Growth differentiation factor-9 induces Smad2 activation and inhibin B production in cultured human granulosa-luteal cells

The TGF beta family member growth differentiation factor-9 (GDF-9) is an oocyte-derived factor that is essential for mammalian ovarian folliculogenesis. GDF-9 mRNAs have been shown to be expressed in the human ovarian follicle from the primary follicle stage onward, and recombinant GDF-9 has been shown to promote human ovarian follicle growth in vitro. In this study with primary cultures of human granulosa-luteal (hGL) cells, we investigated whether recombinant GDF-9 activates components of the Smad signaling pathways known to be differentially activated by TGF beta and the bone morphogenetic proteins (BMPs). As with TGF beta, GDF-9 treatment caused the phosphorylation of endogenous 53-kDa proteins detected in Western blots with antiphospho-Smad2 antibodies (alpha PS2). However, unlike BMP-2, GDF-9 did not activate the phosphorylation of antiphospho-Smad1 antibody (alphaPS1)-immunoreactive proteins in hGL cells. Infection of hGL cells with an adenovirus expressing Smad2 (Ad-Smad2) confirmed that GDF-9 activates specifically phosphorylation of the Smad2 protein. Infection of hGL cells with Ad-Smad7, which expresses the inhibitory Smad7 protein, suppressed the levels of both GDF-9-induced endogenous and adenoviral alpha PS2-reactive proteins. Furthermore, GDF-9 increased the steady state levels of inhibin beta(B)-subunit mRNAs in hGL cells and strongly stimulated the secretion of dimeric inhibin B. Again, Ad-Smad7 blocked GDF-9-stimulated inhibin B production in a concentration-dependent manner. We identify here for the first time distinct molecular components of the GDF-9 signaling pathway in the human ovary. Our data suggest that GDF-9 mediates its effect through the pathway commonly activated by TGF beta and activin, but not that activated by many BMPs. The results are also consistent with the suggestion that in addition to endocrine control of inhibin production by gonadotropins, a local paracrine control of inhibin production is likely to occur via oocyte-derived factors in the human ovary.     

Long-term use of probucol in the multifactorial primary prevention of vascular disease

Over 1,200 middle-aged men with no apparent vascular disease participated in a 5-year multifactorial primary prevention trial, in which 612 received dietetic, hygienic and—when indicated—pharmacologic treatment for the following risk factors: hyperlipidemia, hypertension, smoking, obesity and abnormal glucose tolerance. Pharmacologic therapy included hypolipidemic agents (mainly probucol and clofibrate) and antihypertensive drugs (mainly diuretics and β blockers). At the end of the 5 years, results in these men were compared with findings in 610 high risk and 593 low risk control subjects, none of whom had received treatment. Although intervention decreased the mean risk factor status of the treated men by 33%, their 5-year coronary incidence exceeded that of the high risk control subjects (3.1 % vs 1.5%). Stroke incidence, however, was markedly reduced in the treated subjects (0% vs 1.3%). Multivariate analysis showed that the coronary events occurred in patients taking β blockers or clofibrate, while few occurred in those receiving probucol or the diuretics. The decrease in mean serum cholesterol was 15% in men receiving only probucol, and ranged from 0% to 13% in those receiving different drug combinations, including clofibrate plus probucol (11%). Probucol also markedly decreased high density lipoprotein cholesterol levels, especially when combined with clofibrate.

It is possible that adverse drug effects offset the probable benefit of an improved risk profile in the treated men, thereby explaining the greater than expected occurrence of cardiac events in this group. The probucol data, however, suggest that it may not be harmful to lower the high density lipoprotein cholesterol level when there is a significant decrease in total cholesterol as well.     

Short-Term Bone Biochemical Response to a Single Bout of High-Impact Exercise

Bone response to a single bout of exercise can be observed with biochemical markers of bone formation and resorption. The purpose of this study was to examine the response of bone biochemical markers to a single bout of exhaustive high-impact exercise. 15 physically active young subjects volunteered to participate. The subjects performed continuous bilateral jumping with the ankle plantarflexors at 65 % of maximal ground reaction force (GRF) until exhaustion. Loading was characterized by analyzing the GRF recorded for the duration of the exercise. Venous blood samples were taken at baseline, immediately after, 2h and on day 1 and day 2 after the exercise. Procollagen type I amino terminal propeptide (P1NP, marker of bone formation) and carboxyterminal crosslinked telopeptide (CTx, marker of bone resorption) were analyzed from the blood samples. CTx increased significantly (32 %, p = 0.015) two days after the exercise and there was a tendensy towards increase seen in P1NP (p = 0.053) one day after the exercise. A significant positive correlation (r = 0.49 to 0.69, p ≤ 0.038) was observed between change in P1NP from baseline to day 1 and exercise variables (maximal slope of acceleration, body weight (BW) adjusted maximal GRF, BW adjusted GRF exercise intensity and osteogenic index). Based on the two biochemical bone turnover markers, it can be concluded that bone turnover is increased in response to a very strenuous single bout of exhaustive high-impact exercise.

