Pereira's attack on legalizing euthanasia or assisted suicide: smoke and mirrors.

OBJECTIVE: To review the empirical claims made in: Pereira J. Legalizing euthanasia or assisted suicide: the illusion of safeguards and controls. Curr Oncol 2011;18:e38-45. DESIGN: We collected all of the empirical claims made by Jose Pereira in "Legalizing euthanasia or assisted suicide: the illusion of safeguards and controls." We then collected all reference sources provided for those claims. We compared the claims with the sources (where sources were provided) and evaluated the level of support, if any, the sources provide for the claims. We also reviewed other available literature to assess the veracity of the empirical claims made in the paper. We then wrote the present paper using examples from the review. RESULTS: Pereira makes a number of factual statements without providing any sources. Pereira also makes a number of factual statements with sources, where the sources do not, in fact, provide support for the statements he made. Pereira also makes a number of false statements about the law and practice in jurisdictions that have legalized euthanasia or assisted suicide. CONCLUSIONS: Pereira's conclusions are not supported by the evidence he provided. His paper should not be given any credence in the public policy debate about the legal status of assisted suicide and euthanasia in Canada and around the world.

Changing preferences for information and participation in the last phase of life: a longitudinal study among newly diagnosed advanced lung cancer patients.

PURPOSE: The objective is to explore changes over time in the information and participation preferences of newly diagnosed stage IIIb/IV non-small-cell lung cancer patients. METHODS: Patients were recruited by physicians in 13 hospitals and interviewed every 2 months until the fourth and every 4 months until the sixth interview. RESULTS: Sixty-seven patients were interviewed three times. Over a period of 4 months from diagnosis, half of patients changed their information preferences for palliative care and end-of-life decisions with a possible or certain life-shortening effect (ELDs, e.g., non-treatment decisions) in both directions, from not wanting to wanting the information, but also--and as much--from wanting to no longer wanting it. The latter were more likely to be in a better physical condition. Preferences for participation in medical decision making also changed: 50% to 78%, depending on the type of decision (general, treatment, transfer or ELD), changed their preference towards wanting more or less participation. Pain seemed to be a trigger for patients wanting more involvement, which contrasts with studies suggesting that patients who are more ill tend to give up more control. CONCLUSIONS: Doctors should regularly ask their advanced lung cancer patients how much information and participation they want because preferences do change in unexpected ways.

[Life with Locked-In syndrome]. / Quelle vie après le Locked-In syndrome?

The Locked-In Syndrome (LIS) is classically caused by an anterior pontine vascular lesion and characterized by quadriplegia and anarthria with preserved consciousness and intellectual functioning. We here review the definition, etiologies, diagnosis and prognosis of LIS patients and briefly discuss the few studies on their quality of life and the challenging end-of-life decisions that can be encountered. Some clinicians may consider that LIS is worse than being in a vegetative or in a minimally conscious state. However, preliminary data from chronic LIS survivors show a surprisingly preserved self-scored quality of life and requests of treatment withdrawal or euthanasia, though not absent, are infrequent.

Drugs used for euthanasia in Flanders, Belgium.

PURPOSE: Our aim was to describe and assess the medicinal products and doses used for euthanasia in a series of cases, identified within an epidemiological death certificate study in Belgium, where euthanasia was until recently legally forbidden and where guidelines for euthanasia are not available. METHODS: In a random sample of the deaths in 1998 in Belgium, the physicians who signed the death certificates were identified and sent an anonymous mail questionnaire. The questionnaires of the deaths classified as euthanasia cases were reviewed by a multi-disciplinary panel. RESULTS: A total of 22 among 1925 questionnaires pertained to voluntary euthanasia. In 17 cases, detailed information on the euthanatics (medicinal substances used for euthanasia) used was provided. Opioids were used in 13 cases (in 7 as a single drug). Time between last dose and expiry ranged from 4 to 900 min. The panel judged that only in 4 cases effective euthanatics were used. CONCLUSIONS: In the end-of-life decision cases perceived by Belgian physicians as euthanasia, pharmacological practices were disparate, although dominated by the use of morphine, in the very late phase of dying, in doses which were unlikely to be lethal. Most physicians clandestinely engaging in euthanasia in Belgium seemed unaware of procedures for guaranteeing a quick, mild and certain death. Information on the pharmacological aspects of euthanasia should be included in the medical curriculum and continuing medical education, at least in countries with a legal framework permitting euthanasia under specified conditions.

[A comparative study of the euthanasia laws of Belgium and the Netherlands]. / Similitudes et différences entre les lois belge et néérlandaise relatives à l'euthanasie.

