Vagal Nerve Stimulation-Modulation of the Anti-Inflammatory Response and Clinical Outcome in Psoriatic Arthritis or Ankylosing Spondylitis.

OBJECTIVES: The vagal nerve exerts an essential pathway in controlling the cholinergic anti-inflammatory reflex. Thus, the study is aimed at investigating the acute effect of a noninvasive transcutaneous vagus nerve stimulation on clinical disease activity and systemic levels of inflammation in patients with psoriatic arthritis or ankylosing spondylitis. METHODS: Twenty patients with psoriatic arthritis (PsA) and 20 patients with ankylosing spondylitis (AS) were included and stimulated bilaterally with a handheld vagal nerve stimulator for 120 seconds 3 times a day for 5 consecutive days. All patients were in remission. Cardiac vagal tone, clinical scores, CRP, and cytokine levels were assessed. RESULTS: In PsA and AS, decreased heart rate was observed, confirming compliance. Furthermore, in PsA, a clear reduction of clinical disease activity associated with a 20% reduction in CRP was shown. In AS, a reduction in interferon-γ, interleukin- (IL-) 8, and 10 was shown. No side effects were described. CONCLUSION: This open-label study provides support for an anti-inflammatory effect of transcutaneous vagus nerve stimulation in patients with psoriatic arthritis and ankylosing spondylitis. The modulated immune response and reduced disease activity and CRP-levels raise the fascinating possibility of using neuromodulation as an add-on to existing pharmacological treatments.

Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study.

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.

Vagal influences in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease with a prevalence of 0.5-1% in Western populations. Conventionally, it is treated with therapeutic interventions that include corticosteroids, disease-modifying anti-rheumatic drugs, and biological agents. RA exerts a significant socio-economic burden and despite the use of existing treatments some patients end up with disabling symptoms. The autonomic nervous system (ANS) is a brain-body interface that serves to regulate homeostasis by integrating the external environment with the internal milieu. The main neural substrate of the parasympathetic branch of the ANS is the vagus nerve (VN). The discovery of the role of the ANS and the VN in mediating and dampening the inflammatory response has led to the proposal that modulation of neural circuits may serve as a valuable therapeutic tool. Recent studies have explored the role of the VN in this inflammatory reflex and have provided evidence that stimulation may represent a novel new therapeutic intervention. Accumulating evidence suggests that modulation of the parasympathetic tone results in a broad physiological multi-level response, including decreased pro-inflammatory cytokine response in terms of tumour necrosis factor-α, interleukin-1 (IL-1), and IL-6, and may result in an enhanced macrophage switch from M1 to M2 cells and potentially an increased level of the anti-inflammatory cytokine IL-10. Therefore, therapeutic electrical modulation of the VN may serve as an alternative, non-pharmacological, neuroimmunomodulatory intervention in RA in the future. This review gives a focused introduction to the mechanistic link between the ANS and the immune system.

Skills among young and elderly laypersons during simulated dispatcher assisted CPR and after CPR training.

BACKGROUND: Dispatcher assisted cardiopulmonary resuscitation (DA-CPR) increase the rate of bystander CPR. The aim of the study was to compare the performance of DA-CPR and attainable skills following CPR training between young and elderly laypersons. METHODS: Volunteer laypersons (young: 18-40 years; elderly: > 65 years) participated. Single rescuer CPR was performed in a simulated DA-CPR cardiac arrest scenario and after CPR training. Data were obtained from a manikin and from video recordings. The primary endpoint was chest compression depth. RESULTS: Overall, 56 young (median age: 26, years since last CPR training: 6) and 58 elderly (median age: 72, years since last CPR training: 26.5) participated. Young laypersons performed deeper (mean (SD): 56 (14) mm vs. 39 (19) mm, P < 0.001) and faster (median (25th-75th percentile): 107 (97-112) per min vs. 84 (74-107) per min, P < 0.001) chest compressions compared to elderly. Young laypersons had shorter time to first compression (mean (SD): 71 (11) seconds vs. 104 (38) seconds, P < 0.001) and less hands-off time (median (25th-75th percentile): 0 (0-1) seconds vs. 5 (2-10) seconds, P < 0.001) than elderly. After CPR training chest compressions were performed with a depth (mean (SD): 64 (8) mm vs. 50 (14) mm, P < 0.001) and rate (mean (SD): 111 (11) per min vs. 93 (18) per min, P < 0.001) for young and elderly laypersons respectively. CONCLUSION: Despite long CPR retention time for both groups, elderly laypersons had longer retention time, and performed inadequate DA-CPR compared to young laypersons. Following CPR training the attainable CPR level was of acceptable quality for both young and elderly laypersons.

