Fibroblast response to lanthanoid metal ion stimulation: potential contribution to fibrotic tissue injury.
The purpose of this study was to compare each of the 14 naturally occurring lanthanoid metal ions for ability to stimulate pro-fibrotic responses in human dermal fibroblasts. When fibroblasts were exposed to individual lanthanoids over the concentration range of 1-100 μM, increased proliferation was observed with each of the agents as compared with control cells that were already proliferating rapidly in a growth factor-enriched culture medium. Dose-response differences were observed among the individual metal ions. Matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 levels were also increased in response to lanthanoid exposure but type I procollagen production was not. A dose-response relationship between induction of proliferation and increased MMP-1 was observed. Non-lanthanoid transition metal ions (aluminum, copper, cobalt, iron, magnesium, manganese, nickel, and zinc) were examined in the same assays; there was little stimulation with any of these metals. When epidermal keratinocytes were examined in place of dermal fibroblasts, there was no growth stimulation with any of the lanthanoids. Several of the lanthanoid metals inhibited keratinocyte proliferation at higher concentrations (50-100 μM).


Traditional Chinese medicine: balancing the gut ecosystem.
Gut microflora has become a topic of interest in life sciences in the context of global systems biology, in which human biological system is viewed as 'superorganisms' involving an internal ecosystem of diverse microbiome. We conceive that multi-pathway modulations of the human gut microbial system exerted by traditional Chinese medicines (TCMs) to restore the balance of the gut ecology may account for a large portion of their effectiveness in host during treatment. Such a concept is evidenced by series of studies which have revealed an interactive relationship between gut microflora and TCM, involving the two important aspects: gut microflora-dependent drug metabolism in TCM and gut microflora-targeted modulation of physiological conditions, both of which highlight the significance of gut microflora involvement in the future TCM investigation.


The clinical characteristics and prognosis of acute zonal occult outer retinopathy.
This prospective observational case series study aimed to observe the clinical characteristics of acute zonal occult outer retinopathy (AZOOR) and its prognosis in Chinese Han patients. Six eyes of 5 female patients diagnosed with AZOOR were followed up for 4 months to observe the natural disease course. All enrolled subjects underwent a series of ocular examinations at the onset and each return visit, including best corrected visual acuity (BCVA), split lamp microscopy, fundus photography, optical coherence tomography (OCT), perimetry, multifocal electroretinogram and fundus fluorescein angiography. Over the follow-up, all enrolled patients recovered on BCVA, perimetry and OCT in different degrees. Among them, one patient recovered completely since the ocular examination results returned to normal. AZOOR is a rare ocular disorder in Chinese population. Our results demonstrated that visual functions of enrolled patients significantly improved spontaneously, indicating that Chinese female Han patients with AZOOR have good visual outcomes during the follow-up period without any specific managements.


Enhanced osteogenic activity of anatase TiO2 film: Surface hydroxyl groups induce conformational changes in fibronectin.
In this study, with an attempt to identify the effects of TiO2 crystalline phase compositions on the osteogenic properties, the anatase and rutile TiO2 thin films with similar film thickness, surface topography and hydrophilicity were prepared on Si (100) substrates by atomic layer deposition (ALD), subsequent thermal annealing and ultraviolet irradiation. The films were studied with XRD, XPS, FE-SEM, AFM, FTIR and contact angle measurements. In vitro cellular assays showed that the anatase phase led to better osteoblast compatibility in terms of adhesion, proliferation, differentiation, mineralization as well as osteogenesis-related gene expression when compared with the rutile phase. We investigated the difference between the anatase and rutile TiO2 films at the biomolecular level to explain the enhanced osteogenic activity of the anatase film. It was found that the presence of more TiOH groups on anatase surface induced more cell-binding sites of fibronectin (FN) exposed on its surface, causing a more active conformation of the adsorbed FN for subsequent osteoblast behaviors.


Site-directed gene replacement of the phytopathogen Xanthomonas axonopodis pv. citri.
In this work we defined experimental conditions for site-directed gene replacement of the Xanthomonas axonopodis pv. citri (Xac), an economically relevant pathogen of citrus plants. The procedure involved, first, optimizing the electrotransformation conditions of the Xac 306 strain and, second, constructing non-replicative suicide vectors carrying knockout copies of the target gene. Using specific experimental conditions, transformation efficiencies of Xac were at least 100 fold higher than those achieved with electroporation protocols previously designed for X. campestris transformation. Successful gene replacement events were achieved with a suicide vector derived from R6K plasmid (pWR-SS) but not with those with ColE1 replication origin. We have chosen the oppA as a target gene, encoding the binding component (OppA) of the major oligopeptide uptake system found in the genome of the Xac 306 strain, although not in X. campestris pv. campestris (Xcc). Defining the experimental conditions, which allow for the specific mutagenesis of the Xac 306 strain, represents a step in the understanding of both genetics and physiology of this economically important bacterial species.


Angiogenesis in relation to clinical stage, apoptosis and prognostic score in myelodysplastic syndromes.
The International Prognostic Scoring System (IPSS), based on the number of cytopenias, percentage of bone marrow blasts and cytogenetics, is an important prognostic tool for patients with myelodysplastic syndrome (MDS). In addition, factors such as high bone marrow cellularity and lactate dehydrogenase levels have been associated with an adverse outcome, spontaneously and after chemotherapy. Recently, increased bone marrow angiogenesis, measured as, e.g. microvascular density (MVD), was reported to be more intense in high-risk than in low-risk MDS. To assess the prognostic role of MVD in MDS, a cohort of 56 patients, thoroughly investigated for various clinical and morphological parameters, were followed-up for survival > or =60 months after the diagnostic analysis. As a group MDS patients had higher MVD compared to healthy controls (p<0.02). The highest median MVD value was observed in the RAEB group, but there was no overall significant difference between the FAB groups. No significant correlations were observed between MVD and peripheral blood counts, bone marrow cellularity, percentage of bone marrow blasts and CD34 positive cells, apoptotic index (TUNEL), proliferation index (MIB-1), erythroid index, FAB group and IPSS score. MVD was not correlated to overall survival. In contrast, bone marrow blast count <5%, low or normal cellularity, as well as a high erythroid index, indicated a favorable survival. Thus, our data do not support an important prognostic role of angiogenesis, reflected by microvessel density, in the myelodysplastic syndromes.


Expression of sialic acids in the developing murine tubotympanum.
Sialoglycoconjugates in the developing murine tubotympanum were characterized using lectin histochemistry with wheat germ agglutinin (WGA), Limax flavus agglutinin (LFA), Sambucus nigra agglutinin (SNA), Maackia amurensis agglutinin (MAA), peanut agglutinin (PNA), and neuraminidase treatment. WGA, LFA, MAA, and neuraminidase-PNA labeled epithelial goblet cells, glandular mucous cells, and cell surfaces of adult and newborn murine tubotympanum. SNA did not label any secretory components. PNA labeled secretory cells and cell surfaces of the fetal tubotympanum without neuraminidase treatment. After birth, these secretory cells and cell surfaces were labeled with PNA only after neuraminidase treatment. These results revealed that: Sialoglycoconjugates are produced from glandular mucous cells and epithelial goblet cells and are present on cell surfaces and within the mucous blanket; their terminal tri-saccharide linkage appears to be the sequence Neu5Ac(alpha 2-3)Gal(beta 1-3)GalNAc; sialic acids appear before birth and gradually increase; terminal galactose residues are masked by sialic acids after birth.


The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection.
Covid-19 has caused worldwide devastation. IFIH1 is a pattern recognition receptor that senses coronavirus RNA and triggers interferon production as a first line of viral immune defense. The role of IFIH1 polymorphism, rs1990760 (C>T; aaA946T) in the epidemiology of viral infection is well studied, and the minor allele T resists viral infection. Knock-in mice with mutated IFIH1 protein (946T) for this allele have enhanced interferon production and protection from lethal viral infection. The minor allele frequency (Tmaf) varies widely from Africans (0.06 to 0.35) to Chinese (0.19 to 0.23) to Caucasians (0.56 to 0.69). During the initial days of infection when the social restrictions were not imposed, I show that the infection rate in Italy was lower as expected from its higher Tmaf (0.56) than that in China (Tmaf for southern China, 0.23). The infection rate in the USA and Spain was intermediate between those two countries despite higher Caucasian overall Tmaf (0.69), perhaps due to a more admixed African population in these countries. These analyses suggest that African-Americans and Chinese with low Tmaf of rs1990760 are more vulnerable to SARS-COV2 infection, apart from other genetic factors or socioeconomic conditions in these population. Taken together, an IFN-beta supplement might aid in preventing COVID-19 infection and help in development of herd immunity.


Presentation of orbital solitary fibrous tumours.
To evaluate presenting features of patients with orbital solitary fibrous tumours (SFTs), based on histological phenotype. A retrospective case-note review was performed for demographics and presenting features for patients with orbital SFTs. The tumours were classified as "Group IA" hypocellular SFT phenotype, "Group IB" haemangiopericytoma phenotype and low mitotic activity, and high-grade "Group II" haemangiopericytoma phenotype with high mitotic activity. Sixty-four patients (34 female; 53%) presented at a mean age of 42.2 years (median 38; range 19-82), with Group II patients presenting at an older age (mean 53 years). Median symptom duration was 12 months for Groups IA and IB, compared to 4 months for Group II, the commonest symptoms being proptosis (53%), diplopia (41%), periorbital swelling (31%), and altered vision (19%). Mean LogMAR was 0.17 (median 0.0; range -0.2-4), and 14% had ipsilateral optic neuropathy, with no significant difference between the three groups. Non-axial displacement was noted in 69%, a palpable mass in 45%, and reduced eye movements in 59%; choroidal folds and optic disc swelling were recorded in 12% and 9%. SFTs were mostly extraconal (59%), within the superior and superonasal quadrants (44%), with an average estimated tumour volume of 4.9 ml (median 3.6; range 0.31-14.5 ml). SFTs may present with impaired visual function (∼15%), fundal abnormalities (a fifth), globe displacement (two-thirds), and reduced ocular motility (over a half). High-grade tumours tend to present more than a decade later, with a shorter duration of symptoms.


