Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice.
IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25. Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25(-/-) mice compared to WT mice after exposure to acute DSS. Histological examination showed that DSS-treated IL-25(-/-) mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not in the IL-25(-/-) mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25(-/-) compared to WT mice. IL-25(-/-) mice were also partially protected from chronic DSS challenge especially during the first 2 cycles of DSS exposure. In contrast to IL-25(-/-) mice, IL-13(-/-) mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines. These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.


3D-manufactured patient-specific models of congenital heart defects for communication in clinical practice: feasibility and acceptability.
To assess the communication potential of three-dimensional (3D) patient-specific models of congenital heart defects and their acceptability in clinical practice for cardiology consultations. This was a questionnaire-based study in which participants were randomised into two groups: the 'model group' received a 3D model of the cardiac lesion(s) being discussed during their appointment, while the 'control group' had a routine visit. Outpatient clinic, cardiology follow-up visits. 103 parents of children with congenital heart disease were recruited (parental age: 43±8 years; patient age: 12±6 years). In order to have a 3D model made, patients needed to have a recent cardiac MRI examination; this was the crucial inclusion criterion. Questionnaires were administered to the participants before and after the visits and an additional questionnaire was administered to the attending cardiologist. Rating (1-10) for the liking of the 3D model, its usefulness and the clarity of the explanation received were recorded, as well as rating (1-10) of the parental understanding and their engagement according to the cardiologist. Furthermore, parental knowledge was assessed by asking them to mark diagrams, tick keywords and provide free text answers. The duration of consultations was recorded and parent feedback collected. Parents and cardiologists both found the models to be very useful and helpful in engaging the parents in discussing congenital heart defects. Parental knowledge was not associated with their level of education (p=0.2) and did not improve following their visit. Consultations involving 3D models lasted on average 5 min longer (p=0.02). Patient-specific models can enhance engagement with parents and improve communication between cardiologists and parents, potentially impacting on parent and patient psychological adjustment following treatment. However, in the short-term, parental understanding of their child's condition did not improve.


Inotropes and vasopressors are associated with increased short-term mortality but not long-term survival in critically ill patients.
Limited information is currently available on the impact of vasoactive medications in intensive care (ICU) and long-term outcomes. The main objective of our study was to describe the association between the use of inotropes and/or vasopressors and ICU mortality. Secondary objectives were to evaluate the association between the use of vasoactive drugs and in-hospital as well as 1-year all-cause mortality in ICU survivors. FROG-ICU was a prospective, observational, multi-centre cohort designed to investigate long-term mortality of critically ill adult patients. Cox proportional hazards models were used to evaluate the association between the use of inotropes and/or vasopressors and ICU mortality, as well as in-hospital and 1-year all-cause mortality in a propensity-score matched cohort. The study included 2087 patients, 939 of whom received inotropes and/or vasopressors during the initial ICU stay. Patients treated with vasoactive medications were older and had a more severe clinical presentation. In a propensity score-matched cohort of 1201 patients, ICU mortality was higher in patients who received vasoactive medications (HR of 1.40 [1.10-1.78], p = 0.007). One thousand six hundred thirty-five patients survived the index ICU hospitalisation. There was no significant difference according to the use of inotropes and/or vasopressors in the propensity-score matched cohort on in-hospital mortality (HR of 0.94 [0.60-1.49], p = 0.808) as well as one-year all-cause mortality (HR 0.94 [0.71-1.24], p = 0.643). Inotropic and/or vasopressor therapy is a strong predictor of in-ICU death. However, the use of inotropes and/or vasopressors during ICU admission was not associated with a worse prognosis after ICU discharge.


The context of Stw 573, an early hominid skull and skeleton from Sterkfontein Member 2: taphonomy and paleoenvironment.
The reconstructed taphonomic and paleoenvironmental contexts of a ca. 4 million-year-old partial hominid skeleton (Stw 573) from Sterkfontein Member 2 are described through presentation of the results of our analyses of the mammalian faunal assemblage associated stratigraphically with the hominid. The assemblage is dominated by cercopithecoids (Parapapio and Papio) and felids (Panthera pardus, P. leo, Felis caracal, and Felidae indet.), based on number of identified specimens, minimum number of elements and, minimum number of individuals. In addition, the assemblage is characterized by a number of partial skeletons and/or antimeric sets of bones across all taxonomic groups. There is scant indication of carnivore chewing in the assemblage. These observations, in addition to other taphonomic data, suggest that the remains of many animals recovered in Member 2 are from individuals that entered the cave on their own-whether accidentally by falling through avens connecting the cave to the ground surface above or by intentional entry-and were then unable to escape, rather than primarily through systematic collection by a biotic, bone-accumulating agent. The taphonomic conclusion that animals with climbing proclivities (i.e., primates and carnivores) are preferentially preserved over other taxa, ultimately because of those proclivities, urges caution in assessing the fidelity of the assemblage for reconstruction of the Member 2 paleoenvironment. With that caveat, we infer that the Member 2 paleoenvironment was typified by rolling, rock-littered and brush- and scrub-covered hills, indicated by the abundant F. caracal and cercopithecoid fossils recovered and the identified presence of the extinct Caprinae Makapania broomi. In addition, the valley bottom may have retained standing water year-round, perhaps supporting some tree cover--a setting suitable for the well-represented ambush predator P. pardus and suggested by the presence of Alcelaphini. Finally, the reconstructed taphonomic and paleoenvironmental settings of Sterkfontein Member 2 are compared to penecontemporaneous sites in South and East Africa.


Awareness and attitude towards dehydration and its management amongst mothers and factors influence on in under-five children of Omdurman locality, Sudan.
Dehydration is a significant depletion of body water and electrolytes. The awareness of dehydration signs is essential, and in-home mothers' practice and responses towards professional medical help are crucial. The study is a cross-sectional study enrolled 222 mothers with children under 5 years, and 198 of them participate in a semi-structured questionnaire that involves information of dehydration signs, oral rehydration solution and preparation and in-home practice and remedies used by mothers in the management of dehydration. Fifty-eight participants (29.3%) were found in the age group of 26-30 years, 78 participants (39.4%) received primary school education and 92 (46.5%) had one child under 5 years, whereas 17.7% received educational workshop or counselling. Main management practices performed by the mothers were over-the-counter medications (36.4%) and rice water (33.8%). The majority (88%) of the participants were aware about dehydration signs, which were significantly associated with educational levels, and workshop or counselling received from professional.


Suppression of cell proliferation by inhibition of estrone-3-sulfate transporter in estrogen-dependent breast cancer cells.
The aim of the study is to suppress the progress of estrogen-dependent breast cancer by inhibiting the membrane transporter, which mediates the internalization of estrone-3-sulfate as estrogen precursor in the cancer cells. The uptake of estrone-3-sulfate by estrogen-dependent breast cancer MCF-7 cells was measured, and inhibitory study using various organic anions on estrone-3-sulfate uptake by MCF-7 cells was conducted. The effects of the inhibitor on the transcription of reporter gene and cell proliferation induced by estrone-3-sulfate were examined. The uptake of estrone-3-sulfate by MCF-7 cells was saturable with Km value of 2.32 microM. The uptake was Na+-independent and was inhibited by several anionic compounds such as bromosulfophthalein. Bromosulfophthalein also significantly inhibited the transcription of reporter gene via estrogen response element and cell proliferation induced by estrone-3-sulfate. However, the transcriptional activation or cell proliferation induced by estrone was not inhibited by bromosulfophthalein. Reverse transcription-polymerase chain reaction analysis revealed the expression of mRNA of organic anion transporting polypeptide (OATP)-D and OATP-E as possible candidates to transport estrone-3-sulfate. The uptake of estrone-3-sulfate is mediated by Na+-independent transporter(s). Inhibitor of estrone-3-sulfate transporter suppressed the transcription and cell proliferation induced by estrone-3-sulfate in MCF-7 cells. The results provide the basis of a novel strategy for breast cancer treatment by focusing on the transporter responsible for the uptake of estrone-3-sulfate.


Ethanol-paired stimuli can increase reinforced ethanol responding.
While ethanol-paired stimuli are frequently postulated to increase drinking motivation and thus increase ethanol responding and precipitate relapse, no study has demonstrated increases in ethanol-reinforced responding following presentation of an ethanol-paired stimulus that had not previously been part of a contingent relationship. Previous studies have shown that food-paired stimuli can increase food responding that is at low rates and increase food consumption in food-sated rats. In Experiment 1, we show that an ethanol-paired stimulus can increase ethanol responding that is at low levels late in the experimental session, presumably due to satiation. However, these increases may have resulted from either associative or non-associative mechanisms. In Experiment 2, we compared the effects of an ethanol-paired stimulus to those of the same stimulus in a Truly-Random-Control group. In a Truly-Random-Control, the stimulus and ethanol each are presented on independent random schedules, and thus any differences between the effects of the stimulus in the experimental and control groups is likely attributable to the association between the stimulus and ethanol. The stimulus increased ethanol-reinforced responding in both the experimental and control groups, but these increases were greater in the experimental than the control group. Thus, both stimulus-change and the pairing of the stimulus with ethanol may result in increases in ethanol-reinforced responding.


MicroRNA-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway.
The microRNA (miR) miR-874, a potential tumour suppressor, causes cell death via target gene suppression in various cancer types. Mevalonate pathway inhibition also causes cell death in breast cancer. However, the relationship between the mevalonate pathway and miR-874-induced apoptosis or its association with the tumour suppressor p53 has not been elucidated. We identified phosphomevalonate kinase (PMVK), a key mevalonate pathway enzyme, and sterol regulatory element-binding factor 2 (SREBF2), the master cholesterol biosynthesis regulator, as direct miR‑874 targets. Next-generation sequencing analysis revealed a significant miR-874-mediated downregulation of PMVK and SREBF2 gene expression and p53 pathway enrichment. Luciferase reporter assays showed that miR-874 directly regulated PMVK and SREBF2. miR-874-induced apoptosis was p53 dependent, and single-cell RNA sequencing analysis demonstrated that miR-874 transfection resulted in apoptosis and p53 pathway activation. Downregulation of PMVK expression also caused cell cycle arrest and p53 pathway activation, which was rescued by geranylgeranyl pyrophosphate (GGPP) supplementation. Analysis of The Cancer Genome Atlas (TCGA) database indicated a negative correlation between miR-874 and PMVK expression and between miR-874 and SREBF2 expression. These findings suggest that miR-874 suppresses the mevalonate pathway by targeting SREBF2 and PMVK, resulting in GGPP depletion, which activates the p53 pathway and promotes cycle arrest or apoptosis.