Considering Tangible Benefit for Interdependent Donors: Extending a Risk-Benefit Framework in Donor Selection.

From its infancy, live donor transplantation has operated within a framework of acceptable risk to donors. Such a framework presumes that risks of living donation are experienced by the donor while all benefits are realized by the recipient, creating an inequitable distribution that demands minimization of donor risk. We suggest that this risk-tolerance framework ignores tangible benefits to the donor. A previously proposed framework more fully considers potential benefits to the donor and argues that risks and benefits must be balanced. We expand on this approach, and posit that donors sharing a household with and/or caring for a potential transplant patient may realize tangible benefits that are absent in a more distantly related donation (e.g. cousin, nondirected). We term these donors, whose well-being is closely tied to their recipient, "interdependent donors." A flexible risk-benefit model that combines risk assessment with benefits to interdependent donors will contribute to donor evaluation and selection that more accurately reflects what is at stake for donors. In so doing, a risk-benefit framework may allow some donors to accept greater risk in donation decisions.

Free fruit at workplace intervention increases total fruit intake: a validation study using 24 h dietary recall and urinary flavonoid excretion.

BACKGROUND/OBJECTIVES: To validate 24 h dietary recall of fruit intake by measuring the total 24 h excretion of 10 different flavonoids in 24 h urine during an intervention with free fruit at workplaces. SUBJECTS/METHODS: Employees at workplaces offering a free-fruit program, consisting of daily free and easy access to fresh fruit, and controls employees at workplaces with no free-fruit program were enrolled in this validation study (n=103). Dietary intake was assessed by using a 24 h dietary recall questionnaire at baseline and approximately 5 months later. Ten flavonoids, quercetin, isorhamnetin, tamarixetin, kaempferol, hesperetin, naringenin, eriodictyol, daidzein, genistein, and phloretin, were measured using HPLC-electrospray ionization-MS. RESULTS: The 24 h urinary excretion of total flavonoids and the estimated intake of fruits were significantly correlated (r (s)=0.31, P<0.01). The dietary intake of citrus fruits and citrus juices was significantly correlated with total excretion of citrus specific flavonoids (r (s)=0.28, P<0.01), and orange was positively correlated with naringenin (r (s)=0.24, P<0.01) and hesperetin (r (s)=0.24, P<0.01). Phloretin in urine was correlated with apple intake (r (s)=0.22, P<0.01) and also with overall estimated intake of fruit (r (s)=0.22, P<0.01). CONCLUSIONS: This study shows that a 24 h dietary recall can be used as a valid estimate of the intake of fruits in agreement with an objective biomarker of fruit intake in free fruit at workplace interventions.

Relative bioavailability of the flavonoids quercetin, hesperetin and naringenin given simultaneously through diet.

The bioavailability and urinary excretion of three dietary flavonoids, quercetin, hesperetin and naringenin, were investigated. Ten healthy men were asked to consume a 'juice mix' containing equal amounts of the three flavonoids, and their urine and plasma samples were collected. The resulting mean plasma area under the curve (AUC)(0-48 h) and C(max) values for quercetin and hesperetin were similar, whereas the AUC(0-48 h) of naringenin and, thus, the relative bioavailability were higher after consumption of the same dose. The study consolidates a significantly lower urinary excretion of quercetin (1.5+/-1%) compared with hesperetin (14.2+/-9.1%) and naringenin (22.6+/-11.5%) and shows that this is not due to a lower bioavailability of quercetin, but rather reflects different clearance mechanisms.

