Homogeneity of mesothelial cells with lymphatic endothelium: expression of lymphatic endothelial markers by mesothelial cells.
Mesothelial cell monolayers cover the serous cavities and internal organs, and provide a protective low-friction interface between apposed organs and tissues. The mesothelium also regulates inflammation, fluid and cell exchange, and tissue repair in these compartments and possibly tumor metastasis. In the present study, a stable pleural mesothelial cell line (MIM) was isolated and characterized, and the expression of several lymphatic specific markers by these cells examined. MIM were isolated from mice stably expressing a temperature-sensitive SV40 large T antigen ('Immortomouse', strain: H-2K(b)-tsA58). These cells were compared with lymphatic endothelial cells (LEC) derived from the mesenteric adventitia of the Immortomouse. MIM and LEC expression of lymphatic-specific markers (Flt-4, LYVE-1, and Prox-1) was examined, and the tight junction protein (ZO-1) was studied by immunofluorescence and immunoblotting in these cells. LYVE-1, Prox-1, and Flt-4 were detected in both MIM and LEC, with Prox-1 and LYVE-1 more strongly expressed on LEC than MIM. Conversely, Flt-4 was more densely expressed on MIM than on LEC. Spatially, ZO-1 was prominent at MIM junctions, but was less well organized in LEC. MIM and LEC share several characteristic markers usually associated with lymphatic endothelium. MIM might be useful for studying the biology and pathology of mesothelial cells in vitro and help in the development of therapies for mesothelial-related diseases, such as mesothelioma and pleural effusion.


Selection on an antimicrobial peptide defensin in ants.
Ants live in crowded nests with interacting individuals, which makes them particularly prone to infectious diseases. The question is, how do ants cope with the increased risk of pathogen transmission due to sociality? We have studied the molecular evolution of defensin, a gene encoding an antimicrobial protein, in ants. Defensin sequences from several ant species were analyzed with maximum likelihood models of codon substitution to infer selection. Positive selection was detected in the mature region of defensin, whereas the signal and pro regions seem to be evolving neutrally. We also found a significantly higher rate of nonsynonymous substitutions in some phylogenetic lineages, as well as dN/dS >1, suggesting varying selection pressures in different lineages. Earlier studies on the molecular evolution of insect antimicrobial peptide genes have focused on termites and dipteran species, and detected positive selection only in duplicated termicin genes in termites. These findings, together with our present results, provide an indication that the immune systems of social insects (ants and termites) and dipteran insects may have responded differently to the selection pressure caused by microbial pathogens.


Does a highest pre-ductal O(2) saturation <85% predict non-survival for congenital diaphragmatic hernia?
To analyze operative repair, extracorporeal membrane oxygenation (ECMO) and survival rates based on highest pre-ductal oxygen saturation (Pre-O(2)SAT) in a large infant cohort reported to Congenital Diaphragmatic Hernia Study Group Registry between 2000 and 2010. Analyzed data included gestational age, birth weight, defect side and size, repair, ECMO use, survival and highest reported PaO(2) and Pre-O(2)SAT in first 24 h of life. We excluded 614 infants due to severe anomaly. Pre-O(2)SAT data were available for 1672 infants. Among infants with highest Pre-O(2)SAT value <85%, survival (24/105=23%) and repair (55/105=52%) rates were significantly decreased compared with infants with higher values. Survival increased to 44% for infants with highest Pre-O(2)SAT<85% who underwent operative repair. Of these, 83% (20/24) required ECMO support compared with 15% (144/961) of survivors with Pre-O(2)SAT>99% (P<0.001). The lowest reported Pre-O(2)SAT with survival was 32% and for survival without ECMO was 52%. A reported highest Pre-O(2)SAT<85% in the first 24 h of life was not uniformly fatal; but survival of infants with Pre-O(2)SAT<85% was associated with high ECMO use and prolonged hospitalization.


Diel pattern of pelagic distribution and feeding in planktivorous fish.
The spatial distribution of juvenile roach (Rutilus rutilus), rudd (Scardinius erythrophtalamus), bream (Abramis brama) and bleak (Alburnus alburnus) was registered by echosounding during two years in small Bavarian lakes. The gut contents of the fish were analysed in order to reconstruct their rhythmicity of food intake. Fish were found in the pelagic zone only during the night, feeding before midnight with maximal rate. The vertical position of the fish was dependent on the water transparency following a light intensity in the order of 10-3 Lux. The diel migration between littoral and pelagic zones was a mainly horizontal one with a vertical component. Both the speed of increase of fish density in the open water and of the vertical movement was correlated to the speed of change of light intensity. Shoals broke up into single fish during the offshore migration. The span of presence in the pelagic zone was identical with the duration of the dark period. During winter no diel migration nor periodical feeding took place.


Acute symptomatic seizures in the emergency room: predictors and characteristics.
When treating patients with epileptic seizures in the emergency room (ER), it is of paramount importance to rapidly assess whether the seizure was acute symptomatic or unprovoked as the former points to a potentially life-threatening underlying condition. In this study, we seek to identify predictors and analyze characteristics of acute symptomatic seizures (ASS). Data from patients presenting with seizures to highly frequented ERs of two sites of a university hospital were analyzed retrospectively. Seizures were classified as acute symptomatic or unprovoked according to definitions of the International League Against Epilepsy. Univariate and multivariate analysis were conducted to identify predictors; furthermore, characteristics of ASS were assessed. Finally, 695 patients were included, 24.5% presented with ASS. Variables independently associated with ASS comprised male sex (OR 3.173, 95% CI 1.972-5.104), no prior diagnosis of epilepsy (OR 11.235, 95% CI 7.195-17.537), and bilateral/generalized tonic-clonic seizure semiology (OR 2.982, 95% CI 1.172-7.588). Alcohol withdrawal was the most common cause of ASS (74.1%), with hemorrhagic stroke being the second most prevalent etiology. Neuroimaging was performed more often in patients with the final diagnosis of ASS than in those with unprovoked seizures (82.9% vs. 67.2%, p < 0.001). Patients with ASS were more likely to receive acute antiseizure medication in the ER (55.9% vs. 30.3%, p < 0.001). In one quarter of patients presenting to the ER after an epileptic fit, the seizure had an acute symptomatic genesis. The independently associated variables may help to early identify ASS and initiate management of the underlying condition.


Intravenous recombinant tissue plasminogen activator improves arterial recanalization rates and reduces infarct volumes in patients with hyperdense artery sign on baseline computed tomography.
We sought to evaluate arterial recanalization as measured by changes in the presence of hyperdense artery sign (HAS) on initial and 24-hour computed tomography scans in patients treated with recombinant tissue plasminogen activator (rt-PA) or placebo, and to assess the effect of rt-PA on patient outcomes in this population. Patients in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial composed the study group. We determined the percentage of patients with HAS in rt-PA- and placebo-treated groups who had persistence (HAS +/+) or resolution (HAS +/-) of HAS on 24-hour computed tomography, and compared outcomes in those with resolution or persistence of the sign in these treatment groups. Baseline HAS occurred in 79 of 604 eligible patients (13%). The two treatment groups were similar, although patients treated with rt-PA were significantly older. Of the 79 patients with HAS on baseline computed tomography scan, 14 of 37 (38%) treated with rt-PA had resolution of HAS at 24 hours compared with 7 of 42 (17%) treated with placebo (P = .03). Infarct volumes at 24 hours were significantly smaller in patients treated with rt-PA with resolution of the sign, compared with those who had persistence of the sign (P = .004). In our analysis, functional outcomes were not significantly improved based on resolution of HAS in either treatment group. There were 4 symptomatic ICHs in the rt-PA-treated group with HAS as compared with two in the placebo-treated group. Among patients with HAS at baseline in the NINDS rt-PA Stroke Trial, intravenous rt-PA increased recanalization as measured by resolution of HAS and reduced infarct volumes at 24 hours.


New insights into structure-function relationships between archeal ATP synthase (A1A0) and vacuolar type ATPase (V1V0).
Adenosine triphosphate, ATP, is the energy currency of living cells. While ATP synthases of archae and ATP synthases of pro- and eukaryotic organisms operate as energy producers by synthesizing ATP, the eukaryotic V-ATPase hydrolyzes ATP and thus functions as energy transducer. These enzymes share features like the hydrophilic catalytic- and the membrane-embedded ion-translocating sector, allowing them to operate as nano-motors and to transform the transmembrane electrochemical ion gradient into ATP or vice versa. Since archaea are rooted close to the origin of life, the A-ATP synthase is probably more similar in its composition and function to the "original" enzyme, invented by Nature billion years ago. On the contrary, the V-ATPases have acquired specific structural, functional and regulatory features during evolution. This review will summarize the current knowledge on the structure, mechanism and regulation of A-ATP synthases and V-ATPases. The importance of V-ATPase in pathophysiology of diseases will be discussed.


Ultrastructural investigation of the effect of mitomycin C on the rat exocrine pancreas.
In order to clarify the pathophysiology of digestive disorders which are caused with anticancer agents, Mitomycin C was intravenously administrated to rats and the ultrastructure of the pancreas was studied. The alteration of acinar cells after under 4 daily administrations of 1.0 mg/Kg of Mitomycin C was not remarkable and in an early stage returned to normal structure. In above 8 daily administrations of 1.0 mg/Kg of Mitomycin C, however, pronounced degeneration of acinar cells was induced and acinar cells did not recover to the previous level, but die within one month. The ultrastructural changes induced by Mitomycin C were mainly aggregation of chromatin in the nuclei, tubularly dilatation of the rough endoplasmic reticulum, and swelling of the mitochondria. It was surmised that the biosynthesis and supply of protein such as digestive enzymes were not amply carried on; hence, the ehcmotherapy could give rise to severe digestion disorders. It appeared necessary to further study the dosage and dosage schedule of the anticancer agents, along with the necessity for taking ample care of patients presenting such disorders.


Pain requires processing - How the experience of pain is influenced by Basic Body Awareness Therapy in patients with long-term pain.
Long-term pain is common and entails large costs to society. One physiotherapy treatment with documented positive effects for patients with long-term pain is Basic Body Awareness therapy (BBAT). However, studies are lacking about patients' experience of BBAT's influence on their pain. Therefore, the aim of this study was to investigate how patients experience BBAT's influence on their long-term pain. For this qualitative interview study, participants were selected from two supervised BBAT groups. To qualify for the study, participants had to meet two inclusion criteria: having pain for at least 6 months, and attending BBAT for at least 6 months. Six females between the ages of 25 and 61 years were included. Pain duration ranged from 9 to 20 years, and duration of practicing BBAT ranged from 8 to 120 months. Semi-structured interviews were conducted and qualitative content analysis was performed. The analysis revealed four main categories of BBAT experience: increases motivation, requires processing, increases control over pain and changes attitude to oneself, body and pain. Patients with long-term pain experienced BBAT as being helpful in processing their pain because they were forced to face the pain instead of trying to ignore it. Participants experienced a decrease in pain through development of an increased sense of control as well as a changed attitude to themselves, their bodies and their pain. It is important for physiotherapists to understand that pain can increase during BBAT and to support the patients in this process during the therapy.


