Capacity of Trolox to improve the development and quality of metabolically compromised bovine oocytes and embryos invitro during different windows of development.

Trials to improve oocyte developmental competence under metabolic stress by using antioxidants may start before or after oocyte maturation. In the present conceptual study, we aimed to identify the most efficient timing of antioxidant application in relation to a metabolic insult using a bovine invitro embryo production model. Pathophysiological concentrations of palmitic acid (PA) were used to induce metabolic stress during oocyte maturation or embryo development. Trolox (TR; antioxidant) treatment prior to, during or after the PA insult was tested to evaluate the protective, neutralising and rescuing capacity of TR respectively. Changes in embryo developmental competence, mitochondrial activity, reactive oxygen species (ROS) concentrations, blastocyst cell allocation and apoptosis and cell stress-related gene expression were monitored. The improvement in developmental capacity was most obvious when oocytes were preloaded with TR before the PA insult. This protective effect could be explained by the observed combination of increased mitochondrial activity with reduced ROS production. This resulted in blastocysts with normal cell counts and apoptosis, as well as increased nuclear factor erythroid 2-related factor 2 (NRF2) expression (a marker for redox regulatory processes) and normalised the expression of the mitochondrial transcription factor A (TFAM), a marker of mitochondrial biogenesis. These results indicate that 'pretreatment' of oocytes with antioxidants produces embryos that seem to be more resilient to a metabolic stress insult.

Comparison of PR, QRS, and QT interval measurements by seven ECG interpretation programs.

BACKGROUND: Electrocardiograph-generated measurements of PR, QRS, and QT intervals are generally thought to be more precise than manual measurements on paper records. However, the performance of different programs has not been well compared. METHODS: Routinely obtained digital electrocardiograms (ECGs), including over 500 pediatric ECGs, were used to create over 2000 10 s analog ECGs that were replayed through seven commercially available electrocardiographs. The measurements for PR interval, QRS duration, and QT interval made by each program were extracted and compared against each other (using the median of the programs after correction for program bias) and the population mean values. RESULTS: Small but significant systematic biases were seen between programs. The smallest and largest variation from the population mean differed by 4.7 ms for PR intervals, 5.8 ms for QRS duration, and 12.4 ms for QT intervals. In pairwise comparison programs showed similar accuracy for most ECGs, with the average absolute errors at the 75th percentile for PR intervals being 4-6 ms from the median, QRS duration 4-8 ms, and QT interval 6-10 ms. However, substantial differences were present in the numbers and extent of large, clinically significant errors (e.g at the 98th percentile), for which programs differed by a factor of two for absolute errors, as well as differences in the mix of overestimations and underestimations. CONCLUSIONS: When reading digital ECGs, users should be aware that small systematic differences exist between programs and that there may be large clinically important errors in difficult cases.

Performance of seven ECG interpretation programs in identifying arrhythmia and acute cardiovascular syndrome.

BACKGROUND: No direct comparison of current electrocardiogram (ECG) interpretation programs exists. OBJECTIVE: Assess the accuracy of ECG interpretation programs in detecting abnormal rhythms and flagging for priority review records with alterations secondary to acute coronary syndrome (ACS). METHODS: More than 2,000 digital ECGs from hospitals and databases in Europe, USA, and Australia, were obtained from consecutive adult and pediatric patients and converted to 10 s analog samples that were replayed on seven electrocardiographs and classified by the manufacturers' interpretation programs. We assessed ability to distinguish sinus rhythm from non-sinus rhythm, identify atrial fibrillation/flutter and other abnormal rhythms, and accuracy in flagging results for priority review. If all seven programs' interpretation statements did not agree, cases were reviewed by experienced cardiologists. RESULTS: All programs could distinguish well between sinus and non-sinus rhythms and could identify atrial fibrillation/flutter or other abnormal rhythms. However, false-positive rates varied from 2.1% to 5.5% for non-sinus rhythm, from 0.7% to 4.4% for atrial fibrillation/flutter, and from 1.5% to 3.0% for other abnormal rhythms. False-negative rates varied from 12.0% to 7.5%, 9.9% to 2.7%, and 55.9% to 30.5%, respectively. Flagging of ACS varied by a factor of 2.5 between programs. Physicians flagged more ECGs for prompt review, but also showed variance of around a factor of 2. False-negative values differed between programs by a factor of 2 but was high for all (>50%). Agreement between programs and majority reviewer decisions was 46-62%. CONCLUSIONS: Automatic interpretations of rhythms and ACS differ between programs. Healthcare institutions should not rely on ECG software "critical result" flags alone to decide the ACS workflow.