[Experimental study of regulation in the female genital larval anlage ofTenebrio molitor L.]
The femaleTenebrio molitor genital anlage differentiates from a part of the sternal and abdominal integument of the larva. This epidermal tissue shows a very high regulative capacity during the whole life of the larva. This capacity appears only within the regulative area. The presumptive genital epidermis is composed of labile, morphogenetic fields. It shows however a determined axis of polarity controlled by adjacent abdominal tissues forming a part of the regulative area.


5-fluorouracil and hydroxyurea enhance adenovirus-mediated transgene expression in colon and hepatocellular carcinoma cells.
To investigate the efficient transduction of tumor cells which remains a major limitation of cancer gene therapy. In this study, we tested whether treatment with antimetabolic drugs 5-FU and hydroxyurea (HU) could improve adenovirus-mediated gene expression in tumor cells. We found that 5-FU and HU treatment significantly increased beta-gal activity in adenovirus (Ad.CMVBG)-infected human colon carcinoma (LoVo) and hepatocellular carcinoma (SMMC7721) cells in a dose- and time-dependent manner. These increases were maximized at 5.01+/-0.42-fold and 3.32+/-0.32-fold for 5-FU (50 microM), and at 6.60+/-0.50-fold and 4.82+/-0.43-fold for HU (5 mM) treatment, respectively, after 48 h infection. Transient increases in viral uptake, determined by real-time PCR for viral DNA content and by confocal microscopy for viral particles, were observed in 5-FU or HU-treated cells that partially contribute to the overall increases of beta-gal expression. Moreover, mRNA levels for the beta-gal gene in infected cells were significantly increased in both LoVo and SMMC7721 cells by 5-FU and HU treatment in contrast to the inhibition of viral DNA replication and the unchanged mRNA levels for alpha-actin gene. The induction appeared to be the result of enhanced transcription since beta-gal mRNA half-life was not affected by drug treatment. However, similar induction was not detected in CMV-beta-gal-expressing stable cells, suggesting that an adenovirus-associated mechanism might be involved in this induction. Our findings suggest that it may be possible to improve tumor cell transduction by adenovirus using chemotherapy.


Efficacy of hepatic computed tomography to detect iron overload in chronic hemodialysis.
The diagnostic efficacy of hepatic computed tomography density (HCTD) in comparison with serum ferritin for the detection of iron overload was investigated in uremic patients on maintenance hemodialysis (HD) and in patients with idiopathic hemochromatosis (IHC). Ten IHC patients, 38 HD patients and 40 healthy subjects underwent the CT scanning of the liver and determination of percent saturation of transferrin, serum ferritin concentration and HLA typing. Liver iron content was determined by histochemical grading and direct measurement of liver iron concentration either in IHC patients or in HD patients. Nineteen HD patients were considered to have iron overload on the basis of liver iron concentration exceeding 3.6 mumol/100 mg dry weight. The mean +/- SD values of HCTD in healthy subjects, IHC patients, HD patients with iron overload and without iron overload were 60.2 +/- 5.6, 79 +/- 5.6, 71.4 +/- 3.6, 58 +/- 3.8 Hounsfield units, respectively. HCTD showed positive correlations with liver iron concentration and serum ferritin either in IHC patients or in HD patients. The analysis of the diagnostic efficacy of HCTD in comparison with serum ferritin for the detection of excessive hepatic iron in HD patients demonstrated that HCTD had higher sensitivity, specificity, positive and negative predictive values. Cut-off points were arbitrarily fixed to 66 Hounsfield units for HCTD, 400 micrograms/liter for serum ferritin and 3.6 mumol/100 mg dry weight for liver iron concentration. Seventeen HD patients who possessed the histocompatibility antigens associated with IHC, namely HLA-A3 and/or HLA-B7 and/or HLA-B14, had liver iron concentration, serum ferritin and HCTD values higher than those of the HD patients without these "hemochromatosis alleles".(ABSTRACT TRUNCATED AT 250 WORDS)


Predicting high-grade prostate cancer at initial biopsy: clinical performance of the ExoDx (EPI) Prostate Intelliscore test in three independent prospective studies.
The ability to discriminate indolent from clinically significant prostate cancer (PC) at the initial biopsy remains a challenge. The ExoDx Prostate (IntelliScore) (EPI) test is a noninvasive liquid biopsy that quantifies three RNA targets in urine exosomes. The EPI test stratifies patients for risk of high-grade prostate cancer (HGPC; ≥ Grade Group 2 [GG] PC) in men ≥ 50 years with equivocal prostate-specific antigen (PSA) (2-10 ng/mL). Here, we present a pooled meta-analysis from three independent prospective-validation studies in men presenting for initial biopsy decision. Pooled data from two prospective multi-site validation studies and the control arm of a clinical utility study were analyzed. Performance was evaluated using the area under the receiver-operating characteristic curve (AUC), negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity for discriminating ≥ GG2 from GG1 and benign pathology. The combined cohort (n = 1212) of initial-biopsy subjects had a median age of 63 years and median PSA of 5.2 ng/mL. The EPI AUC (0.70) was superior to PSA (0.56), Prostate Cancer Prevention Trial Risk Calculator (PCPT-RC) (0.62), and The European Randomized Study of Screening for Prostate Cancer (ERSPC) (0.59), (all p-values <0.001) for discriminating GG2 from GG1 and benign histology. The validated cutoff of 15.6 would avoid 23% of all prostate biopsies and 30% of "unnecessary" (benign or Gleason 6/GG1) biopsies, with an NPV of 90%. EPI is a noninvasive, easy-to-use, urine exosome-RNA assay that has been validated across 3 independent prospective multicenter clinical trials with 1212 subjects. The test can discriminate high-grade (≥GG2) from low-grade (GG1) cancer and benign disease. EPI effectively guides the biopsy-decision process independent of PSA and other standard-of-care factors.


Cribriform growth pattern in lung adenocarcinoma: More aggressive and poorer prognosis than acinar growth pattern.
The predictive value of prognosis based on the histopathological subtype is a critical criterion in the new classification of lung adenocarcinoma published in 2011 by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) (IASLC/ATS/ERS). In this new classification, the differences of histopathology and prognosis are two considerable parameters to classify the subtypes of lung adenocarcinoma. Cribriform growth pattern is regarded as a variant of acinar growth pattern in lung adenocarcinoma, however, more and more studies pointed out that cribriform growth pattern is associated with more aggressive histopathological structures, higher proportion of recurrence rates, and shorter postoperative survival than acinar growth pattern. These features are similar to solid or micropapillary predominant adenocarcinoma. In this review, we summarized the clinicopathological features, prognosis, and genetic variations of cribriform growth pattern of lung adenocarcinoma, and provided a novel insight into the diagnosis and treatment of cribriform lung adenocarcinoma.


Students' perceptions, engagement and satisfaction with the use of an e-rubric for the assessment of manual skills in physiotherapy.
In recent years, formative assessment has gained importance in health care education to facilitate and enhance learning throughout the training period. Within the frame of active methodologies, rubrics have become an essential instrument for formative assessment. Most rubric-based assessment procedures focus on measuring the effects of rubrics on teachers. However, few studies focus their attention on the perception that students have of the evaluation process through rubrics. A cross-sectional survey study was carried out with 134 students enrolled in the pre-graduate Physiotherapy education. Assessment of manual skills during a practical examination was performed using an e-rubric tool. Peer-assessment, self-assessment and teacher´s assessment were registered. After completion of the examination process, students' perceptions, satisfaction and engagement were collected. Quantitative results related to students' opinion about e-rubric based assessment, students' engagement, perceived benefits and drawbacks of the e-rubric as well as the overall assessment of the learning experience were obtained. 86.6% of the students agreed upon the fact that "the rubric allowed one to know what it is expected from examination" and 83.6% of the students agreed upon the fact that "the rubric allowed one to verify the level of competence acquired". A high rate of agreement (87.3%) was also reached among students concerning feedback. E-rubrics seemed to have the potential to promote learning by making criteria and expectations explicit, facilitating feedback, self-assessment and peer-assessment. The importance of students in their own learning process required their participation in the assessment task, a fact that was globally appreciated by the students. Learning experience was considered interesting, motivating, it promoted participation, cooperative work and peer-assessment. The use of e-rubrics increased engagement levels when attention was focused on their guidance and reflection role.


Colectomy for acute colitis: is it safe to close the rectal stump?
We report 62 operations for acute colonic inflammatory bowel disease in which the rectal stump was closed. Operative findings were of severe colitis in 46, toxic megacolon in 8 and faecal peritonitis in 8 patients. Histology showed ulcerative colitis in 48, Crohn's disease in 9 and indeterminate colitis in 5 patients. Clinical evidence of stump leakage occurred in only one of 53 patients with a long rectal stump in contrast to 3 of 9 patients who had a short rectal stump. Leaving a very short stump also led to difficulty at subsequent proctectomy in 3 patients and at restorative proctocolectomy in 1 patient. This suggests that careful closure of the rectum above the peritoneal reflection can be a safe means of dealing with the rectal stump after total colectomy and ileostomy for acute colitis.


Sequence-specific DNA-binding activities of the gap proteins encoded by hunchback and Krüppel in Drosophila.
The segmentation of the Drosophila body plan depends on a hierarchy of interactions among approximately 20-25 regulatory genes that are active in the early embryo (refs 1-4; for a review see ref. 5). The gap genes have a key role in this process and are responsible for the periodic expression of certain pair-rule genes and the localized expression of several homoeotic genes. The two best characterized gap genes, hunchback (hb) and Krüppel (Kr), contain homologies with the zinc-finger DNA-binding motif, although their mode of action in the early embryo is unknown. Here we report that both of the proteins encoded by these genes possess sequence-specific DNA-binding activities, which indicates that they might regulate gene expression at the level of transcription. The binding sites of the hb gene product are related by a 10-base pair (bp) consensus sequence, G/A C/C ATAAAAAA, whereas the binding sites of the Kr gene product share a distinct 10-bp motif, AACGGGTTAA. It is possible that the hb and Kr proteins cooperatively regulate gene expression, because they are expressed in broad, overlapping gradients in the early embryo. We also provide evidence that the on/off periodicity of the pair-rule gene even-skipped (eve) involves the interaction of the hb and Kr proteins with defined eve promoter elements.


