Blood steroid levels predict survival in endometrial cancer and reflect tumor estrogen signaling.

OBJECTIVE: Blood-based biomarkers are attractive due to ease of sampling and standardized measurement technology, reducing obstacles to clinical implementation. The objective of this study was to evaluate a clinically available method of steroid hormone measurement for its prognostic potential in endometrial cancer. METHODS: We quantified seven steroid hormones by liquid chromatography-tandem mass spectrometry in 100 endometrial cancer patients from a prospective cohort. Abdominal fat distribution was assessed from abdominal computed tomography (CT) scans. Steroid hormone levels were compared to clinical characteristics, fat distribution and gene expression in primary tumor samples. RESULTS: Low levels of 17OH-progesterone, 11-deoxycortisol and androstenedione were associated with aggressive tumor characteristics and poor disease specific survival (p = .003, p = .001 and p = .02 respectively). Adjusting for preoperative risk based on histological type and grade, low 17OH-progesterone and 11-deoxycortisol independently predicted poor outcome with hazard ratios of 2.69 (p = .033, 95%CI: 1.09-6.68) and 3.40 (p = .020, 1.21-9.51), respectively. Tumors from patients with low steroid level displayed increased expression of genes related to mitosis and cell cycle progression, whereas high steroid level was associated with upregulated estrogen signaling and genes associated with inflammation. Estrone and estradiol correlated to abdominal fat volume in all compartments (total, visceral, subcutaneous, p < .001 for all), but not to the visceral fat proportion. Patients with higher levels of circulating estrogens had increased expression of estrogen signaling related genes. CONCLUSION: Low levels of certain endogenous steroids are associated with aggressive tumor traits and poor survival and may provide preoperative information independent of histological biomarkers already in use.

Observations of growth and postspawning survival of lumpfish Cyclopterus lumpus from mark-recapture studies.

Growth and postspawning survival of lumpfish Cyclopterus lumpus are described by mark-recapture experiments using juveniles in offshore areas in the north-east Atlantic Ocean and spawning adults in coastal Norway and Iceland. A female fish tagged as a juvenile and recaptured as an adult matured in a period of 18 months, providing the first observation on development in a wild C. lumpus. The von Bertalanffy growth function, fitted to data from recaptured fish, was used to estimate K and L∞ and recaptured fish spawning after a year at liberty indicated a postspawning survival of c. 10% in Iceland.

Human papillomavirus infection in progressive and non-progressive cervical intraepithelial neoplasia.

Human papillomavirus (HPV) infection is common in cervical intraepithelial neoplasia (CIN) and is widely held to be responsible for its progression to grade 3. This thesis is examined here. Comparison of the level of HPV changes in 133 lesions that had not progressed to that in those from 197 women with histologically proven CIN 3 failed to reveal significant differences in their level of HPV infection on cytology, histology or in situ hybridization. However, in both these groups, some of the cases that did not show HPV positivity on in situ hybridization with probes reacting with the common HPV types did show evidence of HPV DNA using a general primer-mediated polymerase chain reaction. This may indicate low-copy number infections or non-productive infections. Such reactions were more frequent in the women with progressive lesions, and it is probable that they may also have been at greater risk of cervical infection in general. The present findings suggest that a further factor, a cocarcinogen, may be involved in progression to CIN 3, HPV being a common forerunner, providing a proliferative environment and thus favoring such an event.

Expression of keratin 13, 14 and 19 in oral squamous cell carcinomas from Sudanese snuff dippers: lack of association with human papillomavirus infection.