Neuroendocrine apendicopathy in morphologically normal appendices of patients with diagnosis of acute appendicitis: Diagnostic study.
About 15%-25% of appendices removed to treat acute appendicitis present normal macro- and macroscopic morphology. The objective of this study was to verify an association of proinflammatory, neuroendocrine and immune mediators with morphologically normal appendices removed from patients with clinical laboratorial and imaging characteristics of acute appendicitis. Appendices removed from 121 adult patients of both genders were distributed into three groups according to their following characteristics: group 1: 53 macro- and microscopically normal appendices from patients with clinical, laboratorial and imaging diagnosis of acute appendicitis; group 2: 24 inflamed appendices from patients with clinical, laboratorial, imaging and histopathological diagnosis of acute appendicitis; group 3: 44 normal appendices from patients submitted to right colectomy to treat localized ascending colon adenocarcinoma. All appendices were immunohistochemically studied for gastrin inhibitor peptide, mast cell tryptase, vascular endothelial growth factor; intestinal vasoactive peptide, tumor necrosis factor alpha, interleukin 1, prostaglandin E2, gene-protein product 9.5, CD8 T lymphocytes, synaptophysine, enolase, and S100 protein. The group 1 revealed increased levels of synaptophysine, enolase, mast cell tryptase and PGP-9.5 comparing with the other two groups. The group 2 presented increased levels of interleukin 1, CD8 T lymphocytes and prostaglandin E2 comparing with the other two groups. The group 3 confirmed the normal levels of all these neuroendocrine, immune and proinflammatory mediators. Morphologically normal appendices removed from patients with clinical and complementary exams indicating acute appendicitis have appendicular neuroimmunoendocrine disorder associated with the mediators synaptophysin, enolase, mast cell-related tryptase and gene-protein product 9.5.


Analysis of lectin-specific cell surface glycoprotein on neuroblastoma cells.
The binding sites for the lectins wheat germ agglutinin, Ricinus communis agglutinin and concanavalin A on mouse neuroblastoma cell membranes were identified using SDS-gel electrophoresis in combination with fluorescent lectins. Ricinus communis agglutinin and wheat germ agglutinin were found to bind almost exclusively to a single polypeptide with an apparent molecular weight of 30 000. Concanavalin A labeled over 20 different polypeptides, most with molecular weights greater than 50 000. However, when the neuroblastoma cells were treated with concanavalin A so as to internalize all the concanavalin A binding sites visible at the level of the fluorescent microscope and the purified plasma membranes analyzed for their concanavalin A binding polypeptides, only four of the 20 glycopolypeptides were missing or significantly reduced in amount. Thus, these four high molecular weight concanavalin A-binding polypeptides appear to be the major cell surface receptors for concanavalin A. Binding studies with iodinated concanavalin A indicated that these polypeptides represented the high affinity concanavalin A binding sites (Kd = 2 . 10(-7) M). Low affinity concanavalin A binding sites were present on the cell surface after internalization of high affinity concanavalin A binding sites.


Partial purification of a calcium ionophore from human uremic plasma and normal urine.
A fraction is isolated from human uremic plasma and normal urine using a three step chromatographic separation :gel permeation on Sephadex G15, then chromatography on hydroxyapatite and finally desalting operation on Sephadex G15. The fraction thus separated is ninhydrine positive and uncouples mitochondria principally releasing the resting respiration. Calcium potentiates the uncoupling, while red ruthenium and magnesium inhibit it. These results are in good agreement with a ionophorous activity of the isolated fraction. An hypothetic physiological role of this compound is there being discussed.


Safety evaluation of topically applied amitriptyline in porcine full-thickness wounds.
The tricyclic antidepressant amitriptyline is frequently used in pain clinics for management of pain. It has also been suggested that topical application of amitriptyline could be useful for the treatment of neuropathic pain. In this report we investigated the effect of amitriptyline on porcine full thickness wounds resembling excised burn wounds. We assessed if daily topical application of amitriptyline into the wound chambers for 10 days impedes wound healing as measured by (1) wound contraction and (2) histopathological findings. Full-thickness wounds measuring 1.5 cm square were created on the dorsum of Yorkshire pigs and were enclosed in polyurethane wound chambers. Amitriptyline was applied daily at various concentrations. Bupivacaine (0.5%) or normal saline were used as controls. Daily wound serum levels were obtained and the level of amitriptyline and nortriptyline obtained. Pictures were taken daily and the wound surface analyzed for contraction. Cross-sectional, full-thickness skin biopsies were obtained at days 2, 8 and 10 and evaluated microscopically for re-epithelialization, inflammation, and necrosis. The high serum level of amitriptyline and nortriptyline did not affect wound healing; re-epithelialization, wound contraction, and inflammation were not significantly different between amitriptyline and control groups. Amitriptyline at the concentrations of 0.0625% and 0.125% applied daily via chambers covering wounds in a full-thickness pig excision model has no overt toxic effect on wound healing as measured by wound contraction and histological assessment.


[Psychometric validation of the OAB-V8 and OAB-V3 scales for the screening of patients with probable overactive bladder in the Spanish population].
To perform the psychometric validation in the Spanish population of the Overactive Bladder Awareness Tool (OAB-V8) scale and its abbreviated version OAB-V3 for screening patients with probable overactive bladder (OAB). A cross-sectional study was conducted in a population aged over 18 years, which was representative of the prevalence of OAB in Spain using an online methodology (Internet survey). Psychometric properties included feasibility, reliability, and validity. Subjects were classified according to the likelihood of OAB, using an automated algorithm validated previously. ROC curve analysis was performed, and the sensitivity, specificity, and positive and negative predictive values were also assessed. A total of 2,035 subjects with a mean+SD age of 52.7+12.1 years were included (50.8%) men. In total 13.7% were classified as «Probable», 27.9% «Possible», and 58.3% «No» OAB. The internal consistency of both OAB-V8 and OAB-V3 scales was high (0.894 and 0.851, respectively). The item-total correlation coefficients were high; 0.87-0.88 and 0.71-0.83, respectively. Intraclass correlation coefficient for OAB-V8 was 0.826 (confidence interval 95% 0.695-0.901) and it was 0.828 (confidence interval 0.623-0.922) for OAB-V3. The optimum cut-off value of OAB-V8 for detecting probable OAB was≥8 points (AUC=0.895, sensitivity 0.875, specificity 0.735), while for the OAB-V3 it was ≥ 3 (AUC=0.910, sensitivity 0.828, specificity 0.825). Both OAB-V8 and OAB-V3 scales were considered useful online self-administered screening tools, which were also feasible, reliable and valid for the detection of patients with probable OAB in the general population in Spain.


Telehealth-delivered group smoking cessation for rural and urban participants: feasibility and cessation rates.
Large-group behavioral smoking cessation interventions are effective for helping people quit smoking, but have not been evaluated using videoconferencing technology for rural and remote participants who have no access to in-person cessation programs. The objectives of this study were to provide and evaluate an evidence-based group smoking cessation program for rural/remote smokers wishing to quit through a Telehealth videoconferencing link at their local Health Centre. From September 2005 through April 2008, eight separate eight-session, 4 month long smoking cessation group programs were offered both in person to urban participants in Calgary and at up to six rural sites simultaneously via Telehealth videoconferencing. Quit rates were assessed at program completion, 6 and 12 month follow-up. Participants also provided evaluations of the program and technology. 554 smokers participated in the program: 370 in Calgary and 184 at various remote sites. Sixteen Telehealth sites participated from across Alberta and one site from the Northwest Territories. After program completion, continuous abstinence rates using the most conservative intent-to-treat method were 27.5% in Calgary and 25.5% for the rural Telehealth sites. Quit numbers were much higher using only Available Data at 39.2% for Calgary and 37.2% for the rural sites. Similar rates were maintained over the 12-month follow-up. Program evaluations were positive. It is possible to offer effective smoking cessation to small groups of patients in rural or remote locations through Telehealth videoconferencing technology, which produces quit rates similar to in-person groups.


Can a rheological muscle model predict force depression/enhancement?
A new phenomenological model of activated muscle is presented. The model is based on a combination of a contractile element, an elastic element that engages upon activation, a linear dashpot and a linear spring. Analytical solutions for a few selected experiments are provided. This model is able to reproduce the response of cat soleus muscle to ramp shortening and stretching and, unlike standard Hill-type models, computations are stable on the descending limb of the force-length relation and force enhancement (depression) following stretching (shortening) is predicted correctly. In its linear version, the model is consistent with a linear force-velocity law, which in this model is a consequence rather than a fundamental characteristic of the material. Results show that the mechanical response of activated muscle can be mimicked by a viscoelastic system. Conceptual differences between this model and standard Hill-type models are analyzed and the advantages of the present model are discussed.


Systemic inflammation as a risk factor for portal vein thrombosis in cirrhosis: a prospective longitudinal study.
Various risk factors for portal vein thrombosis (PVT) development in patients with cirrhosis have been identified, but the role of systemic inflammatory reaction is unknown. The study aims to assess the association between markers of systemic inflammation and PVT in cirrhosis. Between January 2014 and October 2015, 107 outpatients with cirrhosis and no PVT were recruited, and followed till February 2017. White blood cell count, serum concentrations of high-sensitive C-reactive protein, ferritin, tumor necrosis factor-alpha and interleukin-6 (IL-6) were evaluated at baseline and every 3 or 6 months till PVT diagnosis or end of follow-up. Median age, model for end-stage liver disease (MELD) score and follow-up period of the studied population was 55 years (IQR 46-62 years), 9.6 points (IQR 7.5-12 points) and 19 months (12-24 months), respectively. PVT developed in 10.3% of the patients. Lymphocyte count below 1.2 ´ 109/L [hazard ratio, 6.04; 95% confidence interval (CI), 1.29-28.2; P = 0.022], IL-6 above 5.5 pg/mL (hazard ratio, 5.64; 95% CI, 1.21-26.33; P = 0.028) and neutrophil-to-lymphocyte ratio (hazard ratio, 1.46; 95% CI, 1.04-2.04; P = 0.028) were associated with a higher risk of PVT development. IL-6 and lymphopenia remained associated with subsequent PVT development after adjustment for nonselective beta-blockers, spleen size, portosystemic collaterals, oesophageal varices (grade ≥2) and ascites, but also with alcohol as the cause for cirrhosis and MELD ≥13. In patients with cirrhosis, markers of systemic inflammation IL-6 and lymphopenia are predictive of PVT independently of markers of portal hypertension. These results draw our attention on a factor so far overlooked in the pathogenesis of PVT.


