Importance of beta-blocker dose in prevention of ventricular tachyarrhythmias, heart failure hospitalizations, and death in primary prevention implantable cardioverter-defibrillator recipients: a Danish nationwide cohort study.

Aims: There is a paucity of studies investigating a dose-dependent association between beta-blocker therapy and risk of outcome. In a nationwide cohort of primary prevention implantable cardioverter-defibrillator (ICD) patients, we aimed to investigate the dose-dependent association between beta-blocker therapy and risk of ventricular tachyarrhythmias (VT/VF), heart failure (HF) hospitalizations, and death. Methods and results: Information on ICD implantation, endpoints, comorbidities, beta-blocker usage, type, and dose were obtained through Danish nationwide registers. The two major beta-blockers carvedilol and metoprolol were examined in three dose levels; low (metoprolol ≤ 25 mg; carvedilol ≤ 12.5 mg), intermediate (metoprolol 26-199 mg; carvedilol 12.6-49.9 mg), and high (metoprolol ≥ 200 mg; carvedilol ≥ 50 mg). Time to events was investigated utilizing multivariate Cox models with beta-blocker as a time-dependent variable. From 2007 to 2012, 2935 first-time ICD devices were implanted. During follow-up, 399 patients experienced VT/VF, 728 HF hospitalizations and 361 died. As compared with patients not on beta-blockers, low, intermediate, and high dose had significantly reduced risk of HF hospitalizations {hazard ratio (HR) = 0.68 [0.54-0.87], P = 0.002; HR = 0.53 [0.42-0.66], P < 0.001; HR = 0.43 [0.34-0.54], P < 0.001} and death (HR = 0.47 [0.35-0.64], P < 0.001; HR = 0.29 [0.22-0.39], P = 0.001; HR = 0.24 [0.18-0.33], P < 0.001). For the endpoint of VT/VF, only intermediate and high dose beta-blocker was associated with significantly reduced risk (HR = 0.58 [0.43-0.79], P < 0.001; HR = 0.53 [0.39-0.72], P < 0.001). No significant difference was found between comparable doses of carvedilol and metoprolol on any endpoint (P = 0.06-0.94). Conclusion: In primary prevention ICD patients, beta-blocker therapy was associated with significantly reduced risk of all endpoints, as compared with patients not on beta-blocker, with the suggestion of a dose-dependent effect. No detectable difference was found between comparable doses of carvedilol and metoprolol.

FURTHER STUDIES ON THE gammaG-HEAVY CHAIN GENE COMPLEXES, WITH PARTICULAR REFERENCE TO THE GENETIC MARKERS Gm(g) AND Gm(n).

The recently described Gm (g) and Gm (n) genetic markers of the gammaG3- and gammaG2-subgroups of gamma-globulin were characterized in detail primarily through studies of myeloma proteins, their polypeptide chains and fragments. Antisera derived from rabbits, non-human primates and rheumatoid arthritis patients gave identical results. This contrasted with the Gm (b) system where the rabbit antisera react with a different genetic determinant (b(0)) than the sera from rheumatoid arthritis patients (b). The Gm (g) and Gm (n) antigens were detected both by precipitin analysis and by hemagglutination inhibition. The Gm (g) antigen was not associated with any of the other genetic antigens of the gammaG3-proteins which all belonged in the Gm (b) class. The genes for the latter were always allelic to the gene coding for Gm (g), with that for Gm (b(0)) constantly present when that for Gm (g) was absent. The Gm (g) and Gm (n) markers were of particular value in tracing the various gene complexes made up of the closely linked subgroup genes. Further support was gained for the concept that the different gene complexes of various population groups arose primarily through crossing-over. The Gm(g) and Gm(b) genes for the gammaG3-subgroup were extremely closely linked to those for the gammaG1-subgroup. However the Gm (n) marker indicated that the gammaG2-subgroup genes were probably further separated on the chromosome. Additional evidence was obtained for the gammaG2-gammaG3-gammaG1-order of the subgroup cistrons. Among the wide range of gene complexes a new type (gammaG2,-,gamma/G1) was described. This complex appeared to have a deletion of the gammaG3-cistron. Lower levels of gammaG3-globulin were found in the sera of the individuals with this gene in the heterozygous state. The possibility that this unusual complex arose through an unequal nonhomologous crossing-over is discussed.

