Effects of disopyramide on repolarisation and intraventricular conduction in man

Summary Right ventricular repolarisation and refractoriness after therapeutic doses of disopyramide have been studied in 10 patients with coronary artery disease by recording monophasic action potentials (MAP) during programmed stimulation. Using 2 catheters, with the tip of one in the apex and the other in the outflow tract of right ventricle, conduction intervals for propagation of stimuli in the ventricle were also measured. Disopyramide increased the duration of MAP signals at 90% repolarisation (MAP₉₀), the QT-interval and the right ventricular effective refractory period (V-ERP). The ratio refractoriness/action potential duration was slightly increased. Early premature action potentials were more markedly prolonged in relation to steady-state action potentials. The differences between the shortest and longest premature action potentials, however, were not changed significantly. The conduction intervals of the normal and premature paced beats were significantly prolonged.The observed effects of disopyramide on conduction and action potential duration may be of major importance for its effect on termination and slowing ventricular tachycardias. Its influence on the duration of premature action potentials in man is consistent with the results of in vitro studies.     

Lack of effect of the calcium antagonist isradipine on cyclosporine pharmacokinetics in renal transplant patients.

Hypertension has emerged as a frequent side effect in transplant recipients on effective doses of cyclosporine (CsA). To control hypertension in renal transplant patients, calcium channel blockers have been used; some of these, however, have been shown to cause significant increases in CsA levels. These findings point out that possible interactions of each calcium antagonist with CsA deserve investigation. We performed an open, placebo-controlled study in 12 stable renal transplant recipients to determine whether short-term isradipine influences CsA pharmacokinetics. All patients had mild to moderate hypertension and received triple immunosuppressive therapy with CsA, azathioprine, and prednisolone. Throughout a 4-week period of isradipine treatment, blood CsA levels (specific and nonspecific monoclonal antibodies) remained stable. The mean trough specific level was 121 +/- 14 micrograms/L following placebo, compared to 120 +/- 14 micrograms/L during isradipine. Corresponding non-specific values were 465 +/- 68 and 474 +/- 63 micrograms/L. Also, values for Cmax, AUC, and t1/2 were not significantly changed following 4 weeks of isradipine. Mean arterial pressure was significantly reduced at the end of the study. This study implies that isradipine does not influence CsA metabolism. Further studies should be carried out to determine its long-term effects on CsA pharmacokinetics and renal function in transplanted patients.     

Drug metabolism and clearance system in tumor cells of patients with multiple myeloma

Resistance to chemotherapy is a major limitation of cancer treatments with several molecular mechanisms involved, in particular altered local drug metabolism and detoxification process. The role of drug metabolism and clearance system has not been satisfactorily investigated in Multiple Myeloma (MM), a malignant plasma cell cancer for which a majority of patients escapes treatment. The expression of 350 genes encoding for uptake carriers, xenobiotic receptors, phase I and II Drug Metabolizing Enzymes (DMEs) and efflux transporters was interrogated in MM cells (MMCs) of newly-diagnosed patients in relation to their event free survival. MMCs of patients with a favourable outcome have an increased expression of genes coding for xenobiotic receptors (RXRα, LXR, CAR and FXR) and accordingly of their gene targets, influx transporters and phase I/II DMEs. On the contrary, MMCs of patients with unfavourable outcome displayed a global down regulation of genes coding for xenobiotic receptors and the downstream detoxification genes but had a high expression of genes coding for ARNT and Nrf2 pathways and ABC transporters. Altogether, these data suggests ARNT and Nrf2 pathways could be involved in MM primary resistance and that targeting RXRα, PXR, LXR and FXR through agonists could open new perspectives to alleviate or reverse MM drug resistance.     

Familial hypercholesterolemia and young patients’ thoughts on own condition and treatment

Objectives

Familial hypercholesterolemia (FH) is a hereditary and usually asymptomatic condition characterized by elevated blood cholesterol and increased risk of premature cardiovascular disease. It is treated with dietary modifications and lipid lowering drugs. The objective was to learn about young FH patients’ perceptions and choices regarding treatment.

