Higher frequency of hospitalization but lower relative mortality for pandemic influenza in people with type 2 diabetes.

BACKGROUND: There is limited evidence linking type 2 diabetes (T2D) to influenza-related complications. OBJECTIVES: To test a set of research questions relating to pandemic influenza vaccination, hospitalization and mortality in people with and without T2D. METHODS: In this population-based cohort study, we linked individual-level data from several national registers for all Norwegian residents aged 30 years or more as of January 2009. People with or without T2D at baseline (n = 2 992 228) were followed until December 2013. We used Cox regression to estimate adjusted hazard ratios (aHRs). RESULTS: Pandemic influenza hospitalization was more common in individuals with T2D (aHR = 2.46, 95% CI 2.04-2.98). The mortality hazard ratio associated with hospitalization for pandemic influenza was lower in people with T2D (aHR = 1.82, 95% CI 1.21-2.74) than in those without T2D (aHR = 3.89, 95% CI 3.27-4.62). The same pattern was observed when restricting to 90-day mortality (aHR = 3.89, 95% CI 1.25-12.06 amongst those with T2D and aHR = 10.79, 95% CI 7.23-16.10 amongst those without T2D). The rate of hospitalization for pandemic influenza was 78% lower in those vaccinated compared to nonvaccinated amongst people with T2D (aHR = 0.22, 95% CI 0.11-0.39), whilst the corresponding estimate for those without T2D was 59% lower (aHR = 0.41, 95% CI 0.33-0.52). Mortality was 25% lower in those vaccinated compared to nonvaccinated amongst people with T2D (aHR = 0.75, 95% CI 0.73-0.77), whilst the corresponding estimate for those without T2D was 9% (aHR = 0.91, 95% CI 0.90-0.92). CONCLUSIONS: There may have been a lower threshold for pandemic influenza hospitalization for people with T2D, rather than more severe influenza infection. Our combined results support the importance of influenza vaccination amongst people with T2D, especially during pandemics.

Hospitalised patients with unexplained chest pain: incidence and prognosis.

BACKGROUND: The prognosis of unexplained chest pain patients provides valuable information for evaluation of health services. OBJECTIVE: To examine prognosis of unexplained chest pain. METHODS: Using data from in- and outpatient hospital visits in Norway of patients discharged with a main diagnosis of unexplained chest pain (ICD-10: R072-R074) in 2010-2012, the 1-year incidence of coronary heart disease (CHD), any cardio-vascular disease (CVD) and mortality was evaluated. Cases with prior 2-year history of CVD or chest pain were excluded. Cox proportional hazards evaluated outcomes by patient characteristics and standardized mortality ratios evaluated observed versus expected mortality. RESULTS: Of 59 569 patients identified (20-89 years of age), the majority (86%) were referred to hospital by out-of-hours emergency care centres. Subsequent CHD was noted for 12.5%, 19.5% and 25.0% of men and 7.2%, 11.0%, 14.0% of women aged 45-64, 65-74 and 75-89 years, respectively. The per cent of deaths attributed to CVD were greatest within the first 2 months of postdischarge. Total mortality rates (per 1000 person-years) were 6.6 in men and 4.7 in women aged 45-64 and 69.2 in men and 39.5 in women aged 75-89 years. Relative to the general population, mortality was 53% and 45% higher for men and women under 65 years of age, respectively, attributed primarily to non-CVD causes. CONCLUSION: Patients in Norway discharged with unexplained chest pain are an at-risk group in terms of incident CHD, any CVD and mortality, including non-CVD mortality during the first-year postdischarge. The results suggest that unexplained chest pain patients may benefit from greater healthcare coordination between medical disciplines.

Excessive computer game playing among Norwegian adults: self-reported consequences of playing and association with mental health problems.

