Physicians and death: Comments and behaviour of 605 doctors in the north-east of Italy

The aim of this study was to determine the influence of socio-demographic and professional factors on physicians' attitudes to the terminally ill. Between May 1992 and May 1993, a survey was conducted in the province of Pordenone (north-east, Italy) in order to analyse a number of specific issues, such as emotional involvement, the need for aggressive treatments and the communication of diagnosis and prognosis. After obtaining a list of board-certified physicians from the Medical Association office in Pordenone, a modification of the cancer questionnaire of Haley and Blanchard (QSPT) was mailed to 916 doctors. Of these, 605 (60%; 487 male, 118 female; mean age 41 ± 11 SD) returned the completed questionnaire. Within the group of responders, we identified three main subgroups, according to their type of activity: general practitioners (175, 29%), hospital doctors (235, 39%) and other doctors (195, 32%). In age, sex and activity, the only significant difference between responders and non-responders was age (mean age 41 and 43 years respeetively). Most of the responders (77%) stated that they were able to deal with the terminally ill patient and his/her needs; 44%, however, admitted that patients' anxiety is sometimes unbearable. For the vast majority of the doctors polled (91%), providing a comfortable environment for an incurable patient was more important than pursuing aggressive treatment, but only 44% were convinced of the uselessness of aggressive care. To the question on whether to disclose information about imminent death to allow patients to prepare spiritually, 37% answered No, 38% Yes, and 25% were uncertain. Almost all responders (95%), however, believed in the beneficial effect of hope on the terminally ill. Ourresults suggest that doctors' professional and, most of all, sociodemographic and cultural factors determine the relationship with the patient on both the emotional and the clinical decision-making levels.     

Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro

The mechanisms producing long duration of action for formoterol and salmeterol are not fully understood. The aim of the current study was to examine how the concentration of long and short acting ₂-adrenoceptor agonists affects their relaxation kinetics in airway smooth muscle. Onset (time to peak relaxation) and offset of action (reassertion of reversible relaxation following repeated -adrenoceptor blockade and washout) were measured in the guinea pig trachea precontracted postjunctionally by carbachol 0.3 M in vitro. At 10–1,000% (C _1O–C _1,000) of the maximally effective concentration (C ₁₀₀: 150 nM formoterol, 10 M salbutamol, 30 M salmeterol), salbutamol had a shorter time to peak relaxation than did salmeterol. Formoterol and salmeterol had a similar time to peak relaxation at C ₁₀, but, in contrast to salmeterol, formoterol's time to peak relaxation became markedly shorter and similar to that of salbutamol as the concentration was increased up to C _1,000. Significant reversible reasserted relaxation was demonstrated for salmeterol alone at C ₁₀. At C ₃₀–C _1,000, however, salmeterol produced irreversible relaxation only, in spite of repeated -adrenoceptor blockade by sotalol 10 M followed by washout. In contrast, formoterol produced an increasing reversible reasserted relaxation at C ₃₀–C _1,000. Salbutamol produced significant, reversible reasserted relaxation at C _1,000 only. In conclusion, the concentration determines the onset and offset of action for formoterol and to a lesser extent for salbutamol, but not for salmeterol. To cause sustained action, a submaximally effective concentration is sufficient for salmeterol, whereas formoterol requires a maximally effective concentration. The rank order of concentration dependence for the relaxation kinetics is not paralleled by the rank order of lipophilicity for formoterol, salbutamol, and salmeterol. Therefore, factors other than lipophilicity may also play a role in determining the relationship between concentration and relaxation kinetics for the investigated ₂-agonists. Offprint requests to: Anders Linden, MD, PhD     