Synthesis and evaluation of substituted diphenyl-1,3,4-oxadiazole derivatives for central nervous system depressant activity.
Substituted 1,3,4-oxadiazoles are of considerable pharmaceutical interest. 2,5-Substituted diphenyl-1,3,4-oxadiazoles are associated with diverse biological activities by the virtue of -N = C-O- grouping. In the view of wide range of biological properties associated with 1,3,4-oxadiazole, we have synthesized substituted derivatives of 1,3,4-oxadiazole (XIII-XXII), a versatile hydrophobic molecule possessing preliminary CNS properties, with the hope to potentiate the biological activities with lesser or limited amount of toxicities. The synthesis was based on ester substitution of substituted benzohydrazide in presence of hydrazine hydrate followed by cyclization in presence of phosphorus oxychloride. All the synthesized compounds were evaluated for their potential CNS depressant activities. Statistical analysis of the anticonvulsant, antidepressant, and antianxiety activity of the synthesized compounds on animals was evaluated using one-way analysis of variance (ANOVA). Two compounds 5-(4-nitrophenyl)-2-(4-chlorophenyl)-1,3,4-oxadiazole (XIV) and 5-(4-nitrophenyl)-2-(4-nitrophenyl)-1,3,4-oxadiazole (XV) were found to be the most promising compounds of the series in antidepressant, anticonvulsant and antianxiety activity with no neurotoxicity when compared with standard. Among the synthesized compounds, it was found that incorporation of electron withdrawing group at C2 and C5 position of the oxadiazole ring led to high degree of pharmacological activity. Thus compounds 5-(4-nitrophenyl)-2-(4-chlorophenyl)-1,3,4-oxadiazole (XIV) and 5-(4-nitrophenyl)-2-(4-nitrophenyl)-1,3,4-oxadiazole (XV) showed excellent CNS depressant activities. The result of the present investigation may encourage us to develop and/or improve similar other related compounds and it may be assumed that further modifications may produce compounds of better activity with lesser side effects.


Splenic arterial hemorrhage in pancreatitis: report of three cases.
Gastrointestinal hemorrhage is a rare complication of pancreatitis and can involve any of the peripancreatic vessels. The three cases reported herein illustrate the involvement of the splenic artery in diverse forms of pancreatitis: chronic pancreatitis, a pancreatic pseudocyst, and necrotizing pancreatitis. Bleeding was controlled in all cases by a bipolar ligation of the bleeding vessel at surgery.


Mito-Tempo alleviates cryodamage by regulating intracellular oxidative metabolism in spermatozoa from asthenozoospermic patients.
As the largest proportion of male infertility population, asthenozoospermia patients often resort to sperm cryopreservation to preserve fertility as well as to enrich motile sperm for assisted reproductive techniques (ART), although it may cause some cryodamage during the freezing-thawing process. The objective of this study was to investigate whether mitochondrial antioxidant Mito-Tempo was effective in preventing cryodamage of asthenozoospermic spermatozoa. Asthenozoospermic semen samples were collected and cryopreserved in media supplemented with different concentrations (0.0, 1.0, 10 and 100 μM) of Mito-Tempo. We measured sperm motility, viability, membrane integrity, DNA fragmentation, mitochondrial membrane potential, oxidation product, and antioxidant enzymes activities. Supplementation of the cryopreservation media with Mito-Tempo (10 and 100 μM) induced a significant improvement in sperm viability, motility, membrane integrity, mitochondrial membrane potential and chromatin integrity (P < 0.05). Significant enhancement of antioxidant enzymes activities accompanied by the decreased formation of oxidation products (ROS and MDA) was also observed in groups supplemented with Mito-Tempo (10 and 100 μM). It is concluded that mitochondria targeted antioxidant Mito-Tempo alleviates cryodamage by regulating intracellular oxidative metabolism in spermatozoa from asthenozoospermic patients after cryopreservation.


ACE inhibitors, angiotensin receptor blockers and endothelial injury in COVID-19.
COVID-19 is caused by the coronavirus SARS-CoV-2, which uses angiotensin-converting enzyme 2 (ACE-2) as a receptor for cellular entry. It is theorized that ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) may increase vulnerability to SARS-CoV-2 by upregulating ACE-2 expression, but ACE-I/ARB discontinuation is associated with clinical deterioration. To determine whether ACE-I and ARB use is associated with acute kidney injury (AKI), macrovascular thrombosis and in-hospital mortality. A retrospective, single-centre study of 558 hospital inpatients with confirmed COVID-19 admitted from 1 March to 30 April 2020, followed up until 24 May 2020. AKI and macrovascular thrombosis were primary end-points, and in-hospital mortality was a secondary end-point. AKI occurred in 126 (23.1%) patients, 34 (6.1%) developed macrovascular thrombi, and 200 (35.9%) died. Overlap propensity score-weighted analysis showed no significant effect of ACE-I/ARB use on the risk of occurrence of the specified end-points. On exploratory analysis, severe chronic kidney disease (CKD) increases odds of macrovascular thrombi (OR: 8.237, 95% CI: 1.689-40.181, P = 0.009). The risk of AKI increased with advancing age (OR: 1.028, 95% CI: 1.011-1.044, P = 0.001) and diabetes (OR: 1.675, 95% CI: 1.065-2.633, P = 0.025). Immunosuppression was associated with lower risk of AKI (OR: 0.160, 95% CI: 0.029-0.886, P = 0.036). Advancing age, dependence on care, male gender and eGFR < 60 mL min-1 /1.73 m2 increased odds of in-hospital mortality. We did not identify an association between ACE-I/ARB use and AKI, macrovascular thrombi or mortality. This supports the recommendations of the European and American Societies of Cardiology that ACE-Is and ARBs should not be discontinued during the COVID-19 pandemic.


Antiviral effect of Chinese herbal prescription JieZe-1 on adhesion and penetration of VK2/E6E7 with herpes simplex viruses type 2.
The Chinese Herbal Prescription JieZe-1(JZ-1), added and subtracted from Yihuang Decoction, a famous formula in the 12th year of Kangxi in Qing Dynasty, has a clear effect on Genital Herpes (GH) and no obvious adverse reactions occur clinically. JZ-1 also has preventive and therapeutic effects on Trichomonas vaginitis, Candida albicans vaginitis and GH in vitro and in vivo experiments. The effect and mechanism of JZ-1 on anti-herpes simplex virus type 2(HSV-2) in vitro focusing on adhesion and penetration stages were investigated. A model of HSV-2 infection of VK2/E6E7 was developed. In order to explore JZ-1's anti-HSV-2 effect in vitro, cell morphology, ultrastructural pathology, cell viability and expression of viral glycoprotein D (gD) were assessed at 6 h, 12 h, 18 h, and 24 h of JZ-1 treatment. Then we measured the exact time required for adhesion and penetration of HSV-2 into VK2/E6E7 among a series of times at room temperature and under temperature control techniques. We treated VK2/E6E7 with JZ-1, penciclovir, or berberine and explored the mechanism of JZ-1 in blocking HSV-2 adhesion and penetration of host cells by assessing the cell ultrastructural pathology, viability, viral proteins gB, gD, VP16, ICP5, and ICP4 and host cell proteins HVEM, Nectin-1, and Nectin-2. HSV-2 can fully adhere and penetrate into VK/E6E7 within 5 mins at room temperature while it takes 60mins under temperature control techniques. JZ-1 and penciclovir showed significant anti-HSV-2 effects, with improved host cell morphologies and increased host cell viabilities observed after treatment for 24 h. The anti-HSV-2 effect of JZ-1 can be detected after treatment for 6 h while that of penciclovir was not obvious until treatment for 12 h. JZ-1 showed distinct effect on HSV-2 adhesion and penetration stages by significantly reducing the expression of viral proteins gB, gD, VP16, ICP5, and ICP4, improving cell morphology and increasing cell viability. However, these effects were not exerted via downregulated expression of membrane fusion-related proteins such as HVEM, Nectin-1, or Nectin-2. The specific anti-HSV-2 mechanism of JZ-1 need to be further explored. The anti-HSV-2 effect of JZ-1 was superior to that of penciclovir and berberine in vitro, and was mainly mediated by enhancing host cell defense and blocking adhesion and penetration of HSV-2.


Help-seeking following a flooding event: a cross-sectional analysis of adults affected by flooding in England in winter 2013/14.
Flooding can cause long-term, significant impacts on mental health in affected populations. We explored help-seeking behaviour of households affected by flooding. A cross-sectional analysis was conducted on National Study of Flooding and Health data on households flooded in England in winter 2013/14. Participants (Year 1: n = 2006; Year 2: n = 988; Year 3: n = 819) were asked if they sought help from health services and other sources. Logistic regression was conducted to calculate odds ratios (ORs) of help-seeking in flooded and disrupted participants compared to unaffected, adjusted for a priori confounders. The odds of seeking help from any source 1 year after flooding were greater for flooded participants [adjusted OR (aOR): 1.71, 95% confidence interval (CI): 1.19-1.45] and those disrupted by flooding (aOR: 1.92, 95% CI: 1.37-2.68) compared to unaffected participants. This continued in the second year (flooded: aOR 6.24, 95% CI: 3.18-13.34; disrupted: aOR: 2.22, 95% CI: 1.14-4.68), and help-seeking remained greater in flooded than unaffected participants in the third year. Flooded and disrupted participants were particularly likely to seek help from informal sources. Help-seeking was more prevalent amongst participants with mental health outcomes, but a notable proportion of individuals with any mental health outcome did not seek help (Year 1: 15.0%; Year 2: 33.3%; Year 3: 40.3%). Flooding is associated with increased demand for formal and informal support, persisting for at least 3 years, and an unmet need for help amongst affected individuals. Our findings should be considered in flood response planning to reduce the long-term adverse health impacts of flooding.


