Varicella-zoster immunoglobulin treatment in pregnant women in Denmark from 2005 to 2015: descriptive epidemiology and follow-up.

Primary infection with varicella-zoster virus in pregnancy poses a risk of severe infection and embryopathies. Upon exposure, seronegative women are candidates for varicella-zoster immunoglobulin (VZIG). The aim of this paper was to describe risk factors for VZIG treatment including sources of varicella exposure and to study how many women developed clinical infection and received postpartum vaccination. We identified all pregnant women who received VZIG from December 2005 to March 2015. Additional information was obtained from Danish registers and a follow-up questionnaire. A total of 104 women were included and 88 completed the questionnaire. Significantly more women had 'other country of origin' than Denmark. They were more often second para (57%) and had most commonly been exposed to varicella by their own child (58%). Five women developed clinical varicella infection, and only 26·5% were vaccinated after delivery. The study concludes that few women developed infection after VZIG and none developed pneumonia. General practitioners should be particularly aware of obtaining varicella anamnesis in parous women from non-temperate countries in order to perform selective vaccination prior to pregnancy. In case of varicella exposure during pregnancy in a seronegative woman, postpartum vaccination is crucial.

Compliance with and short-term adverse events from clarithromycin versus placebo in patients with stable coronary heart disease: the CLARICOR trial.

BACKGROUND: The randomized placebo-controlled double-blind CLARICOR trial investigated the influence of clarithromycin versus placebo on cardiovascular events and mortality in patients with chronic coronary artery disease (ClinicalTrials.gov NCT 00121550). The trial randomized 2172 patients to 500 mg of clarithromycin daily versus 2200 patients to matching placebo for 14 days. This paper presents protocol-specified analysis of the patient-reported information regarding their compliance and non-serious adverse events during the 14 days of treatment as well as serious adverse events (mortality and hospitalizations) during the first 30 days after randomization. METHODS: Randomized clinical trial focusing on patient-reported information regarding their compliance and adverse events. RESULTS: Of the randomized patients, 99% reported information regarding their compliance and adverse events. A 100% tablet intake was reported by 90% of the clarithromycin group and by 93.7% of the placebo group. Of the clarithromycin patients, 39.5% reported at least one non-serious adverse event versus 25.1% of the placebo patients (P < 0.001). Gastrointestinal adverse reactions were reported 950 times by 697 patients (32.3%) in the clarithromycin group and 485 times by 390 patients (17.9%) in the placebo group (P < 0.001). No significant differences were seen in other non-serious or serious adverse events during the first month after inclusion. Short-term non-serious adverse events did not explain the previously reported long-term significantly increased mortality associated with clarithromycin. CONCLUSIONS: Gastrointestinal adverse reactions are common during clarithromycin administration, but at least half are also seen with a placebo.

Verapamil in acute myocardial infarction. The rationales of the VAMI and DAVIT III trials.

Verapamil is well tolerated in patients with stable and unstable angina pectoris, as well as in patients with threatened infarction. No data exist documenting verapamil to be inferior to beta-blockers in these stages of coronary heart diseases. In the pre-thrombolytic era i.v. intervention with verapamil did not add any benefit in the early phase of AMI. However, a retrospective analysis suggests the hypothesis that i.v. verapamil given in combination with thrombolysis may improve the prognosis, and an ongoing study (VAMI trial) examines this hypothesis. When given in the late in-hospital phase of AMI to patients without heart failure verapamil significantly reduces mortality and morbidity. When given in the late in-hospital phase to patients with heart failure verapamil did not cause the course or prognosis to deteriorate and might even improve it in patients with residual ischaemia, especially when given in combination with an ACE-inhibitors. A planned study (DAVIT III study) has to confirm these preliminary data.

Verapamil in acute myocardial infarction. The rationales of the VAMI and DAVIT III trials.

Verapamil is well tolerated in patients with stable and unstable angina pectoris, as well as in patients with threatened infarction. No data exist documenting verapamil to be inferior to beta-blockers in these stages of coronary heart diseases. In the prethrombolytic era i.v. intervention with verapamil did not add any benefit in the early phase of AMI. However, a retrospective analysis suggests the hypothesis that i.v. verapamil given in combination with thrombolysis may improve the prognosis, and an ongoing study (VAMI trial) examines this hypothesis. When given in the late in-hospital phase of AMI to patients without heart failure verapamil significantly reduces mortality and morbidity. When given in the late in-hospital phase to patients with heart failure verapamil did not cause the course or prognosis to deteriorate and might even improve it in patients with residual ischaemia, especially when given in combination with an ACE-inhibitors. A planned study (DAVIT III study) has to confirm these preliminary data.