The Binding of Cyclosporin A to Human Plasma: An in Vitro Microdialysis Study

Purpose. The human plasma binding of cyclosporin A was studied in vitro using the technique of microdialysis. The effect of temperature on the overall binding interaction between cyclosporin A and human plasma was also investigated. Methods. Flow-through loop-type microdialysis probes were constructed from fused silica tubing and regenerated cellulose tubing with a MWCO of 13000 daltons. Probes were perfused with phosphate buffer (0.5 µl/min) and the concentration of ³H-cyclosporin A in the well-mixed medium (plasma or buffer) was 1200 ng/ml. Relative recoveries of cyclosporin A from plasma or buffer were determined for each probe by separate experiments to measure the solute gain or loss with reference to the perfusate. Results. Recoveries determined by loss were significantly greater than those determined by gain and in each case temperature dependent, with higher recoveries at higher temperatures. The plasma free fraction of cyclosporin A calculated from the recovery data and the perfusate to plasma concentration ratios was dependent on temperature in a log-linear fashion. Mean ± s.d. plasma free fractions expressed in percent were 33.5 ± 4.6, 17.9 ± 3.6, 6.2 ± 0.8, 3.0 ± 0.6, and 1.5 ± 0.2 at temperatures of 4, 10, 20, 30, and 37°C, respectively. Assuming that the enthalpy of binding is constant over the temperature range studied and pseudo-first order conditions exist, the binding reaction at these temperatures was spontaneous, endothermic (H = 74.0 kJ/mole), and entropically driven (S = 0.274 kJ/mole/deg). Conclusions. These results show that the free fraction of cyclosporin A in human plasma is dependent on temperature with the fraction unbound decreasing with temperature in the range of 4 to 37°C. The thermodynamic parameters for the binding of cyclosporin A to plasma components indicate that the reaction is a spontaneous endothermic reaction that is mainly entropy driven, similar to the partitioning of lipophilic molecules from an aqueous to a hydrophobic phase. Moreover, these results show that microdialysis is a feasible method to determine the binding interactions between plasma and cyclosporin A, which indicates the method may be suitable for other difficult binding studies where the solutes have nonspecific binding to separation devices.     

The effects of cyclosporin A,tamoxifen, and medroxyprogesterone acetate on the enhancement of Adriamycin cytotoxicity in primary cultures of human breast epithelial cells

Summary Adriamycin (Adr), the single most active agent used in the treatment of breast cancer, may become ineffective as treatment progresses due to the development of multidrug resistant (MDR) tumors. A major mechanism associated with MDR is increased P-glycoprotein (Pgp) expression. This study examined the abilities of the anti-estrogen tamoxifen (TAM) and the progestin medroxyprogesterone acetate (MPA) as well as cyclosporin A (CsA), a known resistance modifier, to enhance the cytotoxic effects of Adr on human breast epithelial cells (HBEC) in primary culture. Pgp and estrogen receptor (ER) expression were determined in each of the cultures by immunocytochemical assays using the monoclonal antibodies C219 and H222 Sp, respectively. The Adr-sensitive, Pgp-, ER+ MCF-7 cell line and the Adr-resistant, Pgp+, ER-MCF7-AdrR cell line were used as controls. Primary cultures were categorized as HBEC from tissues with or without previous chemotherapy. Pgp was detected in 1 of the 15 cell cultures from tissues without previous chemotherapy and in 5 of the 6 cell cultures from tissues previously exposed to chemotherapy. Incubation with either CsA or MPA plus Adr enhanced Adr toxicity in Pgp+ but not Pgp- cell cultures, whereas TAM had no effect on the sensitivity of any of the cultures. Of the 21 primary cultures of HBEC, 3 were ER+. There was no correlation between the enhancement of Adr cytotoxicity and ER status. The data suggest that MPA as well as CsA may be useful as modifying agents in overcoming Pgp-associated multidrug resistance.     

Cross-cultural development of a quality of life measure for men with erection difficulties

Erection difficulties have a profound effect on a man's quality of life, however, the emotional consequences are often overlooked in quantitative research where most sex-related questionnaires focus on a man's functional ability. Consequently, we developed a cross-cultural instrument to measure quality of life specific to male erection difficulties (QOL-MED). The items in the QOL-MED originated from interviewing forty men with erection difficulties in Seattle and Boston. Twelve men in the USA and 29 men in England helped us refine the instrument. Testing the QOL-MED's psychometric properties involved two administrations over a two-week period in the USA (n=40) and the UK (n=29). For discriminant validity, we predicted quality of life would worsen with increased self-perceived severity of the condition. After controlling for years with erection difficulties in a linear regression model, we found a significant negative association between self-perceived severity and quality of life for men in the UK only (p<0.01). The expectation that the measure would produce evidence for convergent validity by being more closely correlated to well-being than functional status was not confirmed. Both the USA and UK instruments were internally consistent (Cronbach's =0.94 and 0.96, respectively), and reproducible (0.78 and 0.95, respectively). This instrument provides a promising tool for studying therapies and understanding quality of life in patients with erectile dysfunction.This research was supported from a research grant from Syntex, Inc.Mr. Wagner is now a doctoral student at the University of California at Berkeley, Berkeley, CA, USA.     

Prevalence survey of movement disorders, epilepsy, hypertension and smoking habit in Vejer de la Frontera, Southern Spain-I. Methodology

A prevalence survey of movement disorders, epilepsy, hypertension and smoking was undertaken in Vejer de la Frontera, Southern Spain in 1988. A validated screening instrument designed for door-to-door tracing of specific disorders was used. Neurological diagnoses were based on: (1) direct anamnesis and examination by a senior neurologist; (2) perusal of existing medical records; and (3) in a proportion of cases, a hospital-based complementary study. This experience suggests that, while door-to-door surveys of neurological disorders have focused on multiple major outcomes: (1) scientific and logistic reasons can exist for screening for specific neurological disorders, and (2) scientific and public health-related interventional objectives can be combined advantageously when such costly investigations are conducted.     