In stratified squamous epithelia, altered expression of keratins (Ks) is one possible marker of malignant potential. In the epithelium of the uterine cervix, presence of human papillomaviruses (HPVs) is increasingly regarded as a marker of risk for cervical cancer. However, a similar role in oral cancer and precancer remains controversial. To address these questions, formalin-fixed, paraffin-embedded oral carcinomas from Sudanese snuff dippers (n=14) and oral carcinomas from Sudanese (n=14), Swedish (n=19) and Norwegian (n=41) non-snuff dippers were examined by immunohistochemistry for expression of K types 13, 14 and 19 using monoclonal antibodies. HPV infection was searched for in all the carcinomas by in situ hybridization (ISH) using the cocktail HPV OmniProbe and the ViraType probe. Carcinomas from Sudanese (snuff dippers/non-snuff dippers) were also examined for HPV infection by polymerase chain reaction (PCR) using the general HPV primers GP5+/GP6+. For the oral carcinomas from snuff dippers, moderate to intense expression of K13 (71%; 10/14), K14 (86%; 12/14) and K19 (93%; 13/14) was found. For the oral carcinomas from non-snuff dippers, weak to moderate expression of K13 (64%; 47/74), K14 (43%; 32/74) and K19 (45%; 33/74) was found. HPV DNA was not detected in any of the carcinomas from three countries when examined by ISH. The Sudanese (from snuff dippers/non-snuff dippers) oral carcinomas were also negative for HPV DNA with the PCR. The present study shows that (i) there is a high level of expression of K13, K14 and K19 in oral carcinomas from snuff dippers compared to those from non-snuff dippers, (ii) this high level of expression may arise from dysregulation of keratinocyte proliferation and maturation caused by damaging effects of snuff, (iii) the HPV genome is not found in Sudanese (snuff dippers/non-snuff dippers), Swedish or Norwegian oral carcinomas, and (iv) this may suggest that these viruses do not play a prominent role in the aetiology of oral carcinomas from these countries.

Effects of caffeine, caffeine-associated stimuli, and caffeine-related information on physiological and psychological arousal.

RATIONALE: To test the classical conditioning and expectancy theories of placebo effects. OBJECTIVE: Two experiments investigated whether administration of caffeine-associated stimuli elicited conditioned arousal, and whether information that a drink contained or did not contain caffeine modulated arousal. METHOD: Experiment 1 (n=21) used a 2 Caffeine (0 and 2 mg/kg) x 2 Solution (Coffee, Juice) x 2 Information (Told caffeine, Told not-caffeine) within-subjects design. Experiment 2 (n=48) used a 2 Solution (Coffee, Orange juice) x 3 Information (Told caffeine, Told not-caffeine, No information) between-subjects design. Indexes of arousal were skin conductance responses and levels, startle eyeblink reflexes, cardiovascular measures, and the Bond and Lader 1974 mood scale. RESULTS: Caffeine-associated stimuli increased alertness, contentedness and skin conductance levels, and information that the drink contained caffeine decreased calmness in Experiment 1. However, unexpected information about the caffeine content of the drink, and the order of the conditions, could have masked some effects of the experimental manipulations. Experiment 2 followed up this hypothesis. The results showed a conditioned increase in startle eyeblink reflexes, and that caffeine-associated stimuli together with information that the drink contained caffeine increased contentedness. CONCLUSIONS: Caffeine-associated stimuli increased arousal, and information about the content of the drink modulated arousal in the direction indicated by the information. Thus, both the classical conditioning and expectancy theories of placebo effects received support, and placebo effects were strongest when both conditioned responses and expectancy-based responses acted in the same direction.

Beef cattle performance and forage characteristics of continuous, 6-paddock, and 11-paddock grazing systems.

Heifer performance, diet composition, and forage composition were compared during rotational and continuous grazing of mixed pasture (alfalfa, tall fescue, orchardgrass). One hundred eighteen yearling heifers were used to compare the three grazing systems during 2 yr. Treatments included continuous (CONT), 6-paddock rotational (6-PADD), and 11-paddock rotational grazing (11-PADD). Rotational paddocks were grazed for 6 d (6-PADD) and 3 d (11-PADD). All rotational paddocks were rested for 30 d. Put-and-take heifers were used to maintain forage availability and measure stocking rate. Forage availability was determined using a rising-plate meter. One ruminally fistulated heifer grazed each pasture during the 1st yr to obtain composition estimates from reticulorumen evacuation samples. Standing forage was sampled before and after grazing to obtain forage availability and nutrient composition during the 1st yr. Daily gain did not differ (P > .5) among treatments. Rotationally grazed pastures had higher (P < .05) stocking rates than CONT. Gain per hectare for 6-PADD was 40% greater (P < .05) for the CONT, and gain per hectare for 11-PADD tended to be higher (34%) (P = .06) than that for CONT. Organic matter intakes expressed as a percentage of BW did not differ (P > .4) among treatments. Diet quality and forage digestibility were similar among treatments. Rotational grazing increased beef production per hectare by increasing stocking rate without decreasing daily gain or diet quality compared with a continuous grazing system.

