Genotype by environment interaction for female fertility traits under conventional and organic production systems in Danish Holsteins.

Conventional and organic production systems mainly differ in feeding strategies, outdoor and pasture access, and the use of antibiotic treatments. These environmental differences could lead to a genotype by environment interaction (G × E) and a requirement for including G × E in breeding decisions. The objectives of this study were to estimate variance components and heritabilities for conventional and organic production systems and investigate G × E under these 2 production systems for female fertility traits in Danish Holsteins. The analyzed traits included the interval from calving to first insemination (ICF), the interval from first to last insemination, number of inseminations per conception (NINS), and non-return rate within 56 d after the first insemination. Records of female fertility in heifers and the first 3 lactations in cows as well as grass ratio of feed at herd level were collected during the period from 2011 to 2016. The performances of a trait in heifers and cows (lactation 1 to 3) were considered as different traits. The (co)variance components and the resulting heritabilities and genetic correlations were estimated using 2 models. One was a bivariate model treating performances of a trait under organic and conventional production systems as 2 different traits using a reduced data set, and the other was a reaction norm model with random regression on the production system and the grass ratio of feed using a full data set. The full data set comprised records of 37,836 females from 112 organic herds and 513,599 females from 1,224 conventional herds, whereas the reduced data set comprised records from all these 112 organic herds and 92,696 females from 185 convention herds extracted from the full data set with grass ratio of feed lower than 0.20. All female fertility performances of the organic production system were superior to those of the conventional production system. Besides, heterogeneities in additive genetic variances and heritabilities were observed between conventional and organic production systems for all traits. Furthermore, genetic correlations between these 2 production systems ranged from 0.607 to 1.000 estimated from bivariate models and from 0.848 to 0.999 estimated from reaction norm models. Statistically significant G × E were observed for NINS in heifers, non-return rate within 56 d after the first insemination in heifers, and ICF from the bivariate model, and for ICF and NINS in cows from the reaction norm model.

Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: randomized controlled trial study.

BACKGROUND AND PURPOSE: Subcutaneous immunoglobulin (SCIG) is effective as maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). We investigated whether multiple subcutaneous infusions are as effective as conventional therapy with intravenous loading doses in treatment-naive patients with CIDP. METHODS: Twenty patients fulfilling the clinical and electrophysiological criteria for CIDP were included and treated with either SCIG (0.4 g/kg/week) for 5 weeks or intravenous immunoglobulin (IVIG) (0.4 g/kg/day) for 5 days. After 10 weeks, patients were switched to the opposite treatment arm and followed for a further 10 weeks. All participants were evaluated at weeks 0, 2, 5 and 10 during both therapies. Primary outcome was combined isokinetic muscle strength (cIKS). Secondary outcomes were disability, clinical evaluation of muscle strength and the performance of various function tests. RESULTS: All participants received both therapies, 14 completing the protocol. Overall, cIKS increased by 7.4 ± 14.5% (P = 0.0003) during SCIG and by 6.9 ± 16.8% (P = 0.002) during IVIG, the effect being similar (P = 0.80). Improvement of cIKS peaked 2 weeks after IVIG and 5 weeks after SCIG. Disability improved during SCIG treatment only. Muscle strength determined by manual muscle testing improved after 5 and 10 weeks during SCIG but only after 5 weeks during IVIG. The remaining parameters improved equally during both treatments. Plasma immunoglobulin G levels at baseline and improvement of cIKS were related. CONCLUSION: In treatment-naive patients with CIDP, short-lasting SCIG and IVIG therapy improve motor performance to a similar degree, but with earlier maximal improvement following IVIG than SCIG treatment.

Clinical and diagnostic features of perioperative hypersensitivity to cefuroxime.