Optimal radiologic position of an umbilical venous catheter tip as determined by echocardiography in very low birth weight newborns.

OBJECTIVE: To compare chest X-ray with echocardiogram (ECHO) in the localization of an umbilical venous catheter (UVC) tip in very low birth weight infants (VLBW). Secondary objectives determined the association between techniques for tip placement by the vertebral body level on X-ray, as well as the length of the thoracic inferior vena cava-right atrial (TIVC-RA) junction by ECHO. STUDY DESIGN: Prospective, sequentially enrolled, masked, single regional perinatal center study. Shortly after birth, one or more anterior-posterior X-rays were ordered by the clinical team to verify that the UVC tip was fixed in the central right atrium (cRA) or at the TIVC-RA junction. An echocardiogram was performed as soon as possible after the last X-ray and UVC tip location was interpreted by a pediatric cardiologist. The pediatric radiologist and cardiologist were masked with regard to each other's reading. RESULTS: The newborns (n = 51) were 27 (±3) weeks by gestational age with birth weights of 1029 (±288) grams (mean±SD). The radiologist read 50 UVC tips (98%) in the cRA or TIVC-RA junction and 1 (2%) in the LA. The cardiologist read 22 (43%) in the cRA or TIVC-RA, 21 (41%) in the LA and 8 (16%) tips could not be located in the heart. When the UVC tip was interpreted by X-ray as located in the TIVC-RA junction 8/29 (28%) were in the LA by echocardiogram. There was no agreement between vertebral level and tip position in the TIVC-RA junction, RA or LA. The TIVC-RA junction measured 6±1 mm and correlated with birth weight r = 0.54 (p < 0.001). CONCLUSION: In VLBW newborns, placement of the UVC tip into the cRA or TIVC-RA junction by X-ray does not avoid misplacement in the left atrium as demonstrated by echocardiography. For VLBW infants, it is suggested that echocardiography may be helpful in verifying that the original placement or migration of the UVC tip into the LA has not occurred.

Population Exposure-Response Modeling of Naloxegol in Patients With Noncancer-Related Pain and Opioid-Induced Constipation.

Naloxegol is a polyethylene glycol derivative of naloxone approved in the US as a once-daily oral treatment for opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were constructed based on data from two phase III studies comprising 1,331 adults with noncancer pain and OIC. In order to characterize the protocol-defined naloxegol responder rate, the number of daily spontaneous bowel movements (SBMs) was characterized by a longitudinal ordinal nonlinear mixed-effects logistic regression dose-response model, and the incidence of diary entry discontinuation was described by a time-to-event model. The mean number of SBMs per week increased with increasing naloxegol dose. The predicted placebo-adjusted responder rates (90% confidence interval) were 10.4% (4.6-13.4%) and 11.1% (4.8-14.4%) for naloxegol 12.5 and 25 mg/day, respectively. Model-predicted response to naloxegol was influenced by the baseline SBM frequency and characteristics of the opioid treatment.

Regional myocardial blood flow in patients with sick sinus syndrome randomized to long-term single chamber atrial or dual chamber pacing--effect of pacing mode and rate.

