The effects of inducing a follicular phase gonadotropin secretory pattern in normal women during the luteal phase

It has been hypothesized that the slowing of the luteinizing hormone (LH) pulse frequency in the luteal phase may be necessary for the demise of the corpus luteum, the intercycle rise in baseline follicle-stimulating hormone (FSH), or ovarian follicular development in the subsequent cycle. For assessment of the physiologic role of the luteal phase LH pulse pattern, this pattern was converted to a follicular pattern in six normal women who used exogenous gonadotropin-releasing hormone administered with a portable pump (dose 50 to 100 ng/kg subcutaneously every 90 minutes beginning in the early luteal [n = 3] and midluteal [n = 3] cycle phases). There was no significant difference between the treated and the subsequent cycle for luteal progesterone production [186.3 versus 159.0 (ng/ml) day], preovulatory follicular size (23.1 versus 22.5 mm), estradiol levels, luteal phase length (15.6 versus 14.3 days), and daily gonadotropin concentrations including the intercycle FSH rise (160.5 versus 139.1 ng/ml). A follicular phase gonadotropin pulse pattern (increased frequency, decreased amplitude) in the luteal phase had no discernible effects on the corpus luteum or on follicular development in the subsequent cycle.     

Abnormal patterns of pulsatile luteinizing hormone in women with luteal phase deficiency

Luteal phase deficiency is usually a problem of inadequate progesterone production associated with inadequate ovarian follicular development. The hypothesis that luteal phase deficiency results from an abnormal secretion pattern of luteinizing hormone (LH) was tested in these women. To this end, the early follicular LH secretion pattern in four women with luteal phase deficiency was characterized and compared with patterns in normal women. Blood samples were obtained through indwelling catheters every ten minutes for eight hours (10 AM to 6 PM), and plasma levels of LH and FSH were measured. Luteinizing hormone and FSH secretion profiles were analyzed for pulse frequency, amplitude, and mean plasma level. A significantly greater LH pulse frequency in women with luteal phase deficiency was observed when compared with the frequency in normal controls (luteal phase deficiency, 10.5 pulses/eight hours; normal, 5.2 pulses/eight hours; P less than or equal to .05). The mean FSH concentration was less in the women with luteal phase deficiency, but the level was not significant. These data suggest that the abnormal LH secretion pattern observed in women with luteal phase deficiency is responsible for their inadequate luteal phase progesterone secretion and their infertility.     

Waiver of consent in studies of acute brain injury

A multicenter trial of hypothermia in patients with acute brain injury, designed to accrue 140 patients per year and randomizing in less than 6 h from injury, enrolled 392 patients. The design was to achieve 33 degrees C within 8 h after injury. For the first 9 months of the trial, the only consent mechanism permitted by federal regulations was prospective, informed consent. In the subsequent 33 months, after a change in federal regulations, waiver of consent could be used when family could not be located. Waiver of consent was used in 62% of patients enrolled. In the first 9 months of the trial, accrual was 65 patients. In the subsequent 3 years, an average yearly accrual was 127 patients. In the first 9 months, time from injury to randomization was 4.5 +/- 1.2 h; time to achievement of target temperature was 11.7 +/- 2.6 h. In years when waiver of consent was permitted, randomization time was 4.1 +/- 1.1 h, and time to target temperature was 7.9 +/- 2.7 h. For all years of the study, waiver of consent was used for 53% of minorities, 47% of unskilled workers, 33% of nonminorities, and 29% of skilled or professional workers. Minorities were underrepresented by 30% in the first 9 months of the study. We conclude that it is impracticable and unjust to perform studies of acute brain injury without use of waiver of consent when the treatment window is less than 6 h.     

