The Swiss catalogue of learning objectives.

PBL philosophy may challenge the need for explicit and specific educational objectives in medical education. From a practical point of view, however, such objectives are essential to achieve a close overlap between learning, teaching and assessment. Since the 1970s medical licensing in Switzerland has been based, among other things, on passing a uniform, centrally prepared MCQ exam for the graduates of all five Swiss medical schools. The need for a set of jointly developed learning, teaching and assessment objectives has become apparent. The Joint Conference of Swiss Medical Schools has therefore charged a small taskforce with the development of such a catalogue. This paper describes the background, process and results of this work.

Metal complexes of a biconcave porphyrin with D4-structure--versatile chiral shift agents.

Representative metal complexes of a biconcave D4-symmetric porphyrin were synthesised by metalion insertion into the porphyrin ligand 1. The NMR spectra suggested D4-symmetry for the ZnII and dioxo-RuVI complexes of 1 and C4-symmetry for the unsymmetrically ligated RuII and RhIII complexes. Metal complexes of 1 proved to be versatile chiral 1H NMR shift agents for a broad spectrum of organic amines, alcohols, carboxylic acids, esters, nitriles and nonpolar fullerene derivatives. A practical analysis of chiral substrates with 1 covers enantiomeric excesses beyond 99%. An X-ray structure of (1:1)-cocrystals of an achiral, biconcave CoII porphyrinate and C60 provided the first detailed insights into the structure of such a biconcave metallo-porphyrinate. It also showed remarkable packing of the carbon sphere against the main concave units of the porphyrin and gave clues about the relevant interactions between biconcave porphyrins and fullerenes.

Structural complexity of a polar perhydrotriphenylene inclusion compound brought to light by synchrotron radiation.

The complex diffraction pattern of the heavily disordered co-crystals of perhydrotriphenylene and 1-(4-nitrophenyl)piperazine (5C(18)H(30) x C(10)H(13)N(3)O(2)) has been investigated with synchrotron radiation and an area detector. Five (almost) complete, three-dimensional data sets have been obtained from the tips and the centre of a needle-like crystal at room temperature and 120 K. They revealed a rich variety of features including one,- two- and three-dimensional diffuse scattering, as well as incommensurate satellites. At the centre and one tip of the crystal the symmetry appears to be orthorhombic, whereas at the other tip the symmetry of the satellites and of some of the diffuse scattering is clearly monoclinic, indicating that the crystal is not homogeneous. Most of the scattering could be assigned to R/S occupational disorder of the chiral host molecules, to positional disorder of the guest molecules or to local distortions of the average structure. Assignments are based on the disorder deduced from the average structure and the molecular form factors of host and guest molecules which show characteristic patterns in reciprocal space. Two smaller, orthorhombic twin fragments and an additional phase with hexagonal symmetry have also been found.

The toxicology of iodate: a review of the literature.

Because it is more stable than iodide, most health authorities preferentially recommend iodate as an additive to salt for correcting iodine deficiency. Even though this results in a low exposure of at most 1,700 microg/d, doubts have recently been raised whether the safety of iodate has been adequately documented. In humans and rats, oral bioavailability of iodine from iodate is virtually equivalent to that from iodide. When given intravenously to rats, or when added to whole blood or tissue homogenates in vitro or to foodstuff, iodate is quantitatively reduced to iodide by nonenzymatic reactions, and thus becomes available to the body as iodide. Therefore, except perhaps for the gastrointestinal mucosa, exposure of tissues to iodate might be minimal. At much higher doses given intravenously (i.e., above 10 mg/kg), iodate is highly toxic to the retina. Ocular toxicity in humans has occurred only after exposure to doses of 600 to 1,200 mg per individual. Oral exposures of several animal species to high doses, exceeding the human intake from fortified salt by orders of magnitude, pointed to corrosive effects in the gastrointestinal tract, hemolysis, nephrotoxicity, and hepatic injury. The studies do not meet current standards of toxicity testing, mostly because they lacked toxicokinetic data and did not separate iodate-specific effects from the effects of an overdose of any form of iodine. With regard to tissue injury, however, the data indicate a negligible risk of the small oral long-term doses achieved with iodate-fortified salt. Genotoxicity and carcinogenicity data for iodate are scarce or nonexisting. The proven genotoxic and carcinogenic effects of bromate raise the possibility of analogous activities of iodate. However, iodate has a lower oxidative potential than bromate, and it did not induce the formation of oxidized bases in DNA under conditions in which bromate did, and it may therefore present a lower genotoxic and carcinogenic hazard. This assumption needs experimental confirmation by proper genotoxicity and carcinogenicity data. These in turn will have to be related to toxicokinetic studies, which take into account the potential reduction of iodate to iodide in food, in the intestinal lumen or mucosa, or eventually during the liver passage.