TAFA4 relieves injury-induced mechanical hypersensitivity through LDL receptors and modulation of spinal A-type K+ current.
Pain, whether acute or persistent, is a serious medical problem worldwide. However, its management remains unsatisfactory, and new analgesic molecules are required. We show here that TAFA4 reverses inflammatory, postoperative, and spared nerve injury (SNI)-induced mechanical hypersensitivity in male and female mice. TAFA4 requires functional low-density lipoprotein receptor-related proteins (LRPs) because their inhibition by RAP (receptor-associated protein) dose-dependently abolishes its antihypersensitive actions. SNI selectively decreases A-type K+ current (IA) in spinal lamina II outer excitatory interneurons (L-IIo ExINs) and induces a concomitant increase in IA and decrease in hyperpolarization-activated current (Ih) in lamina II inner inhibitory interneurons (L-IIi InhINs). Remarkably, SNI-induced ion current alterations in both IN subtypes were rescued by TAFA4 in an LRP-dependent manner. We provide insights into the mechanism by which TAFA4 reverses injury-induced mechanical hypersensitivity by restoring normal spinal neuron activity and highlight the considerable potential of TAFA4 as a treatment for injury-induced mechanical pain.


Analysis of interaction of cloned human and/or sheep fetal hemoglobin gamma-chain and LPS in augmenting induction of inflammatory cytokine production in vivo and in vitro.
We have reported earlier that purified preparations of sheep fetal hemoglobin, but not adult hemoglobin, in concert with non-stimulatory doses of lipopolysaccharide (LPS) (lipid A), act cooperatively to regulate in vitro production of a number of cytokines, including TNFalpha, TGFbeta and IL-6 from murine and human leukocytes. Following in vivo treatment of mice with the same combination of hemoglobin and LPS, harvested spleen or peritoneal cells showed a similar augmented capacity to release these cytokines into culture supernatants. We report below that genetically cloned gamma-chain of human or sheep fetal hemoglobin, but not cloned alpha- or beta-chains, can produce this cooperative effect, as indeed can HPLC purified, heme-free, gamma-chains derived from cord blood fetal hemoglobin, and that purified haptoglobin completely abolishes the cooperative interaction.


The trees and the forest: Characterization of complex brain networks with minimum spanning trees.
In recent years there has been a shift in focus from the study of local, mostly task-related activation to the exploration of the organization and functioning of large-scale structural and functional complex brain networks. Progress in the interdisciplinary field of modern network science has introduced many new concepts, analytical tools and models which allow a systematic interpretation of multivariate data obtained from structural and functional MRI, EEG and MEG. However, progress in this field has been hampered by the absence of a simple, unbiased method to represent the essential features of brain networks, and to compare these across different conditions, behavioural states and neuropsychiatric/neurological diseases. One promising solution to this problem is to represent brain networks by a minimum spanning tree (MST), a unique acyclic subgraph that connects all nodes and maximizes a property of interest such as synchronization between brain areas. We explain how the global and local properties of an MST can be characterized. We then review early and more recent applications of the MST to EEG and MEG in epilepsy, development, schizophrenia, brain tumours, multiple sclerosis and Parkinson's disease, and show how MST characterization performs compared to more conventional graph analysis. Finally, we illustrate how MST characterization allows representation of observed brain networks in a space of all possible tree configurations and discuss how this may simplify the construction of simple generative models of normal and abnormal brain network organization.


Landscape and children's health: old natures and new challenges for the preventorium.
Preventoria were established in the early part of the twentieth century at fresh air sites away from cities for the purposes of rest cures for children, usually for those who were at risk of contracting tuberculosis. This paper discusses preventoria in relation to their general landscapes, and outlines the types of landscapes in which preventoria are found, namely woods and forests, ocean, rivers and lakes, and agricultural settings. The preventorium movement is placed in historical landscape context, with urban planning, national parks, and other nineteenth century trends. Fresh air was the driving force of both treatment and locations of preventoria and sanatoria. Current movements in child health to combat obesity and 'nature-deficit-disorder' also call for greater engagement with fresh air, and stress the therapeutic value of natural landscape. Australia's oldest preventorium is examined as a case study of preventoria and the challenges which old preventoria are facing today to re-invent themselves in predominantly rural landscapes.


Efficacy and safety of tenapanor in hemodialysis patients with hyperphosphatemia: A systematic review and meta-analysis of randomized placebo-controlled trials.
The effects of tenapanor in reducing serum phosphorus in hemodialysis patients with hyperphosphatemia are uncertain and no relevant meta-analysis has been conducted. We performed a meta-analysis of randomized placebo-controlled trials to evaluate the efficacy and safety of tenapanor. All randomized controlled trials of tenapanor were searched up to 1 August 2022. The primary endpoint was the change in serum phosphorus level from baseline with tenapanor and placebo. Data on drug-related adverse events (AEs), gastrointestinal AEs and diarrhea were collected to determine the safety of tenapanor. There were 533 patients throughout five trials that were eligible. Tenapanor significantly lowered blood phosphorus level by 1.79 mg/dl in the mean difference than the placebo. Diarrhea, gastrointestinal AEs, and drug-related AEs were more severe than placebo. This meta-analysis showed that although drug side effects were common, tenapanor significantly reduced serum phosphorus level in hemodialysis patients.


Urinary calcium and oxalate excretion during oral fructose or glucose load in man.
We studied urinary calcium and oxalate excretion in response to oral fructose load and to oral glucose load each on two different randomized mornings in twelve healthy subjects. Oral fructose load provoked an increase in calciuria and a decrease in oxaluria while oral glucose load induced an increase in both calciuria and oxaluria. These results suggested that in healthy subject, the decrease in oxaluria observed during fructose load reduced the product urinary [calcium] x [oxalate] which was the main factor in the genesis of urinary calcium oxalate stones while glucose load increased the risks of urolithiasis by means of the rise in both calciuria and oxaluria.


First molecular approach to diagnose paediatric pulmonary lophomoniasis: A case series.
A prospective study was conducted from 2017 to 2021 at Bouali Hospital in Mazandaran province, Sari, Iran. Out of 58 patients who were enrolled in our study, lophomoniasis was diagnosed in bronchoalveolar lavage fluid of nine patients, for the first time, using an in-house polymerase chain reaction technique. All patients were treated with metronidazole at 7.5 mg/kg/day every 12 h for 14 days. After 6 months of follow-up, symptoms were fully resolved.


Variability and heterogeneity in Alzheimer's disease with cotton wool plaques: a clinicopathological study of four autopsy cases.
We describe three cases of early- (cases 1-3, 28-39 years) and one of late-onset (case 4, 76 years) Alzheimer's disease (AD) with 'cotton wool' plaques (CWPs) but without a family history indicating autosomal dominant inheritance. The early-onset cases, but not the late-onset case, showed remarkable aggression, disinhibition, and impulsiveness. Spastic paraparesis was observed in only one early-onset case. Hematoxylin-eosin-stained sections showed numerous CWPs, especially in the temporal cortex, in all cases. Bielschowsky-stained sections showed neurofibrillary tangles and minor neuritic changes surrounding the CWPs in three cases, but not in case 2. Gallyas-Braak-stained sections showed weak argyrophilia in homogeneous material of the CWPs in cases 2 and 4. Quantitative analysis demonstrated that Abeta42 was deposited more predominantly than Abeta40 in three cases. However, in case 2, approximately twice as much Abeta40 as Abeta42 was deposited. Tau immunostaining demonstrated neuritic changes in three cases, but not in case 2. alpha-Synuclein-positive Lewy bodies (LBs) and astrocytic lesions containing non-Abeta component of AD amyloid (NAC), a central fragment of alpha-synuclein, were found in case 3. In conclusion, (1) a frontal lobe syndrome-like personality change may be one of the characteristic clinical features of early-onset CWP-AD, (2) the deposition pattern of Abeta40 and Abeta42 in CWP-AD is more variable than that of presenilin-1-linked cases, (3) Abeta deposition can result in development of dementia without tau pathology, and (4) CWP-AD with LBs and several other neurodegenerative disorders with LBs share a common process involving alpha-synuclein and NAC deposition.


METTL14 upregulates TCF1 through m6A mRNA methylation to stimulate osteogenic activity in osteoporosis.
Alteration of N6-methyladenosine (m6A) is closely linked to spanning biological processes including osteoporosis (OP) development. This research focuses on the function of methyltransferase like 14 (METTL14) in bone turnover and its interaction with T cell factor 1 (TCF1). A mouse model of OP was established by ovariectomy (OVX). The bone mass parameters were evaluated by micro-CT analysis. Mouse MC3T3-E1 cells and mouse bone marrow macrophages (BMMs) were induced for osteogenic or osteoclastic differentiation, respectively, for in vitro experiments. The osteogenesis or osteoclasis activity was analyzed by measuring the biomarkers such as OPG, ALP, NFATC1, CTSK, RANKL, and TRAP. RT-qPCR and IHC assays identified reduced METTL14 expression in bone tissues of osteoporotic patients and ovariectomized mice. Artificial METTL14 overexpression increased bone mass of mice and promoted osteogenesis whereas suppressed osteoclasis both in vivo and in vitro. METTL14 promoted TCF1 expression through m6A mRNA methylation, and TCF1 increased the osteogenic activity by elevating the protein level of RUNX2, a key molecule linked to bone formation. In rescue experiments, TCF1 restored the RUNX2 level and osteogenic activity of cells suppressed by METTL14 silencing. In summary, this research demonstrates that METTL14 plays a protective role against OP by promoting the TCF1/RUNX2 axis.


Release of e antigen from a Dane particle-rich preparation of hepatitis B virus.
Tween 80 treatment of a Dana particle-rich pellet obtained from sera of a carrier with a hepatitis type B infection resulted in the release of e antigen.