Changes in cyclotorsion and vertical eye alignment during prolonged monocular occlusion

When binocular vision is prevented with monocular occlusion, the two eyes assume a position of rest related to the combination of underlying tonic innervation of the oculomotor system, cross-coupled accommodative-vergence input and vergence responses to perceptual cues for spatial location relative to the head. When the latter two are controlled, the covered eye has been shown in the majority of subjects to turn outward (exophoria) and upward (hyperphoria) after prolonged monocular occlusion. The present study investigates the change in torsional eye alignment and its relation to vertical eye alignment after eight hours of monocular occlusion. The results revealed an excyclophoria during occlusion in four out of five subjects. The patched eye also became elevated in two subjects and depressed in two others. Thus, during prolonged monocular occlusion, the relative directions of cyclophoria and vertical phoria appear to be independent. In addition, there were non-concomitant changes in vertical phoria with horizontal gaze, toward a state where the adducted eye was elevated relative to the abducted eye. Simulations with Orbit(TM) suggest that these non-concomitant changes in vertical phoria with a concomitant excyclophoria may be based upon orbital mechanics. Excyclophoria appears to be the baseline state of binocular alignment.     

Functional genomics of the endocrine pancreas: the pancreas clone set and PancChip,new resources for diabetes research

Over the past 5 years, microarrays have greatly facilitated large-scale analysis of gene expression levels. Although these arrays were not specifically geared to represent tissues and pathways known to be affected by diabetes, they have been used in both type 1 and type 2 diabetes research. To prepare a tool that is particularly useful in the study of type 1 diabetes, we have assembled a nonredundant set of 3,400 clones representing genes expressed in the mouse pancreas or pathways known to be affected by diabetes. We have demonstrated the usefulness of this clone set by preparing a cDNA glass microarray, the PancChip, and using it to analyze pancreatic gene expression from embryonic day 14.5 through adulthood in mice. The clone set and corresponding array are useful resources for diabetes research.     

Polymorphisms in the oxygen-regulated protein 150 gene (ORP150) are associated with insulin resistance in Pima Indians

The ORP150 gene that encodes the human oxygen-regulated protein (150 kDa) maps to chromosome 11q23, a region previously reported to be linked to type 2 diabetes and obesity in Pima Indians. This gene was also found to be differentially expressed in global gene expression studies comparing muscle mRNA from insulin-resistant versus insulin-sensitive subjects. Therefore, ORP150 was analyzed as a candidate gene for susceptibility to diabetes. Twelve variants were identified, and three unique representative polymorphisms were genotyped in 1,338 Pima Indians. None of these polymorphisms were associated with diabetes, but two polymorphisms were significantly associated with measures of insulin resistance. These data indicate that ORP150 has a role in insulin action but does not have a major role in determining susceptibility to type 2 diabetes in Pima Indians.     

Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy

PURPOSE: To analyze acute lung toxicity data of non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy in terms of dosimetric variables, location of dose within subvolumes of the lungs, and models of normal-tissue complication probability (NTCP). METHODS AND MATERIALS: Dose distributions of 49 non-small-cell lung cancer patients treated in a dose escalation protocol between 1992 and 1999 were analyzed (dose range: 57.6-81 Gy). Nine patients had RTOG Grade 3 or higher acute lung toxicity. Correlation with dosimetric and physical variables, as well as Lyman and parallel NTCP models, was assessed. Lungs were evaluated as a single structure, as superior and inferior halves (to assess significance of dose to upper and lower lungs), and as ipsilateral and contralateral lungs. RESULTS: For the whole lung, Grade 3 or higher pneumonitis was significantly correlated (p 0.5 for superior lung indices, and >0.1 for contralateral lung indices studied). CONCLUSIONS: For these patients, commonly used dosimetric and NTCP models are significantly correlated with >or= Grade 3 pneumonitis. Equivalently strong correlations are found in the lower portion of the lungs and the ipsilateral lung, but not in the upper portion or contralateral lung.     

Staging classification of lung cancer. A critical evaluation

The International System for Staging Lung Cancer has been validated as a prognostic index and questioned regarding the implications of factors that require further study. As technology for evaluating the anatomic extent of disease is increasingly refined, the accuracy of clinical staging is greatly improved and provides a major benefit for individualized treatment selection. Advancing knowledge of the origin and development of lung tumors presents the challenge of appropriate integration of this body of science into clinical practice.