Automated reading of a microtitre plate: preliminary evaluation in antimicrobial susceptibility tests and Enterobacteriaceae identification.
An automated microELISA Reader was evaluated for its ability to read and interpret microtitre plates. A total of 309 microtitre plates were investigated by automated and visual methods. There was disagreement between the methods in one hundred and twelve (0.6%) wells. However agreements between the two methods for susceptibility tests and Enterobacteriaceae identification were respectively 98.8% and 89.3%.


KDM5D inhibits the transcriptional activation of FKBP4 by suppressing the expression of E2F1 in colorectal cancer in males.
Colorectal cancer (CRC) remains the most frequently diagnosed malignancy and also a major contributor to cancer-related death throughout the world. Here, we first revealed the role of histone lysine-specific demethylase 5D (KDM5D) in CRC in males. KDM5D expression in tumor and adjacent tissues of male CRC patients was investigated using immunohistochemistry and RT-qPCR, and the correlation between its expression and patients' prognosis was analyzed. Downregulation of KDM5D in CRC patients was associated with poor prognoses. Overexpression of KDM5D significantly inhibited the growth and metastasis of CRC in vitro and in vivo. The downstream mechanism of KDM5D in CRC was investigated using bioinformatics analysis, and the regulatory relationship was confirmed by ChIP-qPCR and luciferase reporter assays. KDM5D suppressed E2F1 expression by mediating H3K4me3 demethylation. E2F1, highly expressed in CRC, promoted the expression of FKBP4 at the transcriptional level by binding to the FKBP4 promoter. Finally, rescue experiments revealed that overexpression of FKBP4 significantly reversed the inhibitory effect of KDM5D on CRC growth and metastasis. Collectively, KDM5D exerted an anti-tumor and anti-metastatic in CRC through demethylation in E2F1 and suppression of FKBP4 transcription, which might represent a novel target in CRC treatment in male.


Ratiometric fluorescent sensing carbendazim in fruits and vegetables via its innate fluorescence coupling with UiO-67.
A ratiometric fluorescent sensor was facilely fabricated using innate fluorescence of carbendazim (MBC) and fluorescent UiO-67 to sensitively and selectively detect MBC in food matrixes. The innate fluorescence of MBC provided a signal at 311 nm (F311), and the fluorescent UiO-67 at 408 nm (F408) could recognize MBC through π-π stacking inducing fluorescent quenching relied on photoelectron transfer (PET). The ratio (F311/F408) of the fluorescence enhancement of MBC and the quenching of UiO-67 linearly responded to the MBC concentrations of 0-47.6 μmol/L with a low limit of detection (LOD) of 3.0 × 10-3 μmol/L. The reverse response signals of the sensor enhanced the sensitivity toward MBC and presented remarkable anti-interference capability in complex matrices. The as-prepared sensor was applied to detect MBC residues in apple, cucumber and cabbage, obtaining satisfactory accuracy and precision with the recovery of 90.82-103.45% and RSDs of lower than 3.03%.


Nanoreactors: Strategies to encapsulate enzyme biocatalysts in virus-like particles.
Enzyme-mediated biocatalysis is generally more selective and environmentally friendly and requires less energy than chemocatalysis. However, factors such as temperature, acidity and the presence of proteases can negate enzyme activity. Encapsulation in virus-like particles is one promising method to mitigate these difficulties. Encapsulation also can be used to create multi-reaction nanoreactors that increase process efficiency by isolating reaction intermediates. To successfully encapsulate enzymes, a variety of methods involving both non-covalent and covalent interactions have been developed. Here we review promising virus-like particle encapsulation strategies, their advantages and remaining challenges.


Clinical efficacy of eucaloric ketogenic nutrition in the COVID-19 cytokine storm: A retrospective analysis of mortality and intensive care unit admission.
Our primary objective was to explore the effect of a eucaloric ketogenic diet (EKD) on mortality, admission to the intensive care unit, and need for non-invasive ventilation in hospitalized patients with COronaVIrus Disease 19 (COVID-19), in comparison to a eucaloric standard diet. Secondary objectives were verification of the safety and feasibility of the diet and its effects on inflammatory parameters, particularly interleukin-6. The study is a retrospective analysis of 34 patients fed with an EKD in comparison to 68 patients fed with a eucaloric standard diet, selected and matched using propensity scores 1:2 to avoid the confounding effect of interfering variables. Our hypothesis was that an EKD would reduce mortality, admission to the intensive care unit, and need for non-invasive ventilation in patients with COVID-19. The preliminary multivariate analysis showed a statistically significant difference in survival (P = 0.046) and need for the intensive care unit (P = 0.049) for the EKD compared with a eucaloric standard diet. Even considering the EKD start day as a time-dependent variable, the results maintain a positive trend for application of the diet, and it is not possible to reject the null hypothesis (P < 0.05). Interleukin-6 concentrations between t0 and t7 (7 d after the beginning of the diet) in the ketogenic nutrition group show a trend that is almost significant (P = 0.062). The EKD was safe and no adverse events were observed. These results show a possible therapeutic role of an EKD in the clinical management of COVID-19. Currently, a prospective controlled randomized trial is running to confirm these preliminary data.


Excision of massive left branchial cleft cyst with secondary hypertension.
Branchial anomalies are heterogeneous congenital malformations that form secondary to incomplete closure of pharyngeal clefts and pouches. There have been no reports of branchial cleft cysts causing carotid artery compression and hypertension. We report a large branchial cleft cyst causing suspected secondary hypertension from carotid artery compression.


Night work and breast cancer in women: a Swedish cohort study.
Recent research has suggested a moderate link between night work and breast cancer in women, mainly through case-control studies, but non-significant studies are also common and cohort studies are few. The purpose of the present study was to provide new information from cohort data through investigating the association between the number of years with night work and breast cancer among women. Cohort study of individuals exposed to night shift work in relation to incidence of breast cancer in women. Individuals in the Swedish Twin registry, with follow-up in the Swedish Cancer Registry. 13,656 women from the Swedish Twin Registry, with 3404 exposed to night work. Breast cancer from the Swedish Cancer Registry (463 cases) during a follow-up time of 12 years. A Cox proportional hazards regression analysis with control for a large number of confounders showed that the HR was HR=1.68 (95% CI 0.98 to 2.88) for the group with >20 years of night work. When the follow-up time was limited to ages below 60 years, those exposed >20 years showed a HR=1.77 (95% CI 1.03 to 3.04). Shorter exposure to night work showed no significant effects. The present results, together with previous work, suggest that night work is associated with an increased risk of breast cancer in women, but only after relatively long-term exposure.


Current outlook of ethics in research with human subjects.
In the last decades, medical care has been increasingly permeated by the concept of evidence-based-medicine, in which clinical research plays a crucial role in establishing diagnostic and treatment. Following the improvements in clinical research, we have a growing concern and understanding that some ethical issues must be respected when the subjects are human beings. Research with human subjects relies on the principles of autonomy, beneficence, no maleficence and justice. Ordinance 196/96 from the National Health Board adds to the Brazilian legislation such renowned bioethical principles. Discuss the main ethical aspects involved in research with human subjects. Critical analysis of Ordinance 196/96 and related literature. Ordinance 196/96 rules research with human subjects; nevertheless, it requires more in-depth discussions regarding the informed consent, use of placebo, research with vulnerable populations and research in developing countries.


Interactions of unconjugated bilirubin with vesicles, cyclodextrins and micelles: new modeling and the role of high pKa values.
Unconjugated bilirubin (UCB) is an unstable substance with very low aqueous solubility. Its aqueous pKa values affect many of its interactions, particularly their pH-dependence. A companion paper shows that only our prior solvent partition studies, leading to pKa values of 8.12 and 8.44, met all essential requirements for valid pKa determinations. Other published values, generally lower, some below 5.0, were shown to be invalid. The present work was designed to derive suitable models for interpreting published data on the pH-dependent binding of UCB with four agents, mentioned below, chosen because they are not, themselves, sensitive to changes in the pH range 4-10, and the data, mainly spectrometric, were of reasonable quality. These analyses indicated that the high pKa values, dianion dimerization constant and solubilities of UCB at various pH values, derived from our partition studies, along with literature-derived pH- and time-dependent supersaturation effects, were essential for constructing useful models that showed good qualitative, and sometimes quantitative, fits with the data. In contrast, published pKa values below 5.0 were highly incompatible with the data for all systems considered. The primary species of bound UCB in our models were: undissociated diacid for phosphatidylcholine, dianion for dodecyl maltoside micelles and cyclodextrins, and both monoanions and dianion for sodium taurocholate. The resulting binding versus pH profiles differed strikingly from each other. The insights derived from these analyses should be helpful to explore and interpret UCB binding to more complex, pH-sensitive, physiological moieties, such as proteins or membranes, in order to understand its functions.


Having the courage to be competent: persons and families living with aphasia.
This paper provides examples and illustrations of how aphasic people can and do demonstrate their competence in managing their lives despite chronic aphasia. It discusses a number of ways in which aphasic persons and their families can learn to live fully despite the intrusion of aphasia. After reading this paper, participants should (1) have a more fully developed appreciation of what it means to live courageously with aphasia, (2) recognize the importance of developing a lifespan perspective following the onset of aphasia, and (3) better understand competence in aphasia.