OBJECTIVES: This study aimed to evaluate regional myocardial blood flow (MBF) and global left ventricular ejection fraction (LVEF) during chronic pacing in patients with sick sinus syndrome (SSS) randomized to either single chamber atrial (AAI) or dual chamber (DDD) pacing. BACKGROUND: Experimental studies indicate that chronic pacing in the right ventricular apex changes regional MBF, thereby compromising left ventricular function. METHODS: Thirty patients (age 74 +/- 10 years) were randomized to AAI (n = 15) or DDD (n = 15) pacemakers. After 22 +/- 7 months of pacing, MBF was quantified with 13N-labeled ammonia positron emission tomography scanning at 60 beats per min and 90 beats per min. Patients in the DDD group furthermore underwent MBF measurement at temporary AAI pacing, 60 beats per min. Myocardial blood flow was assessed in the anterior, lateral, inferior and septal regions, and the global mean MBF was calculated. Left ventricular ejection fraction was determined by echocardiography at pacemaker implantation and at the time of MBF measurements. RESULTS: Myocardial blood flow at rates 60 and 90 beats per min did not differ between the AAI and DDD groups. During temporary AAI pacing in the DDD group, MBF was significantly higher than during DDD pacing in both the inferior (p = 0.001) and septal (p = 0.004) regions and also globally (0.61 +/- 0.15 vs. 0.53 +/- 0.13 mL x g(-1) x min(-1), p = 0.005). In the DDD group, LVEF decreased from pacemaker implantation to time of MBF measurements (0.61 +/- 0.09 vs. 0.56 +/- 0.07, p = 0.013). Left ventricular ejection fraction during temporary AAI pacing at time of MBF measurements was not different from LVEF at pacemaker implantation. CONCLUSIONS: In patients with SSS, chronic DDD pacing reduced inferior, septal and global mean MBF as well as LVEF, as compared with temporary AAI pacing. The LVEF reversed to baseline level during temporary AAI pacing despite 22 months of permanent ventricular pacing preceding it. Augmenting pace rate to 90 beats per min increased MBF equally in the two treatment groups.

Regional distribution of glutathione peroxidase and Glutathione-S-transferase in adult and premature human retinas.

The activities of glutathione peroxidase (GSH-Px) and glutathione-S-transferase (GSH-S-tase) were investigated in adult and premature human retinas. The measurements were done in the vascular and avascular regions of premature retinas at gestational age of 22-33 weeks and in the central, mid-peripheral, and far peripheral regions of mature retinas from the age of 1 month to 73 years. Among the premature infants, those who survived for greater than 24 hours were supplemented with alpha-tocopherol (vitamin E) on a periodic basis. The vascular and avascular regions of premature retinas had higher activities of GSH-Px when compared to the central and far peripheral regions of mature retinas. Infants surviving more than 24 hr had higher activities of GSH-S-tase in the avascular region than infants who survived less than 24 hr. Survival did not affect either enzyme activity in the vascular regions. Mature retinas showed a decrease in GSH-Px specific activity with age, but no age-related changes in GSH-S-tase were observed. These data demonstrate that premature infants are born with relatively high levels of GSH-Px and GSH-S-tase.

The regional distribution of vitamins E and C in mature and premature human retinas.

Vitamin E is used to ameliorate retinopathy of prematurity, but little is known about baseline vitamin E levels in retinas of premature infants or the effect of vitamin E supplementation on these levels. Vitamin E and C levels were measured in mature retinas (1 month to 73 years) and in retinas of premature infants (22 to 33 weeks of gestation). The infants fell into two groups: (1) those who survived less than 12 hr and received no vitamin E, and (2) those who survived greater than 4 days and received vitamin E supplementation. Premature infants are born with 5 to 12 percent the vitamin E levels found in mature retinas. Vitamin E levels in vascular and avascular retina of premature infants increased with gestation. Infants born greater than 27 weeks gestation and surviving at least 4 days with vitamin E supplementation demonstrated markedly elevated vitamin E levels in vascular and avascular retina when compared to supplemented infants less than 27 weeks gestation. Premature infants possessed 35-50% higher levels of retinal vitamin C than those found in mature retinas. These data demonstrate that premature infants are born with relatively low levels of retinal vitamin E, particularly in the avascular region, but contain an abundance of retinal vitamin C. These data further suggest that vitamin E supplementation results in a rapid increase in retinal vitamin E levels, particularly in infants greater than 27 weeks gestational age.

Rabbit photoreceptor outer segments contain high levels of docosapentaenoic acid.

Docosapentaenoic acid (22:5 omega 6), a minor constituent (less than 4%) of photoreceptor outer segment membranes in all vertebrate species examined to date, comprises 23% of the fatty acids in total lipids from rabbit outer segment membranes. This fatty acid is a significant constituent of each of the three major phospholipid classes in these membranes. The levels of docosahexaenoic acid (22:6 omega 3), the major polyunsaturated fatty acid of most other vertebrate outer segments, was 20%. The sum of 22:5 omega 6 and 22:6 omega 3 in rabbit outer segment membrane lipids is similar to the amount of 22:6 omega 3 usually found in membranes from other vertebrate species.

