Complications of long-acting somatostatin analogue therapy.
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Biomedical subjects
Publications and source records attributed to J A Jackson.
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We have recently provided evidence from studies conducted in vivo that the ovary, particularly by means of estrogen, regulates placental androstenedione (delta 4A) production during the second half of rat pregnancy. In the present study, an incubation system of dispersed rat placental cells was established to determine if estrogen acts directly on the placenta to regulate delta 4A production. Placentas were obtained on Days 14-15 of rat gestation and dispersed in Hanks' Balanced Salt Solution containing 0.1% collagenase, 0.1% hyaluronidase, 0.01% DNase, and 1% fetal calf serum. Placental cells were incubated in Medium 199 for 16 h at 37 degrees C. A time-dependent increase (r = 0.96, p less than 0.05) in the release of delta 4A occurred over the 16-h incubation period. Mean +/- SE formation of the steroid intermediate progesterone (P4) and product delta 4A was 1.17 +/- 0.78 and 1.18 +/- 0.22 ng per 10(7) cells respectively. The addition of 1-10 microM diethylstilbestrol (DES) decreased (p less than 0.05-0.01) delta 4A production, and had no significant effect on P4 or pregnenolone (P5) formation. The percent decrease in delta 4A production was 14.2 +/- 12.9, 30.9 +/- 2.3, and 55.0 +/- 4.4 with 1, 5, and 10 microM DES, respectively. Treatment of placental cells with estradiol (E2) also resulted in a decrease (p less than 0.01) in delta 4A production with no effect on P4 formation. The percent inhibition of delta 4A production was 34.2 +/- 11.1 and 77.3 +/- 5.2 with the addition of 1 microM and 10 microM E2, respectively. E2 (10 microM) produced a concomitant threefold increase (p less than 0.01) in P5 formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Monoclonal antibodies were raised against pregnancy-associated endometrial alpha 1-globulin (alpha 1-PEG), a 32 KD insulin-like growth factor binding protein (IGF-BP), which represents a major secretory product of the human decidualized endometrium during pregnancy. This class of IGF-BP has been implicated in the modulation of action, inhibitory and stimulatory, of insulin-like growth factors. Immunization with the protein purified from pregnancy endometrium resulted after myeloma fusion in the isolation of six hybridoma clones and the antibodies produced were characterized. The Ka of the antibodies ranged between 4.75 x 10(9) M-1 and 0.7 x 10(8) M-1. In Western blots all monoclonal antibodies reacted with purified protein of molecular weight 32 KD and specifically detected this IGF-BP species in culture medium and cytosolic extracts of pregnancy endometrium and amniotic fluid. The monoclonal antibodies appear to define three epitope-bearing regions as evidenced by their reactivity to polypeptide fragments of the protein. After synthesis and secretion by tissue explants in vitro the protein is susceptible to cleavage into fragments possessing different monoclonal antibody-defined reactivity. Employing immunohistochemical techniques the protein was principally localized to decidual cells in tissue sections of pregnancy endometrium and solely to these cells after enzymic digestion of the tissue. The implications of these results are discussed with respect to potential role of IGF-BP in the action of IGF upon the IGF-1 receptor-bearing populations, including lymphocytes and trophoblast cells, D in the decidua.
Acromegaly and hyperprolactinemia have been reported in association with the McCune-Albright syndrome, but the pathophysiology of the GH and PRL hypersecretion that occurs in patients with this disorder has not been defined. We studied GH and PRL secretory dynamics in three patients with McCune-Albright syndrome and hypersecretion of these hormones. Each patient had excessive linear growth, glucose-non-suppressible plasma GH concentration, and GH responsiveness to TRH and GHRH. In response to exogenous GHRH, plasma GH concentrations rose approximately 2-fold in all three patients. Plasma GHRH levels were 20-40 ng/L (normal, less than 30). Study of the spontaneous GH secretory pattern in two patients indicated nocturnal augmentation of GH release. Bromocriptine therapy failed to reduce plasma GH in all patients; in one patient treatment with octreotide, a long-acting somatostatin analog, partially suppressed plasma GH and insulin-like growth factor I levels. These results suggest that hypersecretion of GH in the McCune-Albright syndrome is not due to ectopic GHRH production or autonomous somatotroph function. The results are similar to those described in classic acromegaly due to GH-secreting pituitary tumors. However, the lack of radiographic pituitary enlargement, the variable pituitary pathology reported in similar patients, and frequent concordance of GH and PRL excess suggest that the pathogenesis of this disorder may differ fundamentally from other forms of acromegaly or gigantism. The pathophysiology may reflect abnormal hypothalamic regulation and/or an embryological defect in pituitary cellular differentiation and function.
