Evidence for abnormal granulosa cell responsiveness to follicle-stimulating hormone in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) undergoing ovulation induction appear to be extremely sensitive to gonadotropin stimulation and at increased risk for ovarian hyperstimulation syndrome. To determine granulosa cell responsiveness to recombinant human FSH (r-hFSH), dose-response studies were conducted in 16 individual PCOS patients and 7 normal women. Each subject received an iv injection of r-hFSH at doses of 0, 37.5, 75, or 150 IU in a randomized fashion on four separate occasions. Blood samples were obtained at frequent intervals before and for 24 h after r-hFSH administration for measurement of gonadotropins and steroid hormones. Our results showed that administration of r-hFSH produced instantaneous and equivalent dose-related increases in serum FSH in PCOS and normal women, which were followed by similar exponential decreases to baseline levels within 24 h in both groups. In PCOS subjects, the peak mean incremental response of serum estradiol (E(2)) to 150 IU of r-hFSH was 1.8-fold greater (P < 0.0001) and considerably accelerated compared with that found in normal women. In contrast, E(2) responses to 37.5 IU and 75 IU were similar between groups. Regression analysis of maximal E(2) concentrations in response to r-hFSH in each individual subject revealed that the slope of the linear trend line in the group of women with PCOS (r = 0.82) was significantly greater (P < 0.01) than that of normal controls (r = 0.71). The time-course of response revealed that in PCOS women, increases of E(2) were not sustained, compared with those of normal controls, because peak concentrations were followed by an estimated 40% decrement in circulating levels, whereas E(2) levels in normal women persisted for 24 h after reaching maximal values. These findings indicate that women with PCOS exhibit a significantly greater capacity for E(2) production in response to iv r-hFSH, compared with normal women. In PCOS, E(2) production was relatively transient because after peak concentrations a marked decline was detected at each dose, unlike normal women who exhibited persistent elevations of E(2) for up to 24 h. That this distinction was dose-dependent supports the concept of an FSH dose-response threshold, beyond which PCOS but not normal women are susceptible to ovarian hyperresponsiveness.     

Branching out: a molecular fingerprint of endothelial differentiation into tube-like structures generated by Affymetrix oligonucleotide arrays

The process of endothelial differentiation into a network of tube-like structures with patent lumens requires an integrated program of gene expression. To identify genes upregulated in endothelial cells during the process of tube formation, RNA was prepared from several different time points (0, 4, 8, 24, 40, and 48 hours) and from three different experimental models of human endothelial tube formation: in collagen gels and fibrin gels driven by the combination of PMA (80), bFGF (40 ng/ml) and bFGF (40 ng/ml) or in collagen gels driven by the combination of HGF (40 ng/ml) and VEGF (40 ng/ml). Gene expression was evaluated using Affymetrix Gene Chip oligonucleotide arrays. Over 1000 common genes were upregulated greater than twofold over baseline at one or more time points in the three different models. In the present study, we discuss the identified genes that could be assigned to major functional classes: apoptosis, cytoskeleton, proteases, matrix, and matrix turnover, pumps and transporters, membrane lipid turnover, and junctional molecules or adhesion proteins.     

Cardiac dimension and function in patients with childhood onset growth hormone deficiency,before and after growth hormone retreatment in adult age

Background Growth hormone (GH) replacement during childhood has been shown to increase stature; however, there is little information on its long-term effect on the heart is not yet clear. The aim of this study was to assess cardiac size and function in patients with childhood-onset GH deficiency in whom GH treatment had been stopped at the achievement of final height and the effect of a second course of GH replacement in adult age. Methods Cardiac dimensions and function, obtained with echocardiography, of 21 patients (5 women and 16 men, mean age 28 ± 8 years), all of whom were treated during childhood, were compared with 21 age- and sex-matched healthy control subjects. Eight of these patients (2 women and 6 men, mean age 28 ± 8 years) were given a second course of GH replacement therapy for 15 ± 3 months. Results The stature and all cardiac dimensions of patients with GH deficiency who were treated during childhood were significantly smaller than those of the control subjects. After the second course of GH in adulthood, the only significant change observed was an increase in left ventricular (LV) mass (93 ± 21 vs 106 ± 24 g, P = .007) and LV mass index (59 ± 12 vs 66 ± 13 g/body surface area, P = .005). Conclusion The stature and cardiac dimensions of patients with childhood-onset GH deficiency measured in adult age were smaller than those of control subjects, despite long-term GH replacement therapy during childhood. A second course of GH treatment during adulthood caused a significant increase in the estimated LV mass index in patients with both isolated and multiple pituitary hormone deficiency. (Am Heart J 2003;145:549-53.)     

