Impact of hysterectomy on analgesic, psychoactive and neuroactive drug use in women with endometriosis: nationwide cohort study.

OBJECTIVE: To evaluate how hysterectomy affects the prescription of analgesic, psychotropic and neuroactive drugs in women with endometriosis using population-based nationwide registers. DESIGN: Nationwide cohort study. SETTING: Swedish national registers, from 1 January 2009 to 31 December 2018. POPULATION: Women with benign disease undergoing a total hysterectomy during the 4-year period of 2012-2015. Women with endometriosis (n = 1074) were identified and compared with women who did not have endometriosis (n = 10 890). METHODS: Prospectively collected data from two population-based registers were linked: the Swedish National Quality Register of Gynaecological Surgery and the Swedish National Drug Register. Multivariate logistic regression was used as the main statistical method. MAIN OUTCOME MEASURES: Changes in drug prescription over time for 3 years prior to and 3 years after hysterectomy. RESULTS: The frequency of prescription of analgesics was higher in women with endometriosis compared with women without endometriosis (OR 2.2, 95% CI 1.7-2.9). Among women with endometriosis, the prescription of analgesics (OR 1.0, 95% CI 0.8-1.2) did not decrease 3 years after hysterectomy compared with the 3 years prior to surgery. There was also a significantly higher rate of prescription of psychoactive (OR 1.6, 95% CI 1.4-2.0) and neuroactive drugs (OR 1.9, 95% CI 1.3-2.7) in the long term postoperatively. CONCLUSIONS: In women undergoing hysterectomy, endometriosis was associated with a higher prescription rate of analgesics. In the endometriosis group the prescription of analgesic, psychoactive and neuroactive drugs did not decrease when comparing prescription rates for the 3 years prior to and the 3 years after surgery. TWEETABLE ABSTRACT: In women with endometriosis, the long-term prescription of analgesics did not decrease after hysterectomy.

Electron channelling: challenges and opportunities for compositional analysis of nanowires by TEM.

Energy dispersive x-ray spectroscopy in a transmission electron microscope is often the first method employed to characterize the composition of nanowires. Ideally, it should be accurate and sensitive down to fractions of an atomic percent, and quantification results are often reported as such. However, one can often get substantial errors in accuracy even though the precision is high: for nanowires it is common for the quantified V/III atomic ratios to differ noticeably from 1. Here we analyse the origin of this systematic error in accuracy for quantification of the composition of III-V nanowires. By varying the electron illumination direction, we find electron channelling to be the primary cause, being responsible for errors in quantified V/III atomic ratio of 50%. Knowing the source of the systematic errors is required for applying appropriate corrections. Lastly, we show how channelling effects can provide information on the crystallographic position of dopants.

Transient Osteoporosis of the Hip: Risk and Therapy.

OBJECTIVE: The aim of this study was to investigate the impact of occupation in patients with transient osteoporosis of the hip (TOH). The study also compares two different types of management for this condition: conservative treatment and surgical drilling. METHODS: This was a retrospective case series study. The medical records for patients diagnosed with TOH at our institution within the period 2012-2017 were retrieved. General demographic data, clinical features, and diagnostic modalities were obtained. In addition, management procedures and their associated prognostic factors were acquired. The effectiveness of these procedures was assessed by the number of days of sick leave, the time needed for full recovery and the number of recurrences of TOH. Also, pain responses at 24 hrs, 48 hrs, and at 1 week were estimated subjectively through a "pain score" out of 10, and objectively through the degree of improvement in daily activity. The patients had a regular follow-up at 4- to 6-week intervals. RESULTS: In total, 15 cases of TOH, 14 men and one woman, were enrolled in the study. The mean age of the patients was 41 years (range 26-59 years). Out of the 15 cases, nine were healthcare professionals (eight physicians and one nurse). Ten patients underwent hip drilling for core decompression and five patients were treated conservatively. The time needed for full recovery was 5.8 weeks for those who underwent drilling, and 48.3 weeks for three patients receiving conservative treatment. The other two patients who were treated conservatively had not achieved full or near-full recovery at the time of reporting this study. CONCLUSION: Physicians may be at increased risk of developing TOH. Further studies should be conducted to examine the role of this occupation as a risk factor. In addition, hip drilling should be considered as an effective treatment modality, especially in those patients who seek a faster recovery.