[The use of vena cava filters in Denmark]. / Brugen af vena cava-filtre i Danmark.

By means of a questionnaire we studied the current indications for and the extent of the use of vena cava filters (VCF) in 325 Danish hospital departments. Two hundred and eighty (86%) responded. Only six clinical and four radiological departments (4%) used VCF. Eighteen percent did not find any indications for the use of VCF, 32% were not familiar with the method, and 46% replied that they did not have the relevant patient population. The reported indications for VCF are consistent with the international guidelines. We discussed the scientific background, indications and limitations for the use of VCF and concluded that the current use of VCF in Denmark probably is less than optimal. VCF should be considered in patients with pulmonary embolism or at high risk of pulmonary embolism when anticoagulant therapy is contraindicated.

The prognostic significance of angina pectoris experienced during the first month following acute myocardial infarction.

BACKGROUND: Angina pectoris accompanied by transient ST-segment changes during the in-hospital phase of acute myocardial infarction (AMI) is a well established marker of subsequent cardiac death and reinfarction. HYPOTHESIS: This study was undertaken to record the prognostic significance of angina pectoris experienced during the first month following discharge from AMI. METHODS: In all, 803 patients included in the placebo arm of the Danish Verapamil Infarction Trial II were followed up for 18 months in 20 coronary care units in Denmark. The patients were randomized to placebo and were still on study treatment 1 month after discharge. Of these patients, 311 (39%) reported chest pain during the first month following discharge. RESULTS: Patients with angina pectoris had a significantly increased risk of reinfarction [hazard 1.71; 95%-confidence limit (CL): 1.09, 2.69] and increased mortality risk which, however, only reached borderline statistical significance (hazard 1.52; 95%-CL: 0.96, 2.40). When patients were subdivided according to both angina pectoris and heart failure, those with one or both of these risk markers had significantly increased mortality (p 0.03) and reinfarction (p 0.02) rates compared with patients free of both angina pectoris and heart failure. CONCLUSION: Patients with postinfarction angina pectoris have a significantly increased morbidity risk.

How European cardiologists perceive the role of calcium antagonists in the treatment of stable angina.

Some 100 European cardiologists discussed calcium antagonists' role in the management of stable angina. Sixty-two percent of those involved used calcium antagonists rather than beta-blockers as first line therapy; 46% were prepared to use calcium antagonists in patients who had had a myocardial infarction more than 6 months previously. Only one tenth would use calcium antagonists in angina patients with left ventricular dysfunction. There was a broad preference for the use of heart rate-moderating calcium antagonists in most forms of stable angina. The discussions also underlined the diagnostic importance of angiography, exercise testing and lipid profile analysis.

Verapamil and angiotensin-converting enzyme inhibitors in patients with coronary artery disease and reduced left ventricular ejection fraction.

Verapamil is effective as antianginal medication but contraindicated in patients with congestive heart failure. Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure but have limited effect on patients with angina pectoris. No studies have been published on the combined treatment with verapamil and ACE inhibitors in patients with stable angina pectoris and left ventricular dysfunction. We performed an open study in 14 patients with angina pectoris and ejection fraction < 40%. The patients received verapamil 180 mg and trandolapril 2 mg twice daily for 3 months. We found a significant increase in ejection fraction from 28 +/- 6 to 35 +/- 11 (p < 0.03), wall motion index from 1.0 +/- 0.3 to 1.2 +/- 0.3 (p < 0.03), exercise duration from 6.9 +/- 2.5 to 7.7 +/- 2.9 minutes (p < 0.01), and ratio of exercise to rest rate-pressure product from 2.2 +/- 0.4 to 2.5 +/- 0.6 (p < 0.02). Use of nitroglycerin and number of angina pectoris attacks were both significantly reduced after 3 months of treatment. These findings support the hypothesis that the combination of verapamil and trandolapril is useful in patients with attenuated left ventricular function and angina pectoris.

Anti-ischemic intervention as prognosis improvement in patients with coronary artery disease, with special focus on verapamil.