Differential effects of high and low glucose concentrations during lipolysis-like conditions on bovine in vitro oocyte quality, metabolism and subsequent embryo development.

Lipolytic metabolic conditions are traditionally associated with elevated non-esterified fatty acid (NEFA) concentrations, but may also be accompanied by hyperglycaemia in obesity or by hypoglycaemia during a negative energy balance status. Elevated NEFA concentrations disrupt oocyte and embryo development and quality, but little is known about whether the effects of lipolytic conditions on oocyte developmental competence are modulated by glucose availability. To answer this, bovine cumulus-oocyte complexes (COCs) were matured under different conditions: physiological NEFA (72µM) and normal glucose (5.5mM), pathophysiologically high NEFA (420µM) and normal glucose, high NEFA and high glucose (9.9mM), high NEFA and low glucose (2.8mM). Developmental potential, cumulus expansion and metabolism of COCs exposed to high NEFA and low glucose were affected to a greater extent compared with COCs matured under high NEFA and high glucose conditions. High NEFA and high glucose conditions caused a moderate increase in oocyte reactive oxygen species compared with their high NEFA and low glucose or control counterparts. Blastocyst metabolism and the transcriptome of metabolic and oxidative stress-related genes were not affected. However, both lipolytic conditions associated with hyper- or hypoglycaemia led to surviving embryos of reduced quality with regards to apoptosis and blastomere allocation.

Progesterone Alters Kynurenine Pathway Activation in IFN-γ-Activated Macrophages - Relevance for Neuroinflammatory Diseases.

We have previously demonstrated that the kynurenine pathway (KP), the major biochemical pathway for tryptophan metabolism, is dysregulated in many inflammatory disorders that are often associated with sexual dimorphisms. We aimed to identify a potential functional interaction between the KP and gonadal hormones. We have treated primary human macrophages with progesterone in the presence and absence of inflammatory cytokine interferon-gamma (interferon-γ) that is known to be a potent inducer of regulating the KP enzyme. We found that progesterone attenuates interferon-γ-induced KP activity, decreases the levels of the excitotoxin quinolinic acid, and increases the neuroprotective kynurenic acid levels. We also showed that progesterone was able to reduce the inflammatory marker neopterin. These results may shed light on the gender disparity in response to inflammation.

Kynurenines, Gender and Neuroinflammation; Showcase Schizophrenia.

Schizophrenia has a clear sexual dimorphism in age of onset and progression. The underlying mechanisms of this dimorphism are not known, but may be found in the interactions of sex hormones with the tryptophan catabolising kynurenine pathway. Schizophrenia is associated with general inflammation and disruption of glutamatergic and dopaminergic signalling. Metabolites of the kynurenine pathway have been shown to be immunomodulatory and have effects on glutamatergic and dopaminergic signalling. This review discusses the currently available literature on sex hormones and their effect on the kynurenine pathway in the context of the glutamatergic, dopaminergic and immunological features of schizophrenia.

The effect of a negative energy balance status on ß-carotene availability in serum and follicular fluid of nonlactating dairy cows.