Blutgruppenantigenexpression in papillären karzinomen der schilddrüse Eine immunhistochemische und klinische studie über das Vorkommen von Lewis-, AB0- und verwandten antigenen

Zusammenfassung In einer immunhistochemischen Arbeit wurden 104 papilläre Schilddrüsenkarzinome auf das Vorkommen von Blutgruppenantigenen des AB0- und Lewis-Systems sowie verwandter, tumorassoziierter Antigene mit Typ-1- und Typ-2-Grundstruktur untersucht. Folgende Strukturen wurden im Gewebe nachgewiesen: CA-50 (sialinierter Typ-1-Vorläufer), CA-19-9 (Sialyl-Le^a), Le^a, Le^b, A, B, H, Le^x, Sialyl-Le^x und Le^y. Während gesundes, adultes Schilddrüsengewebe keine Blutgruppenantigene exprimierte, waren die papillären Karzinome durch die progressive Expression dieser Strukturen gekennzeichnet. Die meisten Tumoren reagierten mit dem C-50-Antikörper (84%), während deutlich weniger Gewebe das CA-19-9-Antigen aufwiesen (38%). Die Typ-2-Strukturen Le^x (47%) und Le^y (13%) wurden deutlich seltener gefunden als die korrespondierenden Typ-1-Antigene Le^a (71%) und Le^b (62%). Die Vorbehandlung mit Neuraminidase verstärkte die Le^a- und Le^x-Färbeergebnisse in 27 bzw. 44 Fällen. Von den A-, B-, und H-Antigenen wurden die A-Determinanten am häufigsten nachgewiesen (24%). In vergleichenden Untersuchungen von Serienschnitten der gleichen Tumoren wurde eine Koexpression mehrerer Typ-1-Antigene im denselben Tumorarealen festgestellt. Karzinome mit Expression von Typ-1- und Typ-2-Strukturen wiesen häufig eine komplementäre Antigenexpression in verschiedenen Bereichen der Gewebe auf. Einige Tumoren exprimierten Typ-1- und Typ-2-Strukturen auch in den gleichen Zellen, jedoch in verschiedenen Bereichen der jeweiligen Zellen.In 68 Fällen wurde eine Follow-up-Untersuchung durchgeführt. Die Beobachtungszeiträume lagen zwischen 12 und 217 Monaten. In 13 Fällen rezidivierte der Tumor, 7 dieser Patienten verstarben an dem Tumorleiden. Die meisten Rezidive traten bei Patienten auf, deren Tumoren die Grenzen des Organs überschritten hatten (pT4, n=19), während keines der pT1-Karzinome (n=20) zu einem Rezidiv geführt hatte. Während Lymphknotenmetastasen in 39 Fällen auftraten, wiesen 6 Patienten Fernmetastasen auf. Die klinischen Ergebnisse wurden mit den Färbeergebnissen korreliert. Es bestand kein Zusammenhang zwischen Antigenexpression und Tumordifferenzierung. Die pT4-Tumoren zeigten eine signifikant stärkere Expression der CA-50-, CA-19-9-, Le^a und Sialyl-Le^x-Strukturen. Karzinome mit Le^y-Expression wiesen signifikant häufiger Metastasen auf. Le^y, H-Typ-1 und H-Typ-2 traten häufiger in rezidivierenden Tumoren auf. Im Gegensatz dazu waren alle Patienten, deren Karzinom das A-Antigen exprimierte, fernmetastasen- und rezidivfrei (n=14). In der multiplen Regressionsanalyse wies der Faktor Fernmetastasierung die größte prognostische Relevanz auf, während im Vergleich dazu die Färbeergebnisse statistisch von untergeordneter Bedeutung waren.

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Blood group antigen expression in papillary carcinoma of the thyroid — An immunohistochemical and clinical study on the occurrence of Lewis-, AB0, and derived antigens