Multimeric and trimeric subunit SP-D are interconvertible structures with distinct ligand interaction

Surfactant protein-D (SP-D) is a calcium dependent lectin in the innate immune system that facilitates clearance of microbes. The protein is associated with mucosal surfaces, and also found in bronchoalveolar lavage, serum and amniotic fluid. Human SP-D includes trimeric subunits and multimeric assemblies of trimeric subunits, which are stabilized by N-terminal interchain disulfide crosslinks. An N-terminal structural polymorphism (Met11Thr) and associated O-glycosylation are previously shown accompanied by incomplete multimerization and with a relative low proportion of multimeric Thr11 SP-D compared to Met11 SP-D. Multimerization has proven important for enhancement of microbial phagocytosis.In the present study defined multimeric forms of Met11Thr SP-D were isolated from human amniotic fluid. Implementation of ManNAc-affinity chromatography allowed high recovery of natural trimeric SP-D subunits. However, affinity chromatography increased the relative proportion of multimers at the expense of natural trimeric subunits. Multimeric SP-D partially disassembled to form trimeric subunits. The resulting distribution of structural forms was independent of the Met11Thr genotype. Trimeric and multimeric SP-D appeared with distinct patterns of disulphide crosslinking, which partly changed according to interconversion between the structural forms. Solid phase assays demonstrated that trimeric SP-D subunits showed greater binding to LPS and PGN, but lower binding to mannan and LTA, than SP-D multimers. Trimeric SP-D subunits also showed greater binding to endogenous lipoproteins: LDL, oxLDL, and HDL, than multimeric SP-D. In conclusion, purified trimeric and multimeric SP-D represent separate and only partly interconvertible molecular populations with distinct biochemical properties.     

Chest compressions by ambulance personnel on chests with variable stiffness: abilities and attitudes

INTRODUCTION: Quality of cardiopulmonary resuscitation (CPR) performed by professionals is reported to be substandard even with automated corrective feedback. We hypothesised that lack of quality is not due to physical capabilities. MATERIALS AND METHODS: Eighty ambulance personnel from the same services where the quality of clinical CPR was investigated, performed two-rescuer CPR with similar corrective feedback for 5min on each of four manikins with different chest stiffness. The personnel also scored their agreement with statements on clinical CPR performance. RESULTS: All study subjects performed CPR well within Guidelines recommendations on all four manikins with mean compression depth 44+/-3mm, compression rate 101+/-3min(-1), and 7+/-2 ventilations per minute. Three quarters stated that during CPR on patients their personal sense of correct depth and force determined their performance. Fifty-five percent believed that too deep chest compressions could cause serious injury to the patient, and 39% that compressing to Guidelines recommended depth may often result in severe patient injury. A quarter felt that the potential benefits of compressing to the Guidelines depth could not justify the injuries it would cause. Breaking ribs made 54% feel very uncomfortable. CONCLUSIONS: Ambulance personnel were physically capable of consistently compressing to the Guidelines depth even on the stiffest chest. These laboratory results cannot be directly compared to the clinical out-of-hospital ALS situation, but strongly indicate that the inadequate chest compressions found in our clinical study were not due to lack of physical capability. We speculate that this may at least partly be explained by their fear of causing patient injury and trust in their own opinion of what is the correct compression depth and force in preference to the feedback.     

Inflammation and coronary angiography in asymptomatic type 2 diabetic subjects

OBJECTIVE: Coronary artery disease (CAD) is prevalent in patients with type 2 diabetes mellitus (T2DM) and because it is often asymptomatic and extensive in comparison with CAD in subjects without diabetes, it represents a diagnostic challenge. The objective of the study was to investigate the prevalence of CAD in asymptomatic T2DM patients utilizing angiography and to investigate its association with cardiovascular (CV) risk factors, the metabolic syndrome and markers of inflammation. MATERIAL AND METHODS: Eighty-two patients with T2DM without symptoms of CAD, and with >or=1 CV risk factor (hypertension, dyslipidaemia, premature familial CAD, smoking or microalbuminuria) underwent a diagnostic stress test and coronary angiography irrespective of stress test results. Stenosis detected in the main coronary arteries >or=50% of lumen diameter was categorized as one-, two- or three-vessel disease. Inflammatory markers were analysed in fasting samples. RESULTS: Fifteen men and two women had significant CAD (21%) (1-vessel disease, n=10; 2- or 3-vessel disease, n=7). Patients with 2- or 3-vessel disease were significantly older and had a longer duration of diabetes, but the prevalence of other traditional CV risk factors or the metabolic syndrome was similar among those with 1-vessel and those with 2- or 3-vessel disease. Sensitivity for CAD of the stress test was low (0.35). The mean level of the pro-inflammatory marker interleukin-6 was elevated in patients with 2- to 3-vessel CAD as compared to patients with no or 1-vessel CAD (p<0.05). CONCLUSIONS: Significant CAD was found in 21% of asymptomatic patients with T2DM with >or=1 CV risk factor. Inflammatory markers may be helpful in identifying patients that are likely to have significant CAD, but larger studies are warranted.     