Maternal metabolic pressure due to a cow's negative energy balance (NEB) has a negative effect on oocyte quality as a result of increased oxidative stress. In this study, we hypothesized that a NEB status may negatively affect the availability of ß-carotene (bC, an antioxidant) in the micro-environment of the oocyte or follicular fluid (FF) and that daily bC supplementation can increase bC availability. We aimed to (1) determine the effect of a nutritionally induced NEB on bC concentrations in serum and FF as well as on the presence of bC metabolites, oxidative stress levels, and follicular growth in a nonlactating dairy cow model, and (2) investigate how this effect could be altered by dietary bC supplementation. Six multiparous nonlactating Holstein Friesian cows were subjected to 4 consecutive dietary treatments, 28 d each: (1) 1.2 × maintenance (M) or positive energy balance (PEB) without bC supplement (PEB-bC), (2) 1.2 × M with daily supplement of 2,000mg of bC comparable to the level of bC intake at grazing (PEB+bC), (3) 0.6 × M with 2,000mg of bC (NEB+bC), and (4) 0.6 × M (NEB-bC). At the end of each treatment, estrous cycles were synchronized and blood and FF of the largest follicle were sampled and analyzed for bC, retinol, α-tocopherol, free fatty acids, estradiol, and progesterone. Serum cholesterol, triglycerides, urea, insulin growth factor 1, growth hormone, total antioxidant status (TAS), and red blood cell glutathione (GSH) concentrations were determined as well. All cows lost body weight during both energy restriction periods and showed increased serum free fatty acid concentrations, illustrating a NEB. A dietary induced NEB reduced FF bC, but not plasma bC or plasma and FF retinol concentrations. However, bC and retinol concentrations drastically increased in both fluid compartments after bC supplementation. Follicular diameter was increased in supplemented PEB cows. Energy restriction reduced the TAS and red blood cell GSH, whereas daily bC supplementation could restore GSH concentrations, but not the TAS, to levels present in healthy PEB cows. In conclusion, daily bC supplementation can substantially improve bC and retinol availability in the oocyte's micro-environment, irrespective of the energy balance, which may affect follicular development and oocyte quality in the presence of maternal metabolic stress. This knowledge can be of importance to optimize nutritional strategies in the dairy industry to feed for optimal oocyte quality and fertility.

Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study.

BACKGROUND: This study aimed to investigate whether reversal of rocuronium-induced neuromuscular blockade with sugammadex reduced the incidence of residual blockade and facilitated operating room discharge readiness. METHODS: Adult patients undergoing abdominal surgery received rocuronium, followed by randomized allocation to sugammadex (2 or 4 mg kg(-1)) or usual care (neostigmine/glycopyrrolate, dosing per usual care practice) for reversal of neuromuscular blockade. Timing of reversal agent administration was based on the providers' clinical judgement. Primary endpoint was the presence of residual neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio <0.9, using TOF-Watch® SX. Key secondary endpoint was time between reversal agent administration and operating room discharge-readiness; analysed with analysis of covariance. RESULTS: Of 154 patients randomized, 150 had a TOF value measured at PACU entry. Zero out of 74 sugammadex patients and 33 out of 76 (43.4%) usual care patients had TOF-Watch SX-assessed residual neuromuscular blockade at PACU admission (odds ratio 0.0, 95% CI [0-0.06], P<0.0001). Of these 33 usual care patients, 2 also had clinical evidence of partial paralysis. Time between reversal agent administration and operating room discharge-readiness was shorter for sugammadex vs usual care (14.7 vs. 18.6 min respectively; P=0.02). CONCLUSIONS: After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU, and shortened the time from start of study medication administration to the time the patient was ready for discharge from the operating room. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov:NCT01479764.

Knowledge, use and attitude toward eHealth among patients with chronic lung diseases.