Computer games are the most advanced form of gaming. For most people, the playing is an uncomplicated leisure activity; however, for a minority the gaming becomes excessive and is associated with negative consequences. The aim of the present study was to investigate computer game-playing behaviour in the general adult Norwegian population, and to explore mental health problems and self-reported consequences of playing. The survey includes 3,405 adults 16 to 74 years old (Norway 2007, response rate 35.3%). Overall, 65.5% of the respondents reported having ever played computer games (16-29 years, 93.9%; 30-39 years, 85.0%; 40-59 years, 56.2%; 60-74 years, 25.7%). Among 2,170 players, 89.8% reported playing less than 1 hr. as a daily average over the last month, 5.0% played 1-2 hr. daily, 3.1% played 2-4 hr. daily, and 2.2% reported playing > 4 hr. daily. The strongest risk factor for playing > 4 hr. daily was being an online player, followed by male gender, and single marital status. Reported negative consequences of computer game playing increased strongly with average daily playing time. Furthermore, prevalence of self-reported sleeping problems, depression, suicide ideations, anxiety, obsessions/ compulsions, and alcohol/substance abuse increased with increasing playing time. This study showed that adult populations should also be included in research on computer game-playing behaviour and its consequences.

Comorbidity of migraine and epilepsy in a Norwegian community.

BACKGROUND AND PURPOSE: Studies on the comorbidity of migraine and epilepsy have shown conflicting results. We wanted to explore the epidemiological association between migraine and seizure disorders in a population-based material where case ascertainment was enhanced by individual specialist assessments. METHODS: Information concerning migraine and seizure disorders was collected from 1793 participants in an interview-based survey in a circumscribed community. Mixed headache, with features both of migraine without aura and tension-type headache, was excluded from further analyses because of its ambiguous character (n = 137). Thus, data from 1656 participants were included in the study. RESULTS: The number of subjects with epilepsy was small, and a statistically significant association between migraine and the diagnosis of epilepsy was not found. There was a tendency to more active epilepsy in subjects with migraine (1.0%, 5/524), particularly for migraine with aura (1.8%, 3/168), compared with subjects without migraine (0.5%, 6/1132). Migraine was present in five of 11 subjects with active epilepsy (45%) and in four of 28 (14%) with epilepsy in remission (P = 0.09). CONCLUSIONS: An overall association between migraine and seizure disorders could not be demonstrated, but there was a tendency to more migraine in individuals with active epilepsy.

Metabolism of lactate in cultured GABAergic neurons studied by 13C nuclear magnetic resonance spectroscopy.

Primary cultures of mouse cerebral cortical neurons (GABAergic) were incubated for 4 hours in media without glucose containing 1.0 mmol/L [U-13C]lactate in the absence or presence of 0.5 mmol/L glutamine. Redissolved, lyophilized cell extracts were analyzed by 13C nuclear magnetic resonance spectroscopy to investigate neuronal metabolism of lactate and by HPLC for determination of the total amounts of glutamate (Glu), gamma-aminobutyric acid (GABA), and aspartate (Asp). The 13C nuclear magnetic resonance spectra of cell extracts exhibited multiplets for Glu, GABA, and Asp, indicating pronounced recycling of labeled tricarboxylic acid cycle constituents. There was extensive incorporation of 13C label into amino acids in neurons incubated without glutamine, with the percent enrichments being approximately 60% for Glu and Asp, and 27% for GABA. When 0.5 mmol/L glutamine was added to the incubation medium, the enrichments for Asp, Glu, and GABA were 25%, 35%, and 25%, respectively. This strongly suggests that glutamine is readily converted to Glu and Asp but that conversion to GABA may be complex. The observation that enrichment in GABA was identical in the absence and presence of glutamine whereas cycling was decreased in the presence of glutamine indicates that only C-2 units derived from glutamine are used for GABA synthesis, that is, that metabolism through the tricarboxylic acid cycle is a prerequisite for GABA synthesis from glutamine. The current study gives further support to the hypothesis that cellular metabolism is compartmentalized and that lactate is an important fuel for neurons in terms of energy metabolism and extensively labels amino acids synthesized from tricarboxylic acid cycle intermediates (Asp and Glu) as well as the neurotransmitter in these neurons (GABA).

[U-13C]glutamate metabolism in rat brain mitochondria reveals malic enzyme activity.