In-vitro biodegradation and corrosion-assisted cracking of a coated magnesium alloy in modified-simulated body fluid.
A calcium phosphate coating was directly synthesized on AZ91D magnesium (Mg) alloy. Resistance of this coating to corrosion in a modified-simulated body fluid (m-SBF) was investigated by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). Mechanical properties of the bare and coated alloy were investigated using slow strain rate tensile (SSRT) and fatigue testing in air and m-SBF. Very little is reported in the literature on human-body-fluid-assisted cracking of Mg alloys, viz., resistance to corrosion fatigue (CF) and stress corrosion cracking (SCC). This study has a particular emphasis on the effect of bio-compatible coatings on mechanical and electrochemical degradations of Mg alloys for their applications as implants. The results suggest the coating to improve the general as well as pitting corrosion resistance of the alloy. The coating also provides visible improvement in resistance to SCC, but little improvement in CF resistance. This is explained on the basis of pitting behaviour in the presence and absence of the coating.


Complete bioavailability and lack of food-effect on pharmacokinetics of gliclazide 30 mg modified release in healthy volunteers.
A new modified release (MR) formulation containing 30 mg of gliclazide was developed to obtain a better predictable release of the active principle and to allow once-daily dosing regimen. An absolute bioavailability study was carried out to characterise the performance of the new formulation and the food-effect was also investigated in a separate study. Both studies were single dose, randomised, open label, two way cross over studies with a wash out period between doses. For the bioavailability study, each volunteer received 30 mg of gliclazide given either as a 1 h intravenous infusion or as a 30 mg MR tablet. For the food-effect study, the treatment was given either fasted or 10 min after the start of a standardised Melander breakfast. Blood samples were collected up to 72 h after administrations and plasma samples assayed for gliclazide concentrations using a reverse-phase HPLC method with UV detection. Mean absolute bioavailability of gliclazide was 97% and ranged between 79 and 110% showing complete absorption. A similar moderate to low variability was observed after IV and oral administration showing the MR formulation did not add to the overall variability which is solely due to the disposition parameters, in particular metabolism of gliclazide. No significant difference was observed in t(max), t(1/2z), C(max) and AUC of gliclazide after administration of the 30 mg MR tablet under fasted and fed conditions. In conclusion, after single oral administration of a 30 mg MR tablet, gliclazide was completely absorbed both under fasted and fed conditions. A consistent and optimal release of gliclazide from this formulation leads to a low to moderate overall variability of its pharmacokinetic parameters. Diamicron 30 mg MR can be given without regards to meals i.e. before, during or after breakfast.


Development of a novel three-dimensional magnetic polymer aerogel as an efficient adsorbent for malachite green removal.
A novel three-dimensional (3D) magnetic bacterial cellulose nanofiber/graphene oxide polymer aerogel (MBCNF/GOPA) composed of bacterial cellulose nanofibers (BCNFs), Fe3O4 nanoparticles, graphene oxide (GO) nano-sheets, and polyvinyl alcohol (PVA) was developed by combining a facile filler-loaded networks method with a vacuum freeze-drying process for the removal of malachite green (MG) dye from aqueous solution. The influence of various factors on adsorption, including initial dye concentration, adsorbent dosage, contact time, temperature, and pH of dye solution, was then investigated. The adsorbent preserved a high adsorption capacity over a wide range of pH conditions. Moreover, the adsorption isotherms data fitted well with the Langmuir isotherm model with a maximum adsorption capacity of 270.27 mg g-1. Adsorption kinetics followed the pseudo-second-order model, and the thermodynamic parameters showed that the adsorption of MG dye was feasible and endothermic in nature and occurred spontaneously. Therefore, owing to its demonstrated properties such as 3D interconnected porous structure, lightweight, large specific surface area, superparamagnetic behavior at room temperature, excellent adsorbent efficiency (93% removal) and also its simple and eco-friendly synthesis process, MBCNF/GOPA could be considered a promising candidate for removing cationic dye pollutants from aqueous solution, which can easily be collected from aqueous solution by a small magnet. MBCNF/GOPA also showed favorable reusability for MG removal in wastewater treatment, and its application in different water samples for the removal of MG dye molecules from "real" samples was successfully performed.


Corrigendum: Nutrient intake and nutrition status in vegetarians and vegans in comparison to omnivores-the nutritional evaluation (NuEva) study.
[This corrects the article DOI: 10.3389/fnut.2022.819106.].


Bayesian-based decipherment of in-depth information in bacterial chemical sensing beyond pleasant/unpleasant responses.
Chemical sensing is vital to the survival of all organisms. Bacterial chemotaxis is conducted by multiple receptors that sense chemicals to regulate a single signalling system controlling the transition between the direction (clockwise vs. counterclockwise) of flagellar rotation. Such an integrated system seems better suited to judge chemicals as either favourable or unfavourable, but not for identification purposes though differences in their affinities to the receptors may cause difference in response strength. Here, an experimental setup was developed to monitor behaviours of multiple cells stimulated simultaneously as well as a statistical framework based on Bayesian inferences. Although responses of individual cells varied substantially, ensemble averaging of the time courses seemed characteristic to attractant species, indicating we can extract information of input chemical species from responses of the bacterium. Furthermore, two similar, but distinct, beverages elicited attractant responses of cells with profiles distinguishable with the Bayesian procedure. These results provide a basis for novel bio-inspired sensors that could be used with other cell types to sense wider ranges of chemicals.


Peroxidative oxidation of leuco-dichlorofluorescein by prostaglandin H synthase in prostaglandin biosynthesis from polyunsaturated fatty acids.
Prostaglandin H synthase can oxidize arachidonic acid with leuco-dichlorofluorescein as reducing cosubstrate. Addition of 0.5 mM phenol increases the oxidation of leuco-dichlorofluorescein to dichlorofluorescein 5-fold, probably by acting as a cyclic intermediate in the oxidation. Tetramethyl-p-phenylenediamine is also oxidized as cosubstrate. Its oxidation is not influenced by phenol. A stoichiometry of close to one mole of tetramethyl-p-phenylenediamine or leuco-dichlorofluorescein consumed per mole of arachidonic acid was found in the initial phase of the reaction. In the presence of phenol + leuco-dichlorofluorescein, the oxidation rate of arachidonic acid is about 40% lower than with phenol alone as cosubstrate. Since dichlorofluorescein has a molar extinction coefficient of 91 . 10(3) at 502 nm, the oxidation of less than 1 microM leuco-dichlorofluorescein can be detected spectrophotometrically. The rate of extinction change with leuco-dichlorofluorescein (at 502 nm) is about 4-fold more rapid than with tetramethyl-p-phenylenediamine (at 611 nm). With this spectrophotometric assay we have confirmed that arachidonic acid, linolenic acid, adrenic acid, gamma-linolenic acid, eicosapentaenoic acid, are substrates for prostaglandin H synthase with decreasing reaction rates in the mentioned order. The same order of reaction rates were found when oxygen consumption was measured. The assay also shows that docosahexaenoic acid is substrate for the enzyme. The reaction rate of the enzyme evidently is decreased both by a n-3 double bond and by deviation from a 20 carbon chain length of the fatty acid substrate.


MIND-S is a deep-learning prediction model for elucidating protein post-translational modifications in human diseases.
We present a deep-learning-based platform, MIND-S, for protein post-translational modification (PTM) predictions. MIND-S employs a multi-head attention and graph neural network and assembles a 15-fold ensemble model in a multi-label strategy to enable simultaneous prediction of multiple PTMs with high performance and computation efficiency. MIND-S also features an interpretation module, which provides the relevance of each amino acid for making the predictions and is validated with known motifs. The interpretation module also captures PTM patterns without any supervision. Furthermore, MIND-S enables examination of mutation effects on PTMs. We document a workflow, its applications to 26 types of PTMs of two datasets consisting of ∼50,000 proteins, and an example of MIND-S identifying a PTM-interrupting SNP with validation from biological data. We also include use case analyses of targeted proteins. Taken together, we have demonstrated that MIND-S is accurate, interpretable, and efficient to elucidate PTM-relevant biological processes in health and diseases.


Hyperparathyroidism.
Because of the variable and vague clinical symptoms of the disease, diagnosis of hyperparathyroidism may be missed or delayed.Presenting symptoms and findings may be localized to the urological system or to the skeletal framework, with indications of abnormal blood calcium levels.In any case in which the patient's only complaints are malaise, lassitude, or progressive weakness, and in which routine laboratory findings are inconclusive, the blood calcium level should be determined. While not in itself diagnostic, a high level of calcium in the blood will lead to further investigation such as skeletal x-ray studies and blood phosphorus and serum alkaline phosphatase determinations. Vigilance postoperatively to forestall tetany is of great importance.


Epidermal growth factor receptor mutations as a prognostic factor in Korean patients with advanced lung adenocarcinoma who had not been treated with received epidermal growth factor receptor tyrosine kinase inhibitors.
Epidermal growth factor receptor (EGFR) mutations as prognostic marker in patients with non-small cell lung cancers remain controversial. In particular, there is only a limited amount of data on the subject in Asian patients with advanced lung adenocarcinomas. We analyzed 50 patients with advanced lung adenocarcinoma, who received best supportive care with and without cytotoxic chemotherapy, between March 2006 and December 2008. The patients had never been treated with EGFR tyrosine kinase inhibitors. Tumor tissues of all 50 patients were analyzed for the status of EGFR gene mutations. The median age of patients was 64 years (range 32-84) at diagnosis, and the male/female ratio was 2.6/1.0. Thirty-two patients were current or ever smokers. EGFR gene mutations were detected in 11 patients (22%). Seven of them had in-frame deletion within exon 19, resulting in the loss of codon 746 through 750 (delE746-A750), 2 patients had L858R in exon 21, and 2 patients had point mutation at codon 709 in exon 18, resulting in the substitution of glycine either with glutamic acid or alanine. The status of EGFR mutations was not significantly associated with gender, smoking status, ages, metastatic sites and number of metastasized sites. Seventeen patients received best supportive care without cytotoxic chemotherapy and 33 patients received the standard platinum-based doublet chemotherapy. The median overall survival was 8.90 months (95% CI 4.01-13.79). There were no significant differences in overall survival (p = 0.282) according to the status of EGFR mutations. These results suggest that EGFR mutation is not a prognostic marker in Korean patients with advanced lung adenocarcinoma who had not been treated with EGFR tyrosine kinase inhibitors.