Polyunsaturated fatty acids and vitamin E in rat rod outer segments during light damage.

Previous evidence suggests that lipid peroxidation may initiate photoreceptor damage induced by constant light exposure. In order to investigate the role of the antioxidant vitamin E in light damage, Long-Evans (pigmented) rats were atropinized and exposed to constant fluorescent light (Vita-Lite) of 10-20 foot candles for intervals up to 5 days. Following light exposure, retinal rod outer segments (ROS) were prepared and their lipids extracted. Retinas processed in parallel for morphological examination showed progressive ROS deterioration and selective loss of photoreceptor cells at 3 and 5 days of constant light. Similar to previous observations in undilated albino rats, constant illumination resulted in the specific loss of docosahexaenoic acid (22:6 omega 3) in the ROS. A novel finding in this study was an increase in the content of vitamin E relative to lipid phosphorus, stearic acid, and docosahexaenoic acid in the ROS of constant light-exposed animals.

Serial changes and prognostic implications of a Doppler-derived index of combined left ventricular systolic and diastolic myocardial performance in acute myocardial infarction.

The purpose of this study was to investigate the serial changes and prognostic value of a nongeometric Doppler-derived index of myocardial function that combines systolic and diastolic time intervals of the left ventricle in acute myocardial infarction (AMI). The Doppler index was measured in 60 consecutive patients with AMI and in 30 patients admitted to hospital with suspected but disproved AMI who served as controls. The patients were studied at days 1, 5, 90, and 360 after arrival in the coronary care unit. The index was defined as the sum of isovolumetric contraction time, and isovolumetric relaxation time divided by ejection time was measured from mitral inflow and left ventricular outflow Doppler velocity profiles. The index was significantly higher in patients with AMI than in control subjects at days 1 and 360 (day 1, 0.58 +/- 0.09 vs 0.41 +/- 0.08, p <0.0001; day 360, 0.50 +/- 0.09 vs 0.39 +/- 0.07, p <0.01, respectively). The index decreased significantly in patients with AMI during follow-up (p <0.01). The index was significantly higher in patients who developed congestive heart failure or died compared with survivors who were free of congestive heart failure (day 1, 0.63 +/- 0.10 vs 0.53 +/- 0.10, p <0.01; day 360, 0.56 +/- 0.08 vs 0.48 +/- 0.10, p <0.01, respectively). During 20.2 +/- 8.5 months' follow-up, 10 patients died of cardiac causes and 13 developed congestive heart failure. Univariate analyses demonstrated that the Doppler index > or =0.60 (chi-square 8.3, p <0.0001), deceleration time < or =140 ms (chi-square 8.5, p <0.0001), ejection fraction < or =0.40% (chi-square 3.3, p <0.005), anterior wall AMI (chi-square 3.2, p <0.01), and age (chi-square 1.06/ year increase, p <0.01) were significant predictors of outcome. Multivariate stepwise analysis showed that the index < or =0.60 (chi-square 3.4, p <0.05), deceleration time < or =140 ms (chi-square 4.2, p <0.02), and age (chi-square 1.06/year increase, p <0.02) were independent predictors of outcome. The Doppler index reflects severity of left ventricular function and has incremental prognostic value in patients with AMI.

Arterial thromboembolism in patients with sick sinus syndrome: prediction from pacing mode, atrial fibrillation, and echocardiographic findings.

OBJECTIVE: To evaluate whether thromboembolism in sick sinus syndrome can be predicted by pacing mode, atrial fibrillation, or echocardiographic findings. METHODS: Patients were randomised to single chamber atrial (n = 110) or ventricular (n = 115) pacing. They were divided into subgroups with and without brady-tachy syndrome at time of randomisation. The occurrence of atrial fibrillation and thromboembolism during follow up were investigated and compared with echocardiographic findings. RESULTS: The annual risk of thromboembolism was 5.8% in patients with brady-tachy syndrome randomised to ventricular pacing, 3.2% in patients without brady-tachy syndrome randomised to ventricular pacing, 3% in patients with brady-tachy syndrome randomised to atrial pacing, and 1.5% in patients without brady-tachy syndrome randomised to atrial pacing. In atrial paced patients without brady-tachy syndrome at randomisation and without atrial fibrillation during follow up, the annual risk of thromboembolism was 1.4%. Left atrial size measured by M mode echocardiography was of no value in predicting thromboembolism. CONCLUSIONS: Arterial thromboembolism in patients with sick sinus syndrome is very common and is associated primarily with brady-tachy syndrome at randomisation and with ventricular pacing. The risk of thromboembolism is small in atrial paced patients in whom atrial fibrillation has never been documented.

