Outbreak of Cryptosporidium hominis in northern Sweden: persisting symptoms in a 5-year follow-up.

In 2010-2011, a waterborne outbreak of the parasite, Cryptosporidium hominis, affected approximately 27,000 inhabitants in the city of Östersund, Sweden. Previous research suggested that post-infectious symptoms, such as gastrointestinal symptoms and joint pain, could persist for up to 2 years after the initial infection. In this study, we investigated whether the parasite caused post-infectious sequelae for up to 5 years after the outbreak. Prospective cohort study. A randomly selected cohort of individuals residing in Östersund at the time of the outbreak was sent a postal questionnaire in 2011. Responders were sent a follow-up questionnaire in 2016 and completed items on whether they experienced a list of symptoms. We examined whether outbreak cases were more likely than non-cases to report post-infectious symptoms 5 years later. We analysed data using logistic regression and calculated odds ratios with 95% confidence intervals. The analysis included 626 individuals. Among the 262 individuals infected during the outbreak, 56.5% reported symptoms at follow-up. Compared to non-cases, outbreak cases were more likely to report watery diarrhoea, diarrhoea, swollen joints, abdominal pain, bloating, joint discomfort, acid indigestion, alternating bowel habits, joint pain, ocular pain, nausea, and fatigue at the follow-up, after adjusting for age and sex. Our findings suggested that cryptosporidiosis was mainly associated with gastrointestinal- and joint-related post-infectious symptoms for up to 5 years after the infection.

Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients.

BACKGROUND: Sublingual immunotherapy (SLIT) applied to type I respiratory allergies is commonly performed with natural allergen extracts. Herein, we developed a sublingual tablet made of pharmaceutical-grade recombinant Bet v 1.0101 (rBet v 1) and investigated its clinical safety and efficacy in birch pollen (BP)-allergic patients. METHODS: Following expression in Escherichia coli and purification, rBet v 1 was characterized using chromatography, capillary electrophoresis, circular dichroism, mass spectrometry and crystallography. Safety and efficacy of rBet v 1 formulated as a sublingual tablet were assessed in a multicentre, double-blind, placebo-controlled study conducted in 483 patients with BP-induced rhinoconjunctivitis. RESULTS: In-depth characterization confirmed the intact product structure and high purity of GMP-grade rBet v 1. The crystal structure resolved at 1.2 Å documented the natural conformation of the molecule. Native or oxidized forms of rBet v 1 did not induce the production of any proinflammatory cytokine by blood dendritic cells or mononuclear cells. Bet v 1 tablets were well tolerated by patients, consistent with the known safety profile of SLIT. The average adjusted symptom scores were significantly decreased relative to placebo in patients receiving once daily for 5 months rBet v 1 tablets, with a mean difference of 17.0-17.7% relative to the group treated with placebo (P < 0.025), without any influence of the dose in the range (12.5-50 µg) tested. CONCLUSION: Recombinant Bet v 1 has been produced as a well-characterized pharmaceutical-grade biological drug. Sublingual administration of rBet v 1 tablets is safe and efficacious in patients with BP allergic rhinoconjunctivitis.

The Trojan-horse mechanism: How networks reduce gender segregation.

The segregation of labor markets along ethnic and gender lines is socially highly consequential, and the social science literature has long viewed homophily and network-based job recruitments as some of its most crucial drivers. Here, we focus on a previously unidentified mechanism, the Trojan-horse mechanism, which, in contradiction to the main tenet of previous research, suggests that network-based recruitment reduce rather than increase segregation levels. We identify the conditions under which networks are desegregating, and using unique data on all individuals and all workplaces located in the Stockholm region during the years 2000-2017, we find strong empirical evidence for the Trojan-horse mechanism and its role in the gender segregation of labor markets.

A double-blind placebo-controlled birch allergy vaccination study II: correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation.

