Reduction of gonadotropin-releasing hormone pulse frequency is associated with subsequent selective follicle-stimulating hormone secretion in women with polycystic ovarian disease

Polycystic ovarian disease (PCO) is characterized by hyperandrogenism, ovulatory dysfunction, and altered gonadotropin secretion. Mean plasma FSH concentrations are low, while LH is elevated in a majority of patients. LH pulsatile secretion has been shown to occur at rapid follicular phase frequencies (approximately one pulse per h) in PCO, suggesting persistent rapid frequency GnRH secretion in this disorder. Anovulatory women with PCO were given estradiol (E2; Estraderm skin patches) and progesterone (P; vaginal suppositories) to produce midluteal concentrations for 21 days. The aim was to determine if E2 and P would slow LH (GnRH) pulse frequency and if this would result in augmented FSH secretion and follicular development after withdrawal of E2 and P. Plasma LH was measured every 10 min for 8 h before, during (days 10 and 20), and 7 days after withdrawal of E2 and P (day 28). On each of these study days FSH was measured hourly, and E2 and P were measured every 2 h. After sampling, GnRH (25 and 250 ng/kg, iv) was given to assess pituitary responsiveness. Follicular development was monitored by vaginal ultrasound through day 34 of the study. Basal LH frequency was 8.5 +/- 0.5 pulses/8 h (mean +/- SEM). During E2 and P, LH pulse frequency fell to 3.3 +/- 1.0 (10 days) and 2.3 +/- 0.8 (20 days), 39% and 27% of the basal value, respectively, and subsequently increased to 5.6 +/- 0.7 (66% of basal) 7 days after withdrawal of E2 and P. LH pulse amplitude (basal, 7.2 +/- 1.5 IU/L) was not reduced until day 20, but remained suppressed (3.9 +/- 1.1 IU/L) on day 28. As a result, mean LH (basal, 21.0 +/- 3.5 IU/L) fell progressively during E2 and P, to 3.8 +/- 1.2 IU/L on day 20, and remained low (39% of basal) 7 days after steroid withdrawal. Mean plasma FSH (basal, 7.1 +/- 0.9 IU/L) also fell during steroid administration, but in contrast to LH, had risen to 93% of the basal value by 7 days after E2 and P. LH release in response to exogenous GnRH revealed marked initial responses which did not decrease until day 20, but remained suppressed (8% of basal) after withdrawal of E2 and P. FSH responses were also suppressed on day 20, but had increased to 75% of the basal value by day 28. Initiation of follicular development occurred in all patients, and the lead follicle measured 12.3 +/- 0.8 mm 13 days post-E2 and P. Ovulation occurred in one patient.(ABSTRACT TRUNCATED AT 400 WORDS)     

Psychiatric nurses and the practice of psychotherapy: current status and future possibilities

Up to now not many patients have interacted with trained psychiatric nurses, since their numbers have been small. It is only a recent development that nurses are continuing their education to the Master's and Ph.D. levels. Suggestions for courses are made. Because of the growing convergence of the biological and behavioral sciences, nurses will be in a strong position to provide effective patient management. Their traditional involvement in the community, the work place, the schools, as well as the fact that they are in close contact with medical and surgical patients in particular stressful situations, may enable them not only to treat but even mitigate emergent psychopathology. Nurses would be uniquely placed to interact with other members of the mental health professions and to supplement their work.     

Sepsis and cytokines: current status

Sepsis is a constellation of clinical signs and symptoms resulting from excessive systemic host inflammatory response to infection. This inflammatory response is largely mediated by cytokines, which are released into the systemic circulation. Plasma concentrations of specific cytokines, TNF alpha, IL-1 beta, IL-6 and IL-8 are frequently elevated in human sepsis and cytokine concentrations correlate with severity and outcome of sepsis. In addition to pro-inflammatory cytokines, soluble cytokine receptors, cytokine receptor antagonists and counter-inflammatory cytokines are also produced in large quantities in patients with sepsis; however, the specific role of these molecules in sepsis remains undefined. A complex interaction of cytokines and cytokine-neutralizing molecules probably determines the clinical presentation and course of sepsis. Intervening in this sequence of events to modify the host inflammatory responses may prove to be a beneficial treatment strategy for sepsis, but currently tested anticytokine therapies have been largely unsuccessful.      

Intratracheal administration of liposomal clodronate accelerates alveolar macrophage reconstitution following fetal liver transplantation

