurred in patients who were delayed to the OR greater than 3 hours. Mean length of hospitalization was .93 days and 2.81 days, respectively, in nonperforated and perforated appendicitis patients (P < .001). Delays to the OR were associated with increased risk of perforation. Patients with uncomplicated appendicitis had shorter hospitalization and fewer postoperative wound infections.


Ultrasonic atomisation into reduced pressure atmosphere--envisaging aseptic spray-drying for microencapsulation.
A novel spray-drying technique consisting of feeding a fluid through an ultrasonic atomiser, drying the spray under reduced pressure and collecting the particles in a liquid bath was evaluated. Drying by mild vacuum instead of hot air, as employed in conventional spray-drying, and simple particle recovery render this method suitable for aseptic microsphere preparation. As a model system, the protein bovine serum albumin (BSA) was encapsulated in poly(lactic-co-glycolic acid) microspheres. Particle yields of above 80% exceeded largely values found for conventional laboratory-scale spray-drying equipment. BSA encapsulation efficiency mostly ranged in the region of 60%, with losses probably occurring through partitioning into the aqueous collection bath. Mean particle sizes ranged from 13 to 24 microm, depending on the polymer type and solvent; particle size distributions were excellently reproducible. The microspheres were found to be very porous and exhibited a pronounced 24-h burst release of above 50% of total dose, probably promoted by the porosity. However, when more concentrated polymer solutions (8% instead of 5% (w/w)) were employed, burst release reduced to an average of 16%.


Anthropogenic heat variation during the COVID-19 pandemic control measures in four Chinese megacities.
Anthropogenic heat (AH) is an important input for the urban thermal environment. While reduction in AH during the Coronavirus disease 2019 (COVID-19) pandemic may have weakened urban heat islands (UHI), quantitative assessments on this are lacking. Here, a new AH estimation method based on a remote sensing surface energy balance (RS-SEB) without hysteresis from heat storage was proposed to clarify the effects of COVID-19 control measures on AH. To weaken the impact of shadows, a simple and novel calibration method was developed to estimate the SEB in multiple regions and periods. To overcome the hysteresis of AH caused by heat storage, RS-SEB was combined with an inventory-based model and thermal stability analysis framework. The resulting AH was consistent with the latest global AH dataset and had a much higher spatial resolution, providing objective and refined features of human activities during the pandemic. Our study of four Chinese megacities (Wuhan, Shanghai, Beijing, and Guangzhou) indicated that COVID-19 control measures severely restricted human activities and notably reduced AH. The reduction was up to 50% in Wuhan during the lockdown in February 2020 and gradually decreased after the lockdown was eased in April 2020, similar to that in Shanghai during the Level 1 pandemic response. In contrast, AH was less reduced in Guangzhou during the same period and increased in Beijing owing to extended central heating use in winter. AH decreased more in urban centers and the change in AH varied in terms of urban land use between cities and periods. Although UHI changes during the COVID-19 pandemic cannot be entirely attributed to AH changes, the considerable reduction in AH is an important feature accompanying the weakening of the UHI.


Grisel's syndrome, a rare cause of anomalous head posture in children: a case report.
Anomalous head posture (AHP) or torticollis is a relatively common condition in children. Torticollis is not a diagnosis, but it is a sign of underlying disease. Grisel's syndrome (GS) is a rare condition of uncertain etiology characterized by a nontraumatic atlanto-axial subluxation (AAS), secondary to an infection in the head and neck region. It has not been considered, in ophthalmological papers, as a possible cause of AHP. A case of AAS secondary to an otitis media is studied. The children showed neck pain, head tilt, and reduction in neck mobility. The patient had complete remission with antibiotic and anti-inflammatory therapy and muscle relaxants. Signs of GS should always be taken into account during ophthalmological examination (recent history of upper airway infections and/or head and neck surgeries associated to a new onset of sudden, painful AHP with normal ocular exam). In such cases it is necessary to require quick execution of radiological examinations (computer tomography and/or nuclear magnetic resonance), which are essential to confirm the diagnosis. GS is a multidisciplinary disease. We underline the importance of an accurate orthoptic and ophthalmological examination. Indeed, early detection and diagnosis are fundamental to achieve proper management, avoid neurological complications and lead to a good prognosis.


Cancer and coagulation.
Thromboembolism, including both venous and arterial events, occurs commonly amongst patients with cancer. The occurrence of thromboembolism has significant consequences for cancer patients, including direct and indirect associations with mortality, morbidity, requirement for long-term anticoagulant therapy and consumption of healthcare resources. Recent studies have resulted in a better understanding of clinical risk factors and biomarkers of cancer-associated thrombosis, and a risk assessment model incorporating both has now been validated in multiple settings. Thromboprophylaxis with either unfractionated heparin or low-molecular-weight heparins (LMWHs) has been shown to be safe and effective in high-risk settings such as hospitalization for medical illness and the postsurgical period. Emerging new data from randomized studies have focused on outpatient prophylaxis, suggesting potential benefits in this setting as well. Treatment of cancer-associated thrombosis requires long-term anticoagulation with LMWH. Results from ongoing and planned trials of novel anticoagulants in the cancer setting are awaited.


Pulmonary hypertension in older adults.
Pulmonary hypertension is a frequently encountered problem in older patients. True idiopathic pulmonary arterial hypertension can also be seen and requires careful exclusion in older patients. Institution of therapies must be tempered with an appreciation of individual comorbidities and functional limitations that may affect patients' ability to comply and benefit from the complex treatments available for pulmonary arterial hypertension. This article reviews the existing data on the various forms of pulmonary hypertension presenting in older patients and on appropriate therapy in this challenging population.


Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model.
Transplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4-6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an "out-of-hospital" sudden unexpected death with subsequent "in-hospital" cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin-streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V-A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia-reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem. BGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6%, - 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice. Thus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma.


Single centre experience: long term outcomes in spina bifida patients.
To determine our single centre experience of long term renal function and mortality rates of our cohort of spina bifida patients born since 1970. We collected a prospective database and included all patients born with spina bifida between 1970 and 2011 managed by our centre. Data we collected included the glomerular filtration rates, results of renal tract imaging, management strategies and mortalities. Of 160 patients identified, 120 were included for analysis with a mean age of 20 years. In our cohort 48% (58/120) had normal renal function and only 1.6% (2/120) had severe renal impairment or end stage renal failure. There was a mortality rate of 4.4% and there were no deaths from renal failure. Spina bifida patients have been reported to have high mortality rates and high morbidity secondary to renal failure. Historical data does not appear to reflect current advancements and we would therefore be more optimistic when counselling families about long term survival into adulthood.