Ethanol and ethanol-water extracts of endophyte-infected tall fescue seed were effective for extracting toxin(s) responsible for feed intake and average daily weight gain (ADG) depression in Sprague Dawley rats. Although the ethanol extract of endophyte-infected seed depressed serum prolactin (Prl) concentrations, the data were less reflective of overall toxicity than feed intake and weight gain. Inclusion of commercially available ergonovine maleate, ergocryptine and ergotamine tartrate had no effect on rat feed intake, ADG or serum Prl at the levels tested. Dietary addition of a recombination of hexane, ethanol and ethanol-water extracts caused a toxicity response (depressed feed intake, ADG, and serum Prl) equivalent to that of the whole seed. The toxic factor(s) were extracted primarily in more polar solvents such as ethanol and ethanol-water. Rat assays can be used successfully in lieu of cattle assays as a routine evaluation of toxic components in endophyte-infected tall fescue. However, species differences dictate that eventually all suspected toxins be evaluated in the bovine.
Six rumen-fistulated lactating Holstein cows were arranged in a replicated 3 x 3 latin square design with 3-wk periods and offered diets containing concentrate and corn silage in a 60:40 ratio (DM basis). Treatments were: 1) basal diet, 2) basal diet with 1% NaHCO3, and 3) basal diet with 1% sodium sesquicarbonate. There were no differences among treatments in milk production, milk protein, or 3.5% FCM, but sodium sesquicarbonate increased milk fat percentage (3.89, 3.94, 4.06%) compared with that of the control. Rumen pH was higher for cows fed buffered diets than for control cows. Urine pH was higher for cows fed NaHCO3 diet than for those fed sodium sesquicarbonate and control diets. No differences were detected among treatment means for molar percentage of isobutyrate, isovalerate, or total VFA, Dietary sesquicarbonate addition increased molar percentage of acetate, decreased propionate, and resulted in a higher acetate:propionate ratio compared with the cows fed NaHCO3. However, molar percentage of butyrate and valerate decreased in cows fed sodium sesquicarbonate when compared with those fed the control diet. No differences among treatment means were detected for blood pH, pCO2, or HCO3.
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The prostatic complications of testosterone replacement therapy have received little clinical attention. We describe three hypogonadal men who had prostatic disease (adenocarcinoma in two) detected in relation to such therapy. Literature review suggests that surveillance for early prostate cancer is appropriate during replacement therapy in men over the age of 50 years. We discuss the selective use of digital rectal examination, transrectal sonography, directed prostate biopsy, and prostate-specific antigen determinations before therapy and in subsequent follow-up in this age group of men during androgen replacement.
This study was designed to assess the effect of endophyte-infected (Acremonium coenophialum ) tall fescue (KY-31) on reproductive development in bulls. Eighteen Holstein bull calves (2 mo old) were randomly allocated to one of two dietary treatments consisting of 1) noninfected KY-31 fescue hay (NON) supplemented with grain (n=9) and 2) infected (67% infected by Acremonium coenophialum ) KY-31 fescue hay (INF) supplemented with grain (n=9). Both dietary treatments consisted of equal amounts of hay and grain. Data were collected every 14 d. Body weight, hip height and scrotal circumference did not differ (P>0.05) in the two treatments. Mean rectal temperatures also were not different in bulls (P = 0.12); however the infected bulls experienced higher rectal temperatures in all but four collection periods. Animals were sacrificed at 13 mo of age. Testicular weight and dimensions, epididymal weight and length as well as seminal vesicle weight were not different (P>0.05). Maturity of spermatozoa taken from each cauda epididymides was assessed by the incidence of cytoplasmic droplets and was not different (P>0.05) between treatments. Daily sperm production potential was not different (P>0.05) between treatments; however, large variations were noted among the infected bulls. Blood testosterone levels were not different (P=0.29) between the two dietary treatments, but were different over time (P<0.001) with NON and INF bulls having 2.14 +/- 0.21 and 2.41 +/- 0.22 ng/ml, respectively. Prolactin levels were different (P<0.02) between the NOn and INF bulls, 29.35 +/- 3.35 vs 18.31 +/- 3.39 ng/ml, respectively; and over time (P<0.001). The data generated in this study showed some important biological trends. Overall, the results indicate that endophyte infected KY-31 fescue hay fed to growing bulls did not appear to have severe detrimental effects on body growth or reproductive development. However, additional studies will be necessary to further delineate the patterns established in this study.