Sustainable treatment systems for removal of pharmaceutical residues and other priority persistent substances.

Pharmaceutical residues and other emerging substances commonly summarised as micropollutants pass through wastewater treatment plants (WWTPs) and end up in the receiving waters and sludge. Many studies have investigated the removal efficiency of various techniques but a holistic evaluation of various relevant treatment alternatives regarding both the removal efficiency for various micropollutants, investment and operating costs, environmental impacts and future comprehensiveness is still lacking. This paper provides the results from a large 3-year project about the evaluation of sustainable treatment systems for removal of various micropollutants or disruptive effects at Swedish WWTPs and their environmental, economic and future sustainability. The presented results are based on our own pilot tests and related assessment and modelling efforts and provide a holistic view on advanced treatment of wastewater for removal of micropollutants.

Step edge structures on the anatase TiO2 (001) surface studied by atomic-resolution TEM and STM.

Low-coordinate surface sites, such as those present on high-index step edges, often exhibit chemical reactivity that markedly differs from more close-packed facets. To understand the site-specific reactivity, insight into the three-dimensional atomic arrangement of step edges is needed. Here, we employ atomic-resolution transmission electron microscopy (TEM) of nanoparticles in combination with scanning tunneling microscopy (STM) of a single crystal surface to uncover the structure of prevalent step edges on the anatase TiO2 (001) surface.

Design and structure-activity relationships of novel inhibitors of human rhinovirus 3C protease.

Human rhinovirus (HRV) is a primary cause of common cold and is linked to exacerbation of underlying respiratory diseases such as asthma and COPD. HRV 3C protease, which is responsible for cleavage of viral polyprotein in to proteins essential for viral life-cycle, represents an important target. We have designed proline- and azetidine-based analogues of Rupintrivir that target the P2 pocket of the binding site. Potency optimization, aided with X-ray crystallography and quantum mechanical calculations, led to compounds with activity against a broad spectrum of HRV serotypes. Altogether, these compounds represent alternative starting points to identify promising leads in our continual efforts to treat HRV infections.

Effect of environmental factor on some litter traits of sows in the tropics Mexican / Efecto de factores ambientales sobre algunas características de la camada de cerdas en el trópico de México

Objective. To determine the effect of environmental factors on litter traits at birth and weaning, and their repeatabilities in four farms in the sub-humid tropics of Mexico. Materials and methods. Data from 46.249 to 50.316 litters for litter size at birth (LSB), number of piglets born alive (NBA), litter weight at birth (LWB), number of piglets weaned (NPW) and litter weight at weaning (LWW) were used. The statistical model for LSB, NBA and LWB included the effects of farm, farrowing year, farrowing season, parity number, simple interactions, random effects of sow and the error term. NPW and LWW were analyzed using the previous model plus the linear and quadratic effects of lactation length (LL). Results. The means for LSB, NBA, LWB, NPW and LWW were 11.7 piglets, 11.0 piglets, 16.1 kg, 10.3 piglets and 61.3 kg, respectively. All effects in the model affected the litter traits. Farrowing year x season interaction was significant for NPW, LWB and LWW. The dry season had the highest LSB, NBA y NPW. First parity sows had higher LSB and NBA means than for second parity sows. Parity increase until parity 4 to decrease thereafter. LL had a quadratic effect on NPW and LWW. Repeatability estimates for LSB, NBA, and LWB were 0.12, 0.12 and 0.14, respectively. Conclusions. All traits studied were influenced by the environmental factors studied. Repeatabilities for LSB, NBA and LWB were low.