Effect of urinary glucose concentration and pH on signal intensity in magnetic resonance images.
With advances in anti-diabetes drugs, increasing numbers of patients have high urinary glucose concentrations, which may alter magnetic resonance (MR) signal intensity. We sought to elucidate the effect of urinary glucose concentration and pH on transverse relaxation and MR signal intensity. The transverse relaxation rate (R2) was measured in samples with different glucose concentrations (in vitro) and in the urinary bladder of seven patients with diabetes and nine healthy volunteers (in vivo). The glucose concentration and pH in the in vitro samples and urine were measured. The signal intensity ratio of the bladder to adjacent tissues was obtained on T2-weighted imaging (WI), T1WI, and MR urography (in vivo). To clarify the effect of pH further, the urine of two healthy subjects was adjusted with acid and/or base to obtain various pH values (ex vivo). R2 increased significantly with high glucose concentrations in the in vitro study. In the in vivo study, high glucose concentration (p < 0.001) and low pH (p = 0.005) were significantly associated with high R2. R2 was higher (p = 0.002) and the signal in maximum-intensity projection images of MR urography was lower (p = 0.005) in patients with diabetes than in healthy subjects. Ex vivo study revealed that a decrease in pH in acid portion resulted in increased R2. High concentrations of urinary glucose and low pH both enhance transverse relaxation, which, in turn, causes low signal intensity in urinary bladder on long echo time (TE) images, such as MR urography. Radiologists should be aware of this phenomenon when interpreting abnormally low-intensity bladders on long TE images.


Syncope and Dyspnea and Pulmonary Embolism.
Failure to recognize ECG features consistent with acute cor pulmonale in a man with new onset syncope and dyspnea resulted in death from undiagnosed pulmonary emboli.


Crumbotti and rose petals in a ghost mountain valley: foraging, landscape, and their transformations in the upper Borbera Valley, NW Italy.
The abandonment of mountain areas in Europe is a process that started during industrialisation and whose traces are still present nowadays. Initiatives aimed at stopping this decline and preserving the local biological and cultural diversities reflect the crucial issue of fostering sustainable rural development. This article contributes to the ongoing debate in assessing and preserving local ecological knowledge (LEK) in a highly marginalised mountain community in the Piedmontese Apennines to support local development. In so doing, it continues a larger project assessing how local botanical knowledge and landscapes evolve over time, in order to understand in more depth which factors affect how LEK is shaped, eroded, and re-created, and how this could be revitalised. We compared information about the current gathering and use of local wild plants in the upper Borbera Valley (Carrega Ligure municipality, NW Italy), elicited via 34 in-depth open and semi-structured interviews, with the findings of a field study conducted in the same location, most likely carried out at the end of the 1970s and published in 1981. There were remarkable quantitative and qualitative differences between the two ethnobotanies. The gathering and use of some wild medicinal plants growing in meadows, woodlands, and higher mountain environments (Achillea, Centaurea, Dianthus, Ostrya, Picea, Polygonum, Potentilla, and Thymus) seems to have disappeared, whereas the collection of plants growing in more anthropogenic environments, or possibly promoted via contacts with the "reference" city of Genoa (the largest city close to Carrega and historically the economic and cultural centre to which the valley was mostly connected), has been introduced (i.e. ramsons, safflower, bitter oranges, black trumpets) or reinvigorated (rose petals). This trend corresponds to the remarkable changes in the local landscape ecology and agro-silvo-pastoral system that took place from the first half of the twentieth century, dramatically increasing woodland and secondary vegetation, and decreasing coppices, plantations, grasslands and segregating cultivated land. The findings show a very difficult rearrangement of the LEK, as most of the areas the local actors still know are within their villages, and they no longer have daily experience in the rest of the abandoned woodland landscape (except for mushrooming and gathering chestnuts). This situation can be interpreted in two ways: as the start of the complete abandonment of the valley, or as a starting residual resilience lynchpin, which could possibly inspire new residents if the larger political-economic framework would promote measures for making the survival of the mountain settlements of this municipality possible, and not just a chimera.


Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children.
To evaluate acceptability of 2 mm solid dosage forms (mini-tablets) as an alternative administration modality in young children in comparison with syrup. Three hundred six pediatric in- and outpatients aged 6 months-5 years (51 in each of 6 age groups) were recruited. An open, randomized cross-over study was conducted to compare acceptability and capability to swallow 2 mm uncoated or coated mini-tablets vs 3 mL syrup. In the overall patient population of 306 children, the acceptability of uncoated mini-tablets was superior to syrup (difference in proportions 14.8%, 95% CI 10.2-19.4; P < .0001). In line with this finding, the level of capability to swallow was higher for uncoated mini-tablets compared with syrup as well (difference in proportions 12.3%, 95% CI 5.4-19.3; P = .0008). All 3 pharmaceutical formulations were well tolerated, and none of the 306 children inhaled or coughed because of the syrup or the uncoated mini-tablet; only 2 of the 306 children (both in age group 0.5-1 year) coughed because of the coated mini-tablet, in both cases without clinical relevance. Mini-tablets are a valuable alternative to syrup for children 6 months-6 years of age and are more acceptable compared with liquid formulation. Regulatory bodies such as Food and Drug Administration and European Medicine Agency are encouraged to take our data into account for guideline updates and future drug approval processes.


Clinical characteristic and outcome of lymphoplasmacytic lymphoma of non-Waldenstrom macroglobulinemia type: A Swedish lymphoma registry study.
Lymphoplasmacytic lymphoma (LPL) not fulfilling the WHO diagnostic criteria (2017) for Waldenstrom's macroglobulinemia (WM) (named non-WM LPL) is a rare disease and only a few systematic studies have been published. Here, we present a population-based study of non-WM LPL focusing on diagnostic difficulties, patient characteristics, and outcome. From 1511 patients included in the Swedish Lymphoma Registry 1 Jan 2000 - 31 Dec 2014 with a diagnosis of WM/LPL, we could confirm the diagnosis of non-WM LP in only 33 patients. The median age at diagnosis was 69 years. A paraprotein was found in most (IgG in 54%, IgA in 15%) and 12% of the cases were non-secretory. Compared with the WM patients, the non-WM LPL patients were younger, had more adverse prognostic factors such as elevated LDH, anaemia, and lymphocytosis at diagnosis. In addition, the non-WM LPL patients more often were symptomatic and received treatment at diagnosis. The overall survival (OS) did not significantly differ between the non-WM LPL and WM groups (P = 0.247), with a median survival time of 71 and 96 months, respectively. To conclude, we found differences in clinical features between WM and non-WM LPL, but no difference in survival.


Clinical pharmacokinetics of mibefradil.
Mibefradil, a tetralol derivative, is a new long-acting calcium antagonist used for the treatment of patients with hypertension and chronic stable angina pectoris. The drug is virtually completely metabolised, with less than 3% of an oral dose excreted unchanged in urine. Its metabolism occurs via parallel pathways, which fall into 2 broad categories: esterase-catalysed hydrolysis (producing the major plasma metabolite) and cytochrome P450 (CYP) 3A4-mediated oxidation. Plasma protein binding is greater than 99.5%, predominantly to alpha 1-acid glycoprotein. Oral multiple dose administration of mibefradil 50 or 100 mg once daily is associated with inhibition of the CYP3A4 pathway of metabolism, increasing the half-life and bioavailability of the parent compound. The intensity of the inhibition of CYP similarly results in numerous clinically relevant drug interactions which ultimately motivated the voluntary withdrawal of mibefradil from the market. With multiple oral doses of 50 to 100 mg once daily, the time to maximum plasma concentration was approximately 2.4 hours, absolute bioavailability was around 80%, clearance was 5.7 to 7.5 L/h, oral terminal exponential volume of distribution was 180 L, and terminal exponential half-life was 22 hours (ranging between 17 and 25 hours). A NONMEM sparse data analysis indicated that apparent clearance is not affected by race, gender, age or bodyweight. Renal function does not affect the pharmacokinetics of mibefradil.


Social Support and Loneliness Among Black and Hispanic Senior Women Experiencing Food Insecurity: The Nurse as Primary, Secondary, and Tertiary Intervention.
The impact of social determinants of health (SDOH) is understudied and until recently not a focal point in nursing education. The new Essentials coupled with the impact of the coronavirus (COVID-19) pandemic deem it necessary to address the intersection of SDOH and population health. The impact of COVID 19 disproportionately affects Black and Hispanic families. Couple the disproportionate numbers of COVID 19 among these groups with the growing incidence of food insecurity, and there is a need to explore intersecting links. Emerging research link the lack of social support systems and loneliness to food insecurity. In alignment with addressing competency-based education, it is critical to assess factors such as social support systems and loneliness and the intersection of its effects on such determinants as food insecurity. The article provides an overview for its readers in examining the incidence of food insecurity in older ethnic minority women along with postulated social attributes as contributing factors to the growth rates of food insecurity. The incidence of food insecurity among older ethnic minority women has grown exponentially amid the pandemic. The authors illustrate the role nurses can play in addressing primary, secondary, and tertiary interventions using Neuman's Theory. The intervention pathways are delineated through the lens of nursing theoretic framework created by Betty Neuman Systems Model.


Characterizing chemical transformation of organophosphorus compounds by 13C and 2H stable isotope analysis.
Continuous and excessive use of organophosphorus compounds (OPs) has led to environmental contaminations which raise public concerns. This study investigates the isotope fractionation patterns of OPs in the aquatic environment dependence upon hydrolysis, photolysis and radical oxidation processes. The hydrolysis of parathion (EP) and methyl parathion (MP) resulted in significant carbon fractionation at lower pH (pH2-7, εC=-6.9~-6.0‰ for EP, -10.5~-9.9‰ for MP) but no detectable carbon fractionation at higher pH (pH12). Hydrogen fractionation was not observed during any of the hydrolysis experiments. These results indicate that compound specific isotope analysis (CSIA) allows distinction of two different pH-dependent pathways of hydrolysis. Carbon and hydrogen isotope fractionation were determined during UV/H2O2 photolysis of EP and tris(2-chloroethyl) phosphate (TCEP). The constant δ2H values determined during the OH radical reaction of EP suggested that the rate-limiting step proceeded through oxidative attack by OH radical on the PS bond. The significant H isotope enrichment suggested that OH radical oxidation of TCEP was caused by an H-abstraction during the UV/H2O2 processes (εH=-56±3‰). Fenton reaction was conducted to validate the H isotope enrichment of TCEP associated with radical oxidation, which yielded εH of -34±5‰. Transformation products of OPs during photodegradation were identified using Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS). This study highlights that the carbon and hydrogen fractionation patterns have the potential to elucidate the transformation of OPs in the environment.


