Addition of a gonadotropin releasing hormone (GnRH) antagonist and exogenous gonadotropins to unstimulated in vitro fertilization (IVF) cycles: Physiologic observations and preliminary experience

Purpose To describe our preliminary experience with the addition of a GnRH antagonist (Nal-Glu) and exogenous gonadotropins (follicle stimulating hormone; FSH) to unstimulated IVF cycles.Method Seven spontaneously ovulatory women underwent eight unstimulated IVF cycles at our institution. They were treated with a single dose of Nal-Glu, 50 g/ kg, or with a combination of Nal-Glu, 50 g/kg, and exogenous FSH, 150–300 IU, during the late follicular phase of spontaneous cycles. They then received 10,000 IU of human chorionic gonadotropin (hCG) to time accurately follicle aspiration in unstimulated IVF cycles.Results Two women underwent three cycles with Nal-Glu alone on the day of hCG administration. One pregnancy resulted. Five women underwent five cycles with 3 to 6 days of daily Nal-Glu and FSH. Four of these cycles resulted in aspiration after the FSH dose was increased to 300 IU. Nal-Glu and FSH allowed continued development of the dominant follicle without the occurrence of luteinizing hormone (LH) surge.Conclusions (1) Nal-Glu alone given 18 hr prior to hCG did not interfere with continued follicle viability or with the attainment of pregnancy. (2) Simultaneous Nal-Glu and FSH allowed for continued growth and development of the dominant follicle without the occurrence of an LH surge. (3) This preliminary experience confirms the feasibility of this novel approach, which may ultimately enhance the efficacy of unstimulated IVF cycles by eliminating premature ovulation and maximizing control of gonadotropin delivery to the developing follicle.Presented at the 39th Meeting of The Society for Gynecologic Investigation, San Antonio, Texas, March 18–21, 1992.     

Brain activation during dichotic presentations of consonant-vowel and musical instrument stimuli: a 15O-PET study

Dichotic listening means that two different stimuli are presented at the same time, one in each ear. This technique is frequently used in experimental and clinical studies as a measure of hemispheric specialization. The primary aim of the present study was to record regional changes in the distribution of cerebral blood flow (CBF) with the 15O-PET technique to dichotically presented consonant-vowel (CV) and musical instrument stimuli, in order to test the basic assumption of differential hemispheric involvement when stimuli presented to one ear dominate over stimuli presented in the other ear. All stimuli were 380 ms in duration with a 1000 ms interstimulus interval, and were presented in blocks of either CV-syllable or musical instrument pairs. Twelve normal healthy subjects had to press a button whenever they detected a CV-syllable or a musical instrument target in a stream of CV- and musical instrument distractor stimuli. The targets appeared equally often in the right and left ear channel. The CV-syllable and musical instrument targets activated bilateral areas in the superior temporal gyri. However, there were significant interactions with regard to asymmetry of the magnitude of peak activation in the significant activation clusters. The CV-syllables resulted in greater neural activation in the left temporal lobe while the musical instruments resulted in greater neural activation in the right temporal lobe. Within-subjects correlations between magnitude of dichotic listening and CBF asymmetry were, however, non-significant. The changes in neural activation were closely mimicked by the performance data which showed a right ear superiority in response accuracy for the CV-syllables, and a left ear superiority for the musical instruments. In addition to the temporal lobe activations, there were activation tendencies in the left inferior frontal lobe, right dorsolateral prefrontal cortex, left occipital lobe, and cerebellum.     

Visual cortex activation recorded by dynamic emission computed tomography of inhaled xenon 133

Regional cerebral blood flow (CBF) was studied tomographically with ¹³³Xe administered by inhalation over a 1-min period at a concentration of 10 mCi/l. A fast rotating (dynamic) single-photon emission computed tomograph with four detector heads was used, an instrument that has been found to be well suited for detecting focal ischemia. In the present study its ability to detect focal hyperemia was investigated in 13 normal subjects studied during rest and during visual stimulation. A flickering light seen with eyes open and closed, increased blood flow in the visual cortex by 35% and 22% respectively. Looking at different pictures displayed on a screen raised regional CBF by 26%. The most complex task, reading and copying a text, increased blood flow by 45%. Averaging the different tasks resulted in a mean regional CBF increase in the visual cortex of 35%. The result is comparable with that obtained by positron emission tomography. Both forms of isotope tomography offer unique possibilities for the study of brain function in health and disease, possibilities not matched by X-ray tomography. The low cost and ready availability of appropriate single-photon radionucleides (¹³³Xe and ¹²⁷Xe) are mentioned.Supported by the Danish Medical Research Council, the Danish Sclerose Association, and the Johann and Hanne Weimann Foundation.     

The impact of the “cisplatin era” of treatment on survival in testicular cancer

Summary The records of all testicular cancer patients evaluated and treated at our medical center during two consecutive 9-year periods were reviewed and analyzed for prognostic factors, particularly the impact of cisplatin-based combination chemotherapy. The data base of 244 patients was divided into two eras: 1970–1978, defined as the pre-cisplatin era (n=101) and 1979–1987, the cisplatin era (n=143). Statistically improved survival (P=0.024) was noted for the 165 nonseminoma patients and for a grouping of 143 patients treated with combination chemotherapy (P=0.004) during the cisplatin era. Stratification by stage revealed that stage II patients had the most significant survival advantage (P=0.001) during the cisplatin era; cancer mortality improved from 48% to 9%. Cancer death rates for stage III patients decreased from 58% to 39% which is clinically but not statistically significant (P=0.497). Stage I patients and the seminoma population did well during both eras, and the impact of cisplatin could not be statistically confirmed in this study for these subgroups. Multivariate statistical analysis confirmed the importance of the era of treatment for the nonseminoma population.     