A safe strategy for addition of vitamins and minerals to foods.

Addition of vitamins and minerals to foods must be done without health risk to any consumer group. International expert groups have aimed at establishing tolerable upper intake levels (ULs) for vitamins and minerals although lack of solid data on their safety is a major obstacle to this work. In this paper, we summarize the existing ULs and suggest the use of guidance levels (GLs) set by others and temporary guidance levels (TGLs) proposed here, whenever no consensus UL has been established for adults. We suggest the use of body surface area ratios to establish similar levels for younger age groups. The levels are applied in a model for calculation of safe fortification levels for all ages. We have estimated the upper 95(th) percentile intake of vitamins and minerals from food in various Danish age and gender groups and suggest that a daily multivitamin-mineral pill is included in the calculation of total dietary intake levels of all vitamins and minerals. By subtracting this dietary intake level from the UL, GL or TGL, we calculate the amount that can be safely used for fortification. Since safety must be assured for all age groups, the smallest difference relative to energy intake calculated for any age group is proposed as the maximal allowance (MA) for fortification with each nutrient. We suggest that the MA should be expressed in weight units per energy unit in order to distribute it equally between potentially fortifiable food groups according to their usual contribution to total energy intakes.

Plantar fibromatosis: use of magnetic resonance imaging in diagnosis.

For patients presenting with classic features of plantar fibromatosis, a presumptive diagnosis may be made on clinical grounds alone. In less clear cases, a biopsy may allow confirmation of the diagnosis; however, a biopsy exposes the patient to operative complications. Magnetic resonance imaging (MRI) offers a noninvasive method for confirmation of the clinical diagnosis that may obviate the need for a biopsy. We describe a case that demonstrates the potential of this technique.

Changes in circulating blood volume after infusion of hydroxyethyl starch 6% in critically ill patients.

BACKGROUND: The cardiovascular response to a volume challenge with hydroxyethyl starch (HES) (200/0.5) 6% depends on the relation between the volume of HES 6% infused and the expansion of the blood volume in critically ill patients. However, only relatively limited data exist on the plasma expanding effect of infusion of HES 6% in critically ill patients. The purpose of the study was to evaluate the variation in the expansion of the circulating blood volume (CBV) in critically ill patients after infusion of 500 ml of colloid (HES (200/0.5) 6%) using the carbon monoxide method. METHODS: In 20 consecutive patients admitted to the ICU requiring mechanical ventilation and volume expansion, 500 ml of HES (200/0.5) 6% was infused. The CBV was measured immediately before the infusion, 10 min after completing the infusion and then hourly for 8 h. RESULTS: The median volume expansion immediately after infusion was 470 ml (range 270 ml to 840 ml). The corresponding values after 4 h and 8 h were 265 ml (range -30 ml to 460 ml) and 120 ml (range -210 ml to 360 ml), respectively. The increase in CBV was only statistically significant for 4 h. The coefficient of variation of the method for estimation of CBV was 3.6%. CONCLUSIONS: The large interindividual variation of the volume expansion after infusion of HES 6% in critically ill patients illustrates one of the difficulties in optimizing colloid therapy and interpretating the changes in hemodynamic variables after a colloid challenge.

[Prognosis of return to work after streptokinase-treated acute myocardial infarction]. / Erhvervsprognosen 18 måneder efter et streptokinasebehandlet akut myokardieinfarkt.

In order to assess the impact of thrombolytic therapy on return to work 18 months after a first myocardial infarction 32 patients treated with streptokinase were compared to 30 patients not treated with streptokinase. The study was designed as a historical cohort study. The patients in both groups had continuous chest pain of less than six hours prior to admission and electrocardiographic changes consistent with acute myocardial infarction. The two groups were comparable with respect to medical variables related to their myocardial infarction and to educational level. A total of 17 patients (53%) in the streptokinase group and 16 (53%) among controls had stopped working 18 months after their MI. An association between the treatment and the working status could not be found (relative risk = 1.0) nor could it be found if the figures were corrected for deaths and retirements because of age. In conclusion, this study could not demonstrate any beneficial effect of thrombolytic therapy on the return to work 18 months after an initial myocardial infarction.