Protocol for the Metformin Aneurysm Trial (MAT): a placebo-controlled randomised trial testing whether metformin reduces the risk of serious complications of abdominal aortic aneurysm.
Multiple observational studies have associated metformin prescription with reduced progression of abdominal aortic aneurysm (AAA). The Metformin Aneurysm Trial (MAT) will test whether metformin reduces the risk of AAA rupture-related mortality or requirement for AAA surgery (AAA events) in people with asymptomatic aneurysms. MAT is an international, multi-centre, prospective, parallel-group, randomised, placebo-controlled trial. Participants must have an asymptomatic AAA measuring at least 35 mm in maximum diameter, no diabetes, no contraindication to metformin and no current plans for surgical repair. The double-blind period is preceded by a 6-week, single-blind, active run-in phase in which all potential participants receive metformin. Only patients tolerating metformin by taking at least 80% of allocated medication will enter the trial and be randomised to 1500 mg of metformin XR or an identical placebo. The primary outcome is the proportion of AAA events defined as rupture-related mortality or need for surgical repair. Secondary outcomes include AAA growth, major adverse cardiovascular events and health-related quality of life. In order to test if metformin reduced the risk of AAA events by at least 25%, 616 primary outcome events will be required (power 90%, alpha 0.05). Currently, there is no drug therapy for AAA. Past trials have found no convincing evidence of the benefit of multiple blood pressure lowering, antibiotics, a mast cell inhibitor, an anti-platelet drug and a lipid-lowering medication on AAA growth. MAT is one of a number of trials now ongoing testing metformin for AAA. MAT, unlike these other trials, is designed to test the effect of metformin on AAA events. The international collaboration needed for MAT will be challenging to achieve given the current COVID-19 pandemic. If this challenge can be overcome, MAT will represent a trial unique within the AAA field in its large size and design. Australian Clinical Trials ACTRN12618001707257 . Registered on 16 October 2018.


Lipid abnormalities in pediatric kidney transplant recipients on steroid withdrawal maintenance immunosuppression.
Dyslipidemia is a modifiable risk factor for cardiovascular disease. The prevalence of dyslipidemia in pKTR (pediatric kidney transplant recipients) under modern immunosuppression remains unknown. We determined the prevalence, risk factors, co-morbidities, and treatment patterns of lipid abnormalities in pediatric kidney transplant recipients on steroid withdrawal immunosuppression. pKTR (age ≤ 21 years) at a single center on steroid withdrawal immunosuppression underwent lipid screening between January 1, 2020, and September 30, 2022. Continuous and categorical variables were compared using the Wilcoxon rank-sum and chi-square or Fisher's exact tests, respectively. The correlation between total cholesterol and BMI (body mass index) was assessed using Pearson's product-moment correlation, and predictors of lipid abnormalities were evaluated using the multivariable logistic regression. A total of 96 patients were included, with a median post-transplant time of 2.5 years (IQR: 1.3-5.4). Of the total, 64.6% (n = 62) of patients had a fasting lipid abnormality. We found a significant linear correlation between total cholesterol and BMI (r = 0.38, p = 0.0022). After multivariable adjustment, every 1 ml/min/1.73 m2 increase in eGFR was associated with a 2% lower odds of a lipid abnormality (OR 0.979, p = 0.026). Obesity, hypertension, and left ventricular hypertrophy were similar between those with and without lipid abnormalities, while insulin-treated diabetes was more prevalent in recipients with lipid abnormalities (12.9% vs. 0%, p = 0.047). Only 36.5% of patients (n = 19) were referred to a dietician and/or lipid specialist; one received statin therapy. Lipid abnormalities are highly prevalent in pKTR, but therapeutic intervention is infrequent. Calcineurin inhibition without corticosteroids may not be protective; however, higher eGFR is associated with a lower prevalence of lipid abnormalities. A higher resolution version of the Graphical abstract is available as Supplementary information.


Ocular allergy test and biomarkers on the ocular surface: Clinical test for evaluating the ocular surface condition in allergic conjunctival diseases.
Allergic conjunctival diseases (ACDs) are inflammatory diseases of the conjunctiva and cornea caused predominantly by the IgE-mediated immediate hypersensitivity response. Allergic conjunctival diseases include allergic conjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis. In clinical practice of ACDs, an ocular allergy test using biomarker measurement is a crucial examination technique for diagnosing, evaluating severity, and determining the efficacy of medical treatment. The ocular allergy test includes the tear test for evaluating the concentration of biomarkers in tears and an ocular surface test for assessing the expression levels of messenger ribonucleic acid (mRNA) biomarkers on the ocular surface. The clinical usefulness of several biomarkers has been demonstrated in patients with ACDs; specifically, eosinophil cationic protein and eotaxin-2 as eosinophilic inflammation biomarkers; interleukin-4 and thymus and activation regulated chemokine (CCL17/TARC) as Th2 inflammation biomarkers; eotaxin, tumor necrosis factor-alpha and soluble IL-6 receptor as giant papillae biomarkers; and osteopontin and periostin as allergic inflammation and remodeling biomarkers. Furthermore, the ocular allergy test, quantitative evaluation methods using biomarkers have allowed for better understanding of the immunological and pathophysiological mechanisms of ACDs. Therefore, the search for a biomarker is important to make an ocular allergy test useful. In previous ocular allergy tests, the biomarkers for allergic inflammation in patients with chronic ACDs including VKC and AKC were substantial. However, the selection of biomarkers associated with the early phase reaction of immediate hypersensitivity and innate immunity responses needs to be addressed in future investigations.


QT dispersion correlates to myocardial viability assessed by dobutamine stress echocardiography in patients with severely depressed left ventricular function due to coronary artery disease.
QT dispersion is prolonged in numerous cardiac diseases, representing a general repolarization abnormality. To evaluate the influence of viable myocardium on QT dispersion in patients with severely depressed left ventricular (LV) function due to coronary artery disease. 103 patients with ischemic cardiomyopathy (LV ejection fraction [EF]: 25+/-6%) were studied. Patients underwent 12-lead electrocardiography to assess QT dispersion, and two-dimensional echocardiography to identify segmental dysfunction. Dobutamine stress echocardiography (DSE) was then performed to detect residual viability. Resting echo demonstrated 1260 dysfunctional segments; of these, 476 (38%) were viable. Substantial viability (> or =4 viable segments on DSE) was found in 62 (60%) patients. QT dispersion was lower in these patients, than in patients without viability (55+/-17 ms vs. 65+/-22 ms, P=0.012). Viable segments negatively correlated to QT dispersion (r=-0.333, P=0.001). In contrast, there was no correlation between LVEF and QT dispersion (r=-0.001, P=NS). There is a negative correlation between QT dispersion and the number of viable segments assessed by DSE. Patients with severely depressed LV function and a low QT dispersion probably have a substantial amount of viable tissue. Conversely, when QT dispersion is high, the likelihood of substantial viability is reduced.


Biomechanical characterization (fingerprinting) of five novel methods of cervical spine manipulation.
To determine the biomechanical characteristics of five clinically common methods of cervical spine manipulation. Descriptive study. Human Performance Lab, University of Calgary. Five volunteer practitioners treating symptomatic patients from their own clinical populations. Five commonly used methods of cervical spine manipulation: lateral break (LAT), Gonstead (GON), Activator (ACT), toggle (TOG), rotation (ROT). Mean thrust duration (msec), normalized mean peak force (N), slope (N/msec), force profile (graphic representation of the above values. Outcome measures for each manipulative technique were as follows: LAT = normalized mean peak force of 102.2 N at 86.7 msec, GON = 109.8 N at 91.9 msec, ACT = 40.9 N at 31.8 msec, TOG = 117.6 N at 47.5 msec, ROT = 40.5 N at 79.1 msec. The observed differences and similarities in force profiles between the five techniques studied here may partly be the manifestation of how a particular technique delivers force to the cervical spine. The clinical significance of force profile characterization is not yet known.


Significance of bronchial washings smear negativity in 'suspect' pulmonary tuberculosis.
The role of bronchial washings in patients with 'suspect' pulmonary tuberculosis was studied in 55 patients. Bronchial washings increased the diagnostic yield of tuberculosis by 28%. It was also able to accurately exclude active tuberculosis in 94% patients. Hence it is inferred that absence of acid-fast bacilli in smears of bronchial washings is equally important to exclude active tuberculosis.


Idiopathic myelofibrosis: a clinical review.
Idiopathic myelofibrosis (MF) is a chronic myeloproliferative disorder (MPD) in which a clonal haemopoietic stem cell proliferation is accompanied by reactive fibrosis. Despite this clear understanding of pathogenesis, the majority of patients with MF are still poorly treated in comparison to those with other types of MPD. This article reviews the clinical and laboratory features in light of our current knowledge on the pathogenesis and pathopathology of MF; discusses the various prognostic factors to enable stratification of patients to the 'long-lived' group (median survival around 10 years) or the 'short-lived' group (median survival around 2 years); highlights the need to treat patients more effectively with specific therapy directed against the underlying neoplastic clonal stem cell proliferation; argues for long-term, if intermittent, maintenance therapy to improve the quality of life and hopefully, also their life-span; and, provides a summary of the various treatment options currently available for patients with MF.


The use of rest and exercise radionuclide ventriculography in risk stratification in patients with suspected coronary artery disease.
The study examined the value of rest and exercise radionuclide ventriculography in risk stratification in patients with suspected coronary artery disease. There were 604 patients, 474 men and 130 women, aged 55 +/- 11 years (mean +/- standard deviation). At a follow-up of 18 +/- 10 months, there were 43 hard cardiac events: 27 patients died of cardiac causes and 16 had nonfatal acute myocardial infarctions. Univariate and multivariate survival analysis of the 10 most important clinical and exercise variables identified the exercise left ventricular ejection fraction as the most important predictor of death and total cardiac events (chi 2 = 18.1 and 29.6, respectively). The exercise heart rate was a significant, independent, but much weaker predictor of cardiac death and total events (chi 2 = 8.4 and 3.9, respectively), while exercise tolerance was a significant independent predictor of cardiac death only (chi 2 = 6.4). Actuarial life table analysis showed that the risk for future cardiac events increased in stepwise fashion as the exercise ejection fraction decreased. Thus, the exercise left ventricular ejection fraction is a useful prognosticator in patients with suspected coronary artery disease. This finding has important implications in patient management.


Amyloid pathology reduces ELP3 expression and tRNA modifications leading to impaired proteostasis.
Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by accumulation of β-amyloid aggregates and loss of proteostasis. Transfer RNA (tRNA) modifications play a crucial role in maintaining proteostasis, but their impact in AD remains unclear. Here, we report that expression of the tRNA modifying enzyme ELP3 is reduced in the brain of AD patients and amyloid mouse models and negatively correlates with amyloid plaque mean density. We further show that SH-SY5Y neuronal cells carrying the amyloidogenic Swedish familial AD mutation (SH-SWE) display reduced ELP3 levels, tRNA hypomodifications and proteostasis impairments when compared to cells not carrying the mutation (SH-WT). Additionally, exposing SH-WT cells to the secretome of SH-SWE cells led to reduced ELP3 expression, wobble uridine tRNA hypomodification, and increased protein aggregation. Importantly, correcting tRNA deficits due to ELP3 reduction reverted proteostasis impairments. These findings suggest that amyloid pathology dysregulates proteostasis by reducing ELP3 expression and tRNA modification levels, and that targeting tRNA modifications may be a potential therapeutic avenue to restore neuronal proteostasis in AD and preserve neuronal function.