INTRODUCTION: The Danish Anaesthesia Allergy Centre (DAAC) investigated 89 adult patients with suspected perioperative cefuroxime-associated hypersensitivity reactions between 2004 and 2013. The goals were to determine whether the time to index reaction after cefuroxime exposure could be used to implicate cefuroxime as the cause of the reactions and explore different test modalities in diagnosing cefuroxime hypersensitivity. METHOD: Skin tests, in vitro tests, and titrated provocations were used to determine cefuroxime hypersensitivity. Patients were deemed cefuroxime positive on the basis of at least two positive tests and/or a positive provocation. RESULTS: One or more tests were positive for cefuroxime in 24 of 89 (27.0%) patients. One was only specific IgE positive and was deemed cefuroxime negative. Twenty-three (25.8%) were deemed cefuroxime positive. There were four specific IgE-, 4 histamine release test-, 13 skin test-, and 14 provocation positive patients. There were eight (34.8%) patients who were only provocation positive. Data on time to index reaction after cefuroxime exposure were available for 80 patients (22 in the positive group and 58 in the negative group), 22 of 22 (100%) of positive patients reacted in <15 min vs. only 38 of 58 (65.5%) of negative patients. CONCLUSION: All patients with confirmed hypersensitivity to cefuroxime reacted within 15 min of administration, but so did 65.5% of Cefuroxime negative patients, making timing of administration an unreliable predictor of causation in the perioperative setting. Provocations were always positive when carried out in skin test positive patients; however, eight patients had positive provocations only, highlighting the need for provocation in skin test negative patients.

Hemolytic anemia following high dose intravenous immunoglobulin in patients with chronic neurological disorders.

BACKGROUND AND PURPOSE: High dose intravenous immunoglobulin (IVIG) is an established treatment for various neuromuscular disorders. Recently, cases of hemolytic anemia following IVIG have been observed. The objective of this study was to determine the extent of anemia and hemolysis after IVIG and its relationship to the AB0 blood type system. METHODS: In a prospective study 34 de novo treated patients were given 2.0 g/kg bodyweight of Privigen and 50 patients received either Privigen [n = 28; 1.53 ± 0.4 g/kg (mean ± SD)] or Kiovig (n = 22; 1.7 ± 0.4 g/kg) as maintenance therapy. The de novo patients all had a post-polio syndrome, whereas the remaining patients received maintenance therapy for the neuromuscular disorders chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy. Blood sampling was performed before and 2 weeks after infusion of IVIG. RESULTS: Following IVIG treatment blood hemoglobin declined from 8.6 ± 0.9 to 8.0 ± 1.2 mM, P < 0.001. Reticulocyte counts and levels of bilirubin and lactate dehydrogenase were increased and haptoglobin levels decreased. The decline of hemoglobin was 0.9 ± 1.2 mM after de novo therapy versus 0.4 ± 0.8 mM after maintenance therapy with Privigen (P = 0.05) and 0.2 ± 0.3 mM after maintenance therapy with Kiovig (P = 0.47). In de novo patients compared with patients on maintenance therapy reticulocyte count and lactate dehydrogenase level increased whereas haptoglobin level decreased. Anemia correlated with the AB0 blood type system with a significant difference between type 0 (n = 17; +0.3 ± 0.4 mM) and type A, B and AB (n = 48; -1.0 ± 1.0 mM), anemia being most pronounced in type AB. CONCLUSION: Moderate hemolytic anemia is a concomitant complication of high dose IVIG in subjects with blood types A, B and AB.

Subcutaneous immunoglobulin preserves muscle strength in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: Subcutaneous immunoglobulin (SCIG) is superior to placebo treatment for maintenance of muscle strength during 12 weeks in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The present study evaluated whether SCIG preserves muscle strength for 1 year in an open-label follow-up study. METHODS: Seventeen responders to intravenous immunoglobulin (IVIG) who had participated in the previous study of SCIG versus placebo in CIDP were included. After one IVIG infusion 2 weeks prior to baseline, all continued on SCIG treatment at weekly equal dosage and were evaluated after 3, 6 and 12 months. Primary end-points were changes in muscle strength evaluated by isokinetic dynamometry in four affected muscle groups and a composite score of muscle performance and function tests, including Medical Research Council (MRC) score, grip strength, 40-m walking test (40-MWT) and nine-hole peg test (9-HPT). Secondary end-points were changes of each of the listed parameters at each time point as well as an overall disability sum score (ODSS). RESULTS: The dose of SCIG was significantly unaltered during the follow-up period. Overall the isokinetic dynamometry value increased by 7.2% (P = 0.033) and after 3, 6 and 12 months by 5.7%, 8.2% and 6.8% (ns). The overall composite score at all time intervals and for each interval remained unchanged. Amongst the secondary parameters the MRC score increased significantly by 1.7% (P = 0.007), whereas grip strength, 40-MWT, 9-HPT and ODSS remained unchanged. CONCLUSION: SCIG preserves muscle strength and functional ability in patients with CIDP who previously responded to IVIG. SCIG should be considered as an alternative in long-term treatment of CIDP patients.

Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND AND PURPOSE: We hypothesized that subcutaneous administration of immunoglobulins (SCIG) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is feasible, safe and superior to treatment with saline for the performance of muscle strength. METHODS: Thirty patients with motor involvement in maintenance therapy with intravenous immunoglobulin (IVIG) fulfilling the EFNS/PNS criteria for CIDP, aged 18-80 years, were randomized either to SCIG at a dose corresponding to their pre-study IVIG dose or to subcutaneous saline given twice or thrice weekly for 12 weeks at home. At the start and end of the trial as well as 2 weeks before (-2, 0, 10, 12 weeks), isokinetic strength performance of four predetermined and weakened muscle groups was measured. Also, an Overall Disability Sum Score (ODSS), 40-m-walking test (40-MWT), nine-hole-peg test, Neurological Impairment Score (NIS), Medical Research Council (MRC) score, grip strength, standardized electrophysiological recordings from three nerves, and plasma IgG levels were evaluated. RESULTS: SCIG treatment was well tolerated in all 14 patients. Six patients complained of mild side-effects at the injection site. In the SCIG group there was an increase of isokinetic muscle strength of 5.5 ± 9.5% (P < 0.05) as compared with a decline of 14.4 ± 20.3% (P < 0.05) in the placebo group; the difference between the two groups being significant (P < 0.01). ODSS, NIS, MRC, grip strength and 40-MWT improved following SCIG versus saline. CONCLUSIONS: SCIG treatment in CIDP is feasible, safe and effective, and seems an attractive alternative to IVIG.

Structure and function of proteins of the phosphotransferase system and of 6-phospho-beta-glycosidases in gram-positive bacteria.

New information about the proteins of the phosphotransferase system (PTS) and of phosphoglycosidases of homofermentative lactic acid bacteria and related species is presented. Tertiary structures were elucidated from soluble PTS components. They help to understand regulatory processes and PTS function in lactic acid bacteria. A tertiary structure of a membrane-bound enzyme II is still not available, but expression of Gram-positive genes encoding enzymes II can be achieved in Escherichia coli and enables the development of effective isolation procedures which are necessary for crystallization experiments. Considerable progress was made in analysing the functions of structural genes which are in close vicinity of the genes encoding the sugar-specific PTS components, such as the genes encoding the tagatose-6-P pathway and the 6-phospho-beta-glycosidases. These phosphoglycosidases belong to a subfamily of the beta-glycosidase family I among about 300 different glycosidases. The active site nucleophile was recently identified to be Glu 358 in Agrobacterium beta-glucosidase. This corresponds to Glu 375 in staphylococcal and lactococcal 6-phospho-beta-galactosidase. This enzyme is inactivated by mutating Glu 375 to Gln. Diffracting crystals of the lactococcal 6-P-beta-galactosidase allow the elucidation of its tertiary structure which helps to derive the structures for the entire glycosidase family 1. In addition, a fusion protein with 6-phospho-beta-galactosidase and staphylococcal protein A was constructed.

Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia.

PURPOSE: Purine analogs have wide potential indications in the treatment of hematologic malignancies, but intravenous administration has been required. We previously established that the oral bioavailability of cladribine is 50%. Our aim was to evaluate the efficacy and toxicity of oral cladribine to previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Sixty-three patients with symptomatic but previously untreated CLL received cladribine solution 10 mg/m2/d orally for 5 consecutive days in monthly courses. RESULTS: Complete remission (CR) was achieved in 24 patients (38%), and 23 patients (37%) had a partial response (PR). Most patients, including those in whom there was no remission (NR) achieved normal blood lymphocyte counts. Failure to meet response criteria was mostly due to thrombocytopenia. The median response duration was not reached at 2 years. The median survival time among 13 deceased patients was 322 days, whereas the median observation time of surviving patients is 760 days. The overall survival rate at 2 years is 82%. Response rate was associated with clinical stage. Grade III to IV infectious toxicity occurred in one third of patients. CONCLUSION: Orally administered cladribine is an effective and feasible therapy for CLL, and produces durable remissions in three quarters of the patients. However, significant toxicity may occur and further studies are required to assess long-term effects and quality-of-life aspects.