Detection of immobilized amplicons by ELISA-like techniques.

The NucleoLink surface is a physically modified, thermostable, optically clear resin. It allows the covalent binding of 5'-phosphorylated oligonucleotides. Target DNA amplification by polymerase chain reaction (PCR) is accomplished by asymmetric amplification on the covalently immobilized primer that develops into immobilized amplicons. A DNA fragment of bovine leukemia virus is used as a model system for the detection of immobilized amplicons by ELISA-like techniques. Covalently bound oligonucleotides are also utilized as capture probe in the hybridization-based signal amplification for detection of an infectious organism.

The effect of streptokinase on return to work 18 months after a first myocardial infarction.

In order to assess the impact of thrombolytic therapy on return to work eighteen months after a first myocardial infarction, 32 patients treated with streptokinase were compared with 30 patients not treated with streptokinase. The study was designed as a historical cohort study. The patients in both groups had continuous chest pain of less than six hours prior to admission and electrocardiographic changes consistent with acute myocardial infarction (MI). The two groups were comparable with respect to medical variables related to their myocardial infarction and to educational level. A total of 17 patients (53%) in the streptokinase group and 16 (53%) among controls had stopped working eighteen months after their MI. An association between the treatment and the working status could not be found (relative risk = 1.0) nor could it be found if the figures were corrected for deaths and retirements because of age. In conclusion, this study could not demonstrate any beneficial effect of thrombolytic therapy on the return to work eighteen months after an initial myocardial infarction.

Morphine does not affect laser induced warmth and pin prick pain thresholds.

The aim of this double-blind, placebo-controlled study was to evaluate the effect of intravenously administered morphine in humans using an argon laser to induce experimental pain. Thirty volunteers were randomised to receive a total of 0.15 mg.kg-1 morphine intravenously or saline. The argon laser was used to determine the possible change in warmth thresholds and pin prick pain thresholds. Measurements were performed before and at 10, 20, 30 and 40 min after the injection. During the observation period the warmth thresholds increased 20.7% (P < or = 0.05) from baseline (0.82 W +/- 0.42 W) in the morphine group while an increase of 14.3% (P > or = 0.05) was seen in the placebo group (Baseline: 0.91 +/- 0.37). The pinprick pain thresholds of the morphine group increased 9.4% (P < or = 0.05) from baseline (1.39 W +/- 0.7 W) while the corresponding thresholds of the placebo group was 4.6% (P > or = 0.05) (baseline: 1.73 W +/- 0.44 W). The differences seen between the morphine group and the placebo group were not statistically significant and thus it was demonstrated that morphine had no effect of either the feeling of warmth or the pain elicited by the argon laser. The present study supports other investigations and clinical experience suggesting that intermittent pain is not relieved by morphine unlike continuous pain, which can be relieved by morphine.

[Streptokinase as routine treatment in acute myocardial infarction. The effect on pain, arrhythmias and mortality assessed by a historical cohort study]. / Streptokinase som rutinebehandling ved akut myokardieinfarkt. Effekten på smerter, arytmier og letalitet vurderet ud fra en historisk kohorteundersøgelse.

It has been demonstrated that treatment with streptokinase (SK) in acute myocardial infarction (AMI) has an effect in reducing the mortality. The object of this study was, by means of a historical cohort study in a Danish Cardiological Department, to illustrate the effect of streptokinase on the course of pain, occurrence of arrhythmia and the lethality. Seventy-six patients with their first AMI treated with SK and low-dosage acetylsalicylic acid were compared with 76 patients with their first AMI who were not treated with SK. The median value of the employment of intravenous analgesics was significantly lower in the SK group (20 mg nicomorphine compared with 41 mg nicomorphine) as compared with the control group. Similarly, the duration of pain was briefer in the SK group (3.5 hours compared with 24 hours). Significantly more patients in the control group developed atrial fibrillation (12 patients compared with two). No differences were observed in the occurrence of arrhythmias endangering life in the two groups. Four patients in the SK group died during hospitalization whereas 14 died in the control group (p = 0.02). It is concluded that administration of SK intravenously combined with low-dosage acetylsalicylic acid in the acute phase of myocardial infarction has the effect of reducing 1) the duration of pain and thus the consumption of analgesics, 2) the number of cases of atrial fibrillation and 3) the lethality during the period of hospitalization.

