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.

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.

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.

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.

Factors determining electron-transfer rates in cytochrome c oxidase: investigation of the oxygen reaction in the R. sphaeroides enzyme.

We have investigated the kinetics of the single-turnover reaction of fully reduced solubilised cytochrome c oxidase (cytochrome aa3) from Rhodobacter sphaeroides with dioxygen using the flow-flash methodology and compared the results to those obtained with the well-characterised bovine mitochondrial enzyme. The overall reaction sequence was the same in the two enzymes, but the extents and rates of the electron-transfer reactions differed, implying differences in redox potentials, and/or interaction energies between electrons and protons during oxygen reduction. As with the bovine enzyme, the R. sphaeroides enzyme displayed two major kinetic phases of proton uptake with rate constants of approximately 5000 s-1 and approximately 500 s-1 at pH 7.9, concomitant with the peroxy to oxoferryl and oxoferryl to oxidised states. The net number of protons taken up in the R. sphaeroides enzyme was about approximately 1.9, which implies that upon reduction, the enzyme has to pick up approximately 2.1 H+ from the medium. On the basis of the comparison of electron-transfer reactions in the two enzymes, we conclude that the transfer rate of the fourth electron to the binuclear centre is not only determined by the electron-transfer rate from haem a to the binuclear centre, but also by the electron equilibrium between CuA and haem a. In addition, in contrast to the bovine enzyme, where the electron- and proton-transfer rates during oxidation of the fully reduced enzyme by O2 are all faster than the overall turnover rate, in the R. sphaeroides enzyme, the slowest kinetic phase was rate limiting for the overall turnover. Moreover, the comparison of the reactions in the two systems shows that in the R. sphaeroides enzyme, the electrons are more evenly distributed among the redox centres during oxygen reduction. This enables investigations of effects also of minor perturbations on, e.g., the electron-transfer characteristics in mutant enzymes, for which this study forms the basis.

Electron-proton interactions in terminal oxidases.

The cytochrome c and ubiquinol oxidases discussed in this article are membrane-bound redox-driven proton pumps which couple an electron current to a proton current across the membrane. This coupling requires a control of the thermodynamics and/or rates of internal electron- and proton-transfer reactions (termed 'gating'). Therefore, to understand the structure-function relation of these proton pumps, individual electron- and proton-transfer reactions must be investigated. We have undertaken such studies by using a combination of site-directed mutagenesis and spectroscopic techniques. The results show that proton uptake/release upon reduction/oxidation of heme a3 takes place on a ms-time scale through the K-pathway (including Thr(I-359) and Lys(I-362)), but not through the D-pathway (including Asp(I-132) and Glu(I-286)). During reaction of the reduced enzyme with O2, both substrate and pumped protons are taken up through the D-pathway (but not through the K-pathway) in a biphasic process with time constants of 100 microseconds and 1 ms. Thus, the original assignment of the role of the D-pathway (used only for pumped protons) must be revised. Dynamic studies of proton uptake to the enzyme surface show that on the proton-input side, the surface carries a proton-collecting antenna made of carboxylate and histidine residues which enable the enzyme to pick up protons with a rate compatible to the enzyme turnover rate. These results are consistent with the three-dimensional cytochrome c oxidase structure which shows that the entry point to the D-pathway (but not to the K-pathway) is surrounded by a network of histidine residues within a negative electrostatic potential.

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.

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.

Luteal phase deficiency: characterization of reproductive hormones over the menstrual cycle.