Recently, laws on euthanasia have been adopted in the Netherlands and Belgium. In both countries the legality of euthanasia is conditioned by adherence to strict conditions and by confirmation after a notification procedure. Although both laws are rather similar, the Belgian law is more fastidious on the requirements of prudent practice. The Belgian law does and the Dutch law does not distinguish between terminal conditions and non-terminal or slowly evolutive chronic conditions. In Belgium, the law only applies to adults, whereas in the Netherlands, minors over 12 years of age may under certain conditions receive euthanasia. However, the Belgian National Medical Disciplinary Board has recently mitigated differences by drafting guidelines which reflect a broad interpretation of the law. A major difference between the two countries is that in the Dutch society the norm setting on euthanasia developed more through jurisprudence and endorsement by the Medical Association than through legislation. We anticipate that the implementation of the new law and the notification procedure may be more difficult in Belgium than in the Netherlands. In order to promote the quality of the euthanasia practice, the euthanasia notification procedure in the Netherlands is followed by systematic feedback to the physicians. The strict anonymity of the Belgian notification procedure will be broken only when the control commission finds some anomaly or deficiency in the declaration. Therefore, unless the Evaluation and Control Commission makes ample use of its prerogative to contact the physician, the Belgian physicians may be less supported by the notification procedure to improve their knowledge and skills in euthanasia.

The Belgian PCB and dioxin incident of January-June 1999: exposure data and potential impact on health.

In January 1999, 500 tons of feed contaminated with approximately 50 kg of polychlorinated biphenyls (PCBs) and 1 g of dioxins were distributed to animal farms in Belgium, and to a lesser extent in the Netherlands, France, and Germany. This study was based on 20,491 samples collected in the database of the Belgian federal ministries from animal feed, cattle, pork, poultry, eggs, milk, and various fat-containing food items analyzed for their PCB and/or dioxin content. Dioxin measurements showed a clear predominance of polychlorinated dibenzofuran over polychlorinated dibenzodioxin congeners, a dioxin/PCB ratio of approximately 1:50,000 and a PCB fingerprint resembling that of an Aroclor mixture, thus confirming contamination by transformer oil rather than by other environmental sources. In this case the PCBs contribute significantly more to toxic equivalents (TEQ) than dioxins. The respective means +/- SDs and the maximum concentrations of dioxin (expressed in TEQ) and PCB observed per gram of fat in contaminated food were 170.3 +/- 487.7 pg, 2613.4 pg, 240.7 +/- 2036.9 ng, and 51059.0 ng in chicken; 1.9 +/- 0.8 pg, 4.3 pg, 34.2 +/- 30.5 ng, and 314.0 ng in milk; and 32.0 +/- 104.4 pg, 713.3 pg, 392.7 +/- 2883.5 ng, and 46000.0 ng in eggs. Assuming that as a consequence of this incident between 10 and 15 kg PCBs and from 200 to 300 mg dioxins were ingested by 10 million Belgians, the mean intake per kilogram of body weight is calculated to maximally 25,000 ng PCBs and 500 pg international TEQ dioxins. Estimates of the total number of cancers resulting from this incident range between 40 and 8,000. Neurotoxic and behavioral effects in neonates are also to be expected but cannot be quantified. Because food items differed widely (more than 50-fold) in the ratio of PCBs to dioxins, other significant sources of contamination and a high background contamination are likely to contribute substantially to the exposure of the Belgian population.

Cytologic examination to detect clear cell adenocarcinoma of the vagina or cervix.

OBJECTIVE: The aim of this study was to determine the sensitivity of cytopathologic examination for the detection of vaginal or cervical clear cell adenocarcinoma (CCA). METHODS: Systematic collection in the Dutch automated nationwide pathology archive of all cytology and histology data of women with CCA, born in The Netherlands after 1947 was performed. All cytologic examinations within 2 years prior to histological diagnosis of CCA were included. RESULTS: Ninety patients with CCA have been registered. Forty-nine of these patients had cytologic examinations prior to histology. Eighty-five percent of cervical CCAs were preceded by a positive cervical smear. One hundred percent of vaginal CCAs were preceded by a positive vaginal smear. Cervical smears are relatively insensitive to detect vaginal CCA. Vaginal smears were often omitted. Only 2 apparently false-negative smears were found. The mean numbers of smears in diethylstilbestrol (DES)-exposed and nonexposed women were minimally different: 1.0 and 0.8, respectively. This suggests an only modest impact of the awareness of DES as a risk factor. FIGO tumor stage I was preceded more frequently by cytology than the higher tumor stages. CONCLUSION: The majority of CCA cases can be detected at an early stage by yearly clinical and cytological examinations, which must comprise cervical as well as vaginal sampling. Since CCA may also occur in postmenopausal women, for the purpose of secondary prevention of CCA regular cytologic examinations of DES-exposed women must be continued after menopause.

Similia similibus obscurantur: the pharmacological clinical activity bias I. A prototype model to correct a disease-drug interaction leading to misestimations of drug-attributable side effects.