Objetivo. Determinar el efecto de factores ambientales sobre características de la camada al nacer y al destete, y sus repetibilidades en cuatro granjas en el trópico sub-húmedo de México. Materiales y métodos. Se utilizaron los datos de 50.316 a 46.249 camadas para el total de lechones nacidos (LSB), lechones nacidos vivos (NBA) y peso de la camada al nacimiento (LWB), lechones destetados (NPW) y peso de la camada al destete (LWW). El modelo estadístico para LSB, NBA y LWB incluyen los efectos de granja, año, época, número de parto, interacciones simples, efecto aleatorio de cerda y error. El modelo para NPW y LWW incluyó los factores anteriores y además, los efectos lineal y cuadrático de largo de lactación (LL). Resultados. Las medias para LSB, NBA, LWB, NPW y LWW fueron 11.7 lechones, 11.0 lechones, 16.1 kg, 10.3 lechones y 61.3 kg, respectivamente. Todos los factores estudiados afectaron las características de la camada. La interacción de año x época fue significativa para NPW, LWB y LWW. La época seca presentó las mayores medias de LSB, NBA y NPW. Las cerdas primer parto obtuvieron medias de LSB y NBA superiores que las cerdas del segundo parto. Las medias por número de parto incrementaron hasta el cuarto, para después disminuir. La LL obtuvo un efecto cuadrático sobre NPW y LWW. Las repetibilidades estimadas para LSB, NBA, y LWW fueron 0.12, 0.12 y 0.14, respectivamente. Conclusiones. Todos los factores ambientales estudiados afectaron las características de la camada al nacer y al destete. Las repetibilidades estimadas fueron bajas.

Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus.

HMGB1 is a pro-inflammatory cytokine that together with TNF-alpha and IL-1beta is involved in the pathogenesis of spontaneously occurring skin lesions in lupus erythematosus. The purpose of the present study was to explore the sequence of events in HMGB1, TNF-alpha and IL-1beta expression under development and resolution of experimentally induced CLE lesions. The study involved investigation of 38 serial skin biopsies acquired from photoprovoked skin lesions of nine CLE patients, using immunohistochemical staining of tissue sections. In biopsies from the clinically most active phase of skin involvement extracellular, secreted HMGB1 and increased cytoplasmic HMGB1 were found, as compared with the late and fading lesions or non-lesional skin. Besides HMGB1, increased expression of TNF-alpha and IL-1beta was observed in dermal infiltrates of the induced CLE lesions. These cytokines were however not upregulated in all lesions, and increased expression of IL-1beta was seen predominantly in late biopsies.In conclusion, extracellular and cytoplasmic HMGB1 coincides with the clinically most active phase of photoinduced lesions of cutaneous lupus, and suggests that HMGB1 is an important factor in the inflammatory autoimmune process of CLE. HMGB1 can induce expression of TNF-alpha and IL-1beta, and formation of a pro-inflammatory loop between HMGB1, TNF-alpha, and IL-1beta may be responsible for the prolonged and sustained inflammation in CLE.

Pre-clinical evaluation of a CEA DNA prime/protein boost vaccination strategy against colorectal cancer.

In preparation for a clinical trial in patients diagnosed with colorectal cancer, a vaccination strategy targeting the carcinoembryonic antigen (CEA) was evaluated in mice using a GMP-produced plasmid DNA vaccine, CEA66, encoding a truncated form of the tumour-associated antigen, CEA. The GMP-produced CEA DNA vaccine was also evaluated for toxicity. Repeated intradermal administration of the GMP-produced vaccine using a novel needle-free jet injection device (Biojector) induced robust CD4 and CD8 T-cell responses in mice, and did not result in any vaccine-related toxicity. In a heterologous DNA prime/protein boost setting, cellular immune responses were of higher magnitude in animals primed with CEA66 DNA than in animals receiving repeated doses of recombinant CEA protein. These responses were further enhanced if recombinant murine granulocyte-macrophage colony-stimulating factor was given as an adjuvant prior to vaccination. In contrast to repeated administration of recombinant CEA protein as a single modality vaccine, the heterologous CEA66 DNA prime/rCEA boost vaccination strategy resulted in a qualitatively broader immune response, and supports clinical testing of this vaccination regimen in humans.