The differences in the cytological histories of women with high- and low-grade cervical intraepithelial neoplasia.

This study concerns 330 women from each of whom we had received a cervical smear showing cervical intraepithelial neoplasia in 1989. They were divided into two groups. One consisted of 197 cases that had progressed to histologically confirmed cervical intraepithelial neoplasia grade 3 between 1989-90, the other of those that had not done so. Their laboratory records (1981-92) were analysed. These showed clear differences in their cervical histories. Those that had progressed rapidly to grade 3 (on histology) were characterized by a short history of abnormal smears. Those that had not progressed over the years tended to have had a series of fluctuating low-grade lesions. On this basis it is suggested that a woman with a negative cervical-smear history, presenting with intraepithelial neoplasia irrespective of grade, should be carefully monitored over the following year to define the nature of the lesion present.

Risk of cervical intraepithelial neoplasia in women with glomerulonephritis.

OBJECTIVE: To investigate the occurrence of cervical intraepithelial neoplasia in women with glomerulonephritis and its possible association with immunosuppressive treatment. DESIGN: Retrospective study of cytological or histological specimens from women presenting with glomerulonephritis and a group of case and age matched controls. SETTING: University department of pathology, Norway. PATIENTS: 81 women presenting with glomerulonephritis from 1981 to 1988, from whom gynaecological cytological or histological specimens were available. A group of 162 case and age matched controls. MAIN OUTCOME MEASURES: Age when glomerulonephritis of cervical intraepithelial neoplasia was diagnosed, type and characteristics of kidney lesion, stage of cervical intraepithelial neoplasia and presence of human papillomavirus, use of immunosuppressive treatment. RESULTS: Cervical intraepithelial neoplasia was more common in women with glomerulonephritis than in their controls (16/81 (20%) v 7/162 (4%), p less than 0.001) and was more advanced in those with glomerulonephritis than in the controls (9/81 (11%) of the study group had grade III cervical intraepithelial neoplasia compared with 1/162 (1%) of the controls). The increased occurrence of cervical lesions was independent of the use of immunosuppressive treatment, but the individual lesions tended to be more advanced when it was used (four of the seven cervical lesions in women with glomerulonephritis who had received immunosuppressive treatment were carcinoma in situ). Of the nine cervical lesions tested, seven were virus associated. CONCLUSION: Women with glomerulonephritis should have regular cervical smears, irrespective of their use of immunosuppressive treatment.

The cervical smear record: its relevance to the subsequent development of cervical neoplasia.

BACKGROUND: Our aim was to investigate the previous smear history in women with cervical intraepithelial neoplasia grade 1-3 or squamous carcinoma and define its relevance to the lesion present in 1989. METHODS: All 850 women with a laboratory record of cervical intraepithelial neoplasia or cervical squamous carcinoma in 1989 were studied. We retrieved their cytological and histological cervical diagnoses for the period 1981 to 1992 from the laboratory files. On this basis we assessed their previous smear history and short term clinical outcome. RESULTS: Half the women had a negative record prior to 1989, irrespective of the grade of their lesion in that year. Cervical intraepithelial neoplasia grade 1 had previously been found in 16%, grade 2 in 10%, and grade 3 in 7%. These levels were not related to the grade present in '89, but as in those with a negative record, were proportional to the number of women examined, and thus reflect the frequency of such lesions in the screened population in general. In all, 310 were treated operatively for cervical intraepithelial neoplasia grade 3 following abnormal findings in 1989. In such cases abnormal findings were also common in '88, although 45% of them still had a negative smear history. The group with no previous record, i.e. unscreened, contained significantly more invasive cases. CONCLUSIONS: In women with cervical intraepithelial neoplasia in 1989, their previous smear history did not indicate the grade of lesion present. The relevance of their previous abnormal slides to that lesion is thus questionable. The findings, however, suggest that progressive lesions may be acute in origin, superimposed in some cases on a history of similar morphological abnormalities.

Prognostic implications of cervical intraepithelial neoplasia in a single cervical smear. an age-matched case-control study of women with negative smear histories.