Effect of NSAIDS on serum electrolytes and osmolality.
Rabbits and rats were injected two Nonsteroidal anti-inflammatory drugs (aspirin 300 mg/kg or indomethacin 3 mg/kg) intraperitoneally. One hour after injection blood was analyzed for serum electrolytes and osmolality. Administration of both aspirin and indomethacin in rabbits and rats caused increase in serum sodium, potassium, calcium, chloride, magnesium, phosphorus and osmolality. Results suggest the marked similarity in the action of aspirin and indomethacin on electrolytes and osmolality. It is concluded that the ingestion of aspirin and indomethacin can have a major effect on serum electrolytes and osmolality that may influence the interpretation of clinical data in patients taking these drugs.


Degradation of geosmin and 2-methylisoborneol in water with UV/chlorine: Influencing factors, reactive species, and possible pathways.
Geosmin (GSM) and 2-methylisoborneol (2-MIB) are two common odor compounds in drinking water. In this paper, the performance of UV/chlorine was compared with that of chlorine and UV to degrade GSM (100 ng L-1) and 2-MIB (100 ng L-1) in water. UV/chlorine was further exploited, and a steady-state kinetic model was used to conduct a detailed study on efficiency, rate, reactive species and pathway. The results showed that UV/chlorine greatly could improve the removal ratio to 90% within 5 min, from approximately 20% with only UV or dark chlorine in 60 min. The removal ratio and rate depended on UV light intensity, free chlorine dosage, reaction time and water quality parameters (e.g. pH, concentrations of HCO3- and Cl-). Among these factors, the first two obviously could accelerate the rate and increase the ratio. The degradation was also significantly improved in an acidic condition, while alkaline conditions and HCO3- had inhibitory effects, and Cl- created no difference. Contributions of OH and Cl to the degradation of 2-MIB and GSM were further revealed, and OH was found to be the most important reactive species. In the UV/chlorine process, 6 degradation byproducts of 2-MIB, including 1 alcohol, 2 ketones, and 3 olefins, were identified, and 14 degradation byproducts of GSM, including 6 ketones, 1 aldehyde, 2 alcohols, 3 naphthenes, and 2 olefins, were found by using solid-phase microextraction coupled to gas chromatography-mass spectrometry. The possible degradation pathways of GSM and 2-MIB in UV/chlorine thus were proposed.


Accumulation of laminin and type IV collagen in the kidney in congenital nephrosis.
The aim of this study was to evaluate qualitatively the occurrence of the basement membrane proteins laminin and type IV collagen in the kidneys of ten infants with congenital nephrotic syndrome of the Finnish type (CNF) aged from 3 to 23 months and to compare the results with those for age-matched controls. A slow accumulation of basement membrane (BM) material occurred in the glomerular mesangium, the peripheral capillaries, around atrophied tubules, and the renal vessels in the course of the disease. The staining pattern of accumulated material depended on the duration of the disease and subsequent renal parenchymal damage. Young CNF patients with slight morphological changes in the kidney had only focal and minimal increases in the amounts of mesangial matrix, but as the disease advanced, so the BMs of the glomerular capillaries, renal arteries, and atrophied tubules also became involved and were thicker than normal. The staining reaction was in all patients similar with antibodies against the fragment P1 of laminin and the 7-S domain of type IV collagen. The accumulation of BM material in CNF kidneys is regarded as a secondary phenomenon induced by an unknown pathogenetic defect in the metabolism of some BM component.


Microbial community structure and functional prediction in five full-scale industrial park wastewater treatment plants.
The development of industrial parks has become an important global trend contributing significantly to economic and industrial growth. However, this growth comes at a cost, as the treatment of multisource industrial wastewater generated in these parks can be difficult owing to its complex composition. Microorganisms play a critical role in pollutant removal during industrial park wastewater treatment. Therefore, our study focused on the microbial communities in five full-scale industrial park wastewater treatment plants (WWTPs) with similar treatment processes and capacities. The results showed that denitrifying bacteria were dominant in almost every process section of all the plants, with heterotrophic denitrification being the main pathway. Moreover, autotrophic sulfur denitrification and methane oxidation denitrification may contribute to total nitrogen (TN) removal. In plants where the influent had low levels of COD and TN, dominant bacteria included oligotrophic microorganisms like Prosthecobacter (2.88 % ~ 10.02 %) and hgcI_clade (2.05 % ~ 9.49 %). Heavy metal metabolizing microorganisms, such as Norank_f__PHOS-HE36 (3.96 % ~ 5.36 %) and Sediminibacterium (1.86 % ~ 5.34 %), were prevalent in oxidation ditch and secondary settling tanks in certain plants. Functional Annotation of Prokaryotic Taxa (FAPROTAX) revealed that microbial communities in the regulation and hydrolysis tanks exhibited higher potential activity in the nitrogen (N) and sulfur (S) cycles than those in the oxidation ditch. Sulfate/sulfite reduction was common in most plants, whereas the potential occurrence of sulfide compounds and thiosulfate oxidation tended to be higher in plants with a relatively high sulfate concentration and low COD content in their influent. Our study provides a new understanding of the microbial community in full-scale industrial park WWTPs and highlights the critical role of microorganisms in the treatment of industrial wastewater.


Immunohistochemical characterization of intact stromal layers in long-term cultures of human bone marrow.
We have performed an immunohistochemical study of intact adherent layers of human long-term bone marrow cultures (hLTBMC) in order to characterize the cell types present. Our panel of antibodies was selected to demonstrate various mesenchymal and haemopoietically derived cell types and to assess the presence of molecules of potential importance as adhesive ligands between haemopoietic cells and stroma. Subpopulations of fibroblasts and macrophages were identified which differed in immunophenotype. We were able to demonstrate modulation of fibroblast and extra-cellular matrix immunophenotypes between 2 and 12 weeks in culture. Stromal cells and matrix expressed a wide variety of antigens of potential importance in haemopoietic cell adhesion, but no ICAM-1, 2 or 3 could be demonstrated to correspond to the strong LFA-1 expression seen in haemopoietic precursor cells. No localization of antigen expression by stromal elements was found to account for the formation of haemopoietic foci at particular sites. However, granulocyte-predominant foci preferentially occupied the interstices and margins of structures which appeared to be vascular arrays.


Therapeutic use of 90Y microspheres.
Glass microspheres 20-30 microns in diameter containing either 31P or 89Y that can be activated by neutron bombardment to 32P or 90Y respectively, have been produced for intra-arterial radiotherapy of liver tumors. The spheres are insoluble in body fluids, non-toxic, and can concentrate in liver tumors of animals by direct injection into the hepatic artery. This gives a higher radiation dose to the tumor than can be achieved with external beam therapy. Trials in rabbits and dogs have proven successful and this product (90Y TheraSpheres) is now entering limited human clinical trials.


Targeting HIF-1α is a prerequisite for cell sensitivity to dichloroacetate (DCA) and metformin.
Recently, targeting deregulated energy metabolism is an emerging strategy for cancer therapy. In the present study, combination of DCA and metformin markedly induced cell death, compared with each drug alone. Furthermore, the expression levels of glycolytic enzymes including HK2, LDHA and ENO1 were downregulated by two drugs. Interestingly, HIF-1α activation markedly suppressed DCA/metformin-induced cell death and recovered the expressions of glycolytic enzymes that were decreased by two drugs. Based on these findings, we propose that targeting HIF-1α is necessary for cancer metabolism targeted therapy.


Relationship of the Levels of microRNA Gene Methylation with the Level of Their Expression and Pathomorphological Characteristics of Breast Cancer.
We studied the relationship of the levels of microRNA group expression and methylation with clinical and pathomorphological parameters of breast cancer and its immunohistochemical status. Quantitative methylation specific PCR analysis showed a significant (p<0.001) increase in the methylation level of 4 microRNA genes (MIR127, MIR129-2, MIR132, and MIR148A) and a significant (p<0.001) decrease for gene MIR375 relative to paired histologically normal tissue. Real-time PCR analysis revealed a significant (p≤0.001) decrease in the expression of 4 microRNAs (miR-127-5p, miR-129-5p, miR-132-3p, and miR-148a-3p) and a significant (p≤0.001) increase in the expression of miR-375-3p. A significant (rs=-0.6--0.7, p≤0.001) relationship between changes in the expression level of miR-129-5p, miR-132-3p, miR-148a-3p, and miR-375-3p and the levels of methylation of the corresponding genes in breast cancer was showed by using Spearman's rank correlation test. Analysis of the samples with consideration of the pathophysiological characteristics of the tumor revealed two significant markers of tumor progression: MIR129-2/miR-129-5p and MIR375/miR-375-3p. Both factors, the increase in the level of MIR129-2 methylation (p<0.001) and a decrease in the expression level of miR-129-5p (p<0.001), are significantly associated (p<0.001) with stage III/IV and the absence of HER2 expression. For MIR375/miR-375-3p, on the contrary, an association of low methylation level and enhanced expression with increased Ki-67 level (>30%, p<0.05) was revealed. These findings are of interest for understanding the mechanisms of breast cancer development and can provide the basis for the diagnosis and prognosis of the course of this disease. Moreover, the revealed features can be useful for adjusting the course of treatment with consideration of the pathophysiological characteristics of the tumor.


Long-Term Hepatocellular Carcinoma Development and Predictive Ability of Non-Invasive Scoring Systems in Patients with HCV-Related Cirrhosis Treated with Direct-Acting Antivirals.
Patients with hepatitis C virus (HCV)-related cirrhosis treated with direct-acting antivirals (DAA) are still at risk of developing hepatocellular carcinoma (HCC). We investigated the accuracy of non-invasive scoring systems (NSS) for the prediction of de novo HCC development in patients treated with DAA on long-term follow-up (FU). We analyzed data from 575 consecutive patients with cirrhosis and no history of HCC who achieved a sustained virologic response (SVR) to DAA therapy. NSS (i.e., Forns index, APRI, FIB-4, ALBI, and aMAP) were calculated at 3 months after the end of therapy. Performance for de novo HCC prediction was evaluated in terms of area under the curve (AUC) and Harrell's C-index. During a median FU of 44.9 (27.8-58.6) months, 57 (9.9%) patients developed de novo HCC. All five NSS were associated with the risk of de novo HCC. At multivariate analysis, only the ALBI score resulted in being significantly and independently associated with de novo HCC development (adjusted hazard ratio = 4.91, 95% CI 2.91-8.28, p < 0.001). ALBI showed the highest diagnostic accuracy for the detection of de novo HCC at 1-, 3-, and 5-years of FU, with AUC values of 0.81 (95% CI 0.78-0.85), 0.71 (95% CI 0.66-0.75), and 0.68 (95% CI 0.59-0.76), respectively. Consistently, the best predictive performance assessed by Harrell's C-statistic was observed for ALBI (C-index = 0.70, 95% CI 0.62-0.77). ALBI score may represent a valuable and inexpensive tool for risk stratification and the personalization of an HCC surveillance strategy for patients with cirrhosis and previous history of HCV infection treated with DAA.


