The lack of HSD17B3 in male mice results in disturbed Leydig cell maturation and endocrine imbalance akin to humans with HSD17B3 deficiency.

Hydroxysteroid (17ß) dehydrogenase type 3 (HSD17B3) deficiency causes a disorder of sex development in humans, where affected males are born with female-appearing external genitalia, but are virilized during puberty. The hormonal disturbances observed in the Hsd17b3 knockout mice (HSD17B3KO), generated in the present study, mimic those found in patients with HSD17B3 mutations. Identical to affected humans, serum T in the adult HSD17B3KO mice was within the normal range, while a striking increase was detected in serum A-dione concentration. This resulted in a marked reduction of the serum T/A-dione ratio, a diagnostic hallmark for the patients with HSD17B3 deficiency. However, unlike humans, male HSD17B3KO mice were born with normally virilized phenotype, but presenting with delayed puberty. In contrast to the current belief, data from HSD17B3KO mice show that the circulating T largely originates from the testes, indicating a strong compensatory mechanism in the absence of HSD17B3. The lack of testicular malignancies in HSD17B3KO mice supports the view that testis tumors in human patients are due to associated cryptorchidism. The HSD17B3KO mice presented also with impaired Leydig cell maturation and signs of undermasculinization in adulthood. The identical hormonal disturbances between HSD17B3 deficient knockout mice and human patients make the current mouse model valuable for understanding the mechanism of the patient phenotypes, as well as endocrinopathies and compensatory steroidogenic mechanisms in HSD17B3 deficiency.

Accuracy of self-reported anthropometric measures - Findings from the Finnish Twin Study.

OBJECTIVE: To determine the accuracy of self-reported height, weight, body mass index (BMI) and waist circumference (WC) compared to the measured values, and to assess the similarity between self-reported and measured values within dizygotic (DZ) and monozygotic (MZ) twin pairs. METHODS: The data on self-reported and measured height, weight and WC values as well as measured hip circumference (HC) were collected from 444 twin individuals (53-67 years old, 60% women). Accuracies between self-reported and measured values were assessed by Pearson's correlation coefficients, Cohen's kappa coefficients and Bland-Altman 95% limits of agreement. Intra-class correlation was used in within-pair analyses. RESULTS: The correlations between self-reported and measured values were high for all variables (r=0.86-0.98), although the agreement assessed by Bland-Altman 95% limits had relatively wide variation. The degree of overestimating height was similar in both sexes, whereas women tended to underestimate and men overestimate their weight. Cohen's kappa coefficients between self-reported and measured BMI categories were high: 0.71 in men and 0.70 in women. Further, the mean self-reported WC was less than the mean measured WC (difference in men 2.5cm and women 2.6cm). The within-pair correlations indicated a tendency of MZ co-twins to report anthropometric measures more similarly than DZ co-twins. CONCLUSIONS: Self-reported anthropometric measures are reasonably accurate indicators for obesity in large cohort studies. However, the possibility of more similar reporting among MZ pairs should be taken into account in twin studies exploring the heritability of different phenotypes.

Novel epididymal proteins as targets for the development of post-testicular male contraception.

Apart from condoms and vasectomy, modern contraceptive methods for men are still not available. Besides hormonal approaches to stop testicular sperm production, the post-meiotic blockage of epididymal sperm maturation carries lots of promise. Microarray and proteomics techniques and libraries of expressed sequence tags, in combination with digital differential display tools and publicly available gene expression databases, are being currently used to identify and characterize novel epididymal proteins as putative targets for male contraception. The data reported indicate that these technologies provide complementary information for the identification of novel highly expressed genes in the epididymis. Deleting the gene of interest by targeted ablation technology in mice or using immunization against the cognate protein are the two preferred methods to functionally validate the function of novel genes in vivo. In this review, we summarize the current knowledge of several epididymal proteins shown either in vivo or in vitro to be involved in the epididymal sperm maturation. These proteins include CRISP1, SPAG11e, DEFB126, carbonyl reductase P34H, CD52, and GPR64. In addition, we introduce novel proteinases and protease inhibitor gene families with potentially important roles in regulating the sperm maturation process. Furthermore, potential contraceptive strategies as well as delivery methods will be discussed. Despite the progress made in recent years, further studies are needed to reveal further details in the epididymal sperm maturation process and the factors involved, in order to facilitate the development of new epididymal contraceptives.