BACKGROUND: The pathogenesis of IgE-mediated allergic disease is closely related to the production of T-helper type 2 (Th2) cytokines, which lead to IgE production pivotal for activation of mast cells and basophils. Proliferating T cells along with eosinophils expanded and attracted by Th2 cytokines are major contributors to the late-phase reaction. The activation of these Th2 cells is strongly enhanced by CD23-mediated IgE facilitated allergen presentation (FAP). OBJECTIVE: The present study aims to investigate the effect of specific immunotherapy (SIT)-induced allergen-specific non-IgE antibodies (blocking antibodies) on IgE binding to allergen, histamine release (HR) and CD23-mediated allergen uptake in antigen-presenting cells. METHODS: Competition between IgE and non-IgE for allergen binding was studied by Advia Centaur antibody measurements, passively sensitized basophils were used to study HR and IgE-facilitated binding of allergen to B cells (FAP) was studied by flow cytometry. FAP measurements were performed both with and without the addition of a reference IgE serum, which was included to obtain optimal complex formation. The serum samples were obtained from birch pollen immunotherapy (n=21) or placebo control patients (n=21) before and after 1 and 2 years of treatment. RESULTS: Statistically significant reduction of all parameters investigated was observed after 1 year of treatment and the effect was maintained during the second year of treatment. There was a clear correlation between the two FAP measurements and between each of them and the level of T cell activation reported upon previously. Moreover, strong correlations were found between changes in FAP, IgE binding and HR. CONCLUSION: The present study clearly demonstrates that SIT induces changes in the composition of serum antibodies that inhibit IgE binding, HR and FAP to a similar extent. This suggests that these measurements, individually or in combination, may be used to monitor the immunological effect of SIT, even though direct correlations to changes in clinical parameters could not be demonstrated.

Effect of mobile laminar airflow units on airborne bacterial contamination during neurosurgical procedures.

BACKGROUND: Surgical site infections (SSIs) after neurosurgery are potentially life-threatening and entail great costs. SSIs may occur from airborne bacteria in the operating room, and ultraclean air is desired during infection-prone cleaning procedures. Door openings and the number of persons present in the operating room affect the air quality. Mobile laminar airflow (MLAF) units, with horizontal laminar airflow, have previously been shown to reduce airborne bacterial contamination. AIM: To assess the effect of MLAF units on airborne bacterial contamination during neurosurgical procedures. METHODS: In a quasi-experimental design, bacteria-carrying particles (colony-forming units: cfu) during neurosurgical procedures were measured with active air-sampling in operating rooms with conventional turbulent ventilation, and with additional MLAF units. The MLAF units were shifted between operating rooms monthly. Colony-forming unit count and bacterial species detection were conducted after incubation. Data was collected for a period of 18 months. FINDINGS: A total of 233 samples were collected during 45 neurosurgical procedures. The use of MLAF units significantly reduced the numbers of cfu in the surgical site area (P < 0.001) and above the instrument table (P < 0.001). Logistic regression showed that the only significant predictor affecting cfu count was the use of MLAF units (odds ratio: 41.6; 95% confidence interval: 11.3-152.8; P < 0.001). The most frequently detected bacteria were coagulase-negative staphylococci. CONCLUSION: MLAF successfully reduces cfu during neurosurgery to ultraclean air levels. MLAF units are valuable when the main operating room ventilation system is unable to produce ultraclean air in infection-prone clean neurosurgery.

NURR1 mutations in cases of schizophrenia and manic-depressive disorder.

Transgenic mice lacking the nuclear orphan transcription factor Nur-related receptor 1 (Nurr1) fail to develop mesencephalic dopamine neurons. There is a highly homologous NURR1 gene in humans (formerly known as NOT) which therefore constitutes a good candidate gene for neurologic and psychiatric disorders with an involvement of the dopamine neuron system, such as Parkinson's disease, schizophrenia, and manic-depression. By direct sequencing of genomic DNA, we found two different missense mutations in the third exon of NURR1 in two schizophrenic patients and another missense mutation in the same exon in an individual with manic-depressive disorder. All three mutations caused a similar reduction of in vitro transcriptional activity of NURR1 dimers of about 30-40%. Neither of these amino acid changes, nor any sequence changes whatsoever, were found in patients with Parkinson's disease or control DNA material of normal populations. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:808-813, 2000.

Asthma and asthma-like disorder, a 5-year follow-up study.