BACKGROUND: Despite high expectations and numerous initiatives in the area of eHealth, implementation and use of eHealth applications on a national level is no common practice yet. There is no full understanding of patients' attitude on eHealth yet. Aim of this study is to gain insight into the level of knowledge and experiences with eHealth of people with chronic lung diseases. METHOD: A telephone survey among 400 people with a medical diagnosis of asthma or COPD was conducted. All patients participated in the larger research program National Panel of people with Chronic diseases or Disabilities (NPCD) conducted by NIVEL. RESULTS: Eight percent of the asthma and COPD patients knew of the term eHealth. Knowledge of specific eHealth applications (e.g. electronic medical record, electronic consultations, monitoring from a distance) was higher and ranged from 21 to 88%. Most available applications were used by less than 20% of the patients, although figures differ by age and educational level. People who have used applications were in general rather positive about their use. Non-users did not see clear advantages of using eHealth applications. A majority thought that eHealth decreases human contact in health care and will not contribute to a higher quality of care. On the contrary, almost half of the patients considered eHealth as a possibility to take more responsibility in their own care. Asthma and COPD patients were unanimous that the use of eHealth should always be a free choice. CONCLUSION: Although most asthma and COPD patient know of one or more eHealth applications, actual use remains low. Patients who do have experience with the use of eHealth are on the whole positive. However, patients without experience have no clear ideas about the advantages. They should be convinced first, and stressing the possibilities for more personal control might be an important argument to persuade them.

Dietary fat supplementation and the consequences for oocyte and embryo quality: hype or significant benefit for dairy cow reproduction?

In many countries, fat supplementation in the diet has become common in the dairy industry. There are several ideas as to how dietary fat could influence reproductive performance. Saturated fatty acids, such as palm oil, can increase milk yield but may aggravate negative energy balance and thus may impair fertility when fed during the first week post-partum. However, priming the lipid oxidation in the liver by feeding saturated fats during the dry period has recently been shown to be a potentially promising strategy to mitigate fat mobilization and liver accumulation post-partum. Furthermore, polyunsaturated fats (omega-3 fatty acids and conjugated linoleic acids) are fed to reduce the 'de novo' fat synthesis in the udder and thus the milk fat content, which may be of modest benefit for overall energy balance. Furthermore, omega-6 and omega-3 polyunsaturated fatty acids are reported to alter follicular growth, steroid synthesis and prostaglandin metabolism in the ovary and endometrium, respectively. Omega-6 fatty acids are believed to have pro-inflammatory and thus PGF2α-stimulating properties rendering them extra value as 'nutraceutical' early post-partum, while omega-3 fatty acids can weaken this inflammatory potency, leading to a higher chance of survival of the embryo when supplemented during the periconceptual period. Unfortunately, research results rarely provide a consensus in this perspective. The consequences of these fat-feeding strategies on oocyte and embryo quality remain an intriguing issue for debate. Fat feeding may alter the microenvironment of the growing and maturing oocyte of the early and older embryo and thus may affect reproductive outcome. We recently reported that dietary-induced hyperlipidaemic conditions can be harmful for embryo development and metabolism. However, to date, research results remain somewhat conflicting most probably due to differences in fat sources used, in diet and duration of supplementation and in experimental set-up in general.

The development of quality indicators for community pharmacy care.

AIMS: To develop a national system of quality indicators for community pharmacy care, reported by community pharmacies. METHODS: After preliminary validation, an online consensus study was conducted. Pharmacy practice experts (round 1) and practising pharmacists (round 2) were approached. Face-validity scores for risk of harm and quality of care were obtained, as well as data on feasibility and clarity. To field test the data collection a random sample of 30 community pharmacies reported on the indicators, and were visited by a healthcare inspector to discuss practical and interpretation issues. RESULTS: After preliminary validation of 159 topics, 53 indicators were rated in round 1 by 14 of the 16 experts who were approached. The resulting 48 indicators were rated by 76 pharmacists of the 150 pharmacists who were approached (response 50%). Of the 48 indicators in the second round, 33 (69%) were rated face valid (median relevance score ≥ 7) for risk of harm to patients, while 43 (90%) were rated face valid for quality of care. In the field test the participating pharmacies reported on the resulting set of 44 indicators. This resulted in an adjusted set of 42 indicators. The set contains indicators on patient counselling (6), clinical risk management (10), compounding (7), dispensing (3), monitoring of medication use (11) and quality management (5). CONCLUSIONS: A set of 42 quality indicators was developed for community pharmacy care. It is expected that this will have a positive impact on quality and safety of community pharmacy care in the Netherlands.