Characteristics of a 85Kr beta-particle source applied in Series 1 reference irradiations of DIS-1 direct ion storage dosemeters.

Characteristics necessary to specify an ISO 6980 Series 1 reference radiation field were determined for a commercially available 85Kr beta-particle source, using a BEAM EGS4 Monte Carlo code. The characteristics include residual maximum beta energy, E(res), and the uniformity of the dose rate over the calibration area. The E(res) and the uniformity were also determined experimentally, using an extrapolation ionization chamber (EC) and a 0.2 cm3 parallel plate ionization chamber, respectively. The depth-dose curve measured with the EC gave a value 0.62 MeV for the E(res). Series 2 90Sr + 90Y and Series 1(85) Kr beta-particle sources calibrated for H(p)(0.07) at the secondary standard dosimetry laboratory (SSDL) of STUK were used to determine the energy and angular responses of DIS-1 direct ion storage dosemeters. The averaged zero angle H(p)(0.07) responses to the 90Sr + 90Y and 85Kr reference radiations were 135 and 80%, respectively. The responses were normalized to 100%, H(p)(0.07) response to 137Cs photon radiation.

Calibration of a scintillation dosemeter for beta rays using an extrapolation ionization chamber.

A scintillation dosemeter is calibrated for 90Sr/90Y beta rays from an ophthalmic applicator, using an extrapolation ionization chamber as a reference instrument. The calibration factor for the scintillation dosemeter agrees with that given by the manufacturer of the dosemeter within ca. 2%. The estimated overall uncertainty of the present calibration is ca. 6% (2 sd). A calibrated beta-ray ophthalmic applicator can be used as a reference source for further calibrations performed in the laboratory or in the hospital.

Characterisation of projectiles composed of depleted uranium.

Projectiles suspected to be composed of depleted uranium (DU) were found in Kosovo. Their properties were analysed using alpha and gamma ray spectrometry, mass spectrometry and electron microscopy. They were found to be composed of DU with small amounts of other elements such as Ti. 236U was detected in the penetrators, reflecting the use of reprocessed fuel. No transuranium elements were detected. The typical external dose rate meter is not the best option for mapping the location of penetrators from the ground. Monte Carlo calculations were performed in estimating possible skin doses. Penetrators in long-lasting contact with skin may cause a notable equivalent dose to skin.

Role of the human medial frontal cortex in task switching: a combined fMRI and TMS study.

We used event-related functional magnetic resonance imaging (fMRI) to measure brain activity when subjects were performing identical tasks in the context of either a task-set switch or a continuation of earlier performance. The context, i.e., switching or staying with the current task, influenced medial frontal cortical activation; the medial frontal cortex is transiently activated at the time that subjects switch from one way of performing a task to another. Two types of task-set-switching paradigms were investigated. In the response-switching (RS) paradigm, subjects switched between different rules for response selection and had to choose between competing responses. In the visual-switching (VS) paradigm, subjects switched between different rules for stimulus selection and had to choose between competing visual stimuli. The type of conflict, sensory (VS) or motor (RS), involved in switching was critical in determining medial frontal activation. Switching in the RS paradigm was associated with clear blood-oxygenation-level-dependent signal increases ("activations") in three medial frontal areas: the rostral cingulate zone, the caudal cingulate zone, and the presupplementary motor area (pre-SMA). Switching in the VS task was associated with definite activation in just one medial frontal area, a region on the border between the pre-SMA and the SMA. Subsequent to the fMRI session, we used MRI-guided frameless stereotaxic procedures and repetitive transcranial magnetic stimulation (rTMS) to test the importance of the medial frontal activations for task switching. Applying rTMS over the pre-SMA disrupted subsequent RS performance but only when it was applied in the context of a switch. This result shows, first, that the pre-SMA is essential for task switching and second that its essential role is transient and limited to just the time of behavioral switching. The results are consistent with a role for the pre-SMA in selecting between response sets at a superordinate level rather than in selecting individual responses. The effect of the rTMS was not simply due to the tactile and auditory artifacts associated with each pulse; rTMS over several control regions did not selectively disrupt switching. Applying rTMS over the SMA/pre-SMA area activated in the VS paradigm did not disrupt switching. This result, first, confirms the limited importance of the medial frontal cortex for sensory attentional switching. Second, the VS rTMS results suggest that just because an area is activated in two paradigms does not mean that it plays the same essential role in both cases.