Optimal deployment of automated external defibrillators in a long and narrow environment.
Public access to automated external defibrillators (AEDs) plays a key role in increasing survival outcomes for patients with out-of-hospital cardiac arrest. Based on the concept of maximizing "rescue benefit" of AEDs, we aimed to propose a systematic methodology for optimizing the deployment of AEDs, and develop such strategies for long and narrow spaces. We classified the effective coverage of an AED in hot, warm, and cold zones. The AEDs were categorized, according to their accessibility, as fixed, summonable, or patrolling types. The overall rescue benefit of the AEDs were evaluated by the weighted size of their collective hot zones. The optimal strategies for the deployment of AEDs were derived mathematically and numerically verified by computer programs. To maximize the overall rescue benefit of the AEDs, the AEDs should avoid overlapping with each other's coverage as much as possible. Specific rules for optimally deploying one, two, or multiple AEDs, and various types of AEDs are summarized and presented. A methodology for assessing the rescue benefit of deployed AEDs was proposed, and deployment strategies for maximizing the rescue benefit of AEDs along a long, narrow, corridor-like, finite space were derived. The strategies are simple and readily implementable. Our methodology can be easily generalized to search for optimal deployment of AEDs in planar areas or three-dimensional spaces.


Effect of oral alcohol administration on plasma cytokine concentrations in heavy drinking individuals.
Alcohol is known to modulate the immune system, including cytokines, under conditions of both acute consumption and chronic use. The specific pro- and anti-inflammatory effects and mechanisms whereby alcohol consumption modulates circulating cytokine concentrations are not well understood. Few studies in humans have investigated the effect of acute alcohol consumption on plasma cytokine concentrations in individuals who are heavy drinkers. Data were pooled from two studies involving a total of 25 non-treatment seeking, heavy drinking individuals who undertook an oral alcohol administration procedure. Plasma cytokine [Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-18 (IL-18) and Tumor Necrosis Factor-alpha (TNF-α)] concentrations were measured at two baseline timepoints, then three hours after alcohol administration, and finally when breath alcohol concentrations returned to zero. Linear mixed models were conducted to determine whether there was a significant effect of time on cytokine concentrations. There was a significant reduction in TNF-α concentration (F [3, 20.42] = 4.96, p = 0.01, η2p = 0.42) post alcohol administration, compared to baseline concentrations, and a significant increase in IL-6 concentrations (F [3, 27.81] = 9.06, p < 0.001, η2p = 0.49) post alcohol administration, compared to baseline. There were no significant changes in IL-18 or IL-10 concentrations. To our knowledge, this is the first study to examine the acute effect of oral alcohol consumption on peripheral inflammatory markers in individuals with alcohol use disorder. Results indicate a clinically relevant increase in proinflammatory cytokines approximately 3 h after initial alcohol ingestion. Further research should be done to elucidate the complex interaction between alcohol and the immune system.


Continuous high-frequency stimulation in freely moving rats: development of an implantable microstimulation system.
High-frequency stimulation (HFS) of basal ganglia and thalamic nuclei is an established treatment for various movement disorders and has recently been extended to other neuro-psychiatric conditions. Numerous experimental studies in small laboratory animals provided important insights in the mode of action of HFS. However, the interpretation of the results is often limited by the use of short-term HFS, while patients receive continuous stimulation for many years. One reason is the lack of an established model for the application of long-term HFS in small animals. Therefore, we thought to develop an implantable microstimulation system for small laboratory animals and to establish a protocol for long-term HFS by defining non-damaging stimulus parameters with respect to brain integrity. For this purpose, we designed a miniaturized, microcontroller-based, and programmable microstimulator that allows the reliable application of continuous HFS for up to 5 weeks. Chronic HFS (total stimulation time: 3 weeks) of the subthalamic nucleus with up to 100 microA (5.2 nC/phase) through monopolar electrodes comprising activated iridium did not induce significant tissue damage as assessed by various histological techniques (Nissl's, hematoxylin and eosin, Klüver-Barrera, van Gieson's staining, NeuN and GFAP-immunoreactivity). In conclusion, chronic HFS with an implantable stimulator can be successfully applied in small animals.


Atrial Fibrillation After mRNA-1273 SARS-CoV-2 Vaccination: Case Report with Literature Review.
COVID-19 vaccination has been associated with various adverse outcomes. Although studies have reported cases of arrhythmia after COVID-19 vaccination, the precise underlying mechanism remains to be elucidated. Here, we report the case of a patient who developed atrial fibrillation after receiving the mRNA-1273 vaccine and describe our findings in light of relevant cases in the literature. This is a case report and a review of the relevant literature. A 55-year-old woman presented to our clinic with a history of paroxysmal atrial fibrillation, hypertension, and mild mitral valve prolapse. The patient developed atrial fibrillation 3 days after receiving a COVID-19 vaccine. She was diagnosed with moderate-to-severe tricuspid regurgitation and severe mitral regurgitation, and underwent valve repair surgery. To obtain relevant articles (December 2020 through August 2022), we searched the following key words on PubMed: atrial fibrillation and COVID-19 vaccination. A total of 5 relevant case reports were identified. COVID-19 vaccination led to arrhythmia, including atrial fibrillation, within 14 days. Cases of patients developing arrhythmia after COVID-19 vaccination have been increasingly reported. Although the underlying mechanism remains unclear, we hypothesize that mRNA vaccination may lead to arrhythmia and associated valve diseases. Thus, before administering mRNA-1273 vaccines to patients with a history of valvular heart disease or atrial fibrillation, the patients' cardiologists must be consulted.


Case report--death by subcutaneous injection of cyanide in Sri Lanka.
An elderly man was stabbed with a needle and syringe onto his abdomen while asleep. He progressively developed respiratory failure and coma and died an hour later. Autopsy findings and laboratory analysis confirmed the death as being due to poisoning by cyanide. This case highlights the need to consider cyanide as a possible agent where there is a rapid death with progressive respiratory failure after injection of an unknown substance. Cyanide poisoning by ingestion is frequently seen in suicidal, accidental and homicidal deaths. To our knowledge, this is the first reported case of cyanide poisoning by injection in Sri Lanka.


Clinical epidemiology of childhood abdominal migraine in an urban general practice.
The present study examined the epidemiology of abdominal migraine among 1104 children registered with a general practice. There was a similar prevalence of recurrent abdominal pain as in other studies (8.4 per cent). The prevalence of headache was higher among children with recurrent abdominal pain and significantly so among girls. Migrainous headache was not significantly more prevalent in children with recurrent abdominal pain. The prevalence of abdominal migraine with and without migrainous headache was 0.7 and 1.7 per cent, respectively. The peak prevalence of abdominal migraine without migrainous headache was between five and seven years for both sexes. When associated with migrainous headache, it peaked at five to seven years in girls and seven to nine years in boys. The syndrome was associated with travel sickness and was more common among girls and those with a maternal history of migraine. Many children were photo- and phonophobic during an attack.


Low-temperature THz time domain waveguide spectrometer with butt-coupled emitter and detector crystal.
A compact high-resolution THz time-domain waveguide spectrometer that is operated inside a cryostat is demonstrated. A THz photo-Dember emitter and a ZnTe electro-optic detection crystal are directly attached to a parallel copper-plate waveguide. This allows the THz beam to be excited and detected entirely inside the cryostat, obviating the need for THz-transparent windows or external THz mirrors. Since no external bias for the emitter is required, no electric feed-through into the cryostat is necessary. Using asynchronous optical sampling, high resolution THz spectra are obtained in the frequency range from 0.2 to 2.0 THz. The THz emission from the photo-Dember emitter and the absorption spectrum of 1,2-dicyanobenzene film are measured as a function of temperature. An absorption peak around 750 GHz of 1,2-dicyanobenzene displays a blue shift with increasing temperature.


Hepatitis B surface antigen carrier state in hepatosplenic schistosomiasis.
The prevalence of hepatitis B surface antigen (HBsAg) was studied in 103 cases of hepatosplenic schistosomiasis (HSS), 134 control cases with a variety of illnesses including hepatointestinal schistosomiasis, and 600 blood donors, in an area endemic for both schisfosomiasis and viral hepatitis. The patients with HSS proved to be persistent carriers for HBsAg in a significantly higher proportion than the other two groups of cases. The HSS cases who were carriers of HBsAg had more clinical signs of chronic liver disease and strikingly more chronic inflammation of the portal spaces on liver biopsy. It is suggested that abnormal immunological responses in patients with HSS makes them more susceptible to become carriers of HBsAg and that the addition of this injurious factor makes their basic disease worse, and may be responsible for the development of cirrhosis in some cases.


Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.
Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort. We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype-phenotype relationships. Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51). The single-nucleotide polymorphisms rs10273639 at the PRSS1-PRSS2 locus and rs7057398 and rs12688220 at the CLDN2-MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients.


Metabolic and Non-metabolic Roles of Pyruvate Kinase M2 Isoform in Diabetic Retinopathy.
The main therapeutic goal for diabetic retinopathy (DR) is to prevent vision loss in patients with diabetes mellitus. Identifying the visual complications at a preclinical juncture will offer an early therapeutic window for diagnosis and intervention. Very recently, we found that pyruvate kinase M2 isoform (PKM2) regulates visual function through regulation of a key enzyme, phosphodiesterase 6β (Pde6β), involved in modulating photoreceptor functions. A recent study showed that the activation of PKM2 protects mitochondrial integrity in diabetic nephropathy. In the present study, we examined the role of PKM2 in DR in a mouse model that has both phenotypes of obesity and type II diabetes. In DR, we found decreased expression of PKM2 and Pde6β expression, but not PKM1. Consistent with decreased Pde6β expression, the db/db mice had reduced rod photoreceptor function. We found increased pyruvate kinase activity and a decreased ratio of reduced/oxidized redox in db/db mouse retina compared with control retinas. There was no significant difference in the levels of lactate between db/db and control mouse retina. Our findings suggest that reduced expression of PKM2 with unchanged PKM1 expression might be responsible for higher pyruvate kinase activity in db/db mouse retina. Our studies suggest that PKM2 has a role in DR. The results support that PKM2 may serve as a therapeutic target in the treatment of DR.