Monitoring the adequacy of salt iodization in Switzerland: a national study of school children and pregnant women.

BACKGROUND: Several countries with long-standing salt iodization programs, including Switzerland, have recently reported declining and/or low urinary iodine (UI) levels in their populations. In Switzerland, in response to studies indicating low UI levels in children and pregnant women, the salt iodine level was increased in 1998 from 15 to 20 mg/kg. OBJECTIVE: Our objective was to evaluate iodine nutrition in a national sample of Swiss school children and pregnant women 8 16 months after the increase in the salt iodine level. DESIGN: A 3-stage probability proportionate to size cluster sampling method was used to obtain a representative national sample of 600 children aged 6-12 y and 600 pregnant women. We then measured UI in both groups, thyrotropin (TSH) in pregnant women and thyroid volume by ultrasound to determine goiter prevalence in school children. RESULTS: The median UI (range) of the children and pregnant women was 115 microg/l (5-413) and 138 microg/l (5-1881), respectively. The median blood TSH concentration (range) of pregnant women was 0.6 mU/l (0.2-2.1). Based on the current WHO/ICCIDD normative data for thyroid volume, none of the children were goitrous, using either age/sex-specific or BSA/sex-specific cutoffs. CONCLUSIONS: The iodine status of the Swiss population is once again adequate, illustrating the value of periodic monitoring and prudent adjustments to the iodine level in salt. This approach could serve as a model for countries struggling to maintain dietary iodine intake in the face of shifting dietary habits and changes in the food supply.

How to maintain blood supply during computer network breakdown: a manual backup system.

Electronic data management systems using computer network systems and client/server architecture are increasingly used in laboratories and transfusion services. Severe problems arise if there is no network access to the database server and critical functions are not available. We describe a manual backup system (MBS) developed to maintain the delivery of blood products to patients in a hospital transfusion service in case of a computer network breakdown. All data are kept on a central SQL database connected to peripheral workstations in a local area network (LAN). Request entry from wards is performed via machine-readable request forms containing self-adhesive specimen labels with barcodes for test tubes. Data entry occurs on-line by bidirectional automated systems or off-line manually. One of the workstations in the laboratory contains a second SQL database which is frequently and incrementally updated. This workstation is run as a stand-alone, read-only database if the central SQL database is not available. In case of a network breakdown, the time-graded MBS is launched. Patient data, requesting ward and ordered tests/requests, are photocopied through a template from the request forms on special MBS worksheets serving as laboratory journal for manual processing and result report (a copy is left in the laboratory). As soon as the network is running again the data from the off-line period are entered into the primary SQL server. The MBS was successfully used at several occasions. The documentation of a 90-min breakdown period is presented in detail. Additional work resulted from the copy work and the belated manual data entry after restoration of the system. There was no delay in issue of blood products or result reporting. The backup system described has been proven to be simple, quick and safe to maintain urgent blood supply and distribution of laboratory results in case of unexpected network breakdown.

Motion and disorder in crystal structure analysis: measuring and distinguishing them.

Dynamic processes in crystalline solids are reflected in the atomic displacement amplitudes determined, together with the atomic coordinates, by crystal structure analysis. The interpretation of such amplitudes poses two severe problems: (a) The relative phases of the atomic displacements are lost; and (b) the amplitudes may reflect disorder in the structure and systematic error in the diffraction experiment in addition to motion, but the three contributions cannot be separated on the basis of measurements at a single temperature. Several approximate ways to solve these problems, e.g. rigid-body and segmented-rigid-body analysis, are reviewed together with their limitations. A more recent approach that represents a significant advance with respect to both difficulties is also described: Crystal structures are determined over a range of temperatures; the mean square amplitude quantities are interpreted by taking explicit account of their temperature dependence, i.e. by exploiting the difference in behavior of a microscopic oscillator in the low-temperature, quantum regime and in the high-temperature, classical regime. A distinction between low-frequency and high-frequency motion, disorder, and systematic error becomes possible with this model; this is illustrated with the help of case studies.