Considerations made by the general practitioner when dealing with sick-listing of patients suffering from subjective and composite health complaints

Objectives

To explore GPs’ considerations in decision-making regarding sick-listing of patients suffering from SHC.

Design

Qualitative analysis of data from nine focus-group interviews.

Setting

Three cities in different regions of Norway.

Participants

A total of 48 GPs (31 men, 17 women; aged 32–65) participated. The GPs were recruited when invited to a course dealing with diagnostic practice and assessment of sickness certificates related to patients with composite SHCs.

Results

Decisions on sick-listing patients with SHCs were regarded as a very challenging task. Trust in the patient''s own story and self-judgement was deemed crucial, but many GPs missed hard evidence of illness and loss of function. Several factors that might influence decision-making were identified: the patients’ ability to present their story to evoke sympathy, the GP''s prior knowledge of the patient, and the GPs’ own experience as a patient and their tendency to avoid conflicts. The approach to the task of sick-listing differed from patient-led cooperation to resistant confrontation.

Conclusion and implications

Issuing sickness certification in patients with composite health complaints is considered challenging and burdensome. It is seen as mainly patient-driven, and the decisions vary according to GPs’ attitudes, beliefs, and personalities. Guiding the GPs to a more focused awareness of the decision process should be considered.Key Words: Education, family practice, primary health care, sickness certification, sick-listing, subjective health complaints, work incapacityAlthough we have some knowledge concerning GPs’ practices on sick-listing in general, less is known about how GPs make their assessments regarding sick-listing in the more complex cases of patients with subjective health complaints (SHCs).

• Decisions on sick-listing patients with SHCs are considered by GPs as a demanding and challenging task and are seen as mainly patient-driven.
• Handling of the sick leave decisions varies greatly, according to GPs’ attitudes, beliefs, and personalities.
• Focused awareness of the decision process through more specific education and training among students and GPs should be considered.

Subjective health complaints (SHCs) account for a great proportion of the encounters in general practice [1,2], and include conditions like musculoskeletal pain, tiredness, fibromyalgia, gastrointestinal complaints, depression, and anxiety [3–9]. SHCs are characterized by a plurality of symptoms and often a lack of objective findings or specific pathology to fully explain the complaints [7,10–12]. Lack of objective findings makes assessment difficult and leaves room for great variation in assessment of these patients, including the decision on whether to grant sick leave.A sickness certificate may be granted in Norway if a reduction in work capacity is due to disease or injury [13,14]. Some 79% of the total number of sickness certificates are issued by general practitioners (GPs) [13]. This assessment is often difficult and complex, and many physicians are uncomfortable carrying out these duties [15], being caught in the crossfire between the patients’ demands for sick-listing and society''s pressure to act more restrictively [15,16]. Knorring and her collaborators [17] report that many GPs expressed fatigue, despair, and lack of pride in their work concerning sick-listing. GPs find it particularly challenging to deal with issues of sick-listing when the decision is solely based on the patient''s own report of complaints [17,18].The GP''s age, sex, and whether the GP is a specialist or not, and also how the patients present their problem are factors found to influence decisions regarding sick-listing [19,20,22]. Norrmen et al. [21] found that the strongest predictors for granting sickness certification were agreement between patients’ and GPs’ assessment of reduced work capacity. When the patient''s complaints were judged to be non-somatic, the risk of being sick-listed also increased. However, there is scarce knowledge concerning how physicians actually make their assessment, especially in the more complex cases. The aim of this study was to explore what considerations are made by GPs when they decide whether patients with SHCs are eligible for sick-listing.