The influence of heart rate on the Doppler-derived myocardial performance index.

The Doppler-derived myocardial performance index (MPI), defined as the sum of isovolumetric contraction and relaxation durations divided by ejection time and reflecting both systolic and diastolic myocardial function, has been found to be related to morbidity and mortality in cardiac diseases. The MPI is easily obtained, reproducible, and has a narrow range in healthy subjects. The goal of this study was to study the influence of heart rate changes on the MPI. Thirty patients with sick sinus syndrome treated with a pacemaker with a right atrial lead were studied. The patients were paced at increasing rates from 50 to 100 bpm. The MPI increased on average 0.02 +/- 0.03 per 10-bpm increase in rate. The correlation between MPI and heart rate was weak (rho = 0.31, P <.01).

Effect of lipid peroxidation on rhodopsin regeneration.

We have developed an in vitro system in which lipid peroxidation can be produced in a predictable fashion and have studied the effects of peroxidation on regenerability of rhodopsin in rod outer segments (ROS). ROS isolated by sucrose flotation from dark-adapted retinas of Rana pipiens were suspended in various concentrations of FeSO4 and 1 or 2 mM ascorbic acid for 10 minutes. An increase in lipid hydroperoxides (measured as conjugated dienes) and a decrease in 22:6 omega 3 were determined for each Fe+2 concentration and used as an index of peroxidation. Following incubation with and without FeSO4, ROS were pelleted and rhodopsin was regenerated with 15 micron 11-cis-retinal. The regenerability of rhodopsin in ROS in which significant lipid peroxidation had taken place was reduced by 40-50% compared to controls. DTPA (diethylenetriamine pentaacetic acid), EDTA, and EGTA protected against lipid peroxidation by Fe+2 and allowed almost complete regeneration of rhodopsin. Incubation with DTPA also prevented the destruction of vitamin E in ROS. Other compounds containing primary amine groups did not protect against peroxidation or loss of regenerability. These experiments indicate that lipid peroxidation is associated with a loss of regenerability of the visual pigment rhodopsin.

[Breast cancer in the county of Viborg during 1983-1989. A quality control study]. / Mammacancer i Viborg Amt i perioden 1983-1989. Et kvalitetskontrolstudie.

The aim of the present study was to compare the quality of treatment for breast cancer in Viborg County to that provided in the rest of Denmark during the period 1983 to 1989. Women younger than 70 years of age with the diagnosis of invasive breast carcinoma and registered in the DBCG (Danish Breast Cancer Cooperative Group) were included, 435 from Viborg county and 11,434 from the rest of Denmark. No differences were found between the two patient-groups with regard to tumoursize, degree of anaplasia, number of axillary lymph nodes removed or number of positive lymph nodes. There were also no differences in overall survival or recurrence-free survival (RFS). It was concluded that the quality of treatment for breast cancer in Viborg County was equal to that in the rest of Denmark. Moreover, the magnitude of registration of breast cancer patients in the DBCG from Viborg county was evaluated. More than 90% of all breast cancer patients were registered.

[Abuse of Ecstasy (3,4-methylenedioxymethamphetamine). Pharmacological, neuropsychiatric and behavioral aspects]. / Misbrug af Ecstasy (3,4-metylendioxymetamfetamin). Farmakologiske, neuropsykiatriske og adfaerdsmaessige aspekter.