Drugs have side effects that manifest as signs or symptoms which are sometimes undistinguishable from signs or symptoms of active disease. The conventional approximation of the rate of side effects of drugs is by subtracting the rate of signs and symptoms in the placebo group from that in the drug group. This measures net side effects and is adequate in studies with healthy volunteers, in which no interaction between drug and disease exists. For ethical and practical reasons, however, volunteer studies cannot be large and the frequency of non-rare side effects must be estimated in large-scale clinical trials. In the latter, biasing drug disease interactions may occur. We report on such a hitherto undescribed interaction: the pharmacological clinical activity bias. If one is interested in estimating not the net, but the direct or intrinsic, ie, drug-attributable side effects, the conventional approximation is biased whenever, in clinical trials, both of two conditions apply. The first is that the variable on the scale of which a sign or symptom is recorded as a putative side effect, is also in the absence of drug affected by uncontrolled disease. The second is that the drug has pharmacological clinical activity (A) on that sign or symptom, thus reducing the contribution of disease (D) to what is measured. In this case the drug affects the variable under study both directly, through its intrinsic side effect, and indirectly, through its clinical activity, and the rate of attributable side effects differs from the rate of net side effects as calculated by the conventional approximation. We present a simple deterministic model, which assumes that disease remains stable if untreated, additivity of the relative contributions of drug, placebo and disease to the total rate of the sign or symptom, and no other interaction between intrinsic properties of the drug and active disease than pharmacological clinical activity. This theoretical model quantifies the bias as DO(Ad-Ap), in which DO is the baseline frequency of the sign or symptom in the studied patients, and Ad and Ap are the intrinsic clinical activities of drug and placebo, respectively, on the sign or symptom under study. The model confirms that the conventional approximation of drug side effects is unbiased only in healthy volunteers or with drugs devoid of clinical activity. Without correction by such a model, any clinical activity of the drug or manifestation of active disease will cause the conventional approximation of side effects to be biased. This may manifest as artifacts such as attribution of a side effect when there is none, and as under- or overestimation, pseudotachyphylaxis, or pseudo-delayedness of attributable side effects.

Effect of timing of antihypertensive therapy on glomerular injury: comparison between captopril and diltiazem.

Recent studies have suggested that the progression of experimental chronic renal disease may be prevented by early use of antihypertensive drugs. It is unclear, however, whether such therapies may also affect established and progressive renal disease. In the present study we compared the effects of captopril (CEI) and diltiazem (CCB), started either at week 10 or at week 24 on the evolution of adriamycin nephropathy (AN). Rats were studied at weeks 7, 16, 24, 32, and 38 of the disease. None of the treatments influenced the development of nephrotic range proteinuria. The use of CCB from week 10 was even associated with increased proteinuria. The moderate hypertension of ADR rats was reduced to the same degree with both drugs. Inulin clearance (GFR) was significantly reduced in all ADR rats. However, in ADR rats treated with CEI from week 10 and in those treated with CCB from week 24, the GFR was relatively higher. Glomerular injury, evaluated by semiquantitative methods, was not ameliorated by CEI treatment. Earlier CCB treatment (week 10) worsened glomerular lesions, whilst CCB treatment initiated at week 24 reduced significantly the degree of mesangial expansion and focal glomerular sclerosis. We conclude that, in addition to their common antihypertensive action, the specific effect of drug therapy seems to be crucially time dependent.

The role of fluorinated pyrimidine analogues in the induction of the in vitro expression of the fragile X chromosome.

The modes of action of 5-fluoro-2'-deoxyuridine (FdUrd) and 5-fluoro-2'-deoxycytidine (FdCyd) were studied in PHA-stimulated lymphocytes from normal volunteer donors and a fragile X patient. In both cell types, FdUrd and FdCyd inhibited cell proliferation at concentrations of 3 x 10(-8) M. Thymidylate synthetase was identified as the decisive target for the action of both FdUrd and FdCyd, as judged from the following observations: First, addition of thymidine to the culture medium was able to counteract both FdUrd and FdCyd toxicities, whereas addition of dCyd had no observable effect. Second, inhibition of the in situ thymidylate synthetase activity measured as an increase in the level of [3H]-dThd incorporation coincided with the inhibition of cell proliferation. Third, the inhibition of the thymidylate synthetase-dependent incorporation of [3H]-dUrd into newly synthesized DNA coincided with the inhibition of cell proliferation. The effects of FdUrd and FdCyd on the in vitro expression of fragile site Xq27 of fragile X chromosomes was shown to be based on the depletion of the intracellular pool of thymidine-5'-monophosphate (dTMP), as judged from the following observations: First, both the FdUrd- and FdCyd-dependent induction of site Xq27 coincided with the antiproliferative effects of the respective fluoropyrimidines. Second, addition of thymidine (dThd) to the culture medium both prevented the expression of site Xq27 and neutralized the cytotoxicity of FdUrd and of FdCyd. On the basis of these findings, we provide further evidence for the concept that the fragile X site is located in an AT-rich region.