The recurrent deficiency of progesterone (P) secretion by the corpus luteum has been associated with infertility and habitual abortion and given the clinical diagnosis of luteal phase deficiency (LPD). There is evidence that both follicular and luteal phase abnormalities can result in LPD cycles. In this study we have examined reproductive hormone levels and preovulatory follicular size in women with LPD (n = 10). For the purposes of this study, LPD was determined by an endometrial biopsy in the studied cycle that was more than 2 days out of phase. These biopsies were performed in women with infertility or habitual abortion who exhibited an out of phase biopsy in a prior cycle. The control group consisted of 28 normal women. Daily serum levels of the following hormones were determined in each subject: LH and FSH [immuno- and bioactive (LH-immuno and LH-bio)], P, estradiol (E2), and inhibin. The LPD women exhibited significant decreases in integrated luteal phase levels of inhibin [10,615 +/- 898 vs. 13,560 +/- 662 (U/L).days; P less than 0.02] and E2 [5,015 +/- 275 vs. 6,435 +/- 393 (pmol/L).days (1366 vs. 1753 (pg/mL).days); P less than 0.05] in addition to the expected decrease in P [280 +/- 23 vs. 420 +/- 23 (nmol/L).days (88 vs. 132 (ng/mL).days); P less than 0.01]. On days 6-11 after the LH surge (day 0), there was a significant (P less than 0.05) decrease in mean LH-bio levels in LPD compared with those in normal women (146 +/- 26 vs. 212 +/- 24 micrograms/L). The midcycle LH surge was deficient in LPD when both LH-immuno [482 +/- 30 vs. 672 +/- 43 (micrograms/L).days; P less than 0.01] and LH-bio [1711 +/- 179 vs. 2248 +/- 226 (micrograms/L).days; P less than 0.05] levels were compared with normal values. When comparing the follicular phase in LPD with that in normal women, similar follicle size, peak and integrated E2 levels, and mean LH and FSH (immuno and bio) levels were found. The only follicular phase abnormality noted in this study was decreased mean levels of serum inhibin in the early and midfollicular phases (221 +/- 19 vs. 308 +/- 25 U/L; P less than 0.01). In this group of women with LPD, low levels of inhibin in the follicular phase were consistent with the concept of a defect in function of the preovulatory follicle, possibly as a result of previously described defects in gonadotropin secretion in this condition.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.

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.

Stage I vulvar cancer: criteria for microinvasion.

Thirty-eight women with stage I epidermoid carcinoma of the vulva were studied retrospectively in an attempt to define the criteria for conservative therapy in early invasive vulvar cancer. Among the 38 women, 23 met the 6 criteria established for early invasive carcinoma of the vulva. In those 23 women, there were no nodal metastases. Depth of stromal invasion correlated strongly with the degree of tumor differentiation and the presence of carcinoma in situ (CIS). Stromal invasion less than 3 mm and presence of CIS were predictive of no involvement of the lymph nodes or endothelial-like space.

Glassy cell carcinoma of the cervix redefined.

Glassy cell carcinoma of the cervix has been classically regarded as a poorly differentiated adenosquamous carcinoma, infrequently diagnosed and associated with a poor outcome regardless of the modality of therapy. The histologic characteristics associated with this lesion are also frequently encountered among undifferentiated large-cell, nonkeratinizing cervical carcinomas. In a review of all undifferentiated large-cell carcinomas of the cervix encountered at the University Hospital in Seattle, Washington, over an eight-year period, 29 cases appeared to display the characteristic histologic criteria described as typical for glassy cell carcinoma. All cases were stage Ib lesions, and 28 were treated by radical hysterectomy. The mean age was ten years younger than that of the usual patient treated at this institution with stage I carcinoma. Fourteen of these patients (45%) have developed recurrent carcinoma, and in all but one, the interval to recurrence was less than eight months. Only two have survived after second-line salvage therapy. The current survival rate among the 29 women is 55%. These observations suggest that the poor prognosis ascribed to the classically defined glassy cell carcinoma also holds true for this extended group of large-cell, undifferentiated cervical cancers that display similar histologic features and pursue a similarly aggressive clinical course.

Distribution of prostaglandin EP(3) and EP(4) receptor mRNA in the rat parabrachial nucleus.

By using in situ hybridization, the distribution of mRNA for the PGE(2) receptors EP(3) and EP(4) was examined in the rat parabrachial nucleus (PB), a major brain stem relay for autonomic and nociceptive processing. EP(3) receptor mRNA was present in most subnuclei, with the densest labeling in the external lateral, dorsal lateral, superior lateral, central lateral and Kölliker-Fuse nuclei. EP(4) receptor mRNA expressing cells had a more restricted distribution, largely being confined to the superior lateral and adjacent parts of the dorsal and central lateral nuclei in a pattern complementary to that for EP(3) receptor mRNA. These findings suggest that EP(3) and EP(4) receptors in PB have distinct functional roles that include nociceptive processing, blood pressure regulation and feeding behavior.

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.