A Case of Unicornuate Uterus with Atypical Located Hyperstimulated Ovary after in Vitro Fertilization Pre-Embryo Transfer (IVF-ET).
The authors describe a case of a congenital Mullerian anomaly, uterus unicornis with missing right fallopian tube. An in Vitro Fertilization Pre-Embryo Transfer (IVF-ET) procedure was done and presently is known that the patient has left fallopian tube and left ovary, two kidneys, and right ovary is missing. No diagnostic laparoscopy and hysteroscopy were done, only hysterosalpingography (HSG) before the IVF procedure. Several days after the follicular puncture of the left ovary the patient was urgently admitted to the hospital for specialized gynaecology in Varna. Transabdominal ultrasonography showed right ovary atypically located immediately next to the liver and with emerging theca-lutein cysts.


Orexin A Suppresses Oxidized LDL Induced Endothelial Cell Inflammation via MAPK p38 and NF-κB Signaling Pathway.
Orexin A is a multifaceted peptide produced in hypothalamus. We examined the effect of orexin A on vascular endothelial cells. Our study showed that orexin A had a profound inhibitory effect against endothelial inflammation by oxidized low-density lipoprotein (ox-LDL) in endothelial cells. Orexin A partially suppressed ox-LDL-induced monocytes THP-1 cells attachment to endothelial cells by limiting expression of vascular molecules including VCAM-1, ICAM-1, and E-selectin. Mechanistically, orexin A ameliorated endothelial dysfunction by reducing MAP kinase p38 and NF-κB activation via its receptor-OX1R. Orexin A suppressed phosphorylation of MAP kinase p38 and the NF-κB cascade kinases IKKα and IκBα, and prevented the shuttle of p65 protein into nuclear. Additionally, we reported that OX1R was expressed in HUVECs. Silence of OX1R completely abolished the inhibitory function of orexin in attachment of THP-1 cells. Collectively, our data suggest that orexin A ameliorated endothelial dysfunction under inflammatory stimuli. © 2018 IUBMB Life, 70(10):961-968, 2018.


Review of anesthesia for middle ear surgery.
Special considerations for middle ear surgery include a bloodless surgical field, attention to patient head positioning, facial nerve monitoring, and management of postoperative nausea and vomiting. Middle ear surgery can be done under local or general anesthesia; each has advantages and disadvantages.


Understanding negative hallucination: toward a developmental classification of disturbances in reality awareness.
Negative hallucinations are explored from a psychodynamic viewpoint in four cases of neurosis. Next, shifting to the level of clinical theory, negative hallucinations are contrasted with five better-studied disturbances in reality awareness. It is noted that all six function as screen phenomena, and all occur in everyday contexts. These and other phenomenological issues lead to an assertion that negative hallucinations are regressive perceptual phenomena, similar in form to both preconscious perceptions and infantile amnesia. Finally, developmental considerations are used to derive a coherent hierarchy of disturbances in reality awareness.


Protospacer modification improves base editing of a canonical splice site variant and recovery of CFTR function in human airway epithelial cells.
Canonical splice site variants affecting the 5' GT and 3' AG nucleotides of introns result in severe missplicing and account for about 10% of disease-causing genomic alterations. Treatment of such variants has proven challenging due to the unstable mRNA or protein isoforms that typically result from disruption of these sites. Here, we investigate CRISPR-Cas9-mediated adenine base editing for such variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We validate a CFTR expression minigene (EMG) system for testing base editing designs for two different targets. We then use the EMG system to test non-standard single-guide RNAs with either shortened or lengthened protospacers to correct the most common cystic fibrosis-causing variant in individuals of African descent (c.2988+1G>A). Varying the spacer region length allowed placement of the editing window in a more efficient context and enabled use of alternate protospacer adjacent motifs. Using these modifications, we restored clinically significant levels of CFTR function to human airway epithelial cells from two donors bearing the c.2988+1G>A variant.


Molecular characteristics and pathogenicity of an equid alphaherpesvirus 1 strain isolated in China.
Equid alphaherpesvirus 1 (EHV-1) is prevalent in China, and causes notable economic damage to the equine industry. However, there is no information regarding the molecular characteristics and pathogenicity of the Chinese strains. Therefore, an EHV-1 strain, named YM2019, was isolated from the lung tissue of an aborted horse fetus in Xinjiang, China, and its genome and pathogenicity were analyzed. The full genome of the isolate was 150,267 base pairs in length, with 56.7% G + C content. Genetic and phylogenetic analysis showed that strain YM2019 (GenBank: MT063054) belonged to the ORF30 N752 genotype but displayed a high level of similarity with strain Ab4 (ORF30 D752, GenBank: AY665713) isolated in Britain. Fourteen unique amino acid mutations were found when comparing strain YM2019 with the reference strains Ab4 and V592 (ORF30 N752, GenBank: AY464052). Syrian hamsters infected with strain YM2019 exhibited severe respiratory and neurological clinical signs and died. Infection with strain YM2019 in Yili horses caused rhinopneumonitis, viremia, and neurological clinical signs such as hind limb lameness, prostration, and reduced movement. Here, we describe the features of an EHV-1 strain discovered in China, together with the complete genome sequence, and reveal that a nonneurovirulent strain (ORF30 N752) can also cause neurological signs in horses. The data will be useful in providing some reference for further research into the relationship between viral genotypes and pathogenicity.


Comparative study of two commercial tests for Strongyloides stercoralis serologic diagnosis.
Serological diagnosis of Strongyloides stercoralis is often limited by its low specificity due to cross-reactivity with other parasitic nematodes. Novel serological tests assumed to be more specific have been recently developed. The aim of our study was to compare two commercial tests based on different antigens for S. stercoralis diagnosis in humans from a non-endemic area. A retrospective laboratory-based study was conducted in the Hospital Universitario 12 de Octubre, Madrid, Spain. Samples from patients with a requested S. stercoralis serology from January 2013 to October 2016 were tested with two commercial enzyme-linked immunosorbent assay (ELISA) tests (crude larval suspension ELISA [CrAg-ELISA] and recombinant antigen ELISA [NIE-ELISA]). Sensitivity, specificity and predictive values were calculated using primary and composite gold standards. The κ index was calculated. A total of 249 samples from 233 patients were tested (κ=0.735). The CrAg-ELISA yielded sensitivities from 89.2% (95% confidence interval [CI] 80.7 to 94.2) to 94.7% (95% CI 75.4 to 99.0) and the NIE-ELISA from 72.3% (95% CI 58.2 to 83.1) to 78.9% (95% CI 56.7 to 91.5). Specificity ranged from 72.3% (95% CI 58.2 to 83.1) to 89.3% (95% CI 83.1 to 93.4) for the CrAg-ELISA and from 85.1% (95% CI 72.3 to 92.6) to 93.6% (95% CI 88.2 to 96.6) for the NIE-ELISA. The NIE-ELISA is more specific than the CrAg-ELISA, but its low sensitivity limits its use in S. stercoralis screening. New diagnostic tests are needed for the diagnosis of S. stercoralis.


Association between visual acuity and medical and non-medical costs in patients with wet age-related macular degeneration in France, Germany and Italy.
Exudative ('wet') age-related macular degeneration (ARMD) is the major cause of blindness in Western developed countries. Treatments aimed at preserving vision are already available and new compounds are under development. Micro-economics information will be pivotal to justifying forthcoming investment. This study sought to investigate the costs of exudative ARMD in patients who were actively treated at ophthalmology referral centres in three European countries: France, Germany and Italy. This cross-sectional observational study was conducted in France, Germany and Italy in 2004. The following data were collected: ARMD description, visual acuity (VA), and the medical and non-medical resources used for ARMD in the preceding year. The economic perspective was that of society. ANOVA for cost variables estimated the impact of ARMD per eye, adjusted for sex and age. Both hospital and ambulatory eye centres were included. Patients with exudative ARMD were stratified into four levels of severity using VA thresholds of 20/200 for the worst eye (WE) and 20/40 for the best eye (BE). The main outcome measure was medical and non-medical costs. 360 patients were included (females 60%; mean age 77 years; mean interval since diagnosis 2.3 years). The two groups with the greatest difference in severity of VA loss consisted of BE >or= 20/40, WE >or= 20/200 (27.2% of patients) and BE <20/40, WE <20/200 (25.5% of patients). Total cost was two-thirds medical and one-third non-medical. Total costs increased with ARMD severity and were 1.1-2 times greater for severe disease compared with less severe disease. Average medical costs (2004 values) in France were euro 3714, compared with euro 1810 in Germany and euro 2020 in Italy, and showed slight increases with ARMD severity. Non-medical costs were significantly higher for patients with severe disease and highest in Germany. The impact of ARMD on costs was considerable and a positive correlation was found between total costs and ARMD severity. Differences among countries were partly explained by differences in customary care delivery.


JNK modifies neuronal metabolism to promote proteostasis and longevity.
Aging is associated with a progressive loss of tissue and metabolic homeostasis. This loss can be delayed by single-gene perturbations, increasing lifespan. How such perturbations affect metabolic and proteostatic networks to extend lifespan remains unclear. Here, we address this question by comprehensively characterizing age-related changes in protein turnover rates in the Drosophila brain, as well as changes in the neuronal metabolome, transcriptome, and carbon flux in long-lived animals with elevated Jun-N-terminal Kinase signaling. We find that these animals exhibit a delayed age-related decline in protein turnover rates, as well as decreased steady-state neuronal glucose-6-phosphate levels and elevated carbon flux into the pentose phosphate pathway due to the induction of glucose-6-phosphate dehydrogenase (G6PD). Over-expressing G6PD in neurons is sufficient to phenocopy these metabolic and proteostatic changes, as well as extend lifespan. Our study identifies a link between metabolic changes and improved proteostasis in neurons that contributes to the lifespan extension in long-lived mutants.