[Evaluation of the quality of life during treatment]. / Evaluation de la qualité de la vie en cours de traitement.

Biomedical advances to further the quality of life (QL) of cancer patients must nowadays be complemented by psycho-social evaluation and intervention. The challenge is to quantify the qualitative and to objectivate the subjective. To evaluate QL during treatment of individual patients, open interviews are unsurpassed. However, to measure QL of patient groups, questionnaires are necessary. Some examples from the QL literature illustrate the main drawbacks of questionnaires: lack of sensitivity, specificity, and iterative applicability. To circumvent these problems, it is suggested to add a global self-assessment of QL to questionnaires. Such an instrument, Anamnestic Comparative Self-Assessment is briefly described.

Reversible renal failure due to psychogenic urinary retention.

A case of advanced, reversible renal failure due to psychogenic urinary retention occurring in a 17 year old female, is reported. The diagnosis of psychogenic urinary retention was made on the basis of existent florid psychopathology and the concomitant exclusion of an organic cause. Family psychodynamics are discussed. Psychosocial intervention led to a resumption of normal micturition, the disappearance of the urinary retention with resultant improvement of renal function.

5-fluorouracil and 5-fluoro-2'-deoxyuridine follow different metabolic pathways in the induction of cell lethality in L1210 leukaemia.

The mode of action of 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) on L1210 leukaemia has been studied. It is shown that FUra and FdUrd follow different routes of metabolism and have different targets with respect to their cytotoxic activity. FUra is converted to 5-fluorouridine-5'triphosphate ( FUTP ), which is incorporated into nascent RNA. FdUrd is converted to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which inhibits the de novo synthesis of 2'-deoxythymidine-5'-monophosphate (dTMP). Conversion of FUra to FdUMP does occur, but this phenomenon does not contribute to the final cytotoxic effect. No conversion of FdUrd to FUra has been detected.

In vitro assessment of cytotoxic agents in murine cancers: comparison between antiproliferative and antimetabolic assays.

Different methods were compared for the in vitro evaluation of the therapeutic effects of the antineoplastic agents doxorubicin, cisplatin, fluorouracil, and vinblastine sulfate in a model system of murine tumor cell lines consisting of L1210 leukemia, P815 mast cell leukemia, and B16 melanoma. Excellent correlations were found with the in vivo effects with the use of a soft agar clonogenic assay, irrespective of the method of growth assessment (i.e., visual colony counting or incorporation of tritiated thymidine in proliferating colonies). Drug effects on the proliferation of tumor cell lines in liquid medium frequently led to an overestimation or underestimation of the actual in vivo effects. Direct incorporation of the radiolabeled precursors thymidine, uridine, and leucine after pretreatment with drugs always led to the prediction of resistance and was therefore considered unreliable.

Rate of DNA synthesis in exponentially growing cell lines in the presence and absence of antimetabolites.

Experimental tumor cell lines were used to show that in the presence of 5-fluorodeoxyuridine (FdUrd), the rate of DNA synthesis remains unaltered as long as a saturating concentration of thymidine is present. This unimpeded rate of DNA synthesis in combination with FdUrd-blocked de novo thymidylate synthesis makes it possible to accurately measure the total rate of increase of DNA using tritiated thymidine of known specific activity. The observed amount of incorporated tritiated thymidine is in excellent agreement with the calculated theoretical maximal incorporation in cultures with exponentially increasing DNA and cell number.

Parathyroid hormone secretion and responsiveness to parathyroid hormone in primary hypomagnesemia.

Parathyroid function was studied in two infant sisters with primary hypomagnesemia while they were both hypomagnesemic and hypocalcemic. In one of the infants, plasma immunoreactive parathyroid hormone (iPTH) was elevated, the calcemic response to exogenous parathyroid hormone (PTH) was absent, and the phosphaturic response was normal. Restoration of serum magnesium with i.v. magnesium corrected the hypocalcemia, with no further rise of plasma iPTH. In the other infant, plasma iPTH was undetectable, and exogenous PTH produced both phosphaturic and calcemic responses. Normalization of serum magnesium with i.v. magnesium resulted in a prompt release of endogenous PTH and correction of the hypocalcemia. These findings suggest that, in the first patient, hypocalcemia was associated with lack of response of the bone to both endogenous and exogenous PTH, while in the second patient, hypocalcemia was associated with inhibition of PTH release and a normal calcemic response to exogenous PTH. The factors that determine whether magnesium deficiency will result in inhibition of PTH release, in a lack of response of the bone to endogenous and exogenous PTH, or both, remain to be clarified.