Synchronization of neuronal activity in the human primary motor cortex by transcranial magnetic stimulation: an EEG study.

Using multichannel electroencephalography (EEG), we investigated temporal dynamics of the cortical response to transcranial magnetic stimulation (TMS). TMS was applied over the left primary motor cortex (M1) of healthy volunteers, intermixing single suprathreshold pulses with pairs of sub- and suprathreshold pulses and simultaneously recording EEG from 60 scalp electrodes. Averaging of EEG data time locked to the onset of TMS pulses yielded a waveform consisting of a positive peak (30 ms after the pulse P30), followed by two negative peaks [at 45 (N45) and 100 ms]. Peak-to-peak amplitude of the P30-N45 waveform was high, ranging from 12 to 70 microV; in most subjects, the N45 potential could be identified in single EEG traces. Spectral analysis revealed that single-pulse TMS induced a brief period of synchronized activity in the beta range (15-30 Hz) in the vicinity of the stimulation site; again, this oscillatory response was apparent not only in the EEG averages but also in single traces. Both the N45 and the oscillatory response were lower in amplitude in the 12-ms (but not 3-ms) paired-pulse trials, compared with the single-pulse trials. These findings are consistent with the possibility that TMS applied to M1 induces transient synchronization of spontaneous activity of cortical neurons within the 15- to 30-Hz frequency range. As such, they corroborate previous studies of cortical oscillations in the motor cortex and point to the potential of the combined TMS/EEG approach for further investigations of cortical rhythms in the human brain.

Dosimetry of beta-ray ophthalmic applicators: comparison of different measurement methods.

An international intercomparison of the dosimetry of three beta particle emitting ophthalmic applicators was performed, which involved measurements with radiochromic film, thermoluminescence dosimeters (TLDs), alanine pellets, plastic scintillators, extrapolation ionization chambers, a small fixed-volume ionization chambers, a diode detector and a diamond detector. The sources studied were planar applicators of 90Sr-90Y and 106Ru-106Rh, and a concave applicator of 106Ru-106Rh. Comparisons were made of absolute dosimetry determined at 1 mm from the source surface in water or water-equivalent plastic, and relative dosimetry along and perpendicular to the source axes. The results of the intercomparison indicate that the various methods yield consistent absolute dosimetry results at the level of 10%-14% (one standard deviation) depending on the source. For relative dosimetry along the source axis at depths of 5 mm or less, the agreement was 3%-9% (one standard deviation) depending on the source and the depth. Crucial to the proper interpretation of the measurement results is an accurate knowledge of the detector geometry, i.e., sensitive volume and amount of insensitive covering material. From the results of these measurements, functions which describe the relative dose rate along and perpendicular to the source axes are suggested.

Calculation of beta-ray dose distributions from ophthalmic applicators and comparison with measurements in a model eye.

Dose distributions throughout the eye, from three types of beta-ray ophthalmic applicators, were calculated using the EGS4, ACCEPT 3.0, and other Monte Carlo codes. The applicators were those for which doses were measured in a recent international intercomparison [Med. Phys. 28, 1373 (2001)], planar applicators of 106Ru-106Rh and 90Sr-90Y and a concave 106Ru-106Rh applicator. The main purpose was to compare the results of the various codes with average experimental values. For the planar applicators, calculated and measured doses on the source axis agreed within the experimental errors (<10%) to a depth of 7 mm for 106Ru-106Rh and 5 mm for 90Sr-90Y. At greater distances the measured values are larger than those calculated. For the concave 106Ru-106Rh applicator, there was poor agreement among available calculations and only those calculated by ACCEPT 3.0 agreed with measured values. In the past, attempts have been made to derive such dose distributions simply, by integrating the appropriate point-source dose function over the source. Here, we investigated the accuracy of this procedure for encapsulated sources, by comparing such results with values calculated by Monte Carlo. An attempt was made to allow for the effects of the silver source window but no corrections were made for scattering from the source backing. In these circumstances, at 6 mm depth, the difference in the results of the two calculations was 14%-18% for a planar 106Ru-l06Rh applicator and up to 30% for the concave applicator. It becomes worse at greater depths. These errors are probably caused mainly by differences between the spectrum of beta particles transmitted by the silver window and those transmitted by a thickness of water having the same attenuation properties.