[Frontal syndrome resulting from an intracerebral amyloidoma]. / Frontaal syndroom door een intracerebraal amyloïdoom.

A 51-year-old woman suffering an epileptic seizure came to the emergency unit. A ct scan showed a mass lesion in the right frontal lobe. The psychiatric examination indicated a frontal syndrome with severe cognitive impairment. A stereotactical biopsy was carried out. Histopathology produced an unusual diagnosis, namely an intracerebral amyloidoma. By reviewing the literature on intracerebral amyloidoma we were able to compare the psychiatric symptoms of published cases with those of this case.

Risky procedures by nurses in hospitals: problems and (contemplated) refusals of orders by physicians, and views of physicians and nurses.

Occurrence of problems with, refusals of orders and contemplated refusals of orders for risky procedures by nurses in Dutch hospitals and views on the safety of performance was studied using postal questionnaires (600 physicians and 3200 nurses, response 60-71%). Of the respondents, 11-30% experienced problems with and (contemplated) refusals of orders for risky procedures in the previous 12 months. Gynaecologists and internists most frequently mentioned problems concerning the practical performance of the procedure (44% and 30%, respectively). The reason for a problem or a contemplated refusal most frequently given by nurses was that they disagreed with the medication policy (34% and 35%, respectively). The reason for a refusal most frequently given by the gynaecologists, internists and nurses was that the nurses themselves were of the opinion that they did not have the necessary authorisation (95%, 67%, and 62%, respectively). With regard to certain procedures, the views of professionals are more strict than the current legal regulations.

Risky procedures by nurses in hospitals: problems and (contemplated) refusals of orders by physicians, and views of physicians and nurses: a questionnaire survey.

Occurrence of problems with, refusals of orders and contemplated refusals of orders for risky procedures by nurses in Dutch hospitals and views on the safety of performance was studied using postal questionnaires (600 physicians and 3200 nurses, response 60--71%). Of the respondents, 11--30% experienced problems with and (contemplated) refusals of orders for risky procedures in the previous 12 months. Gynaecologists and internists most frequently mentioned problems concerning the practical performance of the procedure (44% and 30%, respectively). The reason for a problem or a contemplated refusal most frequently given by nurses was that they disagreed with the medication policy (34% and 35%, respectively). The reason for a refusal most frequently given by the gynaecologists, internists, and nurses was that the nurses themselves were of the opinion that they did not have the necessary authorisation (95%, 67%, and 62%, respectively). With regard to certain procedures, the views of professionals are more strict than the current legal regulations.

Hepatitis C, interferon alpha and psychiatric co-morbidity in intravenous drug users (IVDU) : guidelines for clinical practice.

The evidence regarding the co-morbidity of chronic hepatitis C, psychiatric illness and intravenous drug abuse is reviewed from the literature. Also the occurrence and the treatment of psychiatric side effects during treatment with interferon in patients with a history of drug abuse are reviewed. There is insufficient evidence for a specific hepatitis C induced depression or fatigue, but a direct link between hepatitis C and cerebral dysfunction is not excluded. Immune system activation rather than drug use may explain cerebral symptoms. In HCV positive substance users anxiety and depression are more prevalent than in HCV negative substance users. During treatment with regular or pegylated (PEG) interferon depression is a frequent side effect (ca 30%) and occurs independently from pre-existing psychiatric disorders or drug abuse. A history of drug abuse per se does not increase the risk of depression as a side effect of interferon treatment. It is extremely important to monitor symptoms of depression in the early weeks of treatment and to start antidepressant treatment as early as possible. Antidepressants should be continued throughout the interferon treatment period. There are insufficient data to assess these situations in which preventive antidepressant treatment should be started before interferon treatment. Clinical judgement can, however, lead to preventive antidepressant treatment, even at subclinical levels of depression. A cut off score of > 10 on the Beck Depression Inventory before interferon treatment is associated with a higher risk of depression during treatment. Both selective serotonin reuptake inhibitors and other classes of antidepressants can be used.

Reserved procedures in Dutch hospitals: knowledge, experiences and views of physicians and nurses.