Fine specificity of the Ro/SSA autoantibody response in relation to serological and clinical findings in 96 patients with self-reported cutaneous symptoms induced by the sun.

Anti-Ro/SSA assays assist the clinician in distinguishing autoimmune diseases such as Sjögrens syndrome (SS), systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE). The objective of the study was to investigate the fine specificity of the autoantibodies in relation to clinical presentation as well as environmental and endogenous factors such as photosensitivity, smoking and immunoglobulin (Ig) levels in patients with Ro/SSA autoantibodies. Serum samples from 96 anti-Ro/SSA positive photosensitive patients were tested for autoantibody levels by enzyme-linked immunosorbent assay (ELISA) using purified recombinant Ro52 kd, Ro60 kd and La proteins as antigens. The highest levels of anti-Ro52 and anti-La were observed in patients with primary SS, and the lowest levels of anti-Ro52 in chronic cutaneous lupus erythematosus (CCLE). SCLE patients with systemic disease (SLE and/or SS) showed higher levels of anti-Ro52 than SCLE limited to the skin. A correlation between high serum levels of IgG and anti-Ro52 (P < 0.01) and between IgA and anti-Ro52 (P < 0.05) and anti-Ro60 (P < 0.05) was found. Polymorphic light eruption (PLE) was common in all diagnostic groups but did not correlate with autoantibody levels. Smoking was more common in lupus patients than in SS patients. Our findings thus propose different mechanisms for different clinical presentations of Ro/SSA positive patients. The testing of anti-Ro52 antibodies might serve as a prognostic tool in photosensitive cutaneous diseases.

Concentration of nutrients from urine and reject water from anaerobically digested sludge.

Experiments with concentration of nutrients from source separated urine and reject water from digestion of sludge in sewage treatment plants (STP) have been performed in laboratory and pilot scale. The methods tested were membrane filtration with reverse osmosis (RO), evaporation, and precipitation of phosphorus and distillation of ammonia. In membrane filtration, pre-filtration with particle separation at 5-10 microm was enough to avoid clogging of the membranes. Separation of phosphorus (P), potassium (K) and sulphur (S) was almost 100%, while separation of nitrogen (N) was dependent on pH. The capacity of flux increased with temperature and pressure. In evaporation, all P, K and S were still in the concentrate, while pH had to be decreased to 4.5 to avoid significant loss of N. In precipitation and distillation, about 90% of P could be recovered from urine as magnesium ammonium phosphate (MAP) just by adding MgO. For the reject water pH was first increased by aeration to remove CO2. Ammonium can be distilled from the water phase after precipitation of MAP, without further increase of pH. At least 80-90% of N can be distilled in 5-10% of the total volume. The article also discusses the quality of different products, cost of separation, and energy and chemical demand.

Microsatellite markers for powdery mildew resistance in pea (Pisum sativum L.).

Powdery mildew is a common disease of field pea, Pisum sativum L., and is caused by the ascomycete fungus Erysiphe pisi. It can cause severe damage in areas where pea is cultivated. Today breeders want to develop new pea lines that are resistant to the disease. To make the breeding process more efficient, it is desirable to find genetic markers for use in a marker-assisted selection (MAS) strategy. In this study, microsatellites (SSR) were used to find markers linked to powdery mildew resistance. The resistant pea cultivar '955180' and the susceptible pea cultivar 'Majoret' were crossed and F2 plants were screened with SSR markers, using bulked segregant analysis. A total of 315 SSR markers were screened out of which five showed linkage to the powdery mildew resistance gene. No single marker was considered optimal for inclusion in a MAS program. Instead, two of the markers can be used in combination, which would result in only 1.6% incorrectly identified plants. Thus SSR markers can be successfully used in marker-assisted selection for powdery mildew resistance breeding in pea.

EP3 and EP4 receptor mRNA expression in peptidergic cell groups of the rat parabrachial nucleus.