Mometasone furoate nasal spray in the treatment of perennial non-allergic rhinitis: a nordic, multicenter, randomized, double-blind, placebo-controlled study.

In order to evaluate the efficacy and safety of mometasone furoate nasal spray (MFNS) in patients with perennial non-allergic rhinitis (PNAR) a phase III, double-blind, randomized, placebo-controlled, Nordic multicenter study was performed at 16 sites (7 in Sweden, 3 in Denmark, 3 in Finland and 3 in Norway). A total of 329 patients (age 18-82 years) with a mean duration of PNAR of 9 years were included in the study. The total duration of the study was 11 weeks: 2 weeks of screening, 6 weeks of treatment and 3 weeks of follow-up. Inclusion criteria were unspecific rhinitis symptoms and exclusion criteria were a positive skin prick test as well as intolerance to aspirin or non-steroidal anti-inflammatory drugs. Endoscopy was performed to exclude patients with structural anomalies and nasal polyps. The primary efficacy variable was the subject's total overall evaluation. In the intention-to-treat (ITT) group of patients (n = 329) the improvement rates were 56% (MFNS) and 49% (placebo). In the per-protocol (PP) group (n = 251) the corresponding figures were 58% and 47%. Stratifying for groups of patients having moderate symptoms, the results were 54% vs 43% in the ITT group and 56% vs 41% in the PP group. The therapeutic response showed greater improvement in total nasal score as recorded by the investigator in the groups treated with MFNS as compared to the placebo group (p = 0.09 [PP], p = 0.14 [ITT]). Adverse events occurred during the study, upper respiratory tract infections and headache being the most frequently reported, but there was no statistically significant difference between MFNS and placebo. The results of this study indicate that MFNS is a safe and effective treatment for patients with PNAR.

Attention systems and the organization of the human parietal cortex.

Event-related functional magnetic resonance imaging was used to compare activity in the human parietal cortex in two attention-switching paradigms. On each trial of the visual switching (VS) paradigm, subjects attended to one of two visual stimuli on the basis of either their color or shape. Trials were presented in blocks interleaved with cues instructing subjects to either continue attending to the currently relevant dimension or to switch to the other stimulus dimension. In the response switching (RS) paradigm, subjects made one of two manual responses to the single stimulus presented on each trial. The rules for stimulus-response mapping were reversed on different trials. Trials were presented in blocks interleaved with cues that instructed subjects to either switch stimulus-response mapping rules or to continue with the current rule. Brain activity at "switch" and "stay" events was compared. The results revealed distinct parietal areas concerned with visual attentional set shifts (VS) and visuomotor intentional set shifts (RS). In VS, activity was recorded in the lateral part of the intraparietal region. In RS, activity was recorded in the posterior medial intraparietal region and adjacent posterior superior and dorsomedial parietal cortex. The results also suggest that the basic functional organization of the intraparietal sulcus and surrounding regions is similar in both macaque and human species.

Improved technique for detection of enhanced green fluorescent protein in transgenic mice.

One of the most exciting recent advances in cell biology is the possibility to use the green fluorescent protein and its various mutated forms as reporter proteins in studies carried out in vitro and in vivo. In the present study, several detection techniques for the enhanced green fluorescent protein (EGFP) were compared in transgenic mice, using fluorescence and confocal microscopy. In addition, different tissue preparation techniques (squash preparations, vibratome sections, frozen sections) were evaluated. As a model we used transgenic mice expressing EGFP under the control of a 5.0-kb fragment of the glutathione peroxidase isoenzyme 5 protein promoter (GPX5-EGFP) or under a 3.8-kb fragment of the cysteine rich protein-1 promoter (CRISP1-EGFP). In the GPX5-EGFP mice, expression of EGFP was observed in the distal part of the caput epididymis, while the CRISP1 promoter directed EGFP expression in the tubular compartment of the testis. Among the various tissue preparation procedures tested, the best morphological and histological preservation, and reproducibility in EGFP detection, were obtained using frozen sections after a slow tissue-freezing protocol developed in the present study. After slow tissue freezing, specimens of testis and epididymis could be stored at -70 degrees C for at least six weeks without any affect on EGFP fluorescence. Hence, the method developed offers the possibility to analyze EGFP fluorescence in tissues several weeks after specimen collection. The sensitivity achieved was equal to that found in immunohistochemistry, applying biotin-streptavidin-FITC detection. Confocal microscopy is known to have the advantage that fluorescence can be detected from cells in different layers. This was found to be important as regards detecting EGFP fluorescence because the fluorescence was destroyed at the cut surfaces of sections produced by either vibratome or cryomicrotome.