The Individual Health Care Professions Act came into force in The Netherlands in 1997, introducing a mixed system for the regulation of the practice of medicine. One of its components, the reserved procedures regulations, was studied in hospitals to gain insight into the knowledge, experiences and views of physicians and nurses with regard to these regulations. Questionnaires were sent to representative samples of 250 gynaecologists, 350 internists, and 3200 nurses, response rates were 65, 60 and 71%, respectively. Almost all respondents were aware that physicians are authorised to perform reserved procedures on their own initiative (93-99%), and 48-63% knew that nurses are not authorised to do this. A substantial percentage of the nurses performed reserved procedures on their own initiative (17-53%). A majority of gynaecologists and internists presumed that the hospital had ensured the proficiency of the nurses to perform reserved procedures (58% resp. 65%), while 82% of the nurses determined their own proficiency for each procedure. Most respondents felt that the reserved procedures regulations offer adequate protection for patients (58-72%). Although recommendations are made for improvement, the functioning of the reserved procedures regulations in hospitals is considered to be moderately positive.

Exogenous interleukin-16 inhibits antigen-induced airway hyper-reactivity, eosinophilia and Th2-type cytokine production in mice.

BACKGROUND: IL-16 has been described as a natural soluble CD4-ligand with immunosuppressive effects in vitro. However, little is known about the effect of IL-16 on immune responses in vivo. OBJECTIVE: In the present study, we examined the effect of IL-16 administration in a murine model of allergic asthma. Next, we determined whether these effects were mediated by modulation of CD4+ T lymphocytes. METHODS AND RESULTS: Intraperitoneal administration of IL-16 completely inhibits antigen-induced airway hyper-responsiveness and largely decreases the number of eosinophils in bronchoalveolar lavage fluid (> 90%) and airway tissue of ovalbumin-sensitized and challenged mice. Firstly, it appears that thoracic lymph node cells isolated from in vivo IL-16-treated ovalbumin-challenged animals produce less IL-4 (77%) and IL-5 (85%) upon antigenic re-stimulation, when compared to vehicle-treated mice. Secondly, pre-incubation of lymphocytes with IL-16 in vitro reduces antigen-induced proliferation (55%) and Th2-type cytokine production (IL-4; 56%, IL-5; 77%). Thirdly, the presence of IL-16 during priming cultures of TCR transgenic T cells (DO11.10), reduces IL-4 (33%) and IL-5 (35%), but not IL-10 and IFNgamma levels upon re-stimulation. CONCLUSION: It can be concluded that IL-16 has potent immunosuppressive effects on a Th2dominated allergic airway response.

Compliance with antidepressants in a primary care setting, 1: Beyond lack of efficacy and adverse events.

BACKGROUND: Treatment guidelines recommend antidepressant treatment be continued for at least 6 months to ensure maximal improvement and to prevent relapse. Naturalistic studies show that the average length of treatment is shorter than 6 months and that dropout rates are high. Factors leading patients to discontinuation of therapy are not well understood. This study investigates when and why patients stop treatment and whether they inform their doctors. METHOD: Patients (N = 272) receiving antidepressant therapy due to an episode of major depressive disorder (DSM-IV) were asked to complete an antidepressant compliance questionnaire. Patients were then telephoned monthly while they continued on antidepressant therapy, up to 6 months. During each call, patients were asked standard questions. RESULTS: By endpoint, 53% of patients had discontinued antidepressant treatment. The most common reason given was "feeling better." However, different dropout reasons were prevalent at different times after initiation of therapy. Overall, 24% of the patients did not inform their physician about stopping the antidepressant medication. The likelihood of patients' informing their physicians differed according to the patients' reasons for discontinuation and according to the patients' perceptions of their relationship with their physicians. CONCLUSION: These results provide new guidelines for improving compliance. Strategy should be adapted to the stage of treatment, as patients' reasons for discontinuation vary as treatment progresses. The attitude of the physician and the information provided by the physician significantly influence whether patients inform the physician when they discontinue antidepressant therapy.