Increase of liver stiffness and altered bile acid metabolism after triple CFTR modulator initiation in children and young adults with cystic fibrosis.
Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor-ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF. A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by acoustic radiation force impulse imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy. A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients <20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p < 0.0001). Glycine-conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97). ARFI SWV and bile acid profiles provide evidence for early increase in liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.


Macronutrient Supplements in Preterm and Small-for-Gestational-Age Animals: A Systematic Review and Meta-analysis.
Early macronutrient supplementation in preterm and/or small-for-gestational-age (SGA) infants may improve growth but have detrimental effects on later cardio-metabolic health which may be sex-specific. We systematically reviewed the long-term effects of early macronutrient supplementation in preterm and SGA animals and whether these differ by sex. Using Cochrane Neonatal and SYRCLE methodologies we included random or quasi-random studies that allocated non-human mammals to macronutrient supplements or no supplements between birth and weaning and assessed post-weaning outcomes. We used random-effects models to calculate standardized mean differences (SMD) with 95% confidence intervals (CIs). Six studies provided low to very-low-quality evidence that macronutrient supplementation increased weight in juvenile rats (SMD; 95% CI: 2.13; 1.00, 3.25; 1 study, n = 24), increased leptin concentrations in older adults (1.31; 0.12, 2.51; 1 study, n = 14 male rats), but decreased leptin concentrations in young adults (-1.13; -2.21, -0.05; 1 study, n = 16 female rats) and improved spatial learning and memory (qualitative data; 1 study). There was no evidence of sex-specific effects and no overall effect on length, serum lipids, body composition, HOMA-IR, or blood pressure. Macronutrient supplements may affect later growth, metabolism, and neurodevelopment of preterm and SGA animals, but evidence is limited and low quality.


Preoperative oral antibiotics with versus without mechanical bowel preparation to reduce surgical site infections following colonic resection: Protocol for an international randomized controlled trial (ORALEV2).
Surgical site infections (SSIs) are common after colonic surgery. SSIs can cause relevant morbidity and increase costs of care. Preoperative oral antibiotics can reduce the incidence of SSIs after resection of the colon, but the role of mechanical bowel preparation (MBP) is debated. This study aims to assess the impact of a combined regimen of oral antibiotics and MBP on SSIs after colonic surgery. An international, multicentre, pragmatic, adaptive, parallel-group, randomized controlled trial will be conducted across Europe. Adult patients scheduled to undergo elective colonic resection will be assessed for inclusion. Patients will be randomized into one of two treatment arms: (1) preoperative oral antibiotics without MBP (control); (2) preoperative oral antibiotics with MBP (experimental). All patients will receive intravenous antibiotics at anaesthetic induction. The primary aim will be 30-day SSI, assessed by a blinded nurse. Additional end-points include safety, morbidity and mortality, satisfaction with the preparation, time to return of bowel function, time to complete recovery and time to discharge, long-term results. Analyses will be performed with a modified intention-to-treat approach. Interim analyses are planned. This will be the first randomized clinical trial to assess the efficacy and safety of preoperative oral antibiotics plus MBP versus preoperative oral antibiotics only, before colonic surgery. The knowledge obtained could help to establish the ideal preparation for patients scheduled to undergo resection of the colon. Full protocol NCT04161599.


Serological Evidence of Infectious Laryngotracheitis Infection and Associated Risk Factors in Chickens in Northwestern Ethiopia.
Infectious laryngotracheitis (ILT) is a disease of high economic consequence to the poultry sector. Gallid herpesvirus 1 (GaHV-1), a.k.a infectious laryngotracheitis virus (ILTV), under the genus Iltovirus, and the family Herpesviridae, is the agent responsible for the disease. Despite the clinical signs on the field suggestive of ILT, it has long been considered nonexistent and a disease of no concern in Ethiopia. A cross-sectional study was conducted from November 2020 to June 2021 in three selected zones of the Amhara region (Central Gondar, South Gondar, and West Gojjam zones), Ethiopia, with the objective of estimating the seroprevalence of ILTV in chickens and identifying and quantifying associated risk factors. A total of 768 serum samples were collected using multistage cluster sampling and assayed for anti-ILTV antibodies using indirect ELISA. A questionnaire survey was used to identify the potential risk factors. Of the 768 samples, 454 (59.1%, 95% CI: 0.56-0.63) tested positive for anti-ILTV antibodies. Mixed-effect logistic regression analysis of potential risk factors showed that local breeds of chicken were less likely to be seropositive than exotic breeds (OR: 0.38, 95% CI: 0.24-0.61). In addition, factors such as using local feed source (OR: 6.53, 95% CI: 1.77-24.04), rearing chickens extensively (OR: 1.97, 95% CI: 0.78-5.02), mixing of different batches of chicken (OR: 14.51, 95% CI: 3.35-62.77), careless disposal of litter (OR: 1.62, 95% CI: 0.49-4.37), lack of house disinfection (OR: 11.05, 95% CI: 4.09-47.95), lack of farm protective footwear and clothing (OR: 20.85, 95% CI: 5.40-80.45), and careless disposal of dead chicken bodies had all been associated with increased seropositivity to ILTV. Therefore, implementation of biosecurity measures is highly recommended to control and prevent the spread of ILTV. Furthermore, molecular confirmation and characterization of the virus from ILT suggestive cases should be considered to justify the use of ILT vaccines.


The effect of pre- and post-mating dietary restriction on embryonic survival in gilts.
The aims of this study were to determine if pre- and post-mating feeding levels interact to affect embryonic survival, and to determine whether feeding to the maintenance requirement would impair embryo survival. Gilts were allocated to a pre-mating treatment of 1 or 0.8× energy maintenance from day 1 to 14 of their oestrous cycle prior to mating. From day 15 to mating all gilts were group housed and fed ad lib. Gilts were artificially inseminated at their third oestrus. The day after mating, gilts were group housed and allocated to post-mating treatments of 1.5 or 1× maintenance. Gilts were slaughtered day 25.5±0.2 post-insemination and reproductive tracts collected. Gilts fed the restricted pre-mating diet lost significantly more weight than gilts fed the increased pre-mating diet (6.7±0.8 versus 3.7±0.7kg). From mating to slaughter, gilts fed the restricted post-mating diet lost 0.5±1.02kg liveweight, while gilts fed the increased post-mating diet gained 5.7±0.90kg liveweight (P<0.05). The pre-mating dietary treatment had no effect on any reproductive measure. Embryonic survival was greater (P<0.05) in gilts fed the high post-mating diet compared with gilts fed the low post-mating diet (88.4±2.5 versus 77.8±4.0%), resulting in more (P<0.05) conceptuses present (14.0±0.6 versus 11.7±0.7). There was no interaction between pre-mating and post-mating feed intake on any reproductive measure. These data demonstrated that reducing post-mating feed intakes to maintenance levels impaired embryo survival.


Reverse transcription recombinase-aided amplification assay for avian influenza virus.
Avian influenza virus (AIV) infection can lead to severe economic losses in the poultry industry and causes a serious risk for humans. A rapid and simple test for suspected viral infection cases is crucial. In this study, a reverse transcription recombinase-aided amplification assay (RT-RAA) for the rapid detection of all AIV subtypes was developed. The reaction temperature of the assays is at 39 °C and the detection process can be completed in less than 20 min. The specificity results of the assay showed that this method had no cross-reaction with other main respiratory viruses that affect birds, including Newcastle disease virus (NDV) and infectious bronchitis virus (IBV). The analytical sensitivity at a 95% confidence interval was 102 RNA copies per reaction. In comparison with a published assay for reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), the κ value of the RT-RAA assay in 384 avian clinical samples was 0.942 (p < 0.001). The sensitivity and specificity of the RT-RAA assay for avian clinical sample detection was determined as 97.59% (95% CI 93.55-99.23%) and 96.79% (95% CI 93.22-98.59%), respectively. The RT-RAA assay for AIV in this study provided an effective and practicable tool for AIV molecular detection.


Extent of surgical resection and adjuvant temozolomide improves survival in pediatric GBM: a single center experience.
Pediatric glioblastoma (pGBM) is an uncommon entity. The importance of concurrent and adjuvant temozolomide is not known in this subset of patients. We retrospectively analyzed our database between 2000 and 2015. All patients were treated with maximally safe surgical resection. This was followed by a uniform treatment schedule of post-operative radiation with concurrent daily temozolomide at 75 mg/m2. Radiation dose was 60 Gy in 30 fractions planned by 3-dimensional conformal radiotherapy. Concurrent and adjuvant temozolomide was used in all patients treated after 2007. Four weeks later, adjuvant temozolomide was started at 150 mg/m2, day 1 to 5 every 28 days and escalated to 200 mg/m2 from the second cycle onwards if well tolerated. Log-rank test was used to compare survival distribution. The data was analyzed using SPSS (version 16). Fifty-one patients were analyzed. Median age was 14 years (range: 5 to 21 years). Thirty-five males and 16 females were noted. Median symptom duration was 4 months. Twenty-eight patients underwent a gross total resection (GTR) while 17 underwent a subtotal resection; six patients underwent decompression. Thirty-three patients received concurrent chemotherapy while 27 received adjuvant chemotherapy. Median progression-free survival (PFS) was 15.1 months. One- and 3-year PFS was 54.4% and 3-year PFS was 24.6.7%. The median overall survival was 17.4 months. In univariate analysis survival was better for gross total resection (17.4 months vs. 11.5 months; p = 0.037), and significance maintained after multivariate analysis p = 0.026, HR 3.069, 95% CI 1.14-8.23. In univariate analysis, survival was better for patients receiving temozolomide but did not achieve significance. However, in multivariate analysis, use of temozolomide was associated with significantly improved survival p = 0.036, HR 3.315, 95% CI 1.07-10.19. GTR improves survival significantly in pGBM. Adjuvant temozolomide may improve survival in pGBM.