Distractible children show abnormal orienting to non-attended auditory stimuli.

Event-related potentials were recorded in response to intermittently presented, non-attended trains of identical auditory stimuli in healthy 9-year-old children. In abnormally distractible children (n =24), the first tone in each train elicited a significantly larger N1 vertex response than in the non-distractible children (n 24), suggesting that increased distractibility may be associated with an abnormally strong cerebral orienting towards non-attended stimuli. A later negativity at around 300 ms, which increases in amplitude with stimulus repetition and may thus reflect the building up of a functional neuronal representation of the stimulus properties, was significantly smaller in the distractible than in the non-distractible children. These findings demonstrate that event-related potential measures may be useful in helping to understand the information processing found in distractible children.

The use of TL detectors in dosimetry of systemic radiation therapy.

A method for determining absorbed doses to organs in systemic radiation therapy (SRT) is evaluated. The method, based on thermoluminescent (TL) dosimeters placed on the patient's skin, was validated and justified through a phantom study showing that the difference between measured (TL dosimeters in the phantom) and derived (TL method) values is within 10%. Six radioimmunotherapy (RIT) patients with widespread intraperitoneal pseudomyxoma were also studied. In dose evaluations, special emphasis was on kidneys. In addition to the TL method, the absorbed doses to kidneys were calculated using MIRD formalism and a point dose kernel technique. We conclude that in SRT the described TL method can be used to estimate the absorbed doses to those critical organs near the body surface within 50% (1 SD).

Dose characteristics of in-house-built collimators for stereotactic radiotherapy with a linear accelerator.

Dose characteristics of a stereotactic radiotherapy unit based on a standard Varian Clinac 4/100 4 MV linear accelerator, in-house-built Lipowitz collimators and the SMART stereotactic radiotherapy treatment planning software have been determined. Beam collimation is constituted from the standard collimators of the linear accelerator and a tertiary collimation consisting of a replaceable divergent Lipowitz collimator. Four collimators with isocentre diameters of 15, 25, 35 and 45 mm, respectively, were constructed. Beam characteristics were measured in air, acrylic or water with ionization chamber, photon diode, electron diode, diamond detector and film. Monte Carlo simulation was also applied. The radiation leakage under the collimators was less than 1% at 50 mm depth in water. Specific beam characteristics for each collimator were imported to SMART and dose planning with five non-coplanar converging 140 degrees arcs separated by 36 degrees angles was performed for treatment of a RANDO phantom. Dose verification was made with TLD and radiochromic film. The in-house-built collimators were found to be suitable for stereotactic radiotherapy and patient treatments with this system are in progress.

Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort.

OBJECTIVE: The 1966 North Finland general population birth cohort was studied to determine whether abnormalities during pregnancy, delivery, and the neonatal period are associated with adult-onset schizophrenia. METHOD: The authors included all 11,017 subjects alive in Finland at age 16. For each individual, standardized assessments made during pregnancy, delivery, and infancy were linked to national psychiatric case registers covering the period up to age 28. Subjects with DSM-III-R schizophrenia were identified by using a two-stage screen that included perusal of individual case records. Associations (adjusted odds ratios) between schizophrenia and specific pregnancy, delivery, and neonatal characteristics were calculated. RESULTS: Within this cohort, 76 cases of DSM-III-R schizophrenia arose by age 28 years; 51 (67.1%) of these persons were men. Demographic characteristics and previous obstetric histories of the mothers were similar in the case and unaffected comparison groups, although the former were more likely to have been more depressed than usual during pregnancy. Low birth weight (< 2500 g) and the combination of low birth weight and short gestation (< 37 weeks) were more common among the schizophrenic subjects. Being small for gestational age (< 10th percentile) was not more common. Of 125 survivors of severe perinatal brain damage, six (4.8%) later developed schizophrenia. CONCLUSIONS: The spectrum of adverse outcomes after fetal and perinatal insults unfolded beyond childhood and included adult-onset schizophrenia. The findings have implications for understanding the mechanisms involved in the development of schizophrenia and, possibly, for its prevention.