Interleukin-15 + thioredoxin induce DNA synthesis in B-chronic lymphocytic leukemia cells but not in normal B cells.

We have previously shown that Staphylococcus aureus Cowan strain 1 particles (SAC) + thioredoxin (Trx) + IL-2 may induce B-chronic lymphocytic leukemia (B-CLL) cells to proliferate. In this paper we have examined IL-15, which has activities similar to IL-2, for its ability to stimulate B-CLL cells and compared its activity with that of IL-2. We found that B-CLL cells could be induced to DNA synthesis upon treatment with IL-15 + Trx. The presence of Trx was essential for the IL-15-induced DNA synthesis. This contrasts to the effect of IL-15 + Trx on normal CD5+ and CD5- B cells, where IL-15 + Trx alone only induced limited DNA synthesis. IL-15 was as effective in the induction of DNA synthesis in B-CLL cells as IL-2, but about 100-fold less potent with an EC50 of 200 ng/ml. In addition we found that the IL-15 + Trx-induced proliferation was inhibited by CD40 stimulation. We conclude that IL-15 together with a proper costimulus can induce B-CLL cells to proliferate in vitro.

Soluble ICAM-1 in Hodgkin's disease: a promising independent predictive marker for survival.

The serum levels of soluble ICAM-1 (sICAM-1, sCD54) were significantly elevated (p = .0006) in patients with Hodgkin's disease (HD) (n = 101) compared to healthy controls (n = 31). Serum levels of sICAM-1 in HD correlated significantly with the presence of B-symptoms, histology and tumour burden as reflected in the Ann Arbor staging system, but not to bulky disease. sICAM-1 was compared to other serum factors claimed to be of prognostic significance in HD, including erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), deoxythymidine kinase (TK), soluble interleukin-2 receptor (sIL-2R, sCD25) and soluble CD30 (sCD30, sKi-1-antigen). Serum levels of sICAM-1 correlated positively with all of these markers. In univariate regression analyses, all but ESR correlated with disease-free survival but only sICAM-1, sIL-2R and sCD30 correlated with overall survival. In multivariate analyses only sIL-2R (as a continuous variable) added independent prognostic information in addition to age, stage and B-symptoms. sICAM-1 and sCD30 approached significance (p = 0.07 and p = 0.08, respectively) for disease-free survival. sCD30 correlated with overall survival (p = 0.03) while sICAM-1 did not. When dichotomised at optimal cut-off levels, sICAM-1 as well as sIL-2R and sCD30 added independent prognostic information for both disease-free and overall survival. Based on the present observations, it appears that sICAM-1 may be a predictor for relapse and survival in HD. Determination of serum levels of sICAM-1 (in addition to sIL-2R and sCD30) may thus be of potential value when selecting HD patients eligible for intensive therapy in clinical trials.

Time course of platelet alpha granule release in acute myocardial infarction treated with streptokinase.

OBJECTIVE: To determine the time course of platelet alpha granule release in patients with acute myocardial infarction treated with streptokinase. DESIGN: A prospective study. SETTING: Coronary care unit. PATIENTS: Nine with myocardial infarction treated with both streptokinase and aspirin, and nine with acute chest pain but without myocardial infarction, who were treated with aspirin only. METHODS: All patients received 250 mg aspirin on admission and 150 mg once daily thereafter. All patients who fulfilled the indications for streptokinase received 1.5 megaunits, in a single infusion. After the initial medication, serial measurements of plasma beta thromboglobulin and plasma platelet factor 4 were performed at fixed intervals after the onset of chest pain. The primary endpoint sought was the peak value of beta thromboglobulin and platelet factor 4 in each individual. RESULTS: The median peak plasma beta thromboglobulin in the infarction group was substantially higher than in those without infarction, at 37 (range 12 to 210) v 15 (9 to 36) mg/litre, P < 0.01. The corresponding values for plasma platelet factor 4 were 4.6 (2.4 to 60.0) v 2.2 (< 2 to 8.5) mg/litre, P < 0.01. Increased values were seen only within the first 12 h after onset of chest pain, and after 12 h there was no difference between the patients with myocardial infarction and those without. Aspirin treatment did not abolish alpha granule release. CONCLUSIONS: In patients with acute myocardial infarction treated with streptokinase the content of the alpha granules is released within the first 12 h after the onset of chest pain. Aspirin apparently does not abolish this release.