ZrIV-tetraphenylporphyrinates as nuclease mimics: structural, kinetic and mechanistic studies on phosphate diester transesterification.

The Zr(IV)-tetraphenylpor-phyrinates Zr(TPP)(X,X'), (X,X' = -OAc, -OMe, Cl ) 4-6, 8 were prepared and their complexing properties as well as catalytic properties towards solvolysis of the phosphate diesters hpp (2), dmp (3) and pmp (16) characterised. The diesters 2 and 16, representing model phosphates for RNA and DNA, were substrates for the catalyst Zr(TPP)Cl2 (4), and rate accelerations over background by 6-9 orders of magnitude were measured. These accelerations are comparable to those of dinuclear transition metal catalysts and lanthanide ions. Catalytic turnover was observed. Kinetic studies revealed that the catalytically active species of 4 in the solvolysis of 2 and 16 in methanol-containing solvents are dinuclear complexes containing either one or two phosphate esters depending upon the phosphate concentration. Besides the usual solvolysis pathway of the RNA model hpp (2), which proceeds via the cyclophosphate 20, a second, unusual pathway via direct substitution of the hydroxypropyl substituent was found. X-ray analysis of the Zr(TPP)(dmp) complex 19 revealed a dinuclear structure with two bridging dmp ligands and one monomethyl phosphate unit. In 19 one of the two dmp residues occurs in a very unusual high energy ac,ap conformation. Based on this structure and on the kinetic data, mechanistic models for the two solvolysis reaction pathways were developed. From an extensive CSD search on phosphodiester structures no correlation between P-O ester bond lengths and diester conformations could be found. However, P-O ester bonds decrease in length with increasing formal charge of the complexing metal ions. This underlines the higher importance of electrostatic activation relative to stereoelectronic effects in phosphodiester hydrolysis.

Crystal structure and optical spectroscopy of Er2[Pt(CN)4]3.21H2O and Er2[Pt(CN)4]2.SO4.11.5H2O.

We have synthesized two forms of erbium tetracyanoplatinates, Er2[Pt(CN)4]3.21H2O (red form) and Er2[Pt(CN)4]2.SO4.11.5H2O (yellow form), and determined their crystal structures by X-ray diffraction. While the red form crystallizes in the orthorhombic space group Pbcn, with a = 15.4848(3) A, b = 13.8186(2) A, c = 19.07820(10) A, alpha = beta = gamma = 90 degrees, and Z = 4, the yellow form precipitates in the tetragonal space group I4cm, with a = b = 14.321(2) A, c = 13.338(3) A, alpha = beta = gamma = 90 degrees, and Z = 4. Both forms show [Pt(CN)4]2- chains but differ markedly in color and morphology. This is due to the incorporation of sulfate ions in the latter modification, leading to an increased Pt-Pt distance. The observed optical absorption and emission behavior of the title compounds is correlated with the Pt-Pt distances.

Thyroid volumes and urinary iodine in Swiss school children, 17 years after improved prophylaxis of iodine deficiency.

Salt iodine content in Switzerland was raised from 7.5 to 15 mg per kg in 1980, and since then dietary iodine intake has been considered to be sufficient, even though a slight decrease due to imported food has recently been reported. The aim of this study was to establish normal values for thyroid volumes of school children who can be assumed to have had a sufficient iodine intake all their lifetime. Moreover. the present investigation was undertaken to verify that iodine sufficiency had been achieved equally in two regions each served by one of the two Swiss salt producers. Mean iodine concentration in urine spot samples from school children was 16.1 microg/dl, and it was identical in both the city of Lausanne (n=215) and the city of Solothurn (n=208). Thus it can be stated that in both cities (served by two different salt producers) iodine intake is equal and sufficient. Accordingly, thyroid volumes measured by ultrasound in school children aged 6 to 16 years were the same in both Lausanne (n=202) and Solothurn (n=207). Moreover, the age-adjusted median volumes at the 97th percentiles closely agree with and validate provisional international reference values recently proposed by the World Health Organisation and by the International Council for Control of Iodine Deficiency Disease.