Reduced occurrence of atrial fibrillation in acute myocardial infarction treated with streptokinase.

In a historical follow-up study of 152 hospital patients with acute myocardial infarction, the frequency of life-threatening arrhythmias (ventricular fibrillation, sustained ventricular tachycardia, 3rd degree AV-block, 2nd degree AV-block (Mobitz type II), and asystole) and atrial fibrillation in 76 patients treated with streptokinase was compared with their frequency in 76 patients who did not receive a thrombolytic therapy. Among those treated with streptokinase two patients (3%) developed atrial fibrillation, compared with 12 (16%) in the control group (P = 0.009). Life-threatening arrhythmias occurred with equal frequency in the two groups. Further studies should confirm and clarify the mechanism of the reduced frequency of atrial fibrillation in the streptokinase-treated patients.

Covalent immobilization of DNA onto polystyrene microwells: the molecules are only bound at the 5' end.

Carbodiimide-mediated condensation of DNA onto microwells is investigated. DNA is bound onto the microwells by formation of a phosphoramidate bond between the 5' terminal phosphate group and the microwells. Immobilization of 25 to 30 ng DNA per well is obtained. DNA molecules bound covalently at only the 5' end are, ideally, perfect for hybridization. The practicability of DNA molecules bound to microwells for hybridization is investigated.

Covalent immobilization of biomolecules onto polystyrene MicroWells for use in biospecific assays.

Modification of polystyrene for higher binding capacity and/or for specific covalent immobilization of biomolecules is discussed. The benefit of covalent coupling of biomolecules onto a new commercially available surface type for covalent immobilization, CovaLink NH, is illustrated. The CovaLink NH solid phase has spacer arms covalently grafted onto the polystyrene solid phase, approximately 10(14) groups/cm2. Coupling procedures for covalent immobilization of biotin and peptides are demonstrated, and the advantage of using carbodiimide for coupling of carboxylic acid containing compounds is shown.

Modulation of beta-galactosidase activity in peritoneal macrophages from C57B1 mice after exposure to Proprionibacterium acnes.

Peritoneal macrophages (PM luminal diameter) from untreated C57B1 mice contain high levels of beta-galactosidase (beta-gal) and these PM luminal diameter are heterogeneous in their expression of this enzyme. Intraperitoneal (i.p.) injection of saline caused a transient depression in the level of enzyme activity in the PM luminal diameter whereas i.p. injection of Proprionibacterium acnes (P. acnes) gave rise to a marked decrease of beta-gal activity in these cells. This reduction in enzymatic activity persisted for as long as the PM luminal diameter were activated for cytotoxicity towards the L929 tumor cell line, up to 35 days after injection. beta-gal activity was present in the lavage fluid from day 2-21 after injection of P. acnes but none was detected in the lavage fluid after injection of saline. It is proposed that the enzymatic activity in the lavage fluid is derived from monocytes which migrate from the blood into the peritoneal cavity. There was an influx of granulocytes in the P. acnes group which persisted up to 35 days after injection. In contrast none were observed in the saline group after 2 days. PM luminal diameter harvested after 1-35 days were large, highly vacuolized and many contained bacteria; these PM luminal diameter had the typical morphology of activated cells. It is suggested that the processing of P. acnes by granulocytes may play a role in the activation of macrophages in the early inflammatory response, with concurrent loss in beta-gal activity. However, in the later stages, interferon-gamma and other induced lymphokines may be instrumental in causing a decrease in beta-gal activity.