Our aim was to investigate the prognostic implications of a single cervical smear showing cervical intraepithelial neoplasia (CIN) in a group of women with a previous series of negative smears, and to estimate their risk of developing histologically confirmed CIN 3. A retrospective case-control study was set up. It consisted of 171 cases and 513 age-matched controls, all with at least 3 negative and no positive smears between 1981 and 1988 inclusive. In all cases CIN had been diagnosed on cytology in 1989, while the controls had remained negative. The women were followed up to the end of 1995. The outcome was recorded in terms of regression, progression, persistence or surgical treatment. In women with a single smear showing CIN 1 or 2, the risk of developing histologically proven CIN 3 was 14 and 26 times that in women with negative smears. Negative control smears in the short term did not exclude subsequent progression. Thus women with a single cervical smear indicating CIN 1 had a greatly enhanced risk of producing a lesion that demanded intervention. Such cases should be observed closely with repeat smears over a period of at least 6 years.

Laser conization of cervical intraepithelial neoplasia grade 3: free resection margins indicative of lesion-free survival.

BACKGROUND: Various grades of cervical intraepithelial neoplasia may occur following laser conization for grade 3 lesions. The aim of this study was to assess lesion-free survival after laser conization in cases with/without free resection margins, and to test whether detection of human papillomavirus infection and/or p53 expression in the cone lesion were useful predictors of lesion-free survival. METHODS: In 598 women treated for cervical intraepithelial neoplasia grade 3 the state of the resection margins was recorded and related to the findings on follow-up, up to 15 years post-operatively. Lesion-free survival times were analyzed by the Kaplan-Meier method. The presence/absence of human papillomavirus infection and/or p53 expression in the primary lesion was investigated in every fifth case by in situ hybridization and immunohistochemistry respectively. RESULTS: Lesion-free survival was significantly more common after complete than incomplete excision of cervical intraepithelial neoplasia. In the latter, lesions tended to appear shortly after surgery, indicating the presence of residual disease. The few lesions appearing later were evenly divided between those with and those without complete excision. The results of the human papillomavirus and p53 investigations added no further information. CONCLUSIONS: The presence of cervical intraepithelial neoplasia in the cone margin gives strong indication of potential treatment failure. In its absence laser conization is highly effective in the treatment of cervical intraepithelial neoplasia, and has the advantage of providing a specimen suitable for the necessary histological investigation.

Gas chromatographic mass spectrometric determination of myo-inositol in humans utilizing a deuterated internal standard.

The isotopic dilution technique was used for determining the content of myo-inositol in human urine, plasma and haemolysed erythrocyte samples. A deuterated myo-inositol, synthesized from inosose-2 by base-catalysed exchange of hydrogens by deuterium, followed by reduction of the inosose with 2H2, was added as internal standard to the samples at an early stage in the analytical procedure. After separation and derivatization to the hexa-acetate, the gas chromatographic mass spectrometric analysis was carried out. A 25 m fused silica capillary column coated with methyl silicone was used, and the ions selected for monitoring were m/z 210 and m/z 214, which are characteristic and abundant fragment ions from unlabelled and hexadeuterated myo-inositolhexa-acetate, respectively. Calibration curves from water, urine, plasma and haemolysed erythrocytes show parallel, linear responses in the ratio between analyte and internal standard in the area of interest (0.2-2.0).

Oral supplementation of myoinositol: effects on peripheral nerve function in human diabetics and on the concentration in plasma, erythrocytes, urine and muscle tissue in human diabetics and normals.

28 young diabetics with short disease duration participated in a double-blind study by taking 6 g of myoinositol or placebo daily for 2 months. The aim was to demonstrate a possible beneficial effect of this compound on subclinical diabetic neuropathy. Measurement of vibratory perception threshold, motor and sensory conduction velocity and amplitude of nerve potential did not disclose any effect of the myoinositol given. In accordance with this, no indication for a lack of myoinositol in human diabetic blood or tissue could be found. The concentration of myoinositol in the plasma and erythrocyte of 4 human diabetics was normal or high, even though the loss of urinary myoinositol was greater than in the case of 4 normals. Further, an analysis of the content of free and lipid-bound myoinositol in muscle biopsies taken from the 4 diabetics did not give any indication of deficiency. The content of myoinositol in their muscle tissue remained uninfluenced by oral supplementation of myoinositol.