Nine monoclonal antibodies, lectin from Ulex europaeus and neuraminidase enzyme were employed to demonstrate the occurrence of type 1 and type 2 blood group antigens in 104 cases of papillary carcinoma of the thyroid. The reagents applied, recognize the following blood group related antigens: CA-50 (sialylated type 1 precursor), CA-19-9 (sialylated Le^a), Le^a, Le^b, A, B, H, Le^x, sialylated Le^x, and Le^y.Immunohistochemical studies revealed that papillary carcinoma of the thyroid, in contrast to histologically normal thyroid tissue, is characterised by a progressive expression of blood group antigens. Most tumours (84%) reacted with C-50 antibody, whereas only a minority of the tissues demonstrated the CA-19-9 antigen (38%). Type 2 structures Le^x (47%) and Le^y (13%) were found less often than their corresponding type 1 isomers Le^a (71%) and Le^b (62%). Desialylation with neuraminidase increased the Le^a and Le^x staining intensity in 27 and 44 cases, respectively. of the A, B, H antigens the A determinants encountered most frequently (24%).Comparative examinations of sequential sections of the same tumour revealed coexpression of type 1 antigens in the same areas. In carcinomas showing type 1 and type 2 antigen reactivity, a complementary distribution of the structures in different tumour areas was often demonstrated. Some tumours presented combined type 1 and type 2 antigen expression in the same cells, however, in distinct areas within the cell.A follow-up examination was carried out in 68 of the 104 cases. The observation time ranged from 12 to 217 months. Thirteen patients suffered from recurrence, of which 7 died. While lymphatic metastases occurred in 39 tumours, distant metastases were detected in 6 patients. Most of the recurrences were found in patients with tumour classification pT4 (n=19), whereas none of the pT1 carcinomas (n=20) showed recurrence.The clinical results were compared to the blood group antigen expression results. There was no correlation between antigen expression and differentiation degree of the tumour. The pT4 tumours showed a significant higher expression of the CA-50, CA-19-9, Le^a and Sialyl Le^x structures. Carcinomas expressing the Le^y antigen were associated with a significant higher level of metastasizing capacity. The Le^y, H type 1 and H type 2 antigens occurred more frequently in recurrent tumours (n=14). In contrast, none of the patients whose carcinomas expressed the Aantigens (n=14) suffered from a recurrence or hematogenous metastasis.Multiple stepwise regression analysis was carried out to check the importance of each staining and clinical factor. In this analysis, distant metastasis was the most important parameter, whereas the staining results were of minor statistical importance.

     

Acceptance of Surgery for Obesity by Academic Surgeons in North America

BACKGROUND: Have surgeons in North America accepted operations for the treatment of severe obesity? This question was posed by organizers of the Ninth International Symposium on Obesity Surgery that met in Stockholm in September, 1995. Study design: In order to obtain opinions which might help to answer the question posed, a 1-page questionnaire was sent to 151 chairmen of academic departments of surgery in North America in December 1994 asking about the acceptance and use of surgical operations for the treatment of severe obesity. RESULTS: Answers, received from 112 or 74%, indicated that operative treatment should be used (74%), was effective (77%) and safe (71 %). However, only 65% of departments provided such operations. Operative treatment for obesity was available outside the department in 53%. The operations most frequently used were Roux-en-Y gastric bypass (RGB) and vertical banded gastroplasty (VBG). A single operation was offered by 44 departments and a choice of two or more operations in 30 departments. RGB and VBG were equally in use. Gastric banding was used as an alternative to VBG in six departments. Other operations were in use in six departments either alone (three) or as alternatives to RGB and VBG (three). CONCLUSIONS: It appears that surgical treatment of obesity is accepted and available in the majority of academic departments of surgery.     

Chick gonadogenesis following early surgical bursectomy

Left ovaries of bursectomized chick embryos were examined on the 17th day of incubation in comparison to normal and sham-operated controls, by histological and histochemical observations. The results show that in bursectomized embryos the cortex appears irregulary developed, with a significant decrease in the mean thickness and in the percentage of the secondary sex cords in the total cortical area. Furthermore, the germinal epithelium appears thicker and the subcortical medulla and the tunica albuginea more compact. The greater activity of the enzyme ⁵–3-hydroxysteroid dehydrogenase ( ⁵3HSD) found in ovaries of bursectomized embryos (histochemical method) could be related to an endocrine dismetabolism affecting the cortical development. On the basis of these results and those of other authors, some hypotheses are advanced. In particular, an action of the bursal factor on GTH receptors could be the factor responsible of the enhanced steroidogenic activity altering the hormonal environment.     

Editor's note for debate Sporadic dementia of Alzheimer type: Role of amyloid in etiology is challenged

Summary Alzheimer's disease is a heterogenous neurodegenerative disorder. Whereas only a minority is due to genetic abnormalities and mostly with early onset, the majority of all Alzheimer cases is sporadic and with late onset. Therefore, in the latter, age-related disturbances in cellular metabolism may come into focus with respect to the etiopathogenesis rather than the primary formation of amyloid. In this Editor's note for debate, the role of amyloid as a causative factor of sporadic Alzheimer's disease is challenged. Instead, as a possible primary abnormal event in sporadic Alzheimer's disease, the perturbations in neuronal glucose metabolism and the subsequent ATP deficit with its impacts on the secondary amyloid formation are discussed to open a new field of research and another aspect for debate.