Consecutive adult patients (n = 70) referred for investigation of suspected asthma were reinvestigated after 5 years with the same diagnostic procedures (airway symptom score, spirometry, methacholine test) as used at the initial investigation. The same diagnostic criteria for asthma, asthma-like disorder (current asthma-like symptoms but negative asthmatests)and chronicobstructive pulmonary disease (COPD) were used at both visits. At the first visit 39/70 patients (56%) fulfilled the asthma criteria, 21/70 (27%) fulfilled the asthma-like criteria and 5/70 (7%) the COPD criteria. Due to lack of current symptoms 5/70 (7%) could not be classified. 5/70 patients (7%) were smokers, however, in the majority (72%) smoke was not tolerated as it induced asthma-like symptoms. At the investigation, 5 years later, 30/39 patients (76%) still fulfilled the asthma criteria and 12/21 patients (57%) still fulfilled the asthma-like criteria. At the 5-year investigation, 10% of patients in the asthma group now fulfilled the asthma-like criteria and 10% of patients in the asthma-like group fulfilled the asthma criteria. It is concluded that asthma as well an asthma-like syndrome may persist for 5 years or more. It is also concluded thatthe two disorders are closely related as patients in the asthma group over time could move into the diagnostic criteria ofthe asthma-like disorder and vice versa.

Exercise-induced respiratory symptoms are not always asthma.

Eighty-eight patients with a history of exercise-induced respiratory symptoms performed a maximal exercise test in order to study the reasons for stopping the test. There was a wide range of percentage maximal fall in peak expiratory flow (PEF), from minus 3% to 63%, mean 11%, recorded 0-30 min, mean 12 min after the break. In the controls the maximal decrease was 0-16%, mean 6%. Diagnostic criteria for asthma were fulfilled by 48 patients (55%). Of these patients 42% had a fall in PEF > or = 15% (exercise-induced asthma). Of the non-asthma patients 10% had a fall > or = 15%. The most common reason for stopping the exercise in the asthma group was breathing troubles (46%), the most common reason in the non-asthma group was chest pain/discomfort (35%). In about 20% of the patients dizziness and/or pricking sensations in arms or legs indicated hyperventilation as an additional reason for stopping the exercise. It is concluded that other kinds of reaction, than bronchial obstruction such as breathing troubles not directly related to bronchial obstruction and chest pain, may be important factors that can restrict physical capacity in patients with exercise-induced respiratory symptoms.

Stroop and mood/memory measures in the study of unconscious "oneness".

Adaptive behavior following subliminal stimulation with "Mommy and I are One" (MIO) is a poorly understood finding. Positive mood may explain adaptive behavior, but we replicated an earlier finding that effects can also include negative mood. Color naming in a Stroop paradigm was slower on "symbiosis" words (Cohen's d = .19 to .56). Perhaps a "oneness" structure if primed has different affective correlates in different participants.

Early and late phase asthmatic response in lower airways of cat-allergic asthmatic patients--a comparison between experimental and environmental allergen challenge.

BACKGROUND: Standardized experimental allergen challenges are usually adopted to investigate the effect of allergen exposure on the lower airways. Environmental (natural) allergen challenges are used less often, mainly because of difficulties in standardizing the method, safety reasons and costs. The aim of this study was to investigate the relationship between an experimental and an environmental bronchial challenge. For this reason a natural challenge model was developed. METHODS: Sixty-two patients with a history of cat allergen-induced symptoms involving the lower airways, positive skin prick test, positive in vitro specific IgE to cat allergen and bronchial hyper-responsiveness were included. All 62 patients underwent an experimental challenge in the laboratory followed by an environmental allergen challenge. RESULTS: All 62 patients developed an early asthmatic response [>or=20% fall in forced expiratory volume in 1 s (FEV1)] in the experimental challenge and 60% (37/62) during the environmental challenge. A late asthmatic response (>or=15% fall in FEV1 within 3-24 h) was seen in 56% (35/62) of the patients after the experimental challenge. Following the environmental challenge 47% (29/62) of the patients developed a late response. Thirty-four per cent (21/62) of the patients developed a late response in both challenge models and 31% (19/62) did not develop a late response in any model. Thus, there was consistency in 65% (40/62) of the patients in both challenge models. CONCLUSION: We found consistency in the pattern of response to inhaled allergen between the two challenge models and we believe that experimental bronchial challenge is likely to reflect the development of relevant inflammation in the lower airways after low-dose allergen exposure in the environment.