Male mice lacking ADAMTS-16 are fertile but exhibit testes of reduced weight.
Adamts16 encodes a disintegrin-like and metalloproteinase with thrombospondin motifs, 16, a member of a family of multi-domain, zinc-binding proteinases. ADAMTS-16 is implicated in a number of pathological conditions, including hypertension, cancer and osteoarthritis. A large number of observations, including a recent report of human ADAMTS16 variants in cases of 46,XY disorders/differences of sex development (DSD), also implicate this gene in human testis determination. We used CRISPR/Cas9 genome editing to generate a loss-of-function allele in the mouse in order to examine whether ADAMTS-16 functions in mouse testis determination or testicular function. Male mice lacking Adamts16 on the C57BL/6N background undergo normal testis determination in the fetal period. However, adult homozygotes have an average testis weight that is around 10% lower than age-matched controls. Cohorts of mutant males tested at 3-months and 6-months of age were fertile. We conclude that ADAMTS-16 is not required for testis determination or male fertility in mice. We discuss these phenotypic data and their significance for our understanding of ADAMTS-16 function.


Strengthening primary health care for effective response to pandemics: a systematic review.
Affordability, accessibility and quality of services provided by a primary healthcare system can contribute significantly to the mitigation and management of a pandemic or disease outbreak. A strong primary healthcare system will mitigate the pressure on health systems during crises. We aimed to identify the specific capabilities required to establish a resilient primary healthcare system that could respond effectively to a health crisis, and highlight any research gaps. A bibliographic search was conducted on PubMed, Scopus, Web of Science, and ProQuest from 2000 to 2021. Using extracted data, we mapped the studies and categorized published research into a framework of 6 building blocks. A graphical and tabular representation of the data was then provided. A total of 4276 studies were retrieved, out of which 28 met the inclusion criteria for the systematic review. Data extraction was based on the study design, year of publication, country, type of communicable disease, and main interventions used for building resilient primary healthcare systems. Most of the studies were conducted in 2020 and 2021 during the COVID-19 pandemic and many of them emphasized digital health. This review summarizes more than 20 years of research on how primary healthcare systems responded to public health emergencies. It provides a broad overview of the subject matter and existing research gaps for intervention planning and policymaking.


MS-related material in blood of multiple sclerosis patients: results with the leucocyte adherence inhibition assay.
To determine the value of laboratory methods proposed as tests for multiple sclerosis (MS), the reactivity of leucocytes to a preparation of an antigen from the blood of patients with MS (MS-related material) was studied in the leucocyte adherence inhibition (LAI) test. The results point to the existence of an antigenic substance in the blood of MS patients. When the LAI test was modified by the addition of calf serum there was a significant reaction of the leucocytes of MS compared to other neurological diseases and controls. The relatively high positive rate in MS previously reported was not detected. Therefore, further analyses concerning the characterisation of the antigen and the conditions of the test system will be necessary before the method can be used for diagnosis.


The clpX gene plays an important role in bacterial attachment, stress tolerance, and virulence in Xanthomonas campestris pv. campestris.
Xanthomonas campestris pv. campestris is a bacterial pathogen and the causal agent of black rot in crucifers. In this study, a clpX mutant was obtained by EZ-Tn5 transposon mutagenesis of the X. campestris pv. campestris. The clpX gene was annotated to encode ClpX, the ATP-binding subunit of ATP-dependent Clp protease. The clpX mutant exhibited reduced bacterial attachment, extracellular enzyme production and virulence. Mutation of clpX also resulted in increased sensitivity to a myriad of stresses, including heat, puromycin, and sodium dodecyl sulfate. These altered phenotypes of the clpX mutant could be restored to wild-type levels by in trans expression of the intact clpX gene. Proteomic analysis revealed that the expression of 211 proteins differed not less than twofold between the wild-type and mutant strains. Cluster of orthologous group analysis revealed that these proteins are mainly involved in metabolism, cell wall biogenesis, chaperone, and signal transduction. The reverse transcription quantitative real-time polymerase chain reaction analysis demonstrated that the expression of genes encoding attachment-related proteins, extracellular enzymes, and virulence-associated proteins was reduced after clpX mutation. The results in this study contribute to the functional understanding of the role of clpX in Xanthomonas for the first time, and extend new insights into the function of clpX in bacteria.


Risk factors associated with depression in patients with type 2 diabetes mellitus.
This study was undertaken in order to identify the prevalence and factors associated with depression in a group of patients with type 2 diabetes mellitus. Our design consisted of a cross-sectional study at the Department of Neurology and Psychiatry of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City. Study units included 189 patients with type 2 diabetes mellitus (DM). Beck Depression Inventory scale was used to measure the presence of depression, while the independent variables evaluated to explain depression were sociodemographic (gender, marital status, religion, education, occupation, socioeconomic status) and characteristics of the disease were disease duration, comorbidity, compliance, and glycemic control. Prevalence of depression was 39% (74 patients). The following risk factors were identified by univariate analysis: being widowed (OR 3.54, confidence interval [CI] 1.56-8.11, p = 0.0007); female (OR 2.95, CI 1.50-5.82, p = 0.006); housewife (OR 2.08, CI 1.10-3.94, p = 0.01); poor compliance (OR 2.14, CI 1.12-4.10, p = 0.01), and presence of comorbidity (OR 5.60, CI 1.51-24.5, p = 0.002). On the other hand, the most constant associations were presence of blood glucose at the last appointment >or=200 (OR 3.23, CI 1.59-6.60, p = 0.0003) and >or=250 (OR 2.15, CI 0.93-5.03, p = 0.05), as the average of the last five blood glucoses >or=200 (OR 3.67, CI 1.76-7.73, p = 0.0001), >or=250 (OR 4.07, CI 1.61-10.49, p = 0.0007) and >or=300 (OR 2.12, CI 1.48-3.02, p = 0.003). Discriminant function analysis of the variables, previously studied in univariate analysis, was carried out for the presence of depression. A stepwise model included the following variables: average of the last five blood glucoses; 2) widowed or divorced, and 3) female. Frequency of depression in patients with type 2 DM was high (39%). High level of blood glucose stands out as a variable associated with presence of depression. Other associations were presence of comorbidity, being a female, and being widowed or divorced.


[The ichthyoses. Pathophysiological models of epidermal differentiation].
The ichthyoses are a heterogeneous group of monogenetically inherited disorders of cornification, and characterized clinically by scaling or hyperkeratosis. Historically, they were classified by clinical features and inheritance patterns. As a result of the recent molecular biological revolution, the ichthyoses are now recognized as comprising many diverse entities. Importantly, identical phenotypes may be caused by mutations in multiple genes, while mutations in a single gene may result in multiple and sometimes widely divergent phenotypes. The considerable complexity of this clinically and genetically heterogeneous group of disorders has prompted the need for a new classification. A classification that uses terminology based on a combination of the clinical and molecular genetic details, for instance loricrin keratoderma, is desirable. In this chapter we will use in principle the nosology adopted recently by an international group of experts at the First Ichthyosis Consensus Conference in Sorèz, France.


Management of Medial Sphenoid Wing Meningioma Involving the Cavernous Sinus: A Single-Center Series of 105 Cases.
Medial sphenoid wing meningiomas are among the three most common intracranial meningiomas. These tumors pose a challenge to neurosurgeons in terms of surgical treatment, as they may involve critical neurovascular structures and invade the cavernous sinus. In case of the latter, a complete resection may not be achievable. The purpose of this study was to investigate prognostic features affecting recurrence and progression-free survival (PFS) of medial sphenoid wing meningiomas involving the cavernous sinus, focusing on the contribution of surgery and postoperative radiotherapy. A retrospective analysis was conducted of the database of our institution, and 105 cases of medial sphenoid wing meningioma with invasion of the cavernous sinus, which were treated between 1998 and 2019, were included. Surgical treatment only was performed in 64 cases, and surgical treatment plus postoperative radiotherapy was performed in 41 cases. Kaplan-Meier analysis was conducted to estimate median survival and PFS rates, and Cox regression analysis was applied to determine significant factors that were associated with each therapeutic modality. The risk of recurrence was significantly reduced after near-total resection (NTR) (p-value = 0.0011) compared to subtotal resection. Progression-free survival was also significantly prolonged after postoperative radiotherapy (p-value = 0.0002). Maximal safe resection and postoperative stereotactic radiotherapy significantly reduced the recurrence rate of medial sphenoid wing meningiomas with infiltration of the cavernous sinus.


BIOMedical Search Engine Framework: Lightweight and customized implementation of domain-specific biomedical search engines.
Text mining and semantic analysis approaches can be applied to the construction of biomedical domain-specific search engines and provide an attractive alternative to create personalized and enhanced search experiences. Therefore, this work introduces the new open-source BIOMedical Search Engine Framework for the fast and lightweight development of domain-specific search engines. The rationale behind this framework is to incorporate core features typically available in search engine frameworks with flexible and extensible technologies to retrieve biomedical documents, annotate meaningful domain concepts, and develop highly customized Web search interfaces. The BIOMedical Search Engine Framework integrates taggers for major biomedical concepts, such as diseases, drugs, genes, proteins, compounds and organisms, and enables the use of domain-specific controlled vocabulary. Technologies from the Typesafe Reactive Platform, the AngularJS JavaScript framework and the Bootstrap HTML/CSS framework support the customization of the domain-oriented search application. Moreover, the RESTful API of the BIOMedical Search Engine Framework allows the integration of the search engine into existing systems or a complete web interface personalization. The construction of the Smart Drug Search is described as proof-of-concept of the BIOMedical Search Engine Framework. This public search engine catalogs scientific literature about antimicrobial resistance, microbial virulence and topics alike. The keyword-based queries of the users are transformed into concepts and search results are presented and ranked accordingly. The semantic graph view portraits all the concepts found in the results, and the researcher may look into the relevance of different concepts, the strength of direct relations, and non-trivial, indirect relations. The number of occurrences of the concept shows its importance to the query, and the frequency of concept co-occurrence is indicative of biological relations meaningful to that particular scope of research. Conversely, indirect concept associations, i.e. concepts related by other intermediary concepts, can be useful to integrate information from different studies and look into non-trivial relations. The BIOMedical Search Engine Framework supports the development of domain-specific search engines. The key strengths of the framework are modularity and extensibilityin terms of software design, the use of open-source consolidated Web technologies, and the ability to integrate any number of biomedical text mining tools and information resources. Currently, the Smart Drug Search keeps over 1,186,000 documents, containing more than 11,854,000 annotations for 77,200 different concepts. The Smart Drug Search is publicly accessible at http://sing.ei.uvigo.es/sds/. The BIOMedical Search Engine Framework is freely available for non-commercial use at https://github.com/agjacome/biomsef.