Effects of attention on dichotic listening: an 15O-PET study

The present study investigated the effect of attention on brain activation in a dichotic listening situation. Dichotic listening is a technique to study laterality effects in the auditory sensory modality. Two different stimuli were presented simultaneously, one in each ear. Twelve subjects listened to lists of consonant-vowel syllables, or short musical instrument passages, with the task of detecting a "target" syllable or musical instrument by pressing a button. The target stimulus appeared an equal number of times in the left and right ear. The subjects were instructed to either concentrate on the stimuli presented in both ears, or only on the left or right ear stimulus. Brain activation was measured with 15O-PET, and significant changes in regional normalized counts (rNC) were evaluated using statistical parametric mapping (SPM96) software. Concentrating on either the right or left ear stimulus significantly decreased activity bilaterally in the temporal lobes compared to concentrating on both ear stimuli, at the expense of an increased activation in the right posterior and inferior superior parietal lobe. The CV-syllables activated areas corresponding to the classic language areas of Broca and Wernicke. The musical instrument stimuli mainly activated areas in visual association cortex, cerebellum, and the hippocampus. An interpretation of the findings is that attention has a facilitating effect for auditory processing, causing reduced activation in the primary auditory cortex when attention is explicitly recruited. The observed activations in the parietal lobe during the focused attention conditions could be part of a modality non-specific "attentional network".     

Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate

The purpose of this study was to investigate the relation between APOE genotype and Multiple Sclerosis (MS) in a genetically homogeneous population. We examined 240 patients consulting the MS-clinic during a period of 3 years (1996 - 1999). The mean age of the patients was 41.7 years (range 19 - 80 Y, SD 10.0 Y). As a measure of the progression rate (PR) the last registered Expanded Disability Status Scale (EDSS) score was divided by the time span (years) from disease onset until the latest assessment. The APOE genotype was determined from saliva and/or blood samples using PCR-techniques. The prevalence of different APOE genotypes was compared with the allele-distribution in a population of 361 persons from a Danish cross-sectional population study. The frequency of APOE-epsilon 4/epsilon 4 homozygotes was significantly higher in the MS-group as compared to controls (P<0.05, odds ratio: 2.3), whereas the frequency distribution of other genotypes did not differ significantly. The rate of progression was significantly faster in the APOE-epsilon 4/epsilon 4 homozygotes compared to other genotypes in the MS group (P<0.05). This study suggests that the APOE-epsilon 4/epsilon 4 homozygotes have an increased risk of developing MS. MS patients with the APOE-epsilon 4/epsilon 4 allele may also have an increased rate of disease progression. Multiple Sclerosis (2000) 6 226 - 230     

Hypospadias trends in two US surveillance systems

OBJECTIVE: Hypospadias is a common congenital anomaly, the cause of which is unknown. Unexplained increases in the rates of hypospadias occurred in five European countries in the 1970s and 1980s. We examined data from two birth defects surveillance systems in the United States for evidence of similar trends. METHODOLOGY: The Metropolitan Atlanta Congenital Defects Program (MACDP) provided birth prevalence rates from 1968 to 1993. The nationwide Birth Defects Monitoring Program (BDMP) provided rates from 1970 to 1993. MACDP data are population-based and could be categorized by the severity of the hypospadias. BDMP data allowed analysis of rate trends for the four census regions of the United States. RESULTS: Data from both surveillance systems showed an approximate doubling of hypospadias rates in the 1970s and 1980s. MACDP data showed that the rate of severe cases increased while the ratio of mild to severe cases decreased. BDMP data showed that hypospadias rates increased markedly in all four regions of the United States. CONCLUSIONS: The observed increases are unlikely to be attributable to increased sensitivity of the surveillance systems or the identification of more mild cases by physicians over time, because either trend would have increased rather than decreased the ratio of mild to severe cases. If real, these trends represent the largest number of cases and the first report of an increase in hypospadias rates outside of Europe. Additional investigation of a possible increase in hypospadias rates is warranted.     

Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancer types exhibiting microsatellite instability. Using intron primers previously reported for examination of the entire coding region of the TGFbetaRII gene, 29 sporadic gastric cancers were screened with non-radioactive single strand conformation polymorphism and subsequent DNA sequencing analysis. Mutations of the TGFbetaRII gene were detected in three out of 29 tumors (10%). Two cases showed deletions in a polyadenine tract in both alleles and was positively associated with replication error. One case had an insertion of GA dinucleotide sequence in one allele. Mutations of the TGFbetaRII gene were restricted to exon 3 and other coding regions were not affected. Loss of heterozygosity was detected by analyzing a polymorphic site in intron 2. Three out of nine (33%) informative cases, which were all of intestinal type and advanced cases, showed loss of heterozygosity but neither TGFbetaRII mutation nor replication error was found in these cases. Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different extent in the gastric cancer with genetically abnormal transforming growth factor. Although the numbers studied are small, homozygous (A)10 deletion or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and progression of at least some part of sporadic gastric cancer.