Musculoskeletal disorders among female and male air traffic controllers performing identical and demanding computer work.

Operators with identical, demanding computer work (90 female and 97 male air traffic controllers) were found to have high prevalences of disorders (assessed by questionnaire and physical examination) in neck, shoulders and upper back. In spite of the identical work, the women displayed higher prevalences than the men (e.g. neck diagnoses 21% vs. 4%). Disorders in elbows, wrists and hands were less common, with similar rates in both genders. Generally, the psychosocial work environment (assessed by questionnaire) was found to be good, but with large inter-individual variation. Women experienced lower decision latitude than men, particularly regarding influence and freedom at work, but perceived higher social support. Physically, the work was characterized by relatively low angular velocities of upper arms (measured by inclinometry) and wrists (right: < 1 degrees/s during 19% of time, measuring by goniometry), dynamic muscular activities and high time fractions of rest in the trapezius and forearm extensor muscles (measuring by electromyography). There were only minor differences between the genders.

Far-field timing effects with passively Q-switched lasers.

Pulse-timing effects in the far field of a passively Q -switched microchip laser that are caused by the changing cavity mode during pulse emission are described. Measurements are performed on a passively Q -switched Nd:YAG laser that produces 3-ns pulses, and delays in pulse arrival times of up to ~270 ps are observed between the center and the off-axis position. The measured data agree well with a simple analytical model. Pulse delays of this order are important, for instance, in high-precision range-finding applications.

Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study.

BACKGROUND: Few placebo-controlled studies have examined the effect of allergen specific immunotherapy (SIT) on early and late phase asthmatic reactions. In this placebo-controlled study we have investigated the effect of 1 year of SIT with standardized birch pollen extract on early and late phase asthmatic reactions in adult asthmatic patients. METHODS: Nineteen patients with a history of birch-pollen-induced seasonal symptoms from upper and lower airways, positive skin prick test and in vitro specific immunoglobulin E to birch pollen extract were included. Allergen and methacholine bronchial challenges were performed and blood samples obtained for analyses of total eosinophil count and eosinophil cationic protein (ECP) in serum, before and after 1 year of immunotherapy treatment. RESULTS: All patients developed early and 16 of 19 both early and late phase asthmatic reactions. A significant increase in allergen dose was required to evoke early asthmatic reaction in the immunotherapy group (P < 0.01) after 1 year of treatment. The difference between the groups was significant (P < 0.01). Also the size of late asthmatic reaction was significantly reduced in the SIT group compared with placebo treated patients (P < 0.01). Twenty-four hours after allergen challenge methacholine sensitivity, number of total eosinophils and ECP increased significantly in the placebo (P < 0.02, P < 0.05 and P < 0.05 respectively), but not in the SIT group. CONCLUSION: Allergen SIT with standardized birch pollen extract decreased early and late asthmatic responses following bronchial challenge in pollen allergic patients, thus confirming anti-inflammatory effect of the treatment.

Evaluation of volume selection methods in in vivo MRS. Design of a new test phantom.

In vivo MR spectroscopy (MRS) requires some kind of volume selection method to be able to measure the signal from a selected part of the body. To be able to interpret the spectra correctly, the quality of the volume selection must be investigated for each new MRS application using phantom measurements. A new phantom, especially suitable for precision measurements of the volume selection performance, is presented. It contains a small, remotely controlled signal source placed inside a larger vessel. This principle can be applied to various body regions, coil types and nuclei. The measurement conditions are close to the clinical situation. The phantom does not have to be repositioned during a signal profile measurement and the signal contribution from each point along the profile is determined regarding sign and amplitude.

Posterolateral lumbar fusion. Outcome of 71 consecutive operations after 4 (2-7) years.