Angina pectoris is a significant risk predictor in patients with atherosclerotic heart disease. The major complications are myocardial infarction, heart failure, and arrhythmias. Plaque rupture turns stable angina pectoris into acute coronary syndrome by provoking platelet aggregation and thereby thrombus formation. Verapamil significantly inhibits platelet aggregation and thrombus formation, which may be one of several reasons for the protective effect of verapamil on reinfarction in patients recovering from myocardial infarction. Ischemia may lead to left ventricular dilation and diastolic dysfunction, and thereby heart failure. In postinfarction patients intervention with verapamil significantly reduced the use of diuretics compared with placebo, indicating that anti-ischemic intervention may prevent heart failure. Ventricular arrhythmias are significantly associated with arrhythmic as well as non-arrhythmic death. The lack of preferential association of ventricular arrhythmias with arrhythmic death rather than nonarrhythmic death may imply that arrhythmias are provoked by ischemia. Antiarrhythmic intervention in postinfarction patients significantly increases death and arrhythmic events compared with placebo, especially in patients with residual ischemia. This may be due to a significant slowing of conduction during ischemia in patients treated with antiarrhythmic agents. In animal studies anti-ischemic agents prevent or suppress ventricular arrhythmias during ischemia, whereas traditional antiarrhythmic drugs have no effect or even worsen the arrhythmias, especially during episodes with elevated sympathetic activity. Verapamil significantly reduces plasma norepinephrine levels and the norepinephrine release during ischemia, whereby ventricular arrhythmias may be prevented. Also, supraventricular arrhythmias are significantly associated with myocardial ischemia and are prevented by verapamil. In patients with atherosclerotic heart diseases, angina pectoris is a significant risk predictor, but anti-ischemic intervention should be considered even in patients in whom the major problem is heart failure or arrhythmias.

Efeito do verapamil sobre o reinfarto e eventos cardiovasculares em pacientes com hipertensåo arterial incluídos no II ensaio dinamarquês do verapamil no infarto / Effect of verapamil on reinfarction and cardiovascular events in patients with arterial hypertension included in Danish Verapamil Infarction Trial II

Tem sido relatada uma crescente incidência de reinfarto e eventos cardiovasculares em pacientes hipertensos que se recuperam de um infarto agudo do miocárdio. Estudamos os efeitos da intervençåo com verapamil sobre o desenvolvimento de infarto do miocárdio e eventos cardiovasculares em 301 pacientes hipertensos incluídos no II Ensaio Dinamarquês do Verapamil no Infarto. Durante a segunda semana depois do infarto confirmado, os pacientes foram aleatoriamente designados para o tratamento com 360 mg de verapamil por dia (n=149) ou placebo (n=152) e acompanhadas durante 18 meses (média 16 meses). As taxas do primeiro reinfarto nos 18 meses foram de 12,5 por cento nos pacientes tratados com verapamil e 19,8 por cento nos pacientes tratados com placebo (relaçåo de risco 0,53, intervalo de confiança de 95 por cento 0,28 - 1,00, p=0,04). As taxas dos primeiros eventos cardiovasculares foram de 21,8 por cento no grupo verapamil e 29,3 por cento no grupo placebo (taxa de risco 0,66, intervalo de confiança de 95 por cento 0,41 - 1,06, p=0,07). Nesta análise restrospectiva de pacientes hipertensos incluídos no II Ensaio Dinamarquês do Verapamil no Infarto, a intervençåo com verapamil reduziu os eventos cardiovasculares, principalmente devido a uma substancial reduçåo dos reinfartos

[Post-infarction, myocardial ischemia: clinical importance and risk factor]. / Post-infarctus, ischémie myocardique: importance clinique et facteur de risque.

The myocardial scar, left behind by an infarct, makes up a potential substrate for complex ventricular arrhythmias due to the presence in such tissue of electrical inhomogeneity, altered refractoriness, and abnormal conduction properties, which facilitate the induction of reentrant arrhythmias and the release of abnormal automatic responses of the partially repolarised cells. The mechanism(s) by which complex ventricular arrhythmias is/are transformed into malignant arrhythmias has/have not yet been definitely proven. The observation that coronary revascularization - in patients with ischaemic heart disease surviving out of hospital cardiac arrest - improves the prognosis, indicates that transient ischaemic attacks might be the trigger of malignant ventricular arrhythmias in patients with prior myocardial infarction. Patients with large infarct scars (heart failure) have an increased incidence of complex ventricular arrhythmias, death, and ischaemic events. Antiarrhythmic medical intervention does not improve the prognosis in these patients. Intervention with ACE-inhibitors reduces the prevalence of complex ventricular arrhythmias, the incidence of death, and reinfarction, but not arrhythmic death, indicating that residual ischaemia might be the major risk variable in patients with heart failure. Ischaemia is one of several risk markers for transient supraventricular arrhythmias in patients recovering from an acute myocardial infarction (AMI). In addition, anti-ischaemic intervention in patients recovering from AMI suppresses residual myocardial ischaemia and thereby reduces major events.