Ego-resiliency in borderline personality disorder and the mediating role of positive and negative affect on its associations with symptom severity and quality of life in daily life

Borderline personality disorder (BPD) is a serious mental health condition associated with severe symptoms of distress and poor quality of life (QoL). Research outside the field of BPD suggests that ego-resiliency is negatively associated with psychopathology and positively associated with a range of positive life outcomes. Thus, ego-resiliency may be a valuable construct for furthering our understanding and treatment of BPD. However, the mechanisms linking ego-resiliency to psychopathology and QoL in relation to BPD have not been examined and explored by research. This study has addressed this gap in the collective knowledge by evaluating whether within-person associations between daily reports of positive affect (PA) and negative affect (NA) mediated the relationship between ego-resiliency, BPD symptom severity, and QoL. For 21 consecutive days, 72 women diagnosed with BPD completed end-of-day electronic assessments regarding ego-resiliency, PA and NA, symptom severity, and QoL. Multilevel structural equation modelling established that PA and NA were parallel mediators linking ego-resiliency with BPD symptom severity and QoL. As hypothesized, the path to QoL was stronger through PA than through NA. The mediation paths through NA and PA to BPD symptom severity were both significant, but their strength did not differ. Our findings align with the assertions of theories on emotion, thus suggesting a two-factor approach to PA and NA. Future research can build on these findings by developing psychotherapeutic interventions designed not only to reduce symptom severity but also to enhance PA in individuals with BPD and determine whether an increase in PA is associated with improved QoL.     

Is there a relation between vitamin D,interleukin-17, and bone mineral density in patients with inflammatory bowel disease?

IntroductionIn inflammatory bowel diseases (IBD), osteopenia and osteoporosis constitute a significant medical problem. Cytokines, especially IL-17, play an important role in the pathogenesis of IBD and osteoporosis. Vitamin D is a regulator of bone metabolism, and helps maintain immune system homeostasis.Material and methodsThe research sample consisted of 208 persons: 83 patients (age 35 ±11.99 years) with Crohn’s disease (CD); 86 patients (age 39.58 ±14.74 years) with ulcerative colitis (UC); and 39 persons (age 30.74 ±8.63 years) in the control group (CG). Clinical data on bone mineral density of the lumbar spine (L2-L4), bone mineral density of the femoral neck (FN), and body mass index (BMI) were collected. 25OHD and IL-17 serum concentrations were also measured.ResultsBody mass index (kg/m²) results: in CD, 21.51 ±3.68; in UC, 23.31 ±4.38; and in CG, 24.57 ±3.45 (p < 0.01). Densitometry results for L2–L4 T-score SD: in CD –0.83 ±1.45; in UC –0.47 ±1.15; in CG 0.09 ±0.70. Densitometry results for FN T-score SD: in CD –0.62 ±1.26; in UC –0.29±1.17; in CG 0.41 ±1.03 25OHD (ng/ml) serum concentrations: in CD, 21.33±12.50; in UC, 22.04±9.56; in CG, 21.56±9.11 (ns). IL-17 (pg/ml) serum concentrations: in CD, 8.55±10.99; in UC, 11.67±12.97; in CG, 5.16±9.11 (ns).ConclusionsInflammatory bowel diseases patients and persons from the CG did not differ in vitamin D or IL-17 levels. Patients with a mild course of the disease had a higher vitamin D concentration and bone mineral density. In UC, higher vitamin D concentrations were associated with lower IL-17 concentrations. The IBD patients with a severe course of the disease had a lower body mass than those in the CG and the patients with a mild course of the disease.     

Invasion pattern and histologic features of tumor aggressiveness correlate with MMR protein expression,but are independent of activating KRAS and BRAF mutations in CRC

KRAS/BRAF mutation testing and mismatch repair (MMR) protein immunohistochemistry have an established role in routine diagnostic evaluation of colorectal carcinoma (CRC). However, since the exact impact of these molecular characteristics on tumor morphology and behavior is still subject to research, the aim of our study was to examine associations between molecular and morphologic features that had not been analyzed in this combination before. KRAS (codons 12, 13, and 61) and BRAF (codon 600) mutation status and MMR protein expression were analyzed in a consecutive series of 117 CRC samples using DNA pyrosequencing and immunohistochemistry. Tumor cell budding, infiltration pattern, and peritumoral lymphocytic (PTL) reaction was assessed applying established criteria. Molecular and morphological findings were correlated applying chi-square and Fisher’s exact test. We found KRAS or BRAF mutations in 40 and 8 % of samples, while loss of MMR protein expression was observed in 11 %. Tumor budding was significantly associated with infiltrative growth, absence of PTLs, and blood and lymph vessel infiltration. Neither KRAS nor BRAF mutations were associated with a certain growth pattern or budding intensity of CRC, but loss of MMR protein expression was found in context with BRAF mutation, expanding growth, and presence of PTLs. Our results confirm an association between loss of MMR protein expression, presence of activating BRAF mutation, expanding growth, and PTL reaction as well as between tumor budding, infiltrative growth pattern, and tumor aggressiveness; however, there was no such association between the presence of an activating KRAS or BRAF mutation and a distinct invasion pattern or tumor aggressiveness in CRC.