We report the outcome of 71 consecutive posterolateral lumbar fusions without spinal instrumentation. The indication for the operation was spondylolysis-olisthesis, degenerative disc disease/facet joint arthrosis, or pain after prior laminectomy. Concerning pain relief, 29/43 patients with spondylolysis-olisthesis were classified as good. The corresponding figures in the group with degenerative disc disease and/or facet joint arthrosis were 8/16 patients and in the group with pain post-laminectomy, 6/12 patients. No surgical complications were noted. In the total material 54 patients had a solid fusion, as defined by radiographic osseous trabecular bridging at all intended levels. One-level fusions tended to heal solidly in a higher frequency than two-level fusions. For the spondylolysis-olisthesis group, healed fusion correlated with a good clinical result. Such a correlation could not be verified for the other diagnostic groups. We conclude that non-instrumented posterolateral lumbar fusion is a valid method for treating low-grade spondylolysis-olisthesis, especially when the aim is to fuse a single level. Improved patient selection methods are required in fusion for degenerative disc disease and pain after laminectomy.

The effect of specific immunotherapy on the expression of costimulatory molecules in late phase reaction of the skin in allergic patients.

BACKGROUND: Specific immunotherapy (SIT) modulates immune responses to allergens resulting in improvement of allergic symptoms. However, the mechanisms behind the clinical changes are not clear. Participation of costimulatory molecules on antigen-presenting cells and T cells in the process of antigen recognition is suggested to be of essential importance. The SIT effect on expression of costimulatory molecules has not been earlier examined. METHODS: Forty-one birch-allergic patients were treated with SIT or placebo. After 1 year of treatment skin biopsies were obtained 24 h following allergen challenge. Sections were stained with antibodies against: EG2 (eosinophils), CD4 (T cells), CD68 (macrophages), CD1a (Langerhans cells), CD28 (on T cells) and costimulatory molecules (CD80, CD86). RESULTS: Following allergen challenge number of the CD4(+) and CD68(+) cells increased significantly (P=0.002, 0.0001, respectively) in the placebo, but not in the SIT-treated patients. The difference between groups was significant (P=0.003, 0.01, respectively). The numbers of EG2(+) cells increased significantly in both groups. CD80(+) cell numbers increased in the placebo (P=0.01) but not in the SIT group. The number of CD86(+) cells increased in both groups (placebo, P=0.001; SIT, P=0.01) but significantly less in the SIT group (P=0.05). The numbers of CD28(+) cells increased in the placebo (P=0.001) but remained unchanged in the SIT group. The difference between the groups was significant (P=0.05). CONCLUSION: There were lower numbers of cells expressing costimulatory molecules in SIT-treated than in placebo-treated patients. Decreased costimulation may lead to diminished immune response following allergen exposure. This could be an important factor contributing to the clinical improvement after SIT.

Activity of the Nurr1 carboxyl-terminal domain depends on cell type and integrity of the activation function 2.

Nurr1, a member of the nuclear hormone receptor superfamily, was recently demonstrated to be of critical importance in the developing central nervous system, where it is required for the generation of midbrain dopamine cells. Nuclear receptors encompass a transcriptional activation function (activation function 2; AF2) within their carboxyl-terminal domains important for ligand-induced transcriptional activation. Since a Nurr1 ligand remains to be identified, the role of the Nurr1 AF2 region in transcriptional activation is unclear. However, here we show that the Nurr1 AF2 contributes to constitutive activation independent of exogenously added ligands in human embryo kidney 293 cells and in neural cell lines. Extensive mutagenesis indicated a crucial role of the AF2 core region for transactivation but also identified unique features differing from previously characterized receptors. In addition, Nurr1 did not appear to interact with, and was not stimulated by, several previously identified coactivators such as the steroid receptor coactivator 1. In contrast, adenovirus protein E1A, stably expressed in 293 cells, was shown to contribute to AF2-dependent activation. Finally, while the AF2 core of RXR is required for ligand-induced transcriptional activation by Nurr1-RXR heterodimers, the functional integrity of Nurr1 AF2 core is not critical. These results establish that the ligand binding domain of Nurr1 has intrinsic capacity for transcriptional activation depending on cell type and mode of DNA binding. Furthermore, these results are consistent with the possibility that gene expression in the central nervous system can be modulated by an as yet unidentified ligand interacting with the ligand binding domain of Nurr1.

Fate of mesencephalic AHD2-expressing dopamine progenitor cells in NURR1 mutant mice.