Key points

• Studies on bone acute biochemical response to loading have yielded unequivocal results.
• There is a paucity of research on the biochemical bone response to high impact exercise.
• An increase in bone turnover was observed one to two days post exercise.

Key words: Bone biochemical marker, jumping, bone turnover, osteogenic index     

Psychotic boys performing well in school are at increased risk of suicidal ideation

Aim:  This study investigated how the level of school performance is associated with suicidal behavior and psychiatric disorders among adolescent psychiatric inpatients aged 12–17 years.
Methods:  Data were collected from 508 adolescents (300 girls, 208 boys; age 12–17 years) admitted to inpatient psychiatric hospitalization between April 2001 and March 2006. Information on the adolescents' school performance, suicidal ideation, suicide attempts and self-mutilation as well as psychiatric DSM-IV diagnoses was obtained using the Schedule for Affective Disorder and Schizophrenia for School-Age Children.
Results:  An elevated risk of suicidal ideation (OR = 3.6, 95% CI 1.3–10.2, P  = 0.017) and of psychotic disorders (OR = 3.2, 95% CI 1.0–10.0, P  = 0.048) was observed among male adolescents performing well in school. In addition, adolescents with poor school performance had an increased likelihood of substance-related disorder both in boys (OR = 2.6, 95% CI 1.1–6.1, P  = 0.027) and girls (OR = 2.5, 95% CI 1.2–5.1, P  = 0.011).
Conclusions:  Our findings indicate that psychotic inpatient male adolescents performing well in school are at an elevated risk of suicidal ideation. Although good school performance is often considered a marker of high intelligence and good general ability, symptoms of major psychiatric disorders and suicidality need to be taken very seriously among adolescents performing well in school.     

Effects of xenon anesthesia on cerebral blood flow in humans: a positron emission tomography study

BACKGROUND: Animal studies have demonstrated a strong neuroprotective property of xenon. Its usefulness in patients with cerebral pathology could be compromised by deleterious effects on regional cerebral blood flow (rCBF). METHODS: 15O-labeled water was used to determine rCBF in nine healthy male subjects at baseline and during 1 minimum alveolar concentration (MAC) of xenon (63%). Anesthesia was based solely on xenon. Absolute changes in rCBF were quantified using region-of-interest analysis and voxel-based analysis. RESULTS: Mean arterial blood pressure and arterial partial pressure for carbon dioxide remained unchanged. The mean (+/-SD) xenon concentration during anesthesia was 65.2+/-2.3%. Xenon anesthesia decreased absolute rCBF by 34.7+/-9.8% in the cerebellum (P<0.001), by 22.8+/-10.4% in the thalamus (P=0.001), and by 16.2+/-6.2% in the parietal cortex (P<0.001). On average, xenon anesthesia decreased absolute rCBF by 11.2+/-8.6% in the gray matter (P=0.008). A 22.1+/-13.6% increase in rCBF was detected in the white matter (P=0.001). Whole-brain voxel-based analysis revealed widespread cortical reductions and increases in rCBF in the precentral and postcentral gyri. CONCLUSIONS: One MAC of xenon decreased rCBF in several areas studied. The greatest decreases were detected in the cerebellum, the thalamus and the cortical areas. Increases in rCBF were observed in the white matter and in the pre- and postcentral gyri. These results are in clear contradiction with ketamine, another N-methyl-D-aspartate antagonist and neuroprotectant, which induces a general increase in cerebral blood flow at anesthetic concentrations.     

Spectral analysis of physiological brain pulsations affecting the BOLD signal

Physiological pulsations have been shown to affect the global blood oxygen level dependent (BOLD) signal in human brain. While these pulsations have previously been regarded as noise, recent studies show their potential as biomarkers of brain pathology. We used the extended 5 Hz spectral range of magnetic resonance encephalography (MREG) data to investigate spatial and frequency distributions of physiological BOLD signal sources. Amplitude spectra of the global image signals revealed cardiorespiratory envelope modulation (CREM) peaks, in addition to the previously known very low frequency (VLF) and cardiorespiratory pulsations. We then proceeded to extend the amplitude of low frequency fluctuations (ALFF) method to each of these pulsations. The respiratory pulsations were spatially dominating over most brain structures. The VLF pulsations overcame the respiratory pulsations in frontal and parietal gray matter, whereas cardiac and CREM pulsations had this effect in central cerebrospinal fluid (CSF) spaces and major blood vessels. A quasi‐periodic pattern (QPP) analysis showed that the CREM pulsations propagated as waves, with a spatiotemporal pattern differing from that of respiratory pulsations, indicating them to be distinct intracranial physiological phenomenon. In conclusion, the respiration has a dominant effect on the global BOLD signal and directly modulates cardiovascular brain pulsations.