13C nuclear magnetic resonance spectroscopy was used to study the activity of malic enzyme in isolated brain mitochondria from rat in the presence of unlabelled malate and [U-13C]glutamate. ADP, inorganic phosphate, malate and [U-13C]glutamate were added to a suspension of oxygenated mitochondria. Typical tricarboxylic acid (TCA) cycle constituents (malate, 2-oxoglutarate and succinate) were labelled from [U-13C]glutamate and detected in the superfusion medium. The labelling patterns in the different atom positions of glutamate revealed entry of both unlabelled and labelled acetyl-CoA into the TCA cycle. Unlabelled acetyl-CoA was derived via pyruvate from exogenously applied malate by the action of mitochondrial malic enzyme, while labelled acetyl-CoA was derived from TCA cycle intermediates, most likely by the action of mitochondrial malic enzyme on malate produced from [U-13C]glutamate. The results demonstrate malic enzyme activity and pyruvate recycling in isolated rat brain mitochondria.

Vasodilation in porcine ophthalmic artery: peptide interaction with acetylcholine and endothelial dependence.

Co-activation of cranial perivascular sensory and parasympathetic fibres in vivo induces simultaneous release of several vasodilatory substances with neurotransmitter or neuromodulatory roles. The role of the endothelium and possible interactions between such substances are poorly understood. The objective of this study was therefore to investigate these aspects with the sensory dilator calcitonin gene-related peptide (CGRP) and the parasympathetic dilators acetylcholine (ACh) and vasoactive intestinal peptide (VIP) in isolated porcine ophthalmic artery. Whilst ACh induced relatively rapid, endothelium-dependent dilation, CGRP and VIP induced slower dilations. Both CGRP and VIP were found to have partial endothelium-dependence in this artery. The simultaneous addition of ACh with CGRP potentiated the relaxation induced by CGRP, as has already been shown for substance P. ACh did not potentiate VIP relaxation, but the results generally indicate a potential role for ACh in initiating rapid dilation prior to strong, sustained relaxation by CGRP or VIP. The potential role of the endothelium and of substances like ACh or substance P in enhancing the rate of dilation of neuropeptides inducing strong and sustained relaxation is discussed.

Mutual modification of vasoactivity by calcitonin gene-related peptide and endothelin-1 in isolated porcine ophthalmic artery.

Vasodilation has been implicated in the pathophysiology of some headaches, but the mechanisms behind such abnormalities remain unknown. Calcitonin gene related peptide (CGRP), a peptide present in sensory trigeminal fibres, induces strong and long lasting vasodilation in cranial vessels, and has been found to be increased in jugular blood during migraine attacks. Endothelin (ET) is a recently identified potent vasoconstrictor peptide, which also induces long-lasting responses. ET-CGRP interactions may be of importance in vascular beds putatively involved in pain development in the head, and were therefore studied in isolated porcine ophthalmic arteries. Both peptides were found to induce strong and long-lasting reactions in this artery. CGRP decreased ET-induced contractions and ET decreased CGRP-induced relaxations. These effects were additive rather than synergistic.

Lactate formation from [U-13C]aspartate in cultured astrocytes: compartmentation of pyruvate metabolism.

Metabolism of [U-13C]aspartate in cultured astrocytes and the effects of inhibitors of malic enzyme and phosphoenolpyruvate carboxykinase (hydroxymalonate and 3-mercaptopicolinic acid, respectively) were studied using 13C nuclear magnetic resonance (NMR) spectroscopy. The labelling of glutamate and glutamine showed entry of aspartate into the tricarboxylic acid (TCA) cycle after conversion to oxaloacetate. Production of [U-13C]pyruvate from [U-13C]aspartate was revealed by the presence of [U-13C]lactate in incubation media. Furthermore, labelling patterns in C-2 and C-3 in intracellular aspartate showed entry of [1,2-13C]acetyl-CoA into the TCA cycle; evidence for pyruvate-recycling. No reduction in [U-13C]lactate was observed in the presence of either enzyme inhibitor. However, 3-mercaptopicolinic acid reduced incorporation of labelled acetyl-CoA into TCA cycle intermediates, indicating compartmentation of pyruvate production in astrocytes.

Applications of neural network analyses to in vivo 1H magnetic resonance spectroscopy of epilepsy patients.