Catheter ablation in children and young adults: is there an additional benefit from remote magnetic navigation?
Although rare, children and young adults can suffer from significant cardiac arrhythmia, especially in the context of congenital malformations and after cardiac surgery. A total of 62 patients (32 female, median age 20 years) underwent an invasive electrophysiology study between 2008-2011: half had normal cardiac anatomy, whereas the remaining patients had various types of congenital heart disease. All patients were treated using either conventional techniques (CVN) or remote magnetic navigation (RMN). Patients treated with the RMN system differed substantially from patients in the CVN group with respect to presence of congenital heart disease (67 % vs. 37 %), previous cardiac surgery (59 % vs. 20 %) or failed previous conventional ablation (22 % vs. 9 %), respectively. Although these more complex arrhythmias resulted in longer median procedure duration (180 vs. 130 min, p = 0.034), the median overall fluoroscopy exposure in the RMN group was significantly lower (4.1 vs. 5.2 min, p = 0.020). Clinical outcome was comparable in both groups without complications caused by the ablation. Catheter ablation using remote magnetic navigation is safe and feasible in children and young adults and is especially valuable in patients with abnormal cardiac morphologies. RMN resulted in significantly lower radiation exposure compared with the conventional technique.


Association of Plasma Magnesium with Prediabetes and Type 2 Diabetes Mellitus in Adults.
Our study aimed to assess the associations of plasma magnesium with prediabetes and type 2 diabetes (T2D) among Chinese adults. We conducted a case-control analysis of 4447 participants: 867 newly diagnosed prediabetes patients, 1475 newly diagnosed T2D patients and 2105 normal glucose tolerance (NGT) individuals. In a subsample of 599 apparently healthy individuals, we measured plasma hs-CRP levels to examine their relation to plasma magnesium. Plasma magnesium and hs-CRP were measured by inductively coupled plasma mass spectrometry and an enzyme-linked immunosorbent assay, respectively. Plasma magnesium decreased from NGT to prediabetes to T2D, and was inversely associated with prediabetes and T2D. After adjustment for potential confounding factors, the ORs from the lowest to highest quartiles of plasma magnesium were 1, 0.57 (95%CI, 0.44-0.74), 0.49 (0.37-0.65) and 0.51 (0.37-0.70) for prediabetes, and 1, 0.26 (0.20-0.33), 0.15 (0.12-0.20) and 0.15 (0.11-0.20) for T2D. Consistently, plasma magnesium was inversely correlated with plasma hs-CRP in our subsample analysis; the geometric mean hs-CRP concentration for ascending quartiles of plasma magnesium were 1.29 (1.06-1.57), 1.16 (0.95-1.41), 1.00 (0.81-1.22), and 0.71 (0.58-0.88) mg/l. Plasma magnesium was independently and inversely associated with prediabetes and T2D in Chinese adults.


Primary cardiac diffuse large B-cell lymphoma with concurrent high MYC and BCL2 expression in an immunocompetent Chinese elderly woman.
Primary cardiac lymphoma is a rare type of extranodal lymphoma that involves only heart and/or pericardium. It is usually observed in immunodeficient people. However, immunocompetent patients may also suffer from this disease. Most primary cardiac lymphomas are of B-cell lineage, and they usually present as diffuse large B-cell lymphoma (DLBCL). Diffuse large B-cell lymphoma with concurrently high MYC and BCL2 expression, which is named as double-expressor lymphoma (DEL), is a rare subtype of DLBCL. Here we report a rare case of a primary cardiac DEL in an immunocompetent 65-year old Chinese woman. Echocardiography and magnetic resonance imaging revealed a mass of 6.6 cm×5.6 cm in the right atrium. No tumor formations were observed in other organs. Histopathologic examination showed that the cardiac tumor was diffuse large B-cell lymphoma, non-germinal center B-cell type by Hans algorithm. The tumor cells showed high MYC and BCL2 protein expression by immunohistochemistry, with high proliferative index.


Pyrene modification leads to increased catalytic activity in minimal hammerhead ribozymes.
Highly active variants of minimal hammerhead ribozymes are generated by the replacement of substantial parts of stem-loop structures with pyrene building blocks.


Negative Ion Formation by Thermal Surface Ionization of Sulfur Dioxide.
The generation of negative ions from SO2 in the gas phase was studied using the thermal surface ionization method. Six anion types were measured: O- , S- , SO- , and SO2- and anions with m/z=96 and m/z=128. The most abundant anion formed was S- and the formation routes are discussed for each of the six anions. O- , S- , and SO- are formed via dissociative electron attachment to the molecule, whereas the generation of SO2- and anions with m/z=96 and m/z=128 are probably associated with the formation of H2 SO4 in the gas inlet system and the ion source. Using statistical thermodynamics the dissociation temperatures of SO2 and SO in the gas phase are calculated and values of above 1800 °C are obtained for both molecules. We also estimated the optimal filament temperatures for the formation of all anions measured, indicating that for SO2 the optimal temperature is related to the electron affinity of the molecules: the optimal temperature increases with decreasing value of the electron affinity for the molecule corresponding to the respective anion.


Localization of genes and anonymous DNA probes on the short arm of chromosome 7.
We have previously described the cytogenetic analysis of two patients with Greig cephalopolysyndactyly syndrome (GCPS) and various microdeletions on the short arm of Chromosome (Chr) 7. Using genes and anonymous DNA probes from 7p we analyzed the DNA of our patients for loss of heterozygosity, or we determined the copy number by semi-quantitative Southern hybridization. We have been able to show hemizygosity for the genes of INHBA, IGFBP1 and GLI3 in both patients and therefore can give the chromosomal assignment 7p12.3-p13. CRI-R944 and CRI-P137 map to the same region, whereas CRI-S207 can be assigned to 7p13-p14.2; TM102L, TS93, TS194, TM77 and TN177 showed no change and these probes map distal to 7p14.2.


Mental workload during endoscopic sinus surgery is associated with surgeons' skill levels.
Surgeons' mental workload during endoscopic sinus surgery (ESS) has not been fully evaluated. The assessment was challenging due to the great diversity of each patient's anatomy and the consequence variety of surgical difficulties. In this study, we examined the mental workload of surgeons with various surgical skill levels during ESS under the standardized condition provided by novel-designed 3D sinus models. Forty-seven participants performed a high-fidelity ESS simulation with 3D-printed sinus models. Surgeons' mental workload was assessed with the national aeronautics and space administration-task load index (NASA-TLX). Associations between the total and subscales score of NASA-TLX and surgical skill index, including the board certification status, the number of experienced ESS cases, and the objective structured assessment of technical skills (OSATS), were analyzed. In addition, 10 registrars repeated the simulation surgery, and their NASA-TLX score was compared before and after the repetitive training. The total NASA-TLX score was significantly associated with OSATS score (p = 0.0001). Primary component analysis classified the surgeons' mental burden into three different categories: (1) the skill-level-dependent factors (temporal demand, effort, and performance), (2) the skill-level-independent factors (mental and physical demand), and (3) frustration. After the repetitive training, the skill-level-dependent factors were alleviated (temporal demand; z = -2.3664, p = 0.0091, effort; z = -2.1704, p = 0.0346, and performance; z = -2.5992, p = 0.0017), the independent factors were increased (mental demand; z = -2.5992, p = 0.0023 and physical demand; z = -2.2509, p = 0.0213), and frustration did not change (p = 0.3625). Some of the mental workload during ESS is associated with surgical skill level and alleviated with repetitive training. However, other aspects remain a burden or could worsen even when surgeons have gained surgical experience. Routine assessment of registrars' mental burdens would be necessary during surgical training to sustain their mental health.


Clomipramine and imipramine in obsessive-compulsive disorder.
Twenty-three outpatients with primary obsessive-compulsive disorder (OCD) were started in a 12-week double-blind clinical trial of clomipramine (CLI) (n = 11) and imipramine (IMI) (n = 12). There was no placebo and no crossover. After 6 weeks of treatment, data on 19 subjects (9 CLI, 10 IMI) were available. After week 12, the sample was reduced to 16 patients (8 CLI, 8 IMI). At both time points, OCD symptoms showed modest reductions (in comparison with the pretreatment baseline) in both CLI and IMI groups. Both drugs showed a major antidepressant effect. Analyses accounting for the differences in the baseline levels indicated a somewhat superior effect of CLI over IMI on OCD as well as depression. The effect of CLI and IMI on OCD was independent of the initial severity of depression. There were no clear differences in the safety of the treatments.


Teniposide (VM-26) in patients with advanced refractory ovarian cancer: a phase II study of the Netherlands Joint Study Group for Ovarian Cancer.
In 23 evaluable patients with advanced ovarian epithelial cancer refractory to combination therapy with cisplatin and an alkylating agent, teniposide (VM-26) was administered as a short-term i.v. infusion at a dose of 100 mg/m2 on days 1 and 2, every 3 weeks. Toxicity was moderate and comparable to the pattern known from other studies. No objective response has been observed, showing that teniposide is not active as second-line therapy in this disease.


Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage.
Intraventricular hemorrhage (IVH) is a cause of significant morbidity and mortality and is an independent predictor of a worse outcome in intracerebral hemorrhage (ICH) and germinal matrix hemorrhage (GMH). IVH may result in both injuries to the brain as well as hydrocephalus. This paper reviews evidence on the mechanisms and potential treatments for IVH-induced hydrocephalus. One frequently cited theory to explain hydrocephalus after IVH involves obliteration of the arachnoid villi by microthrombi with subsequent inflammation and fibrosis causing CSF outflow obstruction. Although there is some evidence to support this theory, there may be other mechanisms involved, which contribute to the development of hydrocephalus. It is also unclear whether the causes of acute and chronic hydrocephalus after hemorrhage occur via different mechanisms; mechanical obstruction by blood in the former, and inflammation and fibrosis in the latter. Management of IVH and strategies for prevention of brain injury and hydrocephalus are areas requiring further study. A better understanding of the pathogenesis of hydrocephalus after IVH, may lead to improved strategies to prevent and treat post-hemorrhagic hydrocephalus.