[Iodine supply at various periods in life and ultrasonographic thyroid volume in school children in a region of Switzerland]. / Jodversorgung in verschiedenen Lebensphasen und sonographische Schilddrüsenvolumina bei Schulkindern in einer Gegend der Schweiz.

In Switzerland the previous severe iodine deficiency has been corrected by iodization of salt. Changing food habits make it mandatory to periodically monitor iodine intake. In 1994 we therefore measured thyroid volume by sonography in 217 schoolchildren, and iodine, creatinine and sodium in casual urine samples of 214 schoolchildren, 40 pregnant women and 30 breast-fed newborns. Iodine was also measured in 30 breast milk samples. In schoolchildren, goiters of WHO grades Ia/Ib/II were found by palpation in 10.6/2.3/ 0.9%. By contrast, only two of the children had a sonographic thyroid volume exceeding the 97 percentile of the WHO, which underlines the difficulty of estimating the size of small goiters by palpation. Mean thyroid volume at 6/7/9/ 10/11 years of age was 2.1/2.2/3.3/3.3/3.1 ml, which is well within the normal range suggested by the WHO. Mean urinary iodine in schoolchildren (118 +/- 49 micrograms per gram creatinine) and in pregnant women (193 +/- 113 micrograms per gram creatinine) is within required limits, albeit with a decrease since 1988. In breast milk (7.8 +/- 5.9 micrograms/dl) and in urine of newborns (6.6 +/- 3.3 micrograms/dl) iodine values are below the Swedish reference values but well above values found in iodine deficient areas. We conclude that the iodine supply in schoolchildren and pregnant women is just sufficient and in newborns slightly below recently recommended limits. Compared to 1988 the iodine supply to schoolchildren is diminishing. The discrepancy between the rather low iodine content in breast milk despite a normal iodine supply during pregnancy remains to be explained.

Type I hereditary angio-oedema. Variability of clinical presentation and course within two large kindreds.

OBJECTIVES: Hereditary angio-oedema (C1-inhibitor deficiency) is a disease with protean manifestations which is often misdiagnosed initially. The purpose of this study was to delineate the clinical spectrum and course of this potentially life-threatening disease. SETTING: Ten members of two unrelated affected kindreds were repeatedly hospitalized in our service with attacks of angio-oedema. Among the 271 members of the two kindreds 69 were identified who reported typical attacks. DESIGN AND SUBJECTS: Detailed information on the clinical course and laboratory data (C1-inhibitor concentration and activity, C4 concentration) were obtained from 59 of the 69 affected subjects. RESULTS: C1-inhibitor concentration and activity were low in all affected patients. The disease had become manifest by age 30 years in 98%. Most patients suffered from attacks of subcutaneous swellings and abdominal pain, and half of the patients have had attacks affecting the airways. The frequency of attacks ranged from less than one to over 26 per year. Forty-two per cent had to be hospitalized at least once. Four have died of acute airway obstruction. Thirty-eight attacks in 10 patients hospitalized in our service were all treated successfully with fresh frozen plasma or with C1-inhibitor concentrate. Trauma, stress, insect stings and foodstuff were triggering factors, but the majority of attacks occurred without an identifiable trigger. Oral contraceptives and pregnancy led to worsening of symptoms. Nonetheless, all 36 pregnancies reported were carried to term. Twenty-five patients were on continuous treatment with attenuated androgens or tranexamic acid, but only seven were free of attacks in the year preceding the survey. CONCLUSION: Hereditary angio-oedema is an autosomal dominant disease with great variability of clinical expression and severity, even within a single kindred. It often goes unrecognized over years, and it may lead to death if, in case of impending airway obstruction, specific therapy is not instituted.

[Detection of RET-proto-oncogene mutations in the diagnosis of Type 2 endocrine neoplasia (MEN 2)]. / Nachweis von RET-Proto-Onkogen-Mutationen zur Diagnostik der multiplen endokrinen Neoplasie Typ 2 (MEN 2).