Ecstasy (3,4-methylenedioxymethamphetamine) is a popular recreational drug, a "designer drug", which has been developed from the basic structure in amphetamine. Ecstasy has now reached the illegal drug market in Denmark via the US, Great Britain and Sweden. The drug is related to a certain youth culture from which it is estimated that many drug abusers have been recruited. The desired effects of ecstasy, namely enhanced openness, awareness and empathy, have previously been used in various therapeutic connections. In later years the drug has led to abuse which, in connection with certain cultural behaviour patterns (for example in discotheques), can cause dangerous psychiatric as well as somatic effects. The undesirable psychiatric effects range from fear through depression to actual psychoses, and the somatic effects vary from symptoms of increased sympathetic activity to malignant hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, renal failure, and lethal hepatotoxicity. The last mentioned symptoms occur in connection with prolonged physical activities such as exhausting dancing sessions. The article discusses the available treatments for conditions of abuse and stresses the need for prophylactic efforts in the form of information and awareness of the problem.

[Treatment with implantable cardioverter-defibrillators. Experiences from Skejby hospital during the period 1989-1994]. / Behandling med implanterbar kardioverter-defibrillator. Erfaringer fra Skejby Sygehus i perioden 1989-1994.

The aim of the present study was to evaluate survival and therapy for ventricular tachyarrhythmia in patients treated with implantable cardioverter-defibrillator (ICD)-implantation at Skejby Hospital. Seventy-two patients, of which 54 were male, have received an ICD since 1989. Mean (range) age was 54 (16-74) years. Forty-nine (68%) had ischaemic heart disease. The patients were followed for a median (range) of 14 (1/2-50) months. Kaplan-Meyer plots are presented for total mortality, cardiac mortality, sudden cardiac mortality, appropriate therapy, and therapy for life-threatening tachyarrhythmia. After one, two and three years respectively, mortality was respectively 13, 27, and 32%, cardiac mortality was 5, 19, and 24%, sudden cardiac mortality was 3, 6, and 12%, cumulative incidence of appropriate therapy was 56, 66, and 90%, and cumulative incidence of therapy for life-threatening tachyarrhythmia was 19, 29 and 52%. It is concluded, that the majority of patients treated with an ICD developed ventricular tachyarrhythmia and had appropriate or lifesaving ICD-therapy during follow-up.

[Single-chamber atrial pacing is better than single chamber ventricular pacing in patients with sick sinus syndrome. Results of long-term follow up in a prospective randomized study]. / Etkammer-atriepacing er bedre end etkammer-ventrikelpacing hos patienter med syg sinusknude. Resultatet af langtidsopfølgning i en prospektiv, randomiseret undersøgelse.

In a study of 225 patients with sick sinus syndrome randomized to single chamber atrial pacing (n = 110) or ventricular pacing (n = 115), atrial pacing was associated with less atrial fibrillation and thromboembolism after 3.3 years follow-up. To determine whether this beneficial effect of atrial pacing is maintained at long-term, follow-up was extended. Follow-up visits were at 3 months, 12 months, and then once every year, and included physical examination, ECG, and pacemaker check-up. After 5.5 years follow-up, all-cause mortality, cardiovascular deaths, atrial fibrillation, thromboembolism, and heart failure were significantly less in the atrial group. AV block occurred in four patients in the atrial group. The beneficial effect of atrial pacing observed previously is enhanced substantially after extended follow-up. Patients with sick sinus syndrome should be treated with an atrial pacing system.

Plasma pharmacokinetics of two consecutive doses of ferumoxytol in healthy subjects.

Intravenous (IV) iron is used to treat iron-deficiency anemia in patients with chronic kidney disease (CKD). Ferumoxytol is a novel iron formulation administered rapidly as two IV boluses of 510 mg each. In this placebo-controlled, double-blind, parallel-group study, 58 healthy volunteers received ferumoxytol in two 510 mg doses administered 24 h apart. Population pharmacokinetics (PK) analysis was conducted, and a two-compartment open model with zero-order input and Michaelis-Menten elimination was found to best describe the data. The population mean estimates for volume of distribution of the central compartment (V(1)), maximal elimination rate (V(max)), and ferumoxytol concentration at which rate of metabolism would be one-half of V(max) (K(m)) were 2.71 l, 14.3 mg/h, and 77.5 mg/l, respectively. When the effect of body weight on V(1) was added in the analysis, interindividual variability was found to be reduced. A noncompartmental analysis of two simulated 510-mg ferumoxytol doses was also performed to provide clinically interpretable data on half life and exposure. Ferumoxytol given as two consecutive 510-mg doses was well tolerated.