Dopamine inhibition of histamine-mediated cutaneous responses.
Several patients receiving dopamine for hypotension were skin tested for possible penicillin sensitivity. Not only were the penicillin skin tests negative but also the histamine control. On the possibility that dopamine might affect cutaneous histamine responses, we examined the effect of dopamine on histamine, antigen, morphine, and compound 48/80 skin responses. Both intradermal and intravenous dopamine selectively inhibited histamine but not antigen, morphine, or compound 48/80 skin responses, and the inhibition was in a dose-related fashion. This observation indicates that histamine should not be used to demonstrate dermal reactivity in patients receiving dopamine. The results of this study also suggest that histamine may not be the sole mast cell-derived mediator involved in the wheal-and-flare reaction characteristic of immediate-type skin tests since dopamine did not affect skin reactions caused by endogenous mast cell degranulation. Finally, the possible use of dopaminergic drugs in diseases with histamine-associated symptoms is discussed.


Workplace wellness participation and the becoming of self.
This paper provides a sociological examination of workplace wellness participation as a process that occurs in two stages or levels. The existential model of self provides the theoretical orientation for this examination, and data are presented from an ethnographic study of a large workplace wellness program. The first stage or level of participation involves the establishment of a sense of competence. Competence refers to the perceived ability to 'fit in' with the program, to master the often subtle skills required for membership in the class. Once a minimal sense of competence is established, the employee may decide to join by viewing participation either as an extension of a commitment to wellness, or as a vehicle for experimenting with or establishing a new style of self, the identity of a 'well person' so highly valued in contemporary western culture. The dynamics of workplace wellness participation illustrate a more general cultural trend towards health-as-accomplishment.


Fluctuation of the number of CD-1(T6)-positive dendritic cells, presumably Langerhans cells, in the nasal mucosa of patients with an isolated grass-pollen allergy before, during, and after the grass-pollen season.
A monoclonal antibody against CD-1(T6) was used for studies in the nasal mucosa of patients with isolated grass-pollen allergy to determine whether the number of CD-1-positive cells, presumably Langerhans cells, depends on the season in which the nasal biopsy is performed. An earlier study had demonstrated that during the grass-pollen season, there are significantly more CD-1-positive cells in nasal mucosa of patients with isolated grass-pollen allergy than in nonallergic control subjects without nasal complaints. During the grass-pollen season, the nasal epithelium of patients with an isolated grass-pollen allergy demonstrated significantly more CD-1-positive cells than before and after the season. Before and after the season, the number of CD-1-positive cells in epithelium of the allergic patients was not significantly greater than the corresponding number in epithelium of nonallergic subjects without nasal complaints.


Identification of SCP2165, a new SCP2-derived plasmid of Streptomyces coelicolor A3(2).
Characterization of SCP2165, a plasmid identified in the Gram-positive bacterium Streptomyces coelicolor A3(2). Pulsed-field gel electrophoresis (PFGE) of mycelia of a S. coelicolor strain embedded in low melting agarose revealed the presence of a plasmid. Restriction enzyme mapping and sequence analysis of a 2.1 kb fragment revealed that this plasmid could be SCP2. SCP2 and its spontaneous derivative SCP2* are self-transmissible plasmids and have chromosome mobilizing ability (c.m.a.). SCP2* has a c. 1000-fold increased c.m.a. compared with SCP2. Interestingly the plasmid, named SCP2165, shows a c.m.a. from 5x10(-2) to 1x10(-1) which is 50-100-fold higher than that described for crosses involving SCP2*. SCP2165 is a SCP2 derivative plasmid with the highest c.m.a. so far described for SCP2 derivative plasmids. PFGE, under conditions we used, seems to be a fast way to identify large circular plasmids in Streptomyces strains. Further knowledge of the SCP2 family may allow the construction of improved SCP2-derived cloning vectors. SCP2165 could be a potential tool for conjugational transfer of gene clusters between different Streptomyces species.


Sciadopitysin protects osteoblast function via its antioxidant activity in MC3T3-E1 cells.
Age-related osteoblast dysfunction is the main cause of age-related bone loss in both men and women. In the present study, the effect of sciadopitysin, a type of biflavonoids, on osteoblast function was investigated in osteoblastic MC3T3-E1 cells. Sciadopitysin caused a significant elevation of alkaline phosphatase activity, collagen synthesis, osteocalcin production, mineralization, and glutathione content in the cells (P<0.05). Sciadopitysin also decreased the production of tumor necrosis factor-a (TNF-α) induced by antimycin A, a mitochondrial electron transport inhibitor. We investigated the protective effects of sciadopitysin on antimycin A-induced toxicity in osteoblastic MC3T3-E1 cells. Exposure of MC3T3-E1 cells to antimycin A caused a significant reduction in osteoblast dysfunction. However, pretreatment with sciadopitysin prior to antimycin A exposure significantly reduced antimycin A-induced cell damage by preventing mitochondrial membrane potential dissipation, adenosine triphosphate (ATP) loss, reactive oxygen species (ROS) release, and nitrotyrosine increase, suggesting that sciadopitysin may be useful for protecting mitochondria against a burst of oxidative stress. Moreover, sciadopitysin increased phosphorylation of cAMP-response element-binding protein (CREB) inhibited by antimycin A. Our results demonstrate that sciadopitysin may reduce or prevent osteoblasts degeneration.


Effect of hypoxia-inducible factor-1alpha silencing on the sensitivity of human brain glioma cells to doxorubicin and etoposide.
Multidrug resistance (MDR) is a significant problem underlying the poor prognosis associated with gliomas. Hypoxia-inducible factor-1alpha (HIF-1alpha) is thought to induce the genes expression involved in MDR. To evaluate the effect of silencing HIF-1alpha in human glioma T98G cells, cells were transfected with HIF-1alpha-small interference RNA (HIF-1alpha-siRNA) and cultured under hypoxic conditions. The effect of HIF-1alpha-siRNA on HIF-1alpha and multidrug resistance-associated protein 1 gene (MRP1) and protein levels was determined. Silencing rates of HIF-1alpha were 90%, 85%, and 88% at 24, 48, 72 h post-transfection, respectively. Corresponding rates of HIF-1alpha protein were 74.5%, 61.1% and 59.1%. MRP1 protein levels decreased by 7.6%, 36.8% and 45.2%. HIF-1alpha-siRNA transfected cells were significantly more sensitive to doxorubicin and etoposide compared to non-transfected cells. These findings suggest that the HIF-1alpha plays a role in mediating chemotherapeutic drug resistance in glioma cells. HIF-1alpha silencing may prove to be an effective therapeutic means of treating gliomas.


Use of best-worst scaling to assess patient perceptions of treatments for refractory overactive bladder.
Refractory overactive bladder (OAB) treatments, including sacral neuromodulation (SNM), onabotulinumtoxin A (OnabotA), and percutaneous tibial nerve stimulation (PTNS), differ considerably. Best-Worst Scaling (BWS) was used to assess patient preferences for these treatments. A cross-sectional Web survey, based on findings from qualitative interviews with 23 OAB patients and 7 clinical experts, was conducted with idiopathic OAB patients in the US and UK. The BWS exercise involved prioritizing subsets of 13 attributes across 13 choice tasks, where patients identified the attribute they considered as best and as worst in each task. Attribute BWS scores, ranging from -1.0 (worst) to 1.0 (best) were calculated based on the rates that each attribute was chosen. Attitudes toward the attributes also were assessed via like/dislike Likert scales, and questions regarding the percentage likelihood (0-100%) of trying each treatment, based on standardized treatment descriptions. The sample included 245 patients (118 US, 127 UK); 79% female, mean age 50 ± 7.8 years. All 13 attribute BWS scores were significantly positive or negative. "Lasting improvement" (0.82), "minimal side effects" (0.67), and "sends signals between bladder and brain" (0.35)' were rated most favorably, and "complications with implant" (-0.65), and "be willing to self-catheterize" (-0.53) were rated worst. All but one of the attribute BWS scores were significantly correlated with the respective like/dislike scores and the percentage likelihood estimates for trying one of the three treatments. BWS was successful in assessing the magnitude of patient preferences for key attributes associated with substantially different refractory OAB therapies. Neurourol. Urodynam. 35:1028-1033, 2016. © 2015 Wiley Periodicals, Inc.


[Carotid aneurysm as a differential diagnosis of a cervical tumor].
This article presents the case of a patient with a submandibular cervical tumor initially suspected to be a large lymph node or glomus tumor. However, the diagnostic workup prior to taking a biopsy sample revealed an extracranial aneurysm of the internal carotid artery. In order to prevent a permanent neurologic deficit arising from thromboembolism, the aneurysm was excluded by resection and arterial continuity was restored. Extracranial aneurysms of the internal carotid artery are rare, but serious differential diagnoses of cervical nodes. It is of paramount importance that this differential diagnosis be considered before initiating invasive diagnostics of these tumors.


Interaction between rancidity and organoleptic parameters of anchovy marinade (Engraulis encrasicolus L. 1758) include essential oils.
This study was carried out to evaluate the lipid oxidation and sensory attributes of anchovy marinated with 10% NaCl+4% alcohol vinegar+0.2% citric acid solution and 0.1% different essential oils. Group A Control: only sunflower seed oil, Group B: sunflower seed oil+0.1% rosemary oil, Group C: sunflower seed oil+0.1% coriander oil, Group D: sunflower seed oil+0.1% laurel oil and Group E: sunflower seed oil+0.1% garlic oil. During storage, lipid oxidation as indicated by the 2-thiobarbituric acid reactive substances (TBARs) values of the control group were significantly higher than the other groups containing essential oils. The results showed that the essential oils have retarding effect on lipids oxidation. This effect was the highest in laurel oil during initial 3 months; and it was similar to laurel oil and rosemary oil in the fourth month; in all the essential oil added groups in 6 month. L*(brightness) values were similar for all groups in first fourth months but, at the last 2 months, group using laurel oil was found better. Yellowness (b*) was similar in all groups during the intial 3 months whereas, after that lower values in the groups that used laurel and rosemary oils were detected. The study concluded that marination with 0.1% laurel oil of anchovy can retard lipid oxidation and improve the sensory attributes of the product during refrigerated storage.


Chemical and spectroscopic analysis of olive mill waste water during a biological treatment.
The treatment of olive mill waste water was studied on the laboratory scale. Physico-chemical analyses showed the final products had a mean pH of 5.4 without neutralisation and 5.7 when lime was added to the process. Raising the pH by adding lime had a positive outcome on the degradation of phenols, whose levels were reduced by over 76%. The lime also changed the structure of the organic matter, as seen in the infra-red spectra. Combining the FT-IR and 13C NMR data showed that with addition of lime, the density of aliphatic groups decreased to the benefit of aromatic groups, indicating that polymerisation of the organic matter occurred during the bioprocess. Under our experimental conditions, the biotransformation of olive mill waste water appears to favour the stabilisation of the organic matter through mechanisms analogous to those that lead to the formation of humus in the soil.