Periocular necrotizing fasciitis in an infant.
Periocular necrotizing fasciitis developed in a 12-month-old boy with swelling of both eyes and redness and a discharge from the left eye approximately 36 hours after blunt trauma. Computed tomography revealed preseptal and soft-tissue edema on the left side, but no signs of orbital involvement, orbital fractures, or drainable abscess in the anterior left lower eyelid. The inflammatory signs worsened over the next day, and there was purulent discharge from the left lower eyelid and an abscess and necrosis of the lower eyelid skin. He did well following surgical debridement and treatment with intravenous antibiotics. His course highlights the difficulty in diagnosing necrotizing fasciitis and the necessity for prompt surgical debridement and empirical broad-spectrum antibiotic therapy.


Reproductive phenology and behaviour of endangered redside dace (Clinostomus elongatus) in urban streams.
Investigation of the reproductive phenology and spawning behaviour of imperilled species in relation to environmental variability is needed to understand a critical component of species life history. In this study, we used redside dace (Clinostomus elongatus), a freshwater leuciscid listed as Endangered under Canada's Species at Risk Act, to model spawning phenology and make predictions about spawning initiation using historical and climate change projected thermal cues (measured as cumulative growing degree days), and provide an ethological description of spawning behaviour. Logistic regression models applied to 4 years of average daily stream water temperature data and field behavioural observations of the onset of spawning activity indicated a 50% probability of spawning initiation when cumulative growing degree days reached 214°C days and a 95% probability of spawning initiation at 288°C days. Using two climate change scenarios (i.e., a mid-century 1.6°C increase and an end of century 3.6°C increase), spawning initiation was predicted to advance 3 days by the year 2050 and 7 days by the year 2100. Underwater video cameras placed at two sites within an urban stream captured 73 unique spawning events revealing that redside dace spawn in pairs as well as in dense, tightly packed groups (more than 20 individuals). Moreover, there is evidence of redside dace having a polygynandrous mating system, as female redside dace spawned with multiple males in 45.2% of the total spawning events recorded. Taken together, this study provides important insights into redside dace spawning initiation and behaviour, key life-history traits having conservation implications for future reproductive success and, ultimately, population dynamics.


Acrylic bone cements: composition and properties.
Cementing endoprostheses is one of the most frequently performed orthopedic procedures in the world today. The bone cements that are currently available commercially are all based on the chemical substance methylmethacrylate. Although all of them have the same chemical basis, acrylic bone cements are not all alike. This article discusses the composition of acrylic bone cements and the influence of the composition on the properties of the material.


[Somatostatin].
Somatostatin, under physiological conditions, is a regulator of thyroid stimulating hormone, growth hormone, pancreatic islet-cell hormones and gastrin. In pharmacological dosage, gastric acid output, splanchnic blood flow and plasma renin levels, are influenced. A possible therapeutic effect on increased growth hormone secretion, disturbances of carbohydrate metabolism, gastroenteropathies and renal hypertension, is discussed. The clinical application is limited by the short biological half-life of the substance and the unspecific action on several organs.


EEG spectral analysis in children with febrile delirium.
Febrile delirium is defined as an acute and transient confusional state with high fever. There are very few reports on febrile delirium, although fever is one of the commonest symptoms in children. We previously found a posterior slowing in the electroencephalogram (EEG) of delirious patients with fever. The purpose of this study is to evaluate the features of occipital slow waves by spectral analysis and to find a parameter associated with clinical improvement. Digital EEG tracings were investigated by Fourier analysis in 20 patients aged from 2 to 13 years. The fast Fourier transform (FFT) was computed for 20 s tracing from the P3-A1 and P4-A2 derivations. The spectral analysis of EEG was repeated in 7 patients. The tracings of 34 control subjects were also analyzed by FFT. EEG of a febrile, nine-year-old girl without delirium was also studied. Febrile delirium was seen during the first three days of fever. The episodes lasted up to 10 min. Four patients showed febrile delirium again after admission but they became conscious a few minutes later. The relative power in the delta frequency band was increased in 65% of patients with preservation of the occipital alpha rhythm. In addition, repeated febrile delirium did not cause worsening of the posterior slowing. The duration of abnormal EEG was only a few days and the decrease of relative power in the delta frequency band was the best parameter of clinical improvement. Posterior slowing was also found in a febrile patient without delirium. Febrile delirious children showed the characteristic clinical and spectral analytical features and the numerical data of EEG facilitate the comparison of the serial findings.


Flows, stocks, and emissions of DEHP products in Japan.
The usage of products containing Bis (2‑ethylhexyl) Phthalate (DEHP) is widespread, mainly through the great variety of PVC products. However, DEHP has become a worldwide concern, due to the potential health and environmental risks it presents. In this study, material flow analysis and emission estimations for DEHP products in Japan, from 1948 to 2030, were performed. Moreover, an evaluation of the potentially damaging impacts on human health and the environment was completed through a lifecycle impact assessment approach. The analysis focused on three representative lifecycle phases - Production, Use and Treatment and Disposal. The peak flows of DEHP from Production to the Use phase were in 1996 with 285,300 tons for shipment and the stocks peaked in 2001 with 1,981,908 tons. Accordingly, in 2006 the peak of DEHP waste to the Treatment and disposal phase was 190,792 tons. The primary emissions were observed in the Use phase, due to the large stocks, with DEHP mostly being released to the pedosphere. The total emissions from the Use phase reached the maximum of 48,960 tons in 2000, whereas in the Production and Treatment and disposal phase it was 248 tons and 15 tons, respectively. Subsequently, concerning the evaluation of impacts, the damage to the human health was the most widespread impact, totaling 13,782 disability-adjusted life years (DALYs), compared with the damage to the ecosystems, with 0.12 species·year. Furthermore, the risk-risk tradeoffs between the lifecycle phases were clarified throughout the years.


The imaging evaluation of acetabular labral lesions.
The acetabular labrum is an important structure that contributes to hip joint stability and function. Diagnosing labral tears involves a comprehensive assessment of clinical symptoms, physical examinations, imaging examinations, and arthroscopic confirmation. As arthroscopy is an invasive surgery, adjuvant imaging of the acetabular labrum is increasingly imperative for orthopedists to diagnose and assess labral lesions prior to hip arthroscopy for surgical management. This article reviews the current imaging strategies for the evaluation of labrum lesions.


Implantable Cardioverter-defibrillator Therapy for Hypertrophic Cardiomyopathy: Usefulness in Primary and Secondary Prevention.
Hypertrophic cardiomyopathy is a frequent cause of sudden death. Clinical practice guidelines indicate defibrillator implantation for primary prevention in patients with 1 or more risk factors and for secondary prevention in patients with a history of aborted sudden death or sustained ventricular arrhythmias. The aim of the present study was to analyze the follow-up of patients who received an implantable defibrillator following the current guidelines in nonreferral centers for this disease. This retrospective observational study included all patients who underwent defibrillator implantation between January 1996 and December 2012 in 3 centers in the province of Barcelona. The study included 69 patients (mean age [standard deviation], 44.8 [17] years; 79.3% men), 48 in primary prevention and 21 in secondary prevention. The mean number of risk factors per patient was 1.8 in the primary prevention group and 0.5 in the secondary prevention group (P=.029). The median follow-up duration was 40.5 months. The appropriate therapy rate was 32.7/100 patient-years in secondary prevention and 1.7/100 patient-years in primary prevention (P<.001). Overall mortality was 10.1%. Implant-related complications were experienced by 8.7% of patients, and 13% had inappropriate defibrillator discharges. In patients with a defibrillator for primary prevention, the appropriate therapy rate is extremely low, indicating the low predictive power of the current risk stratification criteria.


Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.
The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.


Yeast Expressing Gp43 Protein as a Vaccine Against Paracoccidioides brasiliensis Infection.
Paracoccidioidomycosis (PCM) represents the most frequent systemic mycosis in Latin American. The disease is caused by the pathogenic thermally dimorphic fungus Paracoccidioides brasiliensis, and is initially characterized by pulmonary lesions, which can subsequently disseminate to other organs, resulting in secondary injuries. Although its high incidence, there is no commercially available vaccine against fungal diseases. A novel strategy, using Saccharomyces cerevisiae yeast as a vehicle for immunization against PCM, was recently successfully described. Herein, we describe strategies for the construction of the suitable S. cerevisiae vaccine, and protocols of administration and evaluation of the efficacy of the vaccine against experimental PCM.


Safety of not withholding clopidogrel therapy during the immediate several days pre- and post-trans-urethral resection of prostate (TURP): a retrospective cohort study.
Benign prostatic hypertrophy or hyperplasia (BPH) is a frequent urological complain particularly in old-aged individuals. Those patients usually have other risk factors (such as ischemic cardiovascular diseases) for which they might be treated with anti-thrombotic agents chronically. These medicines may induce blood thinning and raise the incidence of hemorrhage. Thus, if those patients needed operative treatment for BPH, they may be at high risk of hemorrhage or its related adverse effects with the usage of anti-thrombotic drugs during the peri-operative time. On the other hand, dis-continuation of these agents can lead to ischemic events in susceptible individuals. Therefore, this research aims to assess the safety of the continuation of using anti-thrombotic agents throughout the peri-operative duration in patients with prostate surgery in form of Transurethral Resection of Prostate (TURP) only for Benign Prostatic Hypertrophy (BPH). Patients' notes were reviewed retrospectively. The entire participants were categorized into two categories. First category was on clopidogrel therapy (CTC) for prolong time and the usage of these agents was carried on throughout the peri-operative period. The second category was not on clopidogrel therapy at all (NCTC). Both of these categories had Transurethral Resection of Prostate (TURP) for Benign Prostatic Hypertrophy (BPH). A comparison had been conducted between the two categories with regards to: (i) the amount of blood lost intra-operatively (ii) the duration of operation (iii) hematocrit concentration per-operatively (iv) transfused packed red blood cells (PRBC) if needed (v) clearance of hematuria postoperatively (vi) secondary hemorrhage and clot retention after discharge. Pearson Chi-square test, Independent sample t test and test for numeric variables were used as appropriate. The study identified 329 patients. One hundred and sixty five participants in the CTC (clopidogrel therapy category) and 164 in the NCTC (non-clopidogrel therapy category). It had been revealed that there was no statistically significant difference between the CTC and NCTC regarding: (i) the amount of blood lost intra-operatively (ii) the duration of operation (iii) hematocrit concentration per-operatively (iv) transfused packed red blood cells (packed RBC) if needed (v) clearance of hematuria postoperatively (vi) secondary hemorrhage and clot retention after discharge (P > 0.65). The continuation of usage of anti-thrombotic therapy (clopidogrel) during peri-operative period in patients with TURP for BPH is a safe practice. It is not associated with high probability of hemorrhage or PRBC transfusion or other adverse effects.