A total of 67 in vivo water-suppressed proton magnetic resonance spectra of the temporal lobes were recorded from 15 patients with long standing temporal lobe epilepsy and 13 healthy volunteers. Conventional data analysis indicated slightly lower N-acetyl aspartate levels in epileptic patients compared with controls. For further analysis of data, a spectral region (4.0-1.5 ppm) was used as input for artificial neural network analysis. Correct classification of spectra was obtained in 66 out of 67 cases, disregarding from which side of the brain the spectra were recorded. The ability of the trained network to recognize spectra recorded both contalaterally and ipsilaterally to the epileptic focus strongly indicates bilateral metabolic changes. Artificial neural networks could also be trained to recognize whether the spectra were recorded from the ipsilateral or contralateral side of the epileptic focus, indicating that neural network analysis of in vivo proton MR spectra can be used as an additional tool for pre-surgical lateralization of seizure foci.

Classification of in vivo 1H MR spectra from breast tissue using artificial neural networks.

BACKGROUND: The study was designed in order to investigate whether artificial neural networks could be used for analysis of in vivo magnetic resonance (MR) spectra from breast cancer patients. MATERIALS AND METHODS: In vivo 1H MR spectra with three different echo times (TE 135, 350 and 450 msec) were acquired from patients with benign and malignant breast lesions and from healthy volunteers, of whom some were breast-feeding. A spectral region (4.0-1.5 ppm) was used as input for artificial neural network analysis, for the attempted classification of the data into different groups. RESULTS: Data recorded at all three echo times were necessary to obtain the best results. Furthermore, malignant tissue was differentiated from benign tumours using this approach, whereas benign tumours were poorly separated from healthy tissue. CONCLUSION: The results presented here indicate that in vivo MR spectroscopy in conjunction with neural network analysis might be useful for the evaluation of breast lesions.

Initial interactions of platelets and plasma proteins in flowing non-anticoagulated human blood with the artificial surfaces Dacron and PTFE.

The purpose of the present study was to investigate and to compare the interactions of platelets and proteins in flowing non-anticoagulated human blood with the biomaterials polyethylene-terephthalate (Dacron) and polytetrafluoroethylene (PTFE, Teflon). The respective biomaterials were positioned in a parallel-plate perfusion chamber, and exposed to flowing blood for 5 min at wall shear rates characteristic for veins (100/s), medium sized (650/s) and moderately stenosed arteries (2,600/s). Blood-material interactions were morphologically quantified as platelet-surface adhesion, thrombus volume and fibrin deposition. Platelet adhesion to Dacron was highest at the lowest shear rate (13%) and decreased with increasing shear (4% at 2600/s). In contrast, platelet adhesion to PTFE was shear rate independent (17-19%), and significantly higher than the adhesion to Dacron at 2600/s (P < 0.05). A hallmark of the platelets adherent to PTFE and Dacron was the large percentage of platelets not spread out on the surface. This indicates that both materials were poor platelet activators, even though immunostaining demonstrated the adsorption of the platelet adhesive proteins von Willebrand factor and fibronectin. Adsorption of fibrinogen was also prevailing on both materials. Virtually no thrombi formed on Dacron, while a few small platelet thrombi were observed on PTFE. Less than 1% of the Dacron and PTFE surfaces were covered by fibrin, irrespective of the shear rate. Thus, Dacron and PTFE interact differently with flowing non-anticoagulated human blood, and Dacron is apparently the least thrombogenic material.

Computerized analysis of isometric tension studies provides important additional information about vasomotor activity.

Concentration-response curves of isometric tension studies on isolated blood vessels are obtained traditionally. Although parameters such as Imax, EC50 and pA2 may be readily calculated, this method does not provide information on the temporal profile of the responses or the actual nature of the reaction curves. Computerized data acquisition systems can be used to obtain average data that represent a new source of otherwise inaccessible information, since early and late responses may be observed separately in detail.

Endothelin-1 inhibits the vasodilation induced by substance P in isolated porcine ophthalmic artery.