Fracture mapping of intra-articular calcaneal fractures.
Calcaneal fractures have complex morphology, which brings great challenges to clinical treatment. The primary fracture lines could help us simplify the fracture. Fracture mapping technology can help surgeons understand the fracture morphology more intuitively. This study aims to develop a further understanding of calcaneal fractures by delineating the primary fracture lines through the fracture mapping technology. Ninety cases of intra-articular calcaneal fractures were reviewed between March 2016 and January 2019 at a level 1 trauma centre. The CT data of these cases were reconstructed and reduced using software. We superimposed the primary fracture lines on a standard model and created the distribution and heat map of the intra-articular calcaneal fractures. SPSS 18.0 was used to count the differences between the different groups. The primary fracture lines concentrated at the Gissane angle and the posterior articular surface, which could be summarized in two ring structures. There were 43 cases of fracture involving calcaneocuboid joint, including 32 cases of joint-depression fracture and 11 cases of tongue-type fracture. The area ratio of lateral fragment of simple tongue-type fracture is larger than joint-depression fracture. The primary fracture lines of calcaneus were distributed in two rings on the surface of calcaneus. Based on the distribution of primary fracture rings, we integrated the classification of calcaneal fracture and proposed some treatment recommendations.


Physical quality of gluten-free doughs and fresh pasta made of amaranth.
Pasta is one of the most consumed foods in the world. Therefore, the development and investigation of the quality parameters of fresh gluten-free pasta made from amaranth was the subject of this study. For this purpose, different doughs (amaranth flour: water 1:2, 1:4, 1:6, 1:8, 1:10) were heat-treated and sodium alginate (1.0 and 1.5%) was added. The pasta was produced by extrusion into a 0.1 M calcium L-lactate pentahydrate-containing bath. Both the dough and the pasta were examined. The doughs for its viscosity properties, water content, and color and the pasta for its firmness, color, water content, water absorption, cooking loss, and swelling index. The pasta was cooked for 5, 10, and 15 min for the cooking quality study. A higher alginate content of 1.5% and a higher proportion of amaranth flour resulted in a significant difference in color, water content, and shear-dependent viscosity of the dough (p < .001). It was also found that both doughs with amaranth flour-water content of 1:2 and 1:10 had significant effects on processing properties and pasta quality, especially on firmness, swelling index, and cooking loss. For the doughs with a 1:2 ratio, the high flour content resulted in very soft pasta, and for the doughs with a 1:10 ratio, the high-water content resulted in very firm pasta with a smooth, watery surface. Overall, cooking loss, swelling index, and water absorption were low for the pasta with 1.5% alginate. Even with cooking times of 15 min, the pasta retained its shape.


Characterisation of potato (Solanum tuberosum L.) extensins: a novel extensin-like cDNA from dormant tubers.
A cDNA library from dormant potato tubers was screened for extensin (Ext)-like cDNAs (PTEL). The cDNAs recovered were partially sequenced and could be divided into two classes. One class, containing the repeating amino acid (aa) motifs, SPPPPSPKYVYK and SPPPPSPSPPPPYYYK, constitutes the potato counterpart of the tomato Ext-encoding gene previously isolated by Zhou et al. [Plant Mol. Biol. 20 (1992) 5-17]. A full-length cDNA from the second class was fully sequenced. The product of this cDNA has the repetitive sequence and proline-rich composition typical of Ext. Features worthy of note are the signal peptide sequence, which shares close homology with signal sequences of a number of Ext of diverse origin, and the presence of a novel, histidine-rich motif (SPPPHHHHPVYK) repeated within the sequence. Wounding of the potato tuber causes a marked increase in Ext-like mRNAs, although the species induced are not those present in dormant tissue.


Thin layer chromatographic determination of aflatoxins, ochratoxins, sterigmatocystin, zearalenone, citrinin, T-2 toxin, diacetoxyscirpenol, penicillic acid, patulin, and penitrem A.
A general method is described for determining 16 mycotoxins in mixed feeds and other food products used in the manufacture of these feedstuffs. The mycotoxins are extracted and cleaned up by extracting with solvents of different pH. Thin layer chromatography is used to separate the toxins; toxins are then quantitated by the limit detection method. The minimum detectable concentration of mycotoxins in various products is: aflatoxin B1 or G1, 4--5 micrograms/kg; ochratoxin A or ethyl ester A 140--145 micrograms/kg; citrinin 600--750 micrograms/kg; zearalenone, 410--500 micrograms/kg; sterigmatocystin, 140--145 micrograms/kg; diacetoxyscirpenol, 2400--2600 micrograms/kg; T-2 toxin, 800--950 micrograms/kg; patulin, 750--800 micrograms/kg; penitrem A 14,000--14,500 micrograms/kg; penicillic acid 3400--3650 micrograms/kg.


Isolated optic neuritis associated with Mycoplasma pneumoniae infection: report of two cases and literature review.
Mycoplasma pneumonia is a major pathogen of primary atypical pneumonia and has been known to cause various kinds of extrapulmonary manifestations involving almost all organs of the human body. Optic neuritis associated with M. pneumoniae infection has rarely been described and mostly, it combined other neurological complications including meningitis, meningoencephalitis, myelitis, and peripheral neuropathy. We report two patients who presented with isolated optic neuritis due to M. pneumoniae infection, and reviewed the literatures on five additional patients. All patients are child or young adults, and optic neuritis was unilateral (n = 3) or bilateral (n = 4). Remarkably, four patients did not have preceding history of respiratory M. pneumonia infection, and ocular pain or headache was accompanied in only three. Although initial visual acuities were severely reduced in most cases, visual outcome was excellent after systemic steroid and/or antibiotics treatment. M. pneumonia infection should be considered in the differential diagnosis of isolated optic neuritis, especially when occurring in a child or young adults, even though there was no preceding pneumonia, accompanying ocular pain, or headache. Various mechanisms including direct local inflammation, vascular occlusion, or indirect immune modulation due to M. pneumonia infection can lead to isolated neurological manifestations without pneumonia.


[Experiences at a neurologico-psychiatric department in Ethiopia].
On three separate occasions, the authors taught at Gondar School of Medicine, attached to the University of Addis Ababa. They found that the neurological group of patients was determined by geographical rather than specifically tropical conditions, and that the psychiatric syndromes resembled those here, considerably influenced, however, by traditional rural medicine. The paper makes observations on comparative psychopathology.


Patterns of familial alcoholism, alcoholism severity, and psychopathology.
The interrelationships among the severity of alcoholism, psychopathology/personality, and the degree of familial alcoholism were examined using the following four familial alcoholism classification schemes, which each differentiated three degrees of familial alcoholism: 1) conventional, compared alcoholics with no, nonparental, and parental alcoholic relatives; 2) lineality, distinguished between subgroups with alcoholism in neither, one, or both sides of their family; 3) generational, compared alcoholics having no, one, or two generations of familial alcoholism; 4) quantitative, credited one point for each first-degree and 1/2 point for each second-degree alcoholic relative. The subjects were 83 male alcoholic Veterans Administration inpatients 50 years of age or under. The Alcohol Use Inventory, various alcohol-related symptoms and behaviors, and laboratory values were used to evaluate the severity/pattern of alcoholism. Psychopathology/personality were measured by the MMPI, the Psychopathic State Inventory, the MacAndrew Alcoholism Scale, the Childhood Problem Behaviors Questionnaire, and the percentage of patients with an antisocial personality disorder (ASP) diagnosis. Surprisingly few subgroup differences were revealed in the severity/pattern of alcoholism. Only age at time of treatment and use of nonalcoholic drugs were associated with increasing familial alcoholism. On the other hand, childhood behavior problems, particularly antisocial behavior, and an ASP diagnosis were found to be associated with an increasing degree of familial alcoholism. The diagnosis of ASP was most apparent in the two-generational and bilineal alcoholics, while an increased degree of familial alcoholism was not associated with ASP for the conventional classification. Bilineal familial alcoholics also exhibited an MMPI profile reflective of a characterological disorder.(ABSTRACT TRUNCATED AT 250 WORDS)


Computerized quality assurance of decisions to transfuse blood components to critically ill patients.
In critically ill patients optimal transfusion therapy for most clinical settings has not been determined. The objective of this study was to evaluate the impact of a computerized audit on transfusion decisions of red blood cells (RBC), fresh frozen plasma (FFP), and platelets among critically ill patients. Two hundred and ninety consecutive patients admitted to nine-bed medical-surgical intensive care unit at a university hospital were included in this prospective study. Prior to the study, the criteria for transfusions of RBCs, FFP and platelets were established. Phase I, the first 3-month period served as a control period. During phase II the fulfilment of these criteria was prospectively monitored by an audit software belonging to the computerized blood request program. If the predefined transfusion criteria were not met the audit software was automatically activated. The last 3-month period, phase III, was to assess if possible effects on transfusion decisions were permanent. The proportion of RBC transfusions administered according to predefined trigger during the study phases I, II, and III were 55.9%, 75.1% and 67.9%, respectively (P < 0.001). The proportion of FFP and platelet transfusions according to a predefined trigger did not differ statistically significantly between the study phases. Logistic multiple regression analysis revealed an independent effect of the audit phase on the decision to transfuse RBCs and FFP. The data suggests that a computerized prospective transfusion audit has impact on the realisation of predefined transfusion decisions.


Chronic fatigue syndrome in adolescents: a follow-up study.
To compare the frequency of persistent symptoms up to 8 years after illness onset in adolescents diagnosed as having chronic fatigue syndrome, idiopathic chronic fatigue, and unexplained fatigue for less than 6 months, and to determine if hospital admission is associated with outcome. A cohort study using questionnaire follow-up. A tertiary referral hospital. Consecutive adolescents referred for assessment of persistent fatigue were identified and retrospectively divided into 3 groups according to the diagnostic criteria for chronic fatigue syndrome and idiopathic chronic fatigue. A questionnaire was designed and administered by telephone at a mean of 4.57 years after the initial examination. The persistence of self-reported symptoms was compared with respect to patient group and admission. Outcome data were obtained for 34 (69%) of the 49 eligible subjects. Twenty-five percent of the chronic fatigue syndrome group showed near to complete improvement, 31% showed partial improvement, and 44% showed no improvement. The idiopathic chronic fatigue group had near to complete recovery in 50%, partial in 10%, and no improvement in 40%. Those with unexplained fatigue for less than 6 months had all recovered. There was no difference between the outcome of the subjects admitted to the hospital and those managed as outpatients. Adolescents with less than 6 months of fatigue have a good outcome. Unexplained fatigue lasting more than 6 months has a similar outcome regardless of the presence of minor criteria for chronic fatigue syndrome.