Pharmacogenetics of osteoporosis.
The challenge of personalized medicine is to move away from the traditional 'one-size-fits-all' pharmacology to genotype-based individualized therapies. As an individual's response to drugs is under the control of genes, personal genetic profiles could help clinicians to predict individual drug response and prescribe the right drug and dose, thereby optimising efficacy and avoiding risk of adverse effects. Currently, the concrete application of pharmacogenetics into clinical practice is limited to a few drugs, and the genetic prediction of drug response is far from clear for many of thve principal complex disorders. This is even more evident in the field of osteoporosis and metabolic bone disorders, for which few pharmacogenetic studies have been conducted, and no conclusive results are available. In this chapter, we review recent research on pharmacogenetics of osteoporosis, evaluate criticisms, and offer possible suggestions for improvements in this field and for possible future applications into clinical practice.


Cloning and characterization of class 1 and class 2 insulin-like growth factor-I mRNA in Songliao black pig.
Insulin-like growth factor-I (IGF-I) plays a fundamental role in postnatal mammalian growth, development, and metabolism. The mammalian IGF-I gene contains at least six exons from which several different mRNAs are transcribed. In this study, IGF-I mRNA in Songliao black pig liver was investigated using RLM-RACE. Using a 3'-RACE technique, we determined that all mRNA transcripts lacked exon 5 sequence and contained only exon 6 sequence. Using a 5'-RACE technique, we investigated the presence of class 1 and class 2 IGF-I mRNAs. In several other species, the class 1 and class 2 IGF-I polypeptides are generated from mRNAs containing exon 1 or exon 2, respectively. Both class 1 and class 2 IGF-I mRNAs were identified in Songliao black pig liver. Transcription is initiatated upstream of exons 1 and 2 at multiple dispersed start sites to yield two distinct IGF-I mRNA transcript classes which differ in the precursor peptides predicted from their individual leader sequences. Tissue distribution of Songliao black pig class 1 and class 2 IGF-I mRNA was investigated by real-time RT-PCR. Both classes of IGF-I mRNA were expressed in a variety of tissues, however, class 1 IGF-I mRNA was more abundant than class 2 in all tissues.


Poor performance of mandatory nutritional screening of in-hospital patients.
Since 2006 it has been mandatory at Copenhagen University Hospital Gentofte to screen all patients for nutritional risk within 24 h of admittance. Audits conducted by department staff estimate that 70-80% of assessments are correctly executed, but the validity of this estimate is unknown. The aim of the present study was to discover the true proportion of hospitalized patients receiving nutritional risk screening within the stipulated time limit and to evaluate the validity of the screening by comparison with medical records. Retrospective examination of medical records of all patients (N = 3278) hospitalized in September 2008 in 11 different medical specialities were analysed in 2009-2010. Of 2393 medical records 24% of the patients were screened, of these only 65% were screened within the stipulated time limit. Half of the conducted screenings were inaccurate, the most common error being underestimation of nutritional status. Forty-six percent of patients required a secondary nutritional risk screening and 30% were found to be nutritionally at risk. Only 8% of patients received the mandatory nutritional risk screening without procedural errors. We conclude that pre-scheduled, self-conducted audits are not viable as the basis of an assessment of the use of nutritional risk screening.


Factors affecting selectivity in ion chromatography.
Methods for separation of ions by ion-exchange, ion-pair, and zwitterion ion chromatography share at least one common thread--the induced formation of a cation-anion pair in the stationary phase. Selectivity can be defined as the relative ability of sample ions to form such a pair. Examples are given in anion-exchange chromatography to show the effect of variations in the geometry, bulkiness and polarity of the resin cation on selectivity. The type of resin matrix, the hydrophobic nature of the resin surface and the degree of solvation also affect chromatographic behavior. The selectivity series observed in ion chromatography seems to be best explained by the interplay of two components: electrostatic attraction (ES) and the enforced-pairing (EP) that is brought about by hydrophobic attraction and by water-enforced ion pairing. Selectivity in ion-pair chromatography (IPC) and in zwitterion ion chromatography (ZIC) is affected by both the mobile phase cation and anion. This leads to elution orders for anions that are different from conventional ion-exchange chromatography (IC) of anions where cations are excluded from the stationary phase and have little effect on a separation. The elution order of anions in ZIC is similar to that in IC except for small anions of 2-charge, which are retained more weakly in ZIC. A unique advantage of ZIC is that sample ions can be eluted as ion pairs with pure water as the eluent and a conductivity detector. The mechanism for separation of anions on a zwitterionic stationary phase has been a subject for considerable debate. The available facts point strongly to a partitioning mechanism or a mixed mechanism in which partitioning is dominant with a weaker ion-exchange component.


Improved pregnancy outcome with the addition of leuprolide acetate to gonadotropins for in vitro fertilization.
In vitro fertilization treatment outcomes were compared prospectively in unselected patients with and without the addition of leuprolide acetate to gonadotropins for ovarian hyperstimulation. While the leuprolide patients required greater quantities of exogenous gonadotropins to achieve ovarian stimulation, significant improvements in the fertilization, implantation, and spontaneous abortion rates were observed compared with patients not receiving leuprolide. The ongoing pregnancy ("take home baby") rates per aspiration with and without leuprolide were 29% and 12%, respectively. Furthermore, the multiple pregnancy rate was markedly increased in the leuprolide group (44% versus 8%), suggesting that the improved pregnancy outcome with pituitary suppression was due primarily to higher oocyte and embryo quality.


Glial heterotopia of the middle ear.
Glial heterotopia is defined as the presence of normal glial tissue in an abnormal site. We report the case of a 63-year-old man who presented with right hearing loss and tinnitus. ENT examination, computed tomography and magnetic resonance imaging showed signs of chronic otitis media. Right mastoidectomy demonstrated a solid mass of the right mastoid and middle ear with no associated dehiscence of the tegmen tympani. Histological examination of the mass revealed normal glial tissue. Glial heterotopia is a rare entity, which must be distinguished from encephalocele. It is usually an incidental surgical finding when the surgeon observes a mass of the mastoid and middle ear not communicating with the central nervous system. Histological examination confirms the diagnosis by revealing normal glial tissue in the ear.


1-substituted phthalazines as probes of the substrate-binding site of mammalian molybdenum hydroxylases.
The interaction of a series of 1-substituted phthalazine derivatives with partially purified aldehyde oxidase from rabbit, guinea-pig and baboon liver, and with bovine milk xanthine oxidase, has been investigated. Of the 18 compounds examined, rabbit liver aldehyde oxidase metabolized 10, whereas guinea-pig and baboon liver enzyme oxidized 13 and 14, respectively. Where metabolites were characterized, oxidation was shown to occur at position four of the phthalazine ring. Km values ranged from 0.003 to 1.8 mM. In contrast, most compounds were competitive inhibitors of bovine milk xanthine oxidase with Ki values ranging from 0.015 to 1.3 mM; the cationic derivative 2-methylphthalazinium iodide was oxidized to 2-methyl-1-phthalazinone by both aldehyde oxidase and, with a much reduced affinity, by xanthine oxidase. In terms of structure-metabolism relationships, Vmax values were relatively insensitive to the electronic effects of substituents, but a trend for the more lipophilic derivatives to show increased affinities (Km and Vmax/Km) towards aldehyde oxidase could be seen. However, calculations of molecular size revealed a species-dependent cut-off threshold above which compounds were not metabolized. Results suggest that the relative size of the active site for hepatic aldehyde oxidase is in the order baboon greater than guinea-pig greater than rabbit, and that in spatial terms the active site of bovine milk xanthine oxidase is similar to that of baboon liver aldehyde oxidase. Thus, the binding site of rabbit liver aldehyde oxidase, a widely used source of the oxidase, is apparently more restricted than in some other species.


The evaluation of free thyroid hormones (FT4 and FT3) in the routine diagnosis of thyroid function.
The validity of the free thyroid hormone parameters (FT4 and FT3) was verified in a random sample of 154 ambulatory patients with thyroid conditions. The "euthyroid range" of FT4 was between 15.67 and 30.66 pmol/l; median 21.98 pmol/l. The distribution of the FT4 readings peaked on the left and sloped to the right (log normal). In our laboratory, the "euthyroid reference range" of FT4 is between 10-28 pmol/l. The "euthyroid range" of FT3 extended from 4.6 to 9.7 pmol/l; median 6.63 pmol/l. The distribution of the readings was likewise log normal. The values of FT4 and FT3 are not significantly influenced by TBG concentration anomalies in otherwise healthy thyroid patients. For purposes of discrimination between euthyroidism and hyperthyroidism, FT3 (95%) and FT4 (90%) are better suited than the corresponding quotients for the free hormone fraction or the total hormone concentrations. On the other hand, the free hormone parameters are less suitable for the diagnosis of hypothyroidism. These results were deduced theoretically from mathematical function analyses between the TBG-independent free hormone parameters and the TBG-dependent hormone concentrations.