The vasoconstrictor effect of endothelin-1 is long-lasting and slow in onset, suggesting that this peptide may be involved with long-term vascular responses. Substance P, a quick-acting, vasodilatory tachykinin present in sensory nerves, may be released by trigeminal fibres and thereby participate in the regulation of vascular tone in the head. Given the potential role of vasoregulatory peptides in the ocular-forehead circulation in the pathophysiology of vascular headaches, the interactions between substance P and endothelin-1 over time were studied in isolated porcine ophthalmic artery. Substance P-induced relaxation of precontracted artery segments was significantly diminished by endothelin-1, despite the fact that endothelin-1 itself had no further significant contractile effect on these arteries. It is also noteworthy that the observed reduction of substance P-induced relaxation occurred much more rapidly than the onset of endothelin-1-induced contraction in relaxed porcine ophthalmic artery. The results suggest an inhibitory synergism between endothelin-1 and substance P in this vascular bed.

Time trends in ectopic pregnancies in a Norwegian county 1970-2004--a population-based study.

BACKGROUND: The study objective was to estimate temporal trends in ectopic pregnancy in a well-defined population. METHODS: We identified patients with ectopic pregnancy in hospital discharge registries in Sør-Trøndelag County, Norway, 1970-2004, and retrieved data from medical records. We calculated age-specific ectopic pregnancy incidence, proportions of patients with first ectopic pregnancy/prior infertility treatment, incidence of ectopic pregnancy by birth cohort and age and ratio of ectopic pregnancy to live births (extrauterine ratio) by age and parity. RESULTS: Age-adjusted ectopic pregnancy incidence rates increased from 4.3 to 16.0 per 10 000 women-years over the period 1970-1974 to 1990-1994 and declined to 8.4 per 10 000 women-years in 2000-2004. Incidences were highest among women aged 25-34 years throughout the study period. We observed decreases in proportions of women with previous ectopic pregnancy and with prior infertility treatment after 1990-1994. Incidence rates were the highest for women born between 1960 and 1964 in all age groups. Extrauterine ratio increased with age and was higher for women with two or more previous births compared with women with none or one prior birth. CONCLUSIONS: The epidemic increase in ectopic pregnancy towards 1990-1994 was followed by a marked decrease.

[U-13C] aspartate metabolism in cultured cortical astrocytes and cerebellar granule neurons studied by NMR spectroscopy.

The metabolism of [U-13C]aspartate was studied in cultured cortical astrocytes and cerebellar granule neurons in the presence of glucose and during inhibition of glycolysis. Redissolved, lyophilized cell extracts and incubation media were analyzed by 13C nuclear magnetic resonance spectroscopy for the determination of metabolites labeled from aspartate. Uniformly labeled lactate was prominent in control media of astrocytes and cerebellar granule neurons. In both cell types, aspartate entered the tricarboxylic acid (TCA) cycle, as shown by labeling patterns in glutamate and, in astrocytes, in glutamine. From the complex labeling patterns in aspartate in astrocytic perchloric acid extracts it was clear that acetylcoenzyme A (acetyl-CoA) derived from aspartate via oxaloacetate and pyruvate could enter the TCA cycle. Such "recycling," however, could not be detected in cerebellar granule neurons. Inhibition of glycolysis reduced aspartate uptake and metabolism in both cell types. Most notably, lactate derived from aspartate showed a large reduction, and in astrocytes, incorporation of labeled acetyl-CoA into the TCA cycle was significantly reduced. Thus, astrocytes and cerebellar granule neurons differ in their handling of aspartate. Furthermore, inhibition of glycolysis clearly affected aspartate metabolism by such cells.

Comparison of lactate and glucose metabolism in cultured neocortical neurons and astrocytes using 13C-NMR spectroscopy.