Anti-ischaemic intervention with verapamil in patients recovering from acute myocardial infarction.

The present review discusses the prognostic significance of post-infarction angina pectoris, and the significance of post-infarction intervention with verapamil on the prevalence of post-infarction ischaemia and prognosis. Angina pectoris during the first month after acute myocardial infarction (AMI) was found to be a significant predictor of subsequent major events (death and reinfarction) (P = 0.03). The prognosis in patients with post-infarction angina pectoris was as poor as that observed in patients with mild to moderate congestive heart failure. Intervention with verapamil significantly reduced the 1 month prevalence of angina pectoris (P = 0.02), and thereby also the number of patients at high risk. In patients with ST-segment depression provoked during a pre-discharge, post-infarction exercise test, intervention with verapamil reduced major events by 41% compared with placebo. In patients with both heart failure and angina pectoris, anti-ischaemic intervention with verapamil reduced the 17 month event rate by 37%, whereas no effect was found in patients with heart failure, but no angina pectoris. We conclude that angina pectoris following AMI is a significant risk predictor in both patients with and without impaired cardiac function. Intervention with verapamil significantly reduces post-infarction ischaemia, thereby reducing the risk of reinfarction and death.

Effects of two mutations detected in medium chain acyl-CoA dehydrogenase (MCAD)-deficient patients on folding, oligomer assembly, and stability of MCAD enzyme.

We have used expression of human medium chain acyl-CoA dehydrogenase (MCAD) in Escherichia coli as a model system for dissecting the molecular effects of two mutations detected in patients with MCAD deficiency. We demonstrate that the R28C mutation predominantly affects polypeptide folding. The amounts of active R28C mutant enzyme produced could be modulated between undetectable to 100% of the wild-type control by manipulating the level of available chaperonins and the growth temperature. For the prevalent K304E mutation, however, the amounts of active mutant enzyme could be modulated only in a range from undetectable to approximately 50% of the wild-type, and the assembled mutant enzyme displayed a decreased thermal stability. Two artificially constructed mutants (K304Q and K304E/D346K) yielded clearly higher amounts of active MCAD enzyme than the K304E mutant but were also responsive to chaperonin co-overexpression and growth at low temperature. The thermal stability profile of the K304E/D346K double mutant was shifted to even lower temperatures than that of the K304E mutant, whereas that of the K304Q mutant was closely similar to the wild-type. Taken together, the results show that the K304E mutation affects (i) polypeptide folding due to elimination of the positively charged lysine and (ii) oligomer assembly and stability due to replacement of lysine 304 with the negatively charged glutamic acid.

Role of ischemia in postinfarction heart failure: hypothetical considerations based on use of verapamil in the DAVIT II Study. Danish Study Group on Verapamil in Myocardial Infarction.

Based on a retrospective analysis of the DAVIT II database, we attempted to propose subgroups of post-infarction patients with heart failure, who might benefit or not benefit from antiischemic medical intervention. In DAVIT II, patients were randomized in a double-blind fashion to either verapamil 360 mg/day or placebo in the second week after the infarct and followed up to 18 months. The endpoint was the first major event; that is, death or reinfarction. In patients with heart failure but no ischemia, the event rate was 17.6% in the verapamil-treated patients and 16.5% in the placebo group (hazard verapamil: 1.01; 95% CL: 0.57, 1.79). In patients with both heart failure and residual ischemia, the event rate was 11.3% and 17.8% in the verapamil and placebo groups, respectively (hazard verapamil: 0.60; 95% CL: 0.24, 1.52). Although the latter reduction in major events was not statistically significant, we propose, in accordance with other studies, that in postinfarction patients with both heart failure and residual myocardial ischemia, the harmful negative inotropic effects of antiischemic drugs might be outweighed by their antiischemic effects, by means of which the prognosis might be improved. Patients without ischemia but with heart failure may, however, be at a disadvantage from such treatment.

The prognostic significance of post-infarction angina pectoris and the effect of verapamil on the incidence of angina pectoris and prognosis. The Danish Study Group on Verapamil in Myocardial Infarction.