This study examines the distribution of prostaglandin E2 receptors of subtype EP3 and EP4 among brain stem parabrachial neurons that were characterized with respect to their neuropeptide expression. By using a dual-labeling in situ hybridization method, we show that preprodynorphin mRNA expressing neurons in the dorsal and central lateral subnuclei express EP3 receptor mRNA. Such receptors are also expressed in preproenkephalin, calcitonin gene related peptide and preprotachykinin mRNA positive neurons in the external lateral subnucleus, whereas preprodynorphin mRNA expressing neurons in this subnucleus are EP receptor negative. In addition, EP3 receptor expression is seen among some enkephalinergic neurons in the Kölliker-Fuse nucleus. Neurons in the central part of the cholecystokininergic population in the regions of the superior lateral subnucleus express EP4 receptor mRNA, whereas those located more peripherally express EP3 receptors. Taken together with previous findings showing that discrete peptidergic cell groups mediate nociceptive and/or visceral afferent information to distinct brain stem and forebrain regions, the present results suggest that the processing of this information in the parabrachial nucleus is influenced by prostaglandin E2. Recent work has shown that prostaglandin E2 is released into the brain following peripheral immune challenge; hence, the parabrachial nucleus may be a region where humoral signaling of peripheral inflammatory events may interact with neuronal signaling elicited by the same peripheral processes.

Activation of prostanoid EP(3) and EP(4) receptor mRNA-expressing neurons in the rat parabrachial nucleus by intravenous injection of bacterial wall lipopolysaccharide.

Systemic inflammation activates central autonomic circuits, such as neurons in the pontine parabrachial nucleus. This activation may be the result of afferent signaling through the vagus nerve, but it may also depend on central prostaglandin-mediated mechanisms. Recently, we have shown that neurons in the parts of the parabrachial nucleus that are activated by immune challenge express prostaglandin receptors of the EP(3) and EP(4) subtypes, but it remains to be determined if the prostaglandin receptor-expressing neurons are identical to those that respond to immune stimuli. In the present study, bacterial wall lipopolysaccharide was injected intravenously in adult male rats and the expression of c-fos mRNA and of EP(3) and EP(4) receptor mRNA was examined with complementary RNA probes labeled with digoxigenin and radioisotopes, respectively. Large numbers of neurons in the external lateral parabrachial subnucleus, a major target of vagal-solitary tract efferents, expressed c-fos mRNA. Quantitative analysis showed that about 60% (range 40%-79%) of these neurons also expressed EP(3) receptor mRNA. Conversely, slightly more than 50% (range 48%-63%) of the EP(3) receptor-expressing neurons in the same subnucleus coexpressed c-fos mRNA. In contrast, few EP(4) receptor-expressing neurons were c-fos positive, with the exception of a small population located in the superior lateral and dorsal lateral subnuclei. These findings show that immune challenge activates central autonomic neurons that could be the target of centrally produced prostaglandin E(2), suggesting that synaptic signaling and paracrine mechanisms may interact on these neurons.

Structure of cytochrome c oxidase: a comparison of the bacterial and mitochondrial enzymes.

It has been almost 5 years since the first structures of cytochrome c oxidase, from Paracoccus denitrificans and bovine heart mitochondria, were revealed. Since then many different proton pumping mechanisms have been proposed for the enzyme; however, no definitive conclusion has been achieved. In this article, we revisit the original structures of bacterial and mitochondrial oxidases and try to clarify similarities as well as differences between the two structures.

Distribution of the EP3 prostaglandin E(2) receptor subtype in the rat brain: relationship to sites of interleukin-1-induced cellular responsiveness.