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This study was conducted to assess the effects of endophyte-infected Acremonium coenophialum tall fescue (KY-31) seed (80% infected) on lactation in CD-1 dams and suckling performance of pups as measured by pup survival and growth rates. Twenty-four pairs of mature CD-1 mice were randomly allocated to four dietary treatments: 1) 100% mouse chow ad libitum; 2) 40% endophyte-infected tall fescue seed and 60% mouse chow (w/w); 3) reduced intake (100% chow), adjusted daily to the intake level of Treatment 2; and 4) 60% infected tall fescue seed and 40% chow. The mice were preconditioned on their respective diets for 100 d prior to 96 h of cohabitation between pairs of males and females. At parturition the litters were removed, and each dam was given a litter of six pups of equal weight, size and sex ratio to suckle for 15 days. All pups given to all the dams were born to other mice that were not part of the study and had not been exposed to endophyte-containing diets. Dams and litter weights were measured daily for 15 consecutive days. The combined body weight measurements of litters from dams fed the tall fescue containing diets (Treatments 2 and 4) were significantly lower (2.07 +/- 0.41 g/d) than that of litters from dams fed the chow containing diets (Treatments 1 and 3) during the suckling trial (P<0.05). Similarly, nine of ten (90%) dams fed the chow containing diets maintained five or more pups (5.5 +/- 0.2) throughout the study as compared to five of nine (55.6%) dams fed the tall fescue containing diets that maintained less than five pups (4.5 +/- 0.2).
Pregnancy-associated endometrial alpha 1-globulin (alpha 1-PEG) is quantitatively the major secretory protein product, synthesized and secreted in vitro, of the human decidualized endometrium during pregnancy. This protein has been purified from cytosolic extracts of this tissue and has now been characterized as a 32 kDa somatomedin/insulin-like growth factor (IGF)-binding protein. Immunoreactive alpha 1-PEG isolated from amniotic fluid exhibited identical physiochemical properties and IGF-I-binding characteristics. In cytosolic extracts of pregnancy endometrium, in incubation medium of this tissue and in amniotic fluid, the 32 kDa protein represented the major alpha 1-PEG immunoreactive protein and major IGF-I-binding component. Purified alpha 1-PEG and incubation medium of pregnancy endometrium competed for IGF-I with placental membrane IGF receptors in vitro. The implications of the endometrial source of IGF-I-binding protein are discussed with reference to the origin of the amniotic fluid and serum small Mr IGF-binding protein and to the suggested paracrine effect upon trophoblast proliferation.
This study was undertaken to determine whether a methanol extract of endophyte-infected tall fescue seed contained the factor(s) that were responsible for the decrease in male reproductive potential when rats were fed toxic tall fescue seed. Twenty-four Sprague-Dawley male rats (ca. 225 g.) were randomly allocated to one of three dietary treatments containing 50% (w/w) rodent chow and 50%: (1) noninfected tall fescue seed; (2) noninfected tall fescue seed treated with concentrated methanol effluent from serial methanol extraction of infected seed; and (3) the extracted seed residue of seed that was greater than 95% infected by Acremonium coenophialum. Parameters assessed were testicular weight, epidydimal weight, parenchymal weight, progressive sperm motility, sperm motility, sperm count and daily sperm production potential. Significant reduction (P less than 0.05) for feed intake, average daily gain, testicular weight, epidydimal weight and daily sperm production potential were observed for treatment 2. These data suggest that the serial methanol extract contains the factor(s) responsible for the lowered reproductive potential in male rats. The extract contained 15,578 micrograms/ml of pyrrolizidine alkaloids and only trace amounts of ergopeptides. These results suggest that N-formyl and N-acetyl loline may play an important role in the fescue toxicity noted in the exposed rats.