We have analyzed 95 blood- and 25 paraffin-derived DNA samples of 120 individuals from Switzerland (MEN 2 family members and patients with medullary thyroid carcinoma or pheochromocytoma) for the presence of RET protooncogene mutations in exons 10, 11, 13, 14 and 16, where recently germline point mutations have been identified in more than 95% of patients with MEN 2A, familial medullary thyroid carcinoma (FMTC) and MEN 2B. Molecular DNA screening of samples was performed by non-radioactive single strand conformation polymorphism (SSCP) and heteroduplex gel electrophoresis method followed by mutation analysis of PCR products by direct cycle sequencing using an automated DNA sequencer. We identified 12 MEN 2A/FMSC and 6 MEN 2B families with 29 gene carriers. Ten different types of mutations were identified in the MEN 2A/FMTC families (620 Cys-->Arg, 618 Cys-->Ser, Gly, 611 Cys-->Tyr; 634 Cys-->Arg, Tyr, Trp, Phe, Ser, Gly) and all 6 MEN 2B families had a 918 Met-->Thr point mutation. Our results indicate that PCR-based DNA testing for RET point mutations is a rapid, accurate and reproducible method of identifying MEN 2 gene carriers using blood or tissue DNA. Early detection of gene carriers allows preventive thyroidectomy without neck dissection or parathyroid transplantation, and non-gene carriers can be released from biochemical testing. Furthermore, it is shown that the distribution and localization of RET mutations in MEN 2 families from Switzerland concur with combined results of larger series and that a "founder effect" of MEN 2 can be excluded for this country.

Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency.

In 1980 the iodide content of salt was increased in Switzerland from 7.5 to 15 mg/kg. This raised the mean urinary iodine excretion from 90 (indicating mild iodine deficiency) to 150 micrograms/g creatinine. We examined whether this public health measure was followed by a change of the incidence of hyperthyroidism in a defined catchment area of 109,000 persons. Except for a 27% rise in the first year of the new salt, the total incidence of hyperthyroidism declined steadily to reach 44% of the control level in 1988/89. This was due to a decrease mostly of toxic nodular goitre (minus 73%), less so of Graves' disease (minus 33%). We conclude that correction of mild iodine deficiency has beneficial effects on the incidence of hyperthyroidism, contrary to what is seen initially after correction of severe deficiency.

[Thyroiditis]. / Thyreoiditis.

The most common form of thyroiditis is undoubtedly chronic lymphocytic thyroiditis (Hashimoto's thyroiditis). It presents in the form of a small insignificant struma without any signs of inflammation, which is easily overlooked in our region (where once goiters due to iodine-deficiency have been common). Therapy is only indicated when the patient is disturbed by the size of the goiter or when he is hypothyroid. The disease can be easily diagnosed by palpation and investigation of autoantibodies. Repeated antibody-tests are not necessary, however, it is useful to measure TSH every two years since some of the patients develop hypothyroidism. In contrast to the relatively mild findings in Hashimoto's thyroiditis the subacute granulomatous thyroiditis (de Quervain) presents with an impressive clinical picture with pain, fever, malaise and elevated blood sedimentation rate, that may alarm the patient as well as the unexperienced physician. Treatment with prednisone is extremely effective and leads to complete remission.

Identification of a subgroup of Graves' disease patients at higher risk for severe ophthalmopathy after radioiodine.

We have analyzed retrospectively the records of 89 patients with Graves' disease who were treated with radioiodine between 1980-88 and whose ophthalmopathy was recorded in a uniform manner initially and after 5 and 12 months. Moreover information on progression of eye disease was obtained by telephone for all patients after an average of 72 months. Pretreatment endocrine ophthalmopathy (class greater than or equal to 1 of classification of American Thyroid Association) was present in 34% of the patients. Eight patients developed proptosis over 20 mm, 7 patients severe ophthalmopathy (classes 4 to 6), 5 patients required special treatment for eye disease. Among the 30 patients with initial ophthalmopathy, severe ophthalmopathy (5 of 30; p less than 0.05) and proptosis greater than 20 mm 16 of 30; p less than 0.05) developed in significantly more cases than in patients with no pretreatment ophthalmopathy. The data suggest that hyperthyroid patients with pretreatment ophthalmopathy are at risk for developing severe ophthalmopathy after 131I treatment.