[A successful attempt with a consulting service for boys]. / Lyckat försök med pojkmottagning.

As adolescence is a critical period of development, and as boys are less inclined than girls to approach the school facility for adolescent counselling, segregated consulting hours were introduced for boys to attract those with problems. The frequency of consultations by boys increased by 25 per cent, and 70 per cent of the boys reported a preference for the segregated consulting hours; 75 per cent appreciated the absence of girls from the waiting room; and of the 42 per cent with special preferences regarding the gender of the staff encountered, half reported preferring a man. Most of the boys presented with defined problems, though many revealed other problems, often relating to sexuality, in the course of consultation. The availability of segregated consulting hours for boys with adolescent problems is important, and often the only way to reach young boys who need help.

PIP: Consultation services in the schools of Stockholm started an experiment to set aside two hours every Friday afternoon only for boys to provide them assistance from a male gynecologist with experience in andrology and a female gynecologist or midwife. After the visit a questionnaire is filled out evaluating the consultation. The total number of boys who sought consultation during the period of April 1995 to April 1997 increased by 25% and 226 boys aged 15-22 years decided to pay visits. 166 visits were new visits and 59 were return visits. In 121 cases the health personnel consisted of a man and in 105 cases it consisted of a woman. 49 boys wished to see a male professional, while 44 preferred a female. 74% of the boys thought that the special consultation service was important for boys. The sources of the information for the boys' consultation were schools (46%), female friends (19%), and friends (16%). 90% of the boys stated that they were satisfied with the visit. 196 of them had female sexual partners, 2 had males, and 4 had both male and female partners. The remaining 24 boys had not experienced their first intercourse yet. In 36 cases problems purely related to sexuality were ascertained: erection disorders, sexual function in connection with anomalies, frenulum changes, masturbation, condom use, coital positions, and bisexuality. 25 individuals had had a sexually transmitted disease; 21 of these were chlamydia cases. 102 boys presented urogenital symptoms. 128 tests were taken for chlamydia diagnosis, 47 for gonococcus cultivation, and 2 for herpes cultivation. The chlamydia tests were positive in 16 cases; the herpes tests, in 2 cases. No case of gonorrhea could be confirmed.

[Enzyme diagnosis of acute myocardial infarction]. / Enzymdiagnostik ved akut myokardieinfarkt.

During the past decade, determinations of enzyme concentrations in the blood in patients admitted with suspected acute myocardial infarction has been of increasing significance not only for early elucidation but also for establishing the correct diagnosis. This is partly the result of methods which can demonstrate the presence of myocardium-related isoenzymes and also because of the physiological basis for the release of enzymes and their metabolism bas been elucidated. In the present report, guidelines for clinical employment of enzyme investigations in acute myocardial infarction are presented. By means of blood sampling twice or thrice within a time interval af approximately 8-24 hours after the presumed time of infarction and determination of a limited number of enzymes in these samples, it is possible to exclude or confirm the presence of an infarct with high probability.

[Treatment of unstable angina pectoris. A questionnaire study]. / Behandling af ustabil angina pectoris. En spørgeskemaundersøgelse.

Questionnaires about therapy in unstable angina pectoris were sent to 63 Danish medical departments and were answered by 52 departments (82.5%). Nitroglycerin is commonly used but only in half of the departments is Nitroglycerin administered intravenously. Calcium-receptor-blockers are used in more departments (65%) than beta-receptor-blockers (35%) (p less than 0.05). Five departments use thrombolytic therapy along local guidelines. All recommend aspirin as prophylaxis against thrombosis and 63% recommend the therapy to be continued for life. An exercise test is always performed during hospital stay in 1/3 of the departments while the rest of the departments often wait till after the patient has been discharged. The estimate of frequency of coronary angiography varied considerably: from less than 5% to 100%. The frequency of coronary angiography was stated to be higher in Copenhagen and Aarhus (median 50%, interval 10-100%) than in the rest of the country (median 15%, interval less than 5-75%) (p less than 0.01).

CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases.

Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of "sarcoidosis with other localization", "other acute disseminating demyelination", "other demyelinating disease in the CNS" or "encephalitis, myelitis or encephalomyelitis". Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75 months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment.