The role of ataxia-telangiectasia heterozygotes in familial breast cancer.

The role of ataxia-telangiectasia (AT) heterozygotes in breast cancer has been controversial. We have found previously an overrepresentation (3.4%) of ATM mutations in a subset of 88 selected breast cancer patients with a family history of breast cancer, leukemia, and lymphoma. This prevalence is comparable to the estimated value (3.8%) from epidemiological study. To further examine the possibility that ATM is correlated to breast cancer, we screened for ATM germ-line mutations in another 100 breast cancer patients with a family history of breast cancer. We used the protein truncating test and found one new germ-line mutation. This figure (1%) is consistent with the observed 0.2-1% carrier frequency for AT. We also studied breast tumors from ATM mutants, and three showed retention of both alleles, whereas the fourth showed loss of the mutant allele. We conclude that the contribution of heterozygous ATM mutations to familial breast cancer is minimal. Even if the ATM gene were causative in these cases, it is not likely to act as a tumor suppressor.

Sestamibi versus thallium subtraction scintigraphy in parathyroid localization: a prospective comparative study in patients with predominantly mild primary hyperparathyroidism.

BACKGROUND: Technetium 99m sestamibi was recently introduced for the preoperative localization of abnormal parathyroid glands in patients with primary hyperparathyroidism with promising results. However, the sensitivity of sestamibi and thallium to detect abnormal parathyroid glands is partly dependent on the gland size. In this study we compared the sensitivity of sestamibi subtraction scintigraphy with thallium subtraction scintigraphy in patients with predominantly mild increase in serum calcium level. METHODS: Thirty-nine patients with primary hyperparathyroidism were included. The mean (+/-SD) serum level of calcium was 2.75 +/- 0.17 mmol/L. In 28 (72%) of the patients the serum level of calcium was less than 2.85 mmol/L. These patients were classified as having mild abnormalities in serum calcium. All patients were investigated before operation with both sestamibi and thallium subtraction scintigraphy. RESULTS: In two patients autonomous thyroid adenomas precluded subtraction scintigraphy. Sestamibi subtraction scintigraphy correctly localized 31 (86%) of 36 parathyroid adenomas compared with only 17 (47%) of 36 by thallium subtraction scintigraphy (p < 0.001). There was one false-positive result in the sestamibi group because of a thyroid adenoma, and two of the scans were negative. Both the sestamibi and the thallium subtraction scintigraphy localized one single enlarged gland in all three patients with multiple gland involvement. In no case was multiglandular disease predicted. CONCLUSIONS: Sestamibi subtraction scintigraphy is superior to thallium subtraction scintigraphy and has a high sensitivity to localize a solitary parathyroid adenoma in patients with mild increase in serum calcium level. The sensitivity decreases in patients with multiglandular parathyroid disease and concomitant thyroid nodular abnormalities.

Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism.

HYPOTHESIS: A variety of clinical and biochemical variables may be associated with hypocalcemia after surgery for parathyroid adenoma. DESIGN: A prospective study of patients who underwent surgery for solitary parathyroid adenoma. SETTING: A university hospital department of surgery. PATIENTS: Eighty-six consecutive patients who underwent surgery for solitary parathyroid adenoma. INTERVENTION: Parathyroidectomy according to the principles of unilateral neck exploration. MAIN OUTCOME MEASURES: Clinical and biochemical risk factors for early (< or =4 days after surgery) and late (1 year after surgery) postoperative symptomatic and biochemical hypocalcemia. RESULTS: Twenty-two patients developed early symptomatic hypocalcemia. The difference in total serum calcium levels between patients, with and without early symptomatic hypocalcemia, was evident on the third and fourth postoperative days. Serum level of osteocalcin greater than 6.0 microg/L, bilateral neck exploration, and history of cardiovascular disease were risk factors for symptomatic hypocalcemia (odds ratios [95% confidence intervals]: 4.4 [1.4-14.1], 3.8 [1.3-11.6], and 0.1 [0.02-0.60], respectively). Patients with up to 1 risk factor had a possibility of only 7% to develop early symptomatic hypocalcemia. One year after surgery, 16 patients had low levels of total serum calcium (late biochemical hypocalcemia) and were asymptomatic. Preoperative intermittent hypercalcemia was associated with an increased risk for late biochemical hypocalcemia (odds ratio, 3.9; 95% confidence interval, 1.0-16.3). CONCLUSIONS: Clinical and biochemical risk factors for early and late postoperative hypocalcemia in patients who underwent surgery for solitary parathyroid adenoma were found. A clinically useful prognostic index for early symptomatic hypocalcemia was constructed using these risk factors.

Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1.

Germline alterations in one of five human DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6) cause hereditary nonpolyposis colorectal cancer. Mutation analyses of these genes reveal gene carriers with a high risk for colorectal cancer, who benefit from surveillance to prevent disease. Equally important, presymptomatic testing allows nondisposed individuals to discontinue surveillance. We tested different mutation screening methods to optimize mutation detection in hMSH2 and hMLH1. Affected members from a total of 142 unrelated colorectal cancer families were analyzed. Denaturant gradient gel electrophoresis (DGGE), RT-PCR, and the protein truncation test (PTT) were used to screen for mutations on a DNA or RNA basis, respectively. In addition, a mutation-specific test on genomic DNA was used to find the Finnish mutation no. 1, a deletion of hMLH1 exon 16. DGGE identified most of the mutations in the mismatch repair genes hMLH1 and hMSH2. The RNA-based techniques were used to identify large deletions; however, these were rare in our materials. We describe our compiled results and experience from all our mutation screening studies, as well as unpublished data from our last DGGE screening of 58 patients and RT-PCR and PTT screening of 73 patients.

Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers.

The pharmacokinetics of triglycyl-lysine-vasopressin (TGLVP) were studied in healthy male volunteers after single i.v. injections of 5, 10 and 20 micrograms/kg b. wt. The half-life of distribution and elimination was 8 and 50 min, respectively. The volume of distribution was 0.7 l/kg b.wt. and the plasma clearance 9 ml/kg b.wt./min. These values are different from those for arginine-vasopressin and lysine-vasopressin (LVP) but confirm to some extent earlier results on TGLVP. No dose-dependent changes of the pharmacokinetics of TGLVP were evident. The LVP formation after TGLVP is described in principle using a combination of pharmacokinetic and pharmacodynamic data. Therapeutically the results in this study suggest a 4-hour interval between injections.

Oxygen reactions in high-pressure nitrogen gas studied with optical emission spectroscopy.

A study of some oxygen reactions in irradiated high-pressure (0.34-3.3MPa) nitrogen gas is presented. Nitrogen gas containing < or =1ppm H(2)O and O(2) was irradiated in a closed target chamber with 4.3MeV protons. Optical emission spectra of the NO-gamma (A(2)Sigma(+)-X(2)Pi), the NO-beta (B(2)Pi-X(2)Pi) and the O ((1)S-(1)D) transitions were recorded as a function of irradiation time at four different nitrogen-gas pressures. The results show a coupling between the NO-gamma build-up half time and the NO-beta decay and the O ((1)S-(1)D) decay half times as a function of irradiation time. The binding of free atomic oxygen in reactions forming NO has implications for the balance of [(11)C]CO(2) versus [(11)C]CO production.

The effect of triglycyl-lysine-vasopressin (terlipressin INN, Glypressin) on skin blood flow, measured with laser Doppler flowmetry, thermography and plethysmography. A dose-response study.

Triglycyl-lysine-vasopressin (TGLVP) has been shown to reduce blood loss in connection with early excision of experimentally induced burns in pigs. In order to determine an appropriate dosage of TGLVP in patients with burns, a dose-response study was undertaken. TGLVP was administered intravenously in various doses to healthy volunteers, and skin blood flow was measured with laser Doppler flowmetry, thermography and plethysmography. Blood pressure, heart rate and electrocardiac activity were monitored as well as serum and urine changes. The doses of 5, 10 and 20 micrograms TGLVP/kg b.wt. caused statistically significant reduction of skin blood flow; minimal values were 35, 26 and 25% of predrug values for the three doses, respectively. Thermography and plethysmography were less sensitive for detecting effects of TGLVP than laser Doppler flowmetry. Minor effects on blood pressure and heart rate were recorded after TGLVP, but no disturbances in electrocardiac activity. Urinalyses revealed an antidiuretic action of TGLVP. The study supports earlier findings and suggests a dose level of TGLVP for the use in excision of burns.

Measurement of the photoemission of two electrons from a multialkali photocathode.

Two-electron emission per incident photon, measured for a multialkali photocathode, shows a steep onset at 2700 A and increases to 14% of the total quantum efficiency at 2000 A.

Premonochromator for stray light rejection in Raman spectroscopy.

A new apparatus for attenuating the Rayleigh light is described. The main components are two concave gratings mounted in a special nondispersive way. By means of the first grating the entrance slit of the apparatus is focused as an intermediate spectrum upon a sharp-edged movable mirror. This mirror reflects all the spectrum except the Rayleigh light to the second grating, which collects the light to an image of the entrance slit. The result is a sharp cutting of the spectrum at any desired position. The rejection of the Rayleigh line has been measured to less than 10(-5) (optimally 10(-6)). Raman lines can be.measured about 10 cm(-1) from the exciting line. The instrument has been used as a preeliminating unit coupled to a conventional double monochromator. It is expected that a system consisting of the instrument and a good single monochromator can be used for Raman studies.

New Eagle-type monochromator mounting with ruled diffraction grating at 45 degrees off-plane.

A new Eagle-type monochromator mounting for ruled concave gratings at off-plane angles of 45 degrees is presented. The monochromator operates at an angle of incidence a range of ~0-15 degrees , where alpha is the angle between the grating normal and the projection of the incident central ray in the Rowland plane. Spherical, cylindrical, ellipsoidal, or toroidal gratings can be used. With toroidal or ellipsoidal grating surfaces one stigmatic image point is obtained, and the amount of astigmatism is strongly reduced in the whole spectral range. In the presence of astigmatism there is no comatic broadening of the line image. With toroidal and ellipsoidal gratings the comatic aberration is small being proportional to the angle alpha and depending only on the groove length. The width-dependent spherical aberration is proportional to alpha(2) and is therefore small. The new monochromator is expected to have applications in the far UV region as the low wavelength limit is expected to be reduced by a factor of radical2 compared to in-plane or near in-plane mountings.

Achromatic imaging of distant objects in selected wavelength bands with plane and concave holographic gratings.

A combination of a plane grating and a spherically concave holographic grating is studied and optimized for imaging of distant objects in selected wavelength bands with a high degree of chromatic correction. The recording conditions for the holographic grating are given, and the aberrations of the image are studied. The arrangement comprises a new type of diffracting telescope. The achromatic imaging is verified by numerical ray-tracing and by experiment, the results of which are given.

Blaze characteristics of echelle gratings.

A new model for the blaze function of the two in-plane mountings of echelle gratings is described and extended to account for defects in the edges of the grooves. Expressions for the relative efficiency are given. The model shows that the wavelength for the maximum blaze intensity differs slightly from the wavelength lambda(0) satisfying mlambda(0) = d[sinalpha + sin(2theta - alpha)], the difference being a function of the spectral order. The off-blaze orders of the wavelengths diffracted at the central blaze for the mounting alpha < theta (alpha = angle of incidence, theta = blaze angle) lie at the minima of the blaze function for a perfect echelle. Results are given from measurements of the blaze angle and the groove edge defects of three echelles.

Multiechelle grating mountings with high spectral resolution and dispersion.

This paper describes a new spectrometer mounting using several echelle gratings as dispersive elements. These gratings are mounted so that a resolution equal to the sum of the resolution of the individual gratings is obtained. In the mounting the dispersions from the gratings coact resulting in very high dispersion in the focal plane. The multiechelle grating mounting can be used to build compact spectrometers with higher resolutions than can be obtained with the widest gratings ever ruled. Results from an experimental verification of the multiechelle grating mounting are given.

Resolving power of multigrating spectrometers.

A theoretical and experimental study of the resolving power of spectrometers employing several gratings with coacting dispersion is performed. It is concluded that the resolving power is equal to the sum of the resolving powers of the separate gratings in contradiction to a recent result obtained by Mazzacurati et al., Opt. Commun. 67, 399-403 (1988); J. Phys. E. 21, 798-804 (1988). Experimental verification of our theoretical prediction is obtained with the MEGA spectrometer containing four echelle gratings. The measured resolving power for the He-Ne 6328-A laser line is (2.05 +/- 0.03) x 10(6), in good agreement with the theoretical value of 2.06 x 10(6).

Tests performed with the improved MEGA spectrometer.

In a previous paper [S. Engman and P. Lindblom, Appl. Opt. 23, 3341 (1984)] a new type of spectrometer, based on the multiechelle grating arrangement (MEGA) principle, was described. The expected resolution and principles of operation were verified. However, at that time the spectrometer was equipped with poor gratings that did not allow its testing in spectroscopic applications. Since then, new gratings have been obtained and improvements made to the system. This paper reports the spectroscopic tests made with the improved instrument. It is shown that the MEGA spectrometer is a useful new tool for optical spectroscopy.

Hemithyroidectomy: long-term effects on parathyroid function--preliminary report.

Early hypocalcemia after thyroid surgery has frequently been reported, whereas data regarding long-term effects on calcium homeostasis are scarce. We have previously studied patients after hemithyroidectomy with an oral calcium load test and found normal parathyroid hormone (PTH) suppression. However, the 1,25-dihydroxyvitamin D concentration was decreased and the phosphate concentration increased, implying parathyroid insufficiency. We therefore proceeded to investigate PTH secretion and suppression in 10 euthyroid patients subjected to hemithyroidectomy due to benign thyroid disease before and at 1 year after surgery. In addition, biochemical variables known to influence calcium homeostasis were analyzed. Basal, maximal, and total PTH secretion were unaltered 1 year postoperatively. However, maximal PTH secretion was reached at a lower serum level of ionized calcium, and there was a tendency toward increased parathyroid sensitivity to ionized calcium. Furthermore, compared to preoperative, total serum calcium, 1,25-dihydroxyvitamin D, and free thyroxine (T4) concentrations were decreased at follow-up. Total serum calcium and 1,25-dihydoxyvitamin D concentrations were decreased 1 year after hemithyroidectomy. These changes were not due to parathyroid insufficiency. Instead, our results imply increased parathyroid sensitivity to calcium and possibly reduced peripheral sensitivity to PTH.

Contractile properties of two varieties of twitch muscle fibres in Xenopus laevis.

The contractile properties of twitch muscle fibres in the iliofibularis muscle of Xenopus laevis with characteristic differences in light-microscopical appearance have been studied under isometric and isotonic conditions. Type 1 fibres (large, pale) have a short contraction time (tc), a shoulder in the relaxation phase, and a high twitch-tetanus ratio. In type 2 fibres (medium-to-large with abundant mitochondria and lipid droplets) tc is longer, half-relaxation time equals tc, and the twitch-tetanus is lower. The capillary density is about 4 times higher for type 2 than for type 1. Computer-fitted hyperbolic force-velocity curves gave the following Hill constants (20 degrees C) for type 1 (2) fibres: P0*/P0 1.03 (1.15), a/P0* 0.48 (0.26), b 3.51 (1.53) 10/s; extrapolated Vmax (0-0.8P0) was 7.60 (6.27) 10/s. Lowered temperature (10 degrees C) increases the curvature of the P-V relation in type 1 fibres, little effect was seen in type 2. Increased PCO2 depressed the isometric tension in both types; in type 1 fibres the P-V relation became less curved, in type 2 fibres no change in curvature was observed. The results suggest that type 1 and type 2 fibres might contain myosin isozymes with slightly different temperature- and pH-sensitivities.