Brain aging: impaired coding of novel environmental cues.

Studies of the spatial memory capacities of aged animals usually focus on performance during the learning of new environments. By contrast, efforts to characterize age-related alterations in spatial firing information processing by hippocampal neurons typically use an environment that is highly familiar to the animals. In the present study we compared the firing properties of hippocampal neurons in young adult and aged rats as they acquired spatial information about new environmental cues. Hippocampal complex spike cells were recorded while rats performed a radial arm maze task in a familiar environment and then recorded again after many of the spatial cues were changed. After the change in the environment, in aged rats 35-42% of place fields retained their original shape and location with respect to the maze center, although they usually rotated to another arm. By contrast, all place fields in young animals either disappeared or appeared in a new location. Some of the new place fields appeared in the new environment during the first 5 min of exploration, whereas others needed more than 30 min to develop fully. In the familiar environment spatial selectivity of place cells was similar in young and aged rats. By contrast, when rats were placed into a new environment, spatial selectivity decreased considerably in aged memory-impaired rats compared with that of young rats and aged rats with intact memory performance.

Oral contraceptive containing natural estradiol for premenopausal women.

An open multicenter trial was performed in six centers in Finland to study the efficacy, safety and acceptability of a new biphasic oral contraceptive pill containing natural estradiol and cyproterone acetate. The participants were 288 women with a mean age of 39.3 +/- 3.4 years (range 30-49) who were willing to use the new pill as their only contraceptive method. In total, 23% of the women were smokers. The cumulative experience was 2800 treatment cycles during the first year. The net 12-month continuation rate was 63%. One pregnancy occurred in a woman who lost 5 tablets in the second treatment cycle, which gives a 12-month cumulative pregnancy rate of 0.4%. Serum progesterone values, determined twice during the third treatment cycle, showed ovulation inhibition in 95% of women. There were no serious side effects. Intermenstrual bleeding was recorded by 35.5% and 24.5% of women at 3 and 12 months, respectively. The bleedings became scantier in most women and dysmenorrhoea disappeared. No changes were observed in total and high density lipoprotein cholesterol concentrations after 1 year. With the exception of intermenstrual spotting, the efficacy, safety and acceptability of the new pill was almost as good as that of the modern low dose oral contraceptives. This is the first pill containing natural estradiol that has gained clinical acceptance and which can also be prescribed for smokers over 35 years old until the climacteric.

PIP: Gynecologists accepted 288 women aged 30-49 from six different clinics in Finland into a clinical trial of a new biphasic oral contraceptive (OC) containing natural estradiol and cyproterone acetate (manufactured by Leiras Oy, Turku, Finland). They aimed to determine the contraceptive efficacy, safety, cycle control, and acceptability of this OC. 24% of the women smoked cigarettes. Gastrointestinal upset in one woman led to failure to take the fourth and fifth tablets at the beginning of the second treatment cycle. She became pregnant (pregnancy rate = 0.35%). 9.3% and 13.3% of women missed pills at the 3-month and 12-month follow-up visits, respectively. 95% of the women had serum progesterone values lower than 9 nmol/l, indicating ovulation suppression. OC use reduced excessive menstrual bleeding (30% before study vs. 3% after 13 cycles; p 0.0005). It also reduced dysmenorrhea (14% vs. 2%; p 0.0005). No one had any serious side effects. The minor side effects (breast tension, edema, headache, and depression) subsided with time. The 12-month continuation rate was 63%. The main reason for discontinuation was side effects (25.9%). Total serum cholesterol and HDL-cholesterol levels did not change significantly, while serum triglyceride levels increased from 0.92 to 1.14 mmol/l (p = 0.02). Even though serum potassium and creatinine levels changed significantly, the 13-month levels fell within the normal range. These findings show that this new OC is an effective contraceptive for premenopausal women. The absence of adverse effects on the blood coagulation system and lipoprotein metabolism make this new OC safe for smokers.