Morbidity and mortality of pneumococcal meningitis and serotypes of causative strains prior to introduction of the 7-valent conjugant pneumococcal vaccine in England.
To assess the incidence of pneumococcal meningitis, associated deaths and serotypes of causative pneumococci in England prior to the inclusion of the 7-valent conjugated pneumococcal vaccine in the routine childhood immunisation programme in 2006. Cases were identified using hospital episode statistics (HES) and voluntary reports or submission of isolates to the Health Protection Agency. Mortality data and population estimates were from the Office for National Statistics. Based on HES, the annual incidence of pneumococcal meningitis was about 1 case per 100,000 population between 1998 and 2005 (an average of approximately 480 cases per year) with case fatality rates increasing from 5% in <15 year olds to 30% in >64 year olds. Enhanced surveillance comprising a combination of voluntary reporting of cases and referral of isolates gave case ascertainment rates of 50-70% compared to those derived from HES, and similar case fatality rates. The age distribution of pneumococcal meningitis was similar with both datasets, infection being reported mostly commonly in children aged less than 5 years, with the highest incidence in children aged 2-11 months. Based on the serotype distribution of isolates obtained in 2005, the serotype coverage afforded by the 7-valent conjugate vaccine is 72% for patients aged less than 2 years. These data provide baseline information on the incidence of pneumococcal meningitis and associated mortality, together with the serotypes of infecting strains of pneumococci, which will be critical for evaluation of the public health impact of the 7-valent conjugated pneumococcal vaccine in England.


Designed sound and music environment in postanaesthesia care units--a multicentre study of patients and staff.
A multicentre study in five postanaesthesia care units (PACUs) was performed to investigate patient and staff opinion of a specially designed music environment (DME), related to geographical location. Patients (325) and staff (91) described their opinion by means of a questionnaire-anonymously in the case of staff. Patients were not asked beforehand for permission to play music. Amongst patients 267 (83%) found the sound environment with DME pleasant or very pleasant, 26 (6%) found it unpleasant, whereas 32 (11%) answered "no opinion". The opinion of the patients did not differ significantly with geographical location. A strong correlation (P<0.05) between a positive attitude towards DME and degree of relaxation and satisfaction with stay was found. The staff had an equally positive attitude towards the DME; but theirs varied significantly with location. The opinion of the staff was more similar concerning the beneficial effect on working conditions and distress, but varied still significantly. The opinion of the staff had no demonstrable impact on that of the patients.


RalB degradation by dihydroartemisinin induces autophagy and IFI16/caspase-1 inflammasome depression in the human laryngeal squamous cell carcinoma.
Interferon-inducible 16 (IFI16)/caspase-1 inflammasome activates and secretes IL-1β. However, it is still unclear whether the IFI16 inflammasome is involved in human laryngeal squamous cell carcinoma. Autophagy directly removed inflammasome components and limited early IL-1β production. RalB is required for the crosstalk between inflammasome and autophagy in macrophages. Dihydroartemisinin (DHA), the main derived ingredient of artemisinin, has a variety of biological activities. The mechanism of DHA in regulating the crosstalk between IFI16 inflammasome and autophagy by inhibiting RalB expression was analyzed in order to provide clues for new therapeutic methods in laryngeal cancer. The expression of IFI16 was analyzed by Oncomine and GEPIA databases and detected by Western blot and immunohistochemistry. The relationship between IFI16 inflammasome and autophagy was investigated by transmission electron microscopy, immunofluorescence assay, etc. in Hep-2, Cal-27 and HeLa cells treated with DHA. The xenograft tumor of hep-2 cell in nude mice were used to assess the effect of DHA on laryngeal cancer. It was reported for the first time in this study that IFI16 was overexpressed and positively correlated with caspase-1 in laryngeal carcinoma tissues. DHA significantly inhibited the activation of inflammasome and reduced IL-1β production in the microenvironment of Hep-2 cell xenograft tumor in nude mice. Mechanistically, we found that DHA degraded RalB, inhibited USP33 expression, and triggered autophagy. Meanwhile, enhanced autophagy can reduce the expression of RalB and USP33. Furthermore, DHA promotes autophagy, which suppresses the activation of IFI16/caspase-1 inflammasome and IL-1β production. Therefore, our findings demonstrate that DHA may act as a RalB inhibitor to regulate the crosstalk between autophagy and IFI16/caspase-1 inflammasome, which inhibits IL-1β production in tumor microenvironment.


Patient-derived xenografts: A platform for accelerating translational research in prostate cancer.
Recently, there has been renewed interest in the development and characterization of patient-derived tumour xenograft (PDX) models. Numerous PDX models have been established for prostate cancer and, importantly, retain the principal molecular, genetic, and histological characteristics of the donor tumour. As such, these models provide significant improvements over standard cell line xenograft models for biological studies, preclinical drug development, and personalized medicine strategies. This review summarizes the current state of the art in this field, illustrating the opportunities and limitations of PDX models in translational prostate cancer research.


Coronary aneurysm and purulent pericardial effusion: old disease with an unusual cause.
We describe the case of a 60-year-old man with prior rotational atherectomy and drug-eluting stent to the left anterior descending artery (LAD) who presented with shortness of breath and chest pain 8 weeks after stent placement. Further workup revealed a large pericardial effusion with gram stain positive for methicillin-resistant Staphylococcus aureus. Subsequently, this was shown to be related to an aneurysm at the site of the prior LAD stent. This case demonstrated coronary stent infection with mycotic aneurysm and purulent pericardial effusion as an extremely rare but serious complication of percutaneous coronary intervention.


"Post-Gay" Yet? The Relevance of the Lesbian and Gay Scene to Same-Sex Attracted Young People in Contemporary Australia.
In recent years, the lesbian and gay "scene" of bars, nightclubs, and dance parties has been undergoing a structural decline in many Western cities. This article aimed to examine the relevance of the scene to same-sex attracted young adults amid these changes. An online survey was conducted with 572 same-sex attracted young women and men in Sydney. Only a minority of respondents participated in the scene at least weekly (16%), and the majority did not regard the scene as important to their leisure time (60%). However, respondents valued the scene as a space to connect with other same-sex attracted people and display same-sex affection without fear of hostility. Lesbian and gay identified respondents tended to be more socially engaged with the scene compared to other same-sex attracted respondents. The findings suggest that while the scene continues to be valued by many same-sex attracted young people, improved social attitudes have made participating in the scene less of an imperative.


Efficacy of a fabricated customized splint and tendon and nerve gliding exercises for the treatment of carpal tunnel syndrome: a randomized controlled trial.
To compare the effects of a neutral wrist and metacarpophalangeal (MCP) splint with a wrist cock-up splint, with and without exercises, for the treatment of carpal tunnel syndrome (CTS). A 2x2x3 randomized factorial design with 3 main factors: splint (neutral wrist and MCP and wrist cock-up), exercise (exercises, no exercise), and time (baseline, 4wk, 8wk). Subjects were evaluated in an outpatient hand therapy clinic. Sixty-one subjects with mild to moderate CTS; 51 subjects completed the study. There were 4 groups: the neutral wrist and MCP group and the neutral wrist and MCP-exercise group received fabricated customized splints that supported the wrist and MCP joints; the wrist cock-up group and the wrist cock-up-exercise group received wrist cock-up splints. The neutral wrist and MCP-exercise and wrist cock-up-exercise groups also received tendon and nerve gliding exercises and were instructed to perform exercises 3 times a day. All subjects were instructed to wear the assigned splint every night for 4 weeks. We used the CTS Symptom Severity Scale (SSS) and the Functional Status Scale (FSS) to assess CTS symptoms and functional status. Analysis of variance showed a significant main effect for splint and time on the SSS (P<.001, P=.014) and FSS (P<.001, P=.029), respectively. There were no interaction effects. Our results validate the use of wrist splints for the treatment of CTS, and suggest that a splint that supports the wrist and MCP joints in neutral may be more effective than a wrist cock-up splint.


Multicenter study of emergency department visits for insect sting allergies.
An earlier study of food-related anaphylaxis in the emergency department (ED) suggested low concordance with national guidelines for anaphylaxis management. To extend these findings, we performed a chart review study to describe current ED management of insect sting allergy. The Multicenter Airway Research Collaboration performed a chart review study in 15 North American EDs. Investigators reviewed 617 charts of patients with insect sting allergy. Patients were identified by using International Classification of Diseases, 9th Revision, codes 989.5 (toxic effect of venom), 995.0 (other anaphylactic shock), and 995.3 (allergy, unspecified). The cohort was 42% female and 61% white, with a mean age of 36+/-19 years. In this cohort, 58% had local reactions, 11% had mild systemic reactions, and 31% had anaphylactic reactions, as defined by multisystem organ involvement or hypotension. Among patients with systemic reactions (mild or anaphylaxis), most (75%) were stung within 6 hours of ED arrival. While in the ED, 69% of systemic reaction patients received antihistamines, 50% systemic corticosteroids, and 12% epinephrine. Almost all systemic reaction patients (95%) were discharged to home. At ED discharge, 27% (95% CI, 22% to 33%) of systemic reaction patients received a prescription for self-injectable epinephrine. Only 20% (95% CI, 15% to 26%) had documentation of referral to an allergist. Although guidelines suggest specific approaches for the emergency management of insect sting allergy, concordance with these guidelines appears low in patients with a severe insect sting reaction.


Pyridinium 3-nitro-benzoate-3-nitro-benzoic acid (1/1).
The crystal structure of the product of the neutralization reaction between 3-nitro-benzoic acid and pyridine is reported. The entities that crystallized are a pyridinium cation, a 3-nitrobenzoate anion and a 3-nitrobenzoic acid molecule in a 1:1:1 molar ratio, C5H6N+·C7H4NO4 -·C7H5NO4. Distinct sets of hydrogen bonds link the pyridinium and benzoate ions (N-H⋯O) and the acid and benzoate moieties (O-H⋯O). The hydrogen bonding along with π-π stacking between the acid and benzoate moieties accounts for the long-range ordering of the crystal.


Structural organization of free and esterified cholesterol in human high density lipoproteins. A 100.6 MHz 13C NMR study.
The structural organization of free and esterified cholesterol in human high density lipoproteins has been studied by high-field 1H and 13C NMR. The measurements are consistent with free cholesterol being present in at least two different environments. Part of the free cholesterol is oriented in the outer surface layer of the high density lipoprotein particle in contact with phospholipid or apoprotein, or both. The rest is probably present in the liquid, hydrophobic core of the HDL particle.