The prognostic significance of angina pectoris and the effect of intervention with verapamil on the incidence of angina pectoris were studied in patients recovering from myocardial infarction and included in the Danish Verapamil Infarction Trial II. During the second week after admission patients were doubly-blindly randomized to treatment with verapamil 360 mg.day-1 or placebo. Treatment was continued for up to 18 months. At discharge angina pectoris was reported in 11% of 869 patients randomized to verapamil and in 12% of 888 randomized to placebo (ns). One month after discharge a significant increase in the prevalance of angina pectoris was reported in both the verapamil (33%) (P < 0.001) and the placebo groups (39%) (P < 0.001). The one month prevalence of angina pectoris (P = 0.03) and the 18 months overall incidence of angina pectoris (P = 0.002) were both significantly lower in the verapamil group compared with placebo. Stable angina pectoris during the first month of follow-up was a significant predictor of major events (i.e. death or reinfarction) (hazard ratio = 1.45; 95% confidence limits: 1.10, 1.89). As verapamil significantly reduced the incidence of angina pectoris during daily activities, and thereby the number of patients at high risk, the beneficial effect of verapamil in reducing major events in patients recovering from myocardial infarction is likely to be due to abolishing myocardial ischaemia.

Effect of verapamil on reinfarction and cardiovascular events in patients with arterial hypertension included in the Danish Verapamil Infarction Trial II. The Danish Study Group on Verapamil in Myocardial Infarction.

An increased incidence of reinfarction and cardiovascular events has been reported in patients with hypertension recovering from acute myocardial infarction. We studied the effect of intervention with verapamil on the development of myocardial infarction and cardiovascular events in 301 patients with hypertension enrolled in the Danish Verapamil Infarction Trial II. During the second week after the index infarct, patients were randomly assigned to treatment with verapamil 360 mg per day (n = 149) or placebo (n = 152) and followed-up to 18 months (mean 16 months). The 18 months first reinfarction rates were 12.5% in verapamil and 19.8% in placebo treated patients (hazard ratio 0.53, 95% confidence limits 0.28-1.00, P = 0.04). The first cardiovascular event rates were 21.8% in the verapamil and 29.3% in the placebo group (hazard ratio 0.66, 95% confidence limits 0.41-1.06, P = 0.07). In this retrospective analysis of patients with hypertension included in the Danish Verapamil Infarction Trial II, intervention with verapamil reduced cardiovascular events primarily due to a substantial reduction in reinfarctions.

Production and specificity of poly- and monoclonal antibodies raised against Shewanella putrefaciens.

Polyclonal antibodies were raised in rabbits and mice against Shewanella putrefaciens. Murine monoclonal antibodies were produced against the type strain (ATCC 8071) as well as wild type strains isolated from fish products. The specificities of four polyclonal and 12 monoclonal antibodies were tested by dot-blotting, an indirect and a competitive ELISA against 16 Gram-negative strains; including six strains of S. putrefaciens and one strain of Pseudomonas rubescens (NC 10695). All polyclonal antibodies reacted strongly with S. putrefaciens and with Ps. rubescens and cross-reacted with the nine other bacteria (Pseudomonas spp., Aeromonas spp. and Vibrio anguillarum). The monoclonal antibodies could be divided into three groups with different patterns of specificity. The largest group (8 monoclonal antibodies) reacted strongly with S. putrefaciens and with Ps. rubescens and showed only weak reactions with the other strains. The results confirm that Ps. rubescens should be classified as S. putrefaciens.

The effect of verapamil on major events in patients with impaired cardiac function recovering from acute myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction.

In the Danish Verapamil Infarction Trial II (DAVIT II) intervention with verapamil significantly decreased the first major event rate (i.e. reinfarction or death) in patients recovering from acute myocardial infarction. As calcium channel antagonists might have a detrimental effect in patients with heart failure, the effect of verapamil on major events in patients with and without impaired left ventricular function was analysed. Eight hundred and seventy-eight patients were randomized to verapamil 120 mg t.i.d. and 897 to placebo. Patients were followed up to 18 months. The endpoint was the first major event while on trial medication. In patients treated for heart failure during the acute phase of myocardial infarction, the lowest 18-month event rate was seen in the verapamil group (21.2% vs 22.2%) (absolute numbers: events/patients verapamil 47/291; placebo 60/323) (ns). Similarly, in patients treated with diuretics at randomization, the lowest 18-month event rate was seen in those randomized to verapamil (22.4 vs 24.3%) (absolute numbers: events/patients verapamil 57/349; placebo 76/375 (ns). When patients were subdivided according to New York Heart Association functional classes, verapamil reduced the event rate in all classes, but none of these differences was statistically significant. In patients without heart failure during the acute phase and in patients without diuretic treatment at randomization, treatment with verapamil caused a significant reduction in major events (hazard ratio (95% confidence limits): 0.66 (0.47, 0.92); 0.66 (0.45, 0.96) respectively). Long-term treatment with verapamil after acute myocardial infarction caused a significant reduction in major events.(ABSTRACT TRUNCATED AT 250 WORDS)