Apolipoprotein D is down-regulated during malignant transformation of neurofibromas.
Apolipoprotein D (apoD) expression was studied in nonneoplastic peripheral nerve, neurofibromas (NFs), and malignant peripheral nerve sheath tumors (MPNSTs) by quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. Multiplex quantitative polymerase chain reaction for messenger RNA was performed on a series of formalin-fixed and paraffin-embedded specimens that included 9 MPNSTs, 12 NFs, and 4 normal peripheral nerves. The average apoD expression was 108-fold decreased (DeltaCt = -7.3) in the MPNSTs compared with the NFs (P < .05). ApoD expression levels were 3.0-fold elevated (DeltaCt = 1.7) in the NFs compared with nonneoplastic peripheral nerve (P < .05). In situ hybridization for apoD RNA was performed on a separate series of 10 cases in which each microscopic section included both MPNST and the NF from which it arose. These studies confirmed elevated apoD expression in NFs compared with MPNSTs and demonstrated that this expression was variable among individual cells within the NFs. Differential expression by immunohistochemistry could only be demonstrated in selected areas, most likely because apoD protein is a small molecule that is secreted out of the cell into the extracellular space and plasma. ApoD expression initially increases a small amount with the formation of NFs from nonneoplastic peripheral nerve and subsequently decreases markedly as NFs transform into MPNSTs. This expression pattern may serve as a marker for cell cycle inhibition during peripheral nerve tumorigenesis.


Identification and characterization of an LCAT-like Arabidopsis thaliana gene encoding a novel phospholipase A.
A previously uncharacterized Arabidopsis lecithin:cholesterol acyltransferase (LCAT) family gene (At4g19860) was functionally expressed in yeast, where it was demonstrated to encode a novel cytosolic and calcium-independent phospholipase A with preferences for the sn-2 position. This enzyme shows optimal activity at pH 5.0, exhibits a headgroup specificity for phosphatidylcholine>phosphatidic acid>phosphatidylethanolamine>phosphatidylglycerol>phosphatidylserine and has an acyl chain specificity for oleoyl>linoleoyl>ricinoleoyl. The expression of AtLCAT-PLA inhibited yeast cell growth and fatty acid accumulation. AtLCAT-PLA transcript in Arabidopsis was detected at high levels in roots and siliques.


Mechanistic studies on the activation of biphenyl 2-hydroxylation by glucocorticoids.
In order to establish the mechanism by which the selective activation of biphenyl 2-hydroxylation by betamethasone occurs the effect of modifying possible critical factors in the hydroxylation process has been examined. Activation of biphenyl 2-hydroxylation by betamethasone was found in detergent-solubilized rat liver microsomes indicating that intact microsomal membranes are probably not necessary for the activation. Betamethasone had no effect on the spectrally apparent binding of biphenyl or of other type I, type II or reverse type I model substrates. The activation process did not appear to be greatly influenced by changing the ratio of cytochrome P-450 reductase to cytochrome P-450 nor by changing the amount of NADPH. Addition of NADH increased the extent of activation suggesting that betamethasone facilitates transference of the second electron to cytochrome P-450. However, betamethasone also stimulated cumene hydroperoxide supported biphenyl 2-hydroxylation; therefore a step subsequent to cytochrome P-450 reduction is also involved in the activation. Activation did not correlate with increased uncoupling of an active oxygen-cytochrome P-450 complex to form hydrogen peroxide.


Long-term recurrence-free survival after metachronous surgery of the stomach and liver for gastric adenocarcinoma and multiple, synchronous liver metastases: a case report and review of literature.
This report describes a 58-year-old woman with gastric adenocarcinoma and liver metastases, who survives for more than 18 years after diagnosis. At diagnosis and first surgery, a moderately differentiated gastric adenocarcinoma with subserosal invasion was detected, along with 2 regional lymph node metastases and 2 liver metastases. She underwent gastrectomy and regional lymph node dissection but did not undergo liver operation then. After gastrectomy, she received adjuvant chemotherapy for 1 month but discontinued it due to severe diarrhea. Another metastasis in another area of the liver was detected, for which she underwent excision of the right lobe of the liver (subsegments 5, 6, and 7) about 30 months later. No signs of recurrence have been detected for 18 years (as of March 2012). This patient represents a rare case of long-term survival of gastric adenocarcinoma without recurrence after surgical treatment, despite multiple, synchronous, liver and regional lymph node metastases.


Improvement of a synthetic live bacterial therapeutic for phenylketonuria with biosensor-enabled enzyme engineering.
In phenylketonuria (PKU) patients, a genetic defect in the enzyme phenylalanine hydroxylase (PAH) leads to elevated systemic phenylalanine (Phe), which can result in severe neurological impairment. As a treatment for PKU, Escherichia coli Nissle (EcN) strain SYNB1618 was developed under Synlogic's Synthetic Biotic™ platform to degrade Phe from within the gastrointestinal (GI) tract. This clinical-stage engineered strain expresses the Phe-metabolizing enzyme phenylalanine ammonia lyase (PAL), catalyzing the deamination of Phe to the non-toxic product trans-cinnamate (TCA). In the present work, we generate a more potent EcN-based PKU strain through optimization of whole cell PAL activity, using biosensor-based high-throughput screening of mutant PAL libraries. A lead enzyme candidate from this screen is used in the construction of SYNB1934, a chromosomally integrated strain containing the additional Phe-metabolizing and biosafety features found in SYNB1618. Head-to-head, SYNB1934 demonstrates an approximate two-fold increase in in vivo PAL activity compared to SYNB1618.


Low dose of arsenic exacerbates toxicity to mice and IPEC-J2 cells exposed with deoxynivalenol: Aryl hydrocarbon receptor and autophagy might be novel therapeutic targets.
Deoxynivalenol (DON) and arsenic (As) are widespread environmental contaminants, which are frequently found in human and animal food products. The intestine is a common target of As and DON when they are digested. Numerous studies mainly evaluate the individual effects whereas their combined toxicity has rarely been elucidated. Hence, this study was to assess the effect of low dose of NaAsO2 on DON-induced intestinal damage and explore the underling mechanism in mice and IPEC-J2 cells. The results showed that low dose of NaAsO2 exacerbated DON-induced intestinal impairment by increasing intestinal permeability and decreasing the abundance of tight junction proteins (ZO-1, Occludin, Claudin-1). Further, low dose of NaAsO2 enhanced the AhR signaling pathway and autophagy-related mRNA/protein expressions induced by DON. Interestingly, FICZ, an AhR activator, instead of CH223191, an AhR inhibitor, could alleviate toxicity of the low dose of NaAsO2 in the mice and IPEC-J2 cells. Compared to the WT IPEC-J2 cells, the intestinal barrier damage was more serious in LC3B-/- IPEC-J2 cells induced by low dose of NaAsO2 combination with DON. Collectively, our study demonstrated that low dose of NaAsO2 exacerbated DON-induced intestinal barrier impairment in vivo and in vitro. The present study also demonstrated that activation of AhR-mediated autophagy might be a self-protection mechanism. Hence, AhR and autophagy might be novel therapeutic targets to prevent or alleviate NaAsO2 combined with DON-induced intestinal barrier impairment.


Pre-hospital advanced airway management by anaesthesiologists: is there still room for improvement?
Endotracheal intubation is an important part of pre-hospital advanced life support that requires training and experience, and should only be performed by specially trained personnel. In Norway, anaesthesiologists serve as Helicopter Emergency Medical Service HEMS physicians. However, little is known about how they themselves evaluate the quality and safety of pre-hospital advanced airway management. Using a semi-structured questionnaire, we interviewed anaesthesiologists working in the three HEMS programs covering Western Norway. We compared answers from specialists and non-specialists as well as full- and part-time HEMS physicians. Of the 17 available respondents, most (88%) felt that their continuous exposure to intubations was not sufficient. Additional training was mainly acquired through other clinical practice and mannequin- or cadaver-based skills training. Of the respondents, 77% and 35% reported having experienced difficult and failed intubations, respectively. Further, 59% reported knowledge of airway management-related deaths in their HEMS program. Significantly more full- than part-time HEMS physicians had experienced these problems. All respondents had airway back-up equipment in their service, but 29% were not familiar with all the equipment. The majority of anaesthesiologists working as HEMS physicians view pre-hospital advanced airway management as a high-risk procedure. Relevant airway management competencies for HEMS physicians in Norway seem to be insufficiently trained and maintained. A better-defined level of competence with better training methods and systems seems warranted.


Apolipoprotein A-I and apolipoprotein SAA half-lives during acute inflammation and amyloidogenesis.
The half-lives of two apolipoproteins of mouse high-density lipoproteins, apo A-I and apo SAA, were determined in normal animals and compared with those having an inflammatory condition, or inflammation leading to AA amyloid deposition. The apo A-I half-life was considerably shorter in animals with inflammation and in those that were preamyloidotic, than in controls (t1/2 of 3-3.5 h vs. 10-12 h). The average loss of apo A-I in controls over the first 10 h was 31.1 micrograms/ml per h, while that in inflamed animals was 58.7 micrograms/ml per h a 2-fold increase in apo A-I clearance. The apo SAA half-life was similar in all groups of animals and was of the order of 1.5 h. The concentration of apo SAA during inflammation is however considerably higher (500-1000-fold) than in controls, which implies a much greater clearance rate during inflammation and involving a process which is apparently not saturable. In addition to hypertriglyceridemia and Tangier's disease, ordinary acute inflammation can now be added to those pathological conditions which lead to a significant decrease in apo A-I half-life.


Kinetic factors limiting the synthesis of ATP by chromatophores exposed to short flash excitation.
ATP synthesis was measured after chromatophores from Rhodopseudomonas capsulata had been subjected to illumination by single turnover flashes fired at variable frequencies. Three processes were examined, which under different conditions can limit the net yield of ATP. (1) A process with an apparent relaxation time of 10-20 ms. This reaction probably limits the rate of ATP synthesis in continuous illumination. It has similar time dependence to the stimulation of the carotenoid shift decay by ADP after a single flash. (2) An active state of the ATPase only persists when the chromatophores are excited more often than once in 10 s. This state decays with similar kinetics to the entire carotenoid shift decay. Full activation is achieved after two flashes. (1) and (2) are not significantly affected by concentrations of antimycin A sufficient to block electron flow through the cytochrome b/c2 oxidoreductase and abolish phase III in the generation of the carotenoid shift. (3) In the presence of antimycin A, after the third, fourth and subsequent flashes ATP synthesis is limited by the quantity of reducing equivalents transported through the reaction centre rather than by the level of the electrochemical proton gradient.