A 55-yr-old man presented with an atypical relapsing meningitis and was found to have intense unilateral adrenal uptake by 67Ga imaging. Computed tomography showed a 4-cm right adrenal mass which was hypointense on the T1-weighted images and mildly hyperintense on the T2-weighted images of a magnetic resonance (MR) scan. At surgery, a coincidental benign adrenocortical adenoma was found. Because 67Ga uptake is usually associated with inflammatory or malignant lesions and malignant adrenal lesions are hyperintense on T2-weighted MR images, these findings contributed to diagnostic uncertainty in this patient. Thus, a nonhyperfunctional adrenocortical adenoma may be associated with abnormal 67Ga uptake and atypical MR findings.
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The present study was undertaken to assess the effects of endophyte-infected Acremonium coenophialum tall fescue (KY 31) seed (80% infected) on the reproductive performance of male and female CD-1 mice by combination crosses. Forty-eight male and 48 female 30-d-old mice were randomly allocated to two diet treatments. Twenty-four males and 24 females were fed Diet 1, consisting of 50% non-infected fescue and 50% mouse chow; the remaining animals were fed Diet 2, containing 50% infected fescue. At the end of 50 d, the animals were paired in groups (n = 12) as follows: 1) Diet 1 males and females; 2) Diet 2 males and Diet 1 females; 3) Diet 1 males and Diet 2 females; and 4) Diet 2 males and females. The pairs were maintained on the diets of their female partners and were allowed to cohabitate for 96 h. After this period the males were removed and the females were carried to term. Pregnancy rates among the four treatment groups were 100, 83.3, 75.0 and 54.5%, respectively. Similarly, the average number of pups born per litter among the four groups were 11.5, 8.0, 9.7, and 7.5, respectively. Also, the weights (grams) of pups born per litter were 17.5, 12.6, 12.4, and 9.8, respectively. The results point out that the reproductive capacity of both male and female mice are affected (P < 0.05) by the ingestion of endophyte-infected fescue seeds. Such negative effects were more severe in the female than the male (P < 0.05).
This study was designed to assess the effect of endophyte-infected (Acremonium coenophialum ) tall fescue (KY-31) seed (80% infected) on reproductive performance in CD-1 mice by continuous breeding. Twenty-four pairs of 70-d-old CD-1 mice were randomly allocated to four diets: 1) mouse chow ad libitum; 2) 40% infected fescue seed and 60% chow (w/w); 3) reduced intake (100% chow) similar to the intake, adjusted daily, in Diet 2; and 4) 60% infected fescue seed and 40% chow. Males and females were randomly paired (six pairs/treatment) and placed on the above diets. The mice were fed the corresponding diets for 80 d, although the pairs were separated on Day 60 (prior to the birth of the 3rd litter) and the females were monitored for one additional gestation period (20 d). The pregnancy data (litters produced) among the four treatments were 100.0 (18), 77.8 (14), 100.0 (18) and 80.0% (12) respectively. Similarly, the average number of pups born per litter among the four treatments was 11.8, 9.3, 10.1, and 9.8. When the chow treatment (1 and 3) and the fescue treatments (2 and 4) were pooled and compared, the percent pregnancy was 100.0 (n = 36) and 78.8 (n = 26), and the pups born per litter (means +/- SEM) were 11.0 +/- 0.5 and 9.5 +/- 0.6, respectively. Also the intervals between the three litters born during the 60-d cohabitation period were 21.6 +/- 1.1 and 24.5 +/- 0.9 d for the chow and fescue treatments, respectively. The results point out that 40 and 60% infected fescue seed in the diet of mice does influence (P < 0.05) their reproductive capacity as measured by percent pregnancy and litter size.
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