The activation of neurosecretory neurons that express corticotropin-releasing hormone (CRH) in response to increased circulating levels of interleukin-1beta (IL-1beta) depends on prostaglandin E(2) (PGE(2)) acting locally within the brain parenchyma. To identify potential central targets for PGE(2) relevant to pituitary-adrenal control, the distribution of mRNA encoding the PGE(2) receptor subtype EP3 (EP3R) was analyzed in rat brain. Hybridization histochemistry revealed prominent labeling of cells in discrete portions of the olfactory system, iso- and hippocampal cortices, and subcortical telencephalic structures in the septal region and amygdala. Labeling over the midline, intralaminar, and anterior thalamic groups was particularly prominent. EP3R expression was enriched in the median preoptic nucleus and adjoining aspects of the medial preoptic area (MPO) implicated in thermoregulatory/febrile responses and sleep induction. EP3R-expressing cells were also prominent in brainstem cell groups involved in nociceptive information processing/modulation (periaqueductal gray, locus coeruleus (LC), parabrachial nucleus (PB), caudal raphé nuclei), arousal and wakefulness (LC, midbrain raphé and tuberomammillary nuclei); and in conveying interoceptive input, including systemic IL-1 signals, to the endocrine hypothalamus (nucleus of the solitary tract (NTS) and rostral ventrolateral medulla [VLM]). Combined hybridization histochemical detection of EP3R mRNA with immunolocalization of IL-1beta-induced Fos protein expression identified cytokine-sensitive, EP3R-positive cells in the medial NTS, rostral VLM, and, to a lesser extent, aspects of the MPO. These findings are consistent with the view that increased circulating IL-1 may stimulate central neural mechanisms, including hypothalamic CRH neurons, through an EP3R-dependent mechanism involving PGE(2)-mediated activation of cells in the caudal medulla and/or preoptic region.

The structure of the ubiquinol oxidase from Escherichia coli and its ubiquinone binding site.

Cell respiration is catalyzed by the heme-copper oxidase superfamily of enzymes, which comprises cytochrome c and ubiquinol oxidases. These membrane proteins utilize different electron donors through dissimilar access mechanisms. We report here the first structure of a ubiquinol oxidase, cytochrome bo3, from Escherichia coli. The overall structure of the enzyme is similar to those of cytochrome c oxidases; however, the membrane-spanning region of subunit I contains a cluster of polar residues exposed to the interior of the lipid bilayer that is not present in the cytochrome c oxidase. Mutagenesis studies on these residues strongly suggest that this region forms a quinone binding site. A sequence comparison of this region with known quinone binding sites in other membrane proteins shows remarkable similarities. In light of these findings we suggest specific roles for these polar residues in electron and proton transfer in ubiquinol oxidase.

Proton-coupled structural changes upon binding of carbon monoxide to cytochrome cd1: a combined flash photolysis and X-ray crystallography study.

We have investigated dynamic events after flash photolysis of CO from reduced cytochrome cd(1) nitrite reductase (NiR) from Paracoccus pantotrophus (formerly Thiosphaera pantotropha). Upon pulsed illumination of the cytochrome cd(1)-CO complex, at 460 nm, a rapid (<50 ns) absorbance change, attributed to dissociation of CO, was observed. This was followed by a biphasic rearrangement with rate constants of 1.7 x 10(4) and 2.5 x 10(3) s(-1) at pH 8.0. Both parts of the biphasic rearrangement phases displayed the same kinetic difference spectrum in the region of 400-660 nm. The slower of the two processes was accompanied by proton uptake from solution (0.5 proton per active site at pH 7.5-8.5). After photodissociation, the CO ligand recombined at a rate of 12 s(-1) (at 1 mM CO and pH 8.0), accompanied by proton release. The crystal structure of reduced cytochrome cd(1) in complex with CO was determined to a resolution of 1.57 A. The structure shows that CO binds to the iron of the d(1) heme in the active site. The ligation of the c heme is unchanged in the complex. A comparison of the structures of the reduced, unligated NiR and the NiR-CO complex indicates changes in the puckering of the d(1) heme as well as rearrangements in the hydrogen-bonding network and solvent organization in the substrate binding pocket at the d(1) heme. Since the CO ligand binds to heme d(1) and there are structural changes in the d(1) pocket upon CO binding, it is likely that the proton uptake or release observed after flash-induced CO dissociation is due to changes of the protonation state of groups in the active site. Such proton-coupled structural changes associated with ligand binding are likely to affect the redox potential of heme d(1) and may regulate the internal electron transfer from heme c to heme d(1).