In cerebral cortical neurons, synthesis of the tricarboxylic acid (TCA) cycle-derived amino acids, glutamate and aspartate as well as the neurotransmitter of these neurons, gamma-aminobutyrate (GABA), was studied incubating the cells in media containing 0.5 mM [U-13C]glucose in the absence or presence of glutamine (0.5 mM). Lyophilized cell extracts were analyzed by 13C nuclear magnetic resonance (NMR) spectroscopy and HPLC. The present findings were compared to results previously obtained using 1.0 mM [U-13C]lactate as the labeled substrate for the neurons. Regardless of the amino acids studied, incubation periods of 1 and 4 h resulted in identical amounts of 13C incorporated. Furthermore, the metabolism of lactate was studied under analogous conditions in cultured cerebral cortical astrocytes. The incorporation of 13C from lactate into glutamate was much lower in the astrocytes than in the neurons. In cerebral cortical neurons the total amount of 13C in GABA, glutamate and aspartate was independent of the labeled substrate. The enrichment in glutamate and aspartate was, however, higher in neurons incubated with lactate. Thus, lactate appears to be equivalent to glucose with regard to its access to the TCA cycle and subsequent labeling of glutamate, aspartate and GABA. It should be noted, however, that incubation with lactate in place of glucose led to lower cellular contents of glutamate and aspartate. The presence of glutamine affected the metabolism of glucose and lactate differently, suggesting that the metabolism of these substrates may be compartmentalized.

External standard method for the in vivo quantification of choline-containing compounds in breast tumors by proton MR spectroscopy at 1.5 Tesla.

Quantification of choline-containing compounds observed with (1)H MRS of breast tumors is of interest since such compounds have been linked to malignancy. Experiments were performed at 1.5 T with an external standard containing phosphocholine for calibration. In phantom studies, good precision was achieved after correction for T(1)/T(2) effects. T(2) values for choline were estimated for two breast cancer patients. A choline concentration of 2.0 mM was calculated for a third patient, a result comparable to in vitro findings. Magn Reson Med 46:189-192, 2001.

Sumatriptan relaxes isolated porcine ophthalmic artery, but inhibits VIP-induced relaxation.

Sumatriptan, a 5-hydroxytryptamine (5HT)1-like receptor agonist, is a new antimigraine drug which is also effective in cluster headache (CH), a disorder with marked ocular circulatory abnormalities. Sumatriptan could putatively exert a therapeutic effect in this vascular bed. The present study is an attempt to assess sumatriptan's vasoactivity in isolated porcine ophthalmic artery (POA) and to verify whether it has similar activity to 5HT, and whether it interferes with the vasodilation induced by calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP). In contrast to 5HT, sumatriptan induced only slight contraction in POA at high concentrations. However, in some artery segments pre-contracted with PGF2 alpha, sumatriptan induced a slight and short-lasting but marked relaxation. In addition, relaxations induced by VIP were inhibited significantly by sumatriptan, whereas CGRP effects were not influenced by the drug. Such reactions suggest that sumatriptan's effect in CH is probably unrelated to direct ocular arterial vasoconstriction.

[U-13C]glutamate metabolism in astrocytes during hypoglycemia and hypoxia.

The ability of cultured astrocytes to metabolize [U-13C]glutamate in the absence of glucose was investigated by utilizing 13C nuclear magnetic resonance spectroscopy to identify 13C-labeled metabolites. Control cultures (3 mM glucose), hypoglycemic cultures (glucose-deprived), severe hypoglycemic cultures (glucose-deprived, 0.5 mM iodoacetate as an inhibitor of glycolysis), hypoglycemic/hypoxic cultures, and cultures deprived of all additional substrates were incubated for 2 hr in medium containing 0.5 mM glutamate (50% [U-13C]glutamate). Glucose deprivation alone had little effect on removal of glutamate from the culture medium, but the presence of iodoacetate or incubating cultures in a low-oxygen atmosphere decreased glutamate clearance. Only the withdrawal of all substrates other than glutamate decreased glutamine synthesis. Metabolism of glutamate through the tricarboxylic acid (TCA) cycle was evident by the appearance of [1,2,3-13C]glutamate and [U-13C]aspartate in cell extracts and [U-13C]lactate in cell media. Lactate derived from TCA cycle intermediates was significantly reduced after glucose deprivation and even more so after severe hypoglycemia. Release of glutamate from astrocytes was observed under all incubation conditions. [U-13C]Aspartate was not detected in control media but was released from glucose-deprived cells when oxygen was available. Increased release was observed in the presence of iodoacetate. After withdrawal of all substrates other than glutamate, [U-13C]aspartate was the only metabolite observed intracellularly, whereas aspartate, glutamine, and 5-oxoproline were detected in the incubation medium. The present results indicate that glutamate-to-aspartate conversion is preferentially utilized by astrocytes when oxygen is available but glycolysis is impaired.