Elevated C-reactive protein increases diagnostic accuracy of algorithm-defined stroke-associated pneumonia in afebrile patients.
Pyrexia-dependent clinical algorithms may under or overdiagnose stroke-associated pneumonia. This study investigates whether inclusion of elevated C-reactive protein as a criterion improves diagnosis. The contribution of C-reactive protein ≥30 mg/l as an additional criterion to a Centers for Disease Control and Prevention-based algorithm incorporating pyrexia with chest signs and leukocytosis and/or chest infiltrates to diagnose stroke-associated pneumonia was assessed in 1088 acute stroke patients from 37 UK stroke units. The sensitivity, specificity, and positive predictive value of different approaches were assessed using adjudicated stroke-associated pneumonia as the reference standard. Adding elevated C-reactive protein to all algorithm criteria did not increase diagnostic accuracy compared with the algorithm alone against adjudicated stroke-associated pneumonia (sensitivity 0.74 (95% CI 0.65-0.81) versus 0.72 (95% CI 0.64-0.80), specificity 0.97 (95% CI 0.96-0.98) for both; kappa 0.70 (95% CI 0.63-0.77) for both). In afebrile patients (n = 965), elevated C-reactive protein with chest and laboratory findings had sensitivity of 0.84 (95% CI 0.67-0.93), specificity of 0.99 (95% CI 0.98-1.00), and kappa 0.80 (95% CI 0.70-0.90). The modified algorithm of pyrexia or elevated C-reactive protein and chest signs with infiltrates or leukocytosis had sensitivity of 0.94 (95% CI 0.87-0.97), specificity of 0.96 (95% CI 0.94-0.97), and kappa of 0.88 (95% CI 0.84-0.93) against adjudicated stroke-associated pneumonia. An algorithm consisting of pyrexia or C-reactive protein ≥30 mg/l, positive chest signs, leukocytosis, and/or chest infiltrates has high accuracy and can be used to standardize stroke-associated pneumonia diagnosis in clinical or research settings. http://www.isrctn.com/ISRCTN37118456.


Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiency.
Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high-responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62-year-old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL-1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL-1 with an inhibitor titre of 48 BU. She received 90 microg kg-1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 microg kg-1 h-1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117-->Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy.


Monocrotaline pyrrol is cytotoxic and alters the patterns of GFAP expression on astrocyte primary cultures.
Dehydromonocrotaline (DHMC) is the main monocrotaline active cytochrome P450's metabolite, and has already been assessed in the CNS of experimentally intoxicated rats. DHMC effects were here investigated toward rat astroglial primary cultures regarding cytotoxicity, morphological changes and regulation of GFAP expression. Cells, grown in DMEM supplemented medium, were treated with 0.1-500 microM DHMC, during 24- and 72-h. According to MTT and LDH tests, DHMC was toxic to astrocytes after 24-h exposure at 1 microM, and induced membrane damages at 500 microM. Rosenfeld dying showed hypertrophic astrocytes after 72-h exposure to 0.1-1 microM DHMC. GFAP immunocytochemistry and western immunoblot revealed an increase of GFAP labelling and expression, suggesting an astrogliotic reaction to low concentrations of DHMC. At higher concentrations (10-500 microM), astrocytes shrank their bodies and retracted their processes, presenting a more polygonal phenotype and a weaker expression on GFAP labelling Nuclear chromatin staining by Hoechst-33258 dye, revealed condensed and fragmented chromatin in an important proportion (+/-30%) of the astrocytes exposed to 100-500 microM DHMC, suggesting signs of apoptosis. Our results confirm a cytotoxic and dose-dependent effect of DHMC on cultures of rat cortical astrocytes, leading to apoptotic figures. These effects might be related to the neurological damages and clinical signs observed in animals intoxicated by Crotalaria.


Antibiotic stewardship in the ICU: time to shift into overdrive.
Antibiotic resistance is a major health problem and will be probably one of the leading causes of deaths in the coming years. One of the most effective ways to fight against resistance is to decrease antibiotic consumption. Intensive care units (ICUs) are places where antibiotics are widely prescribed, and where multidrug-resistant pathogens are frequently encountered. However, ICU physicians may have opportunities to decrease antibiotics consumption and to apply antimicrobial stewardship programs. The main measures that may be implemented include refraining from immediate prescription of antibiotics when infection is suspected (except in patients with shock, where immediate administration of antibiotics is essential); limiting empiric broad-spectrum antibiotics (including anti-MRSA antibiotics) in patients without risk factors for multidrug-resistant pathogens; switching to monotherapy instead of combination therapy and narrowing spectrum when culture and susceptibility tests results are available; limiting the use of carbapenems to extended-spectrum beta-lactamase-producing Enterobacteriaceae, and new beta-lactams to difficult-to-treat pathogen (when these news beta-lactams are the only available option); and shortening the duration of antimicrobial treatment, the use of procalcitonin being one tool to attain this goal. Antimicrobial stewardship programs should combine these measures rather than applying a single one. ICUs and ICU physicians should be at the frontline for developing antimicrobial stewardship programs.


Hydrogen fluoride damage to vegetation from peri-urban brick kilns in Asia: a growing but unrecognised problem?
The rapid urbanisation of many cities in south and south-east Asia has increased the demand for bricks, which are typically supplied from brick kilns in peri-urban areas. We report visible foliar damage to mango, apricot and plum trees in the vicinity of traditional Bull's Trench brick kilns in Peshawar, Pakistan. Visible injury symptoms, hydrogen fluoride concentrations in air, and foliar fluoride concentrations were all greater in the vicinity of brick kilns than at more distant sites, indicating that fluoride emissions from brick kilns were the main cause of damage. Interviews with local farmers established the significant impact of this damage on their livelihoods. Since poorly regulated brick kilns are often found close to important peri-urban agricultural areas, we suggest that this may be a growing but unrecognised environmental problem in regions of Asia where emission control in brick kilns has not been improved.


Effectiveness of a multi-modal hospital-wide doctor mental health and wellness intervention.
Doctors report high rates of workplace stress and are at increased risk of mental health disorders. However, there are few real-world studies evaluating the effectiveness of interventions aimed at addressing workplace risk factors and improving doctors' mental health in a hospital setting. This study was conducted over two years (2017-2019) to assess the effects of a multi-modal intervention on working conditions doctors' mental health and help-seeking for mental health problems in two Australian teaching hospitals. The multimodal intervention consisted of organisational changes, such as reducing unrostered overtime, as well as strategies for individual doctors, such as mental health training programs. Hospital-based doctors at all career stages were eligible to participate in two cross-sectional surveys. 279 doctors completed the baseline survey (19.2% response rate) and 344 doctors completed the follow-up survey (31.3% response rate). A range of workplace risk and protective factors, mental health (psychological distress and suicidal ideation) and help-seeking outcomes were assessed. There were significant improvements in key workplace protective factors, with small effects found for doctors' job satisfaction, stress, work-life balance and perceived workplace support and a significant reduction in workplace risk factors including a moderate reduction in reported bullying behaviour between baseline to follow-up (job satisfaction p < 0.05, all other outcomes p < 0.01). However, no significant changes in doctors' mental health or help-seeking outcomes were found over the intervention period. Following the implementation of individual and organisational-level strategies in two Australian tertiary hospitals, doctors reported a reduction in some key workplace stressors, but no significant changes to their mental health or help-seeking for mental health problems. Further research is warranted, particularly to determine if these workplace changes will lead to improved mental health outcomes for doctors once maintained for a longer period.


Linear free energy relationship models for the retention of partially ionized acid-base compounds in reversed-phase liquid chromatography.
The LFER model of Abraham is applied to the retention of the neutral and ionic forms of 94 solutes in a C18 column and 40% v/v acetonitrile/water mobile phase. The results show that polarizability and cavity formation interactions increase retention, whereas dipole and hydrogen bonding interactions favours partition to the mobile phase and thus, they decrease retention. The coefficients of the ionic descriptors measure the effect of the electrostatic interactions and their contribution to partition of the cation or anion between the two mobile and stationary chromatographic phases. A new LFER model for application to the retention of partially dissociated acids and bases is derived averaging the descriptors of the neutral and ionic forms according to their degrees of ionization in the mobile phase. This new LFER model is satisfactorily compared to other literature modified Abraham models for a set of 498 retention data of partially dissociated acids and bases. All tested models require the calculation of the ionization degrees of the compounds at the measuring pH. Calculation of the ionization degrees in the chromatographic mobile phase (i.e. from pH and pKa in the eluent) give good correlations for all tested models. However, estimation of these ionization degrees from pH - pKa data in pure water gives biased estimations of the retention of the partially ionized solutes.


A novel gene, TARDBP, and the protein it encodes can predict glioma patient prognosis and establish a prediction model.
TDP-43 (43-kD transactive response DNA-binding protein) is a DNA-/RNA-binding protein that plays an important role in several nervous system diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Whether it plays an important role in glioma patients is unknown. Datasets were downloaded from the Chinese Glioma Genome Atlas (CGGA) website ( http://www.cgga.org.cn/ ). Cox survival analysis was performed to determine the relationship between TARDBP gene expression and the overall survival of glioma patients. GO analyses were performed to determine the biological functions of the TARDBP gene. Finally, we used PRS type, age, grade, IDH mutation status, 1p/19q codeletion status, and expression value of the TARDBP gene to construct a prediction model. With this model, we can predict patients' 1-, 2-, 3-, 5-, and 10-year survival rates. The TARDBP gene plays an important role in glioma patients. The expression of the TARDBP gene has a significant correlation with glioma patient survival. We also constructed an ideal prediction model. Our findings suggest that the TARDBP gene and the protein it encodes play important roles in glioma patients. The expression of the TARDBP gene has a significant correlation with the overall survival of glioma patients.


Spontaneous zygogenesis, a wide-ranging mating process in bacteria.
Spontaneous zygogenesis (or Z-mating) in Escherichia coli, unlike F-mediated conjugation, promotes formation of complete zygotes. Most Z-mating products have proven to be phenotypically unstable, losing part of the phenotype for which they were selected. Persistent Z-mating products appear as stable genetic recombinants or yield subclones of two types: either both parental types or one of them plus a recombinant type, and the ability to promote spontaneous zygogenesis can appear in all emerging types. Here it is shown that spontaneous zygogenesis-promoting E. coli strains can Z-mate with strains of Shigella flexneri, Salmonella enterica Serovar Typhimurium and Serratia marcescens, giving rise to products that behave like those of homospecific Z-matings. When genetic recombination was prevented in products of Z-mating between E. coli and S. enterica or S. marcescens, phenotype switching was observed in purified isolates exhibiting a single phenotype, thus providing further evidence of interspecies genotypic mixing. The presence of two distinct replicons within a cell introduces a new situation that contrasts with classical conjugation between heterologous strains, where the partially transferred chromosomal segment is subject to restriction, is unable to replicate and is limited in genetic recombination.