The orphan nuclear receptor NURR1 was previously demonstrated to be required for the generation of mesencephalic dopamine (DA) cells. However, even in the absence of NURR1, which is normally expressed as cells become postmitotic, neuronal differentiation is induced and expression of several genes detected in developing dopamine cells appears normal during early stages of development. These include the homeobox transcription factors engrailed and Ptx-3 as well as aldehyde dehydrogenase 2, here defined as the earliest marker identified in developing DA cells, expressed already in mitotic DA progenitors. We have used the expression of these dopaminergic markers, retrograde axonal tracing, and apoptosis analyses to study the fate of the DA progenitor cells in the absence of NURR1. We conclude that NURR1 plays a critical role in the maturation, migration, striatal target area innervation, and survival of differentiating mesencephalic DA cells.

A double-blind, placebo-controlled birch allergy vaccination study: inhibition of CD23-mediated serum-immunoglobulin E-facilitated allergen presentation.

BACKGROUND: The clinical efficacy of specific allergy vaccination (SAV), previously called specific immunotherapy is well documented. The working mechanism of this treatment is not completely known at present. Allergen-specific CD4+ T lymphocytes are activated at extremely low allergen concentrations in vivo possibly as a result of serum IgE-facilitated allergen presentation (S-FAP). Previously, we have shown that this process can be inhibited by long-term birch SAV sera. METHODS: In the present study, we have analysed sera from birch-allergic patients in a randomized double-blind, placebo-controlled clinical trial for their ability to mediate S-FAP. Birch-specific IgE levels were not changed after SAV. Bet v 1-specific IgE levels, however, were significantly decreased (P<0.05) and Bet v 1-specific IgG4 levels were strongly increased after SAV (P<0.001). None of these changes were observed in the placebo group. When the sera were tested for their ability to induce S-FAP, a complete abrogation of this effect was noted in the sera from patients receiving active treatment (P<0.001), but not in the control group. This inhibition of S-FAP seemed to be associated with the reduction in the ratio between Bet v 1-specific IgE and IgG4 antibodies in serum, but a clear correlation could not be demonstrated. CONCLUSION: In conclusion, the present study clearly shows that SAV leads to an inhibition of the S-FAP needed to obtain optimal T cell activation at the low allergen concentrations present in vivo. This novel mechanism may explain the increased allergen threshold levels found in allergen provocation tests and the reduction of late-phase reactions observed after SAV.

Haplotypes of the interleukin-4 receptor alpha chain gene associate with susceptibility to and severity of atopic asthma.

BACKGROUND: Development of asthma is likely to depend on a complex interaction between environmental and genetic factors. Several groups have suggested the gene of the IL-4 receptor alpha chain (IL4R) as a candidate gene for the development of asthma, although association with single polymorphisms has shown contradicting results. OBJECTIVE: We chose to analyse IL4R gene haplotypes and assess their possible relevance in susceptibility to asthma and to certain clinical phenotypes. METHODS: IL4R gene haplotypes were analysed, based on the three markers C-3223T, Q551R and I50V, using the expectation-maximization algorithm, in 170 atopic asthma patients and 350 controls, all adult Swedish Caucasians. RESULTS: Our data showed significantly higher levels of soluble IL-4R (sIL-4R) in asthma patients compared with controls (P<0.0001). Furthermore, we showed a significant association between the IL4R haplotype containing the alleles T-3223, V50 and R551 (TVR) of the IL4R gene, and susceptibility to atopic asthma, with a frequency of 6.5% in the patients compared with 1% in the controls (P<0.0005). A subgroup of patients with heterozygous or homozygous state for the T-3223, V50 and R551 alleles, also had lower levels of sIL-4R in their circulation compared with patients with homozygous state in the C-3223, I50 and Q551 alleles (P<0.05) and showed less severe asthma according to lung function test (P<0.05). Analysis of single markers showed the T-3223 IL4R allele to associate with lower serum levels of sIL-4 receptor (P<0.0001) and patients carrying the T allele also had more symptoms of active asthma (wheezing, P<0.01; coughing, P<0.05 and breathing difficulties, P<0.01). CONCLUSION: Our data suggest that asthmatic patients with low levels of sIL-4 receptor may represent a genetically distinct subgroup of atopic asthma. TVR haplotype analyses confirm the importance of IL4R as a candidate gene for susceptibility to asthma. This finding may have implications for the understanding of the pathogenesis of asthma and possibly for the development of more specific therapies.