To facilitate study of alveolar macrophages in vivo, we developed a method to rapidly and efficiently replace resident alveolar macrophages with macrophages of a different (donor) genotype. Chimeric mice were generated by lethal irradiation followed by fetal liver transplantation (FLT) using green fluorescent protein (GFP) transgenic reporter mice as donors. Kinetics of peripheral blood monocyte (PBM) and alveolar macrophage reconstitution was determined 4 and 10 weeks post-FLT by quantifying the percentage of GFP+ cells. To enhance the recruitment of donor monocytes into the lung after FLT, mice were treated with intratracheal administration of liposomal clodronate to deplete host alveolar macrophages at 6 weeks post-FLT. PBM reconstitution occurred by 4 weeks after FLT (85.7+/-1.6% of CD11b+/Gr-1+ monocytes were GFP+), and minimal alveolar macrophage repopulation was observed (9.5% GFP+). By 10 weeks following FLT, 48% of alveolar macrophages were GFP+ by immunostaining of macrophages on lung tissue sections, and 55.1 +/- 1.6% of lung lavage macrophages were GFP+ by fluorescein-activated cell sorter analysis. Clodronate treatment resulted in a significant increase in GFP+ alveolar macrophages 10 weeks after FLT. By immunostaining, 90% of macrophages were GFP+ on lung tissue sections and 87.5 +/- 1.1% GFP+ in lung lavage (compared with GFP-transgenic controls). The ability of newly recruited alveolar macrophages to clear Pseudomonas aeruginosa and activate nuclear factor-kappaB in response to Eschericia coli lipopolysaccharide demonstrated normal macrophage function. Optimizing this methodology provides an important tool for the study of specific genes and their contribution to alveolar macrophage function in vivo.     

Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells

In cystic fibrosis (CF), inflammatory mediator production by airway epithelial cells is a critical determinant of chronic airway inflammation. To determine whether altered signal transduction through the nuclear factor (NF)-kappaB pathway occurs in CF epithelial cells and results in excessive generation of inflammatory cytokines, we evaluated tumor necrosis factor (TNF)-alpha-induced production of the NF-kappaB-dependent cytokine interleukin (IL)-8 and activation of NF-kappaB in three different human bronchial epithelial cell lines: (1) BEAS cells that express wild-type CF transmembrane conductance regulator (CFTR), (2) IB3 cells with mutant CFTR, and (3) C38 cells, which are "corrected" IB3 cells complemented with wild-type CFTR. Treatment of cells with TNF-alpha (30 ng/ml) resulted in markedly elevated NF-kappaB activation and production of IL-8 by IB3 cells compared with BEAS and C38 cells. Despite the differences in NF- kappaB activation, no differences in basal levels of IkappaB-alpha or TNF-alpha- induced IkappaB-alpha processing and degradation were detected among the cell lines. In contrast, the basal level of IkappaB-beta was increased in the IB3 cells. Treatment with TNF-alpha resulted in increased formation of hypophosphorylated IkappaB-beta and increased nuclear localization of IkappaB-beta in IB3 cells compared with the other cell types. These findings provide additional evidence of a dysregulated inflammatory response in CF.     

Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer.

Individuals with the major hemochromatosis (HFE) allele C282Y and iron overload develop hepatocellular and some extrahepatic malignancies at increased rates. No association has been previously reported between the C282Y allele and breast cancer. We hypothesized that due to the pro-oxidant properties of iron, altered iron metabolism in C282Y carriers may promote breast carcinogenesis. Because 1 in 10 Caucasians of Northern European ancestry carries this allele, any impact it may have on breast cancer burden is potentially great. We determined C282Y genotypes in 168 patients who underwent high-dose chemotherapy and blood cell transplantation for cancer: 41 with breast cancer and 127 with predominantly hematological cancers (transplant cohort). Demographic, clinical, and tumor characteristics were reviewed in breast cancer patients. The frequency of C282Y genotypes in breast cancers was compared with the frequency in nonbreast cancers, an outpatient sample from Tennessee (n = 169), and a published United States national sample. The frequency of at least one C282Y allele in breast cancers was higher (36.6%, 5 homozygotes/10 heterozygotes) than frequencies in Tennessee (12.7%, P < 0.001), the general population (12.4%, P < 0.001), and similarly selected nonbreast cancers (17.0%, P = 0.008). The likelihood of breast cancer in the transplant cohort increased with C282Y allele dose (P(trend) = 0.010). These results were supported by the finding in a nontransplant cohort of a higher frequency of C282Y mutations in Caucasian (18.4%, P = 0.039) and African-American (8.5%, P = 0.005) women with breast cancer than race-specific national frequency estimates. A high prevalence of C282Y alleles in women with breast cancer with and without poor risk features suggests that altered iron metabolism in C282Y carriers may promote the development of breast cancer and/or more aggressive forms of the disease.     

The effects of varying levels of hemispheric activation on episodic memory

Bilateral saccadic eye movements enhance episodic memory retrieval; however, this usually only occurs for consistent-handed, not inconsistent-handed, individuals. It was hypothesized that inconsistent-handers begin closer to the peak of a Yerkes–Dodson-type inverted-U curve and increasing activation pushes them along the curve eventually decreasing performance, while consistent-handers start at a lower baseline and therefore increasing activation increases their performance. The current study tested this hypothesis by using hand clenching (grip strength) to increase activation at 5 different levels for both consistent- and inconsistent-handers. A total of 316 participants were presented with a list of 36 words after which they squeezed a hand dynamometer to induce cortical activation, and then recalled as many of the words as they could. Results showed that, as predicted, both inconsistent- and consistent-handers demonstrated an inverted-U pattern of memory performance as the strength of squeeze increased with inconsistent-handers peaking at a lower level of grip strength than consistent-handers. These results may help explain past findings, not only with episodic memory but also a variety of other cognitive tasks. They may also have interesting theoretical and real-world implications, which are discussed.