Chlamydophila abortus infection in a pregnant woman associated with indirect contact with infected goats.

Reported here is the case of a pregnant woman who developed a severe Chlamydophila abortus infection after indirect contact with infected goats resulting in preterm stillbirth. The woman fully recovered after treatment with doxycycline. In the goat herd with which her husband worked Chlamydophila abortus was actively circulating, as shown by positive serology. When pregnant women present with rapidly worsening influenza-like illness, special attention should be given to possible contact (direct or indirect) with animals when recording the anamnesis. Pregnant women, especially those who live in rural areas, should generally be made aware of the risks of zoonotic diseases and how to avoid them.

Growth hormone replacement does not elevate albuminuria in GH-deficient adults.

Minor elevations in urinary albumin excretion rate (Ualb.V) are likely to be associated with renal function loss and increased cardiovascular risk. Since urinary albumin excretion is affected by the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis, we evaluated the effect of 6 months GH replacement (1U/day, n=8 and 2U/day, n=16) on urinary protein handling in 24 non-diabetic, normotensive GH-deficient adults (12 men and 12 women), of whom 8 patients received placebo during 6 months, followed by active GH treatment. Plasma IGF-1 increased from 11.4 (8.1-15.8) nmol/L (median, interquartile range) to 35.4 (22.3-44.1) nmol/L (p<0.001 versus change after placebo; median Z-score reached +0.2) after 6 months GH. and remained unaltered after placebo. Overnight Ualb.V was 4.0 (3.1-4.9) microg/min before and 4.6 (2.4-8.2) microg/min after GH (p>0.10). Likewise, urinary IgG excretion rate did not significantly change after GH (0.71 (0.52-1.20) microg/min before GH versus 0.80 (0.51-1.56) microg/min after GH; p>0.10). No significant changes were observed in creatinine clearance (p>0.10) and mean arterial pressure (p>0.10). No changes in any of these parameters were observed after placebo. Individual changes in Ualb.V were positively correlated with changes in plasma IGF-1 (r(s)=0.41, p=0.05) and with changes in mean arterial pressure (r(s)=0.49, p<0.02). The present study shows that 6 months GH replacement, increasing plasma IGF-1 within the physiological range, does not result in a clinically relevant increase in urinary protein excretion in GH-deficient adults. The correlation between changes in plasma IGF-1 and in albuminuria supports the rationale to avoid supraphysiological IGF-1 levels.

Reduced capillary permeability and capillary density in the skin of GH-deficient adults: improvement after 12 months GH replacement.

OBJECTIVE: Several lines of evidence suggest that the GH-IGF-1 axis affects capillary permeability and angiogenesis. We evaluated skin capillary permeability and capillary density in GH-deficient adults, before and after GH replacement therapy. PATIENTS: Seven normotensive, nondiabetic GH-deficient adults (two women) were matched with 14 control subjects. MEASUREMENTS: Large-window videodensitometry with sodium fluorescein was performed in all subjects. Capillary permeability was expressed as the average relative light intensity over the first 7 min after the appearance of fluorescein in the skin capillaries; Iav(7). Skin capillary density was determined by counting the visualized capillaries and was expressed as n/mm2. The GH-deficient patients were restudied after 12 months of GH replacement therapy (2 U/day). RESULTS: Both capillary permeability and capillary density were lower in untreated GH-deficient patients than in control subjects (median, interquartile range): Iav(7) in GH-deficient patients 47.1 (45.1-52.2)% vs. 57.5 (50.5-64.8)% in controls, P < 0.05; capillary density in GH-deficient patients 18 (12-24)/mm2 vs. 32 (26-36)/mm2 in controls, P < 0.05. GH treatment normalized plasma IGF-1 from 4.3 (1.0-13.4) to 22.2 (19.8-48.2) nmol/l (P < 0.05). Furthermore, both capillary permeability [Iav(7) 53.1 (48.8-58.4)%, P < 0.05] and capillary density [26 (17-34)/mm2, P < 0.05] increased to a level that was not different from that in control subjects. CONCLUSIONS: The present study demonstrates that the growth hormone deficiency syndrome is associated with microvascular alterations, which are responsive to growth hormone replacement therapy.

Hormones in the critically ill patient: to intervene or not to intervene?

Critically ill patients show a variety of hormonal changes that appear to differ considerably in acute and prolonged critical illness. Whether these endocrine alterations serve as physiological adaptation or contribute to further deterioration remains an intriguing question. We review the recent literature and discuss whether measuring circulating hormone concentrations, performing stimulation tests, and intervening with hormone substitution could contribute to the recovery of critically ill patients.

Effects of growth hormone replacement on cortisol metabolism in hypopituitary patients treated with cortisone acetate.

Growth hormone (GH) replacement may inhibit 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) activity, resulting in diminished conversion of cortisone to cortisol. Moreover, GH replacement may lower bioavailability of hydrocortisone tablets. Therefore, substitution therapy with cortisone acetate could be disadvantageous during GH replacement. We conducted a randomized, placebo-controlled GH replacement (1 to 2 U GH/day) study during 6 months, followed by a 6-month open extension study (2U GH/day). Twelve men and 12 women with GH deficiency, of whom 17 received cortisone acetate (25 to 37.5 mg/day), participated. Eight patients were randomized to placebo initially. At baseline, after 6 and 12 months, urinary cortisol and cortisone metabolites were measured. No changes in urinary cortisol metabolites were observed after 6 months placebo (n=8). After 6 months GH the urinary (tetrahydrocortisol+allotetrahydrocortisol)/tetrahydrocortison ratio ((THF+alloTHF)/THE ratio) was unaltered in cortisone acetate treated patients (n = 17) and in patients with intact adrenal function (n = 7), whereas after 12 months GH the (THF + alloTHF)/THE ratio decreased only in cortisone acetate treated patients (1 dropout, n=9). Urinary THF and alloTHF were higher in cortisone acetate treated patients than in patients with intact adrenal function before GH and remained so after 12 months GH (p < 0.05 to p < 0.01). The sum of cortisol + cortisone metabolites did not change after GH in either group. The urinary free cortisol/free cortisone ratio, presumably reflecting renal 11betaHSD2 activity, tended to decrease in cortisone acetate treated patients (p<0.07 and p<0.05 after 6 and 12 months GH, respectively), as well as in patients with intact adrenal function (p<0.05 and a decrease in five/six patients after 6 and 12 months GH, respectively). In conclusion, these results suggest that GH replacement decreases 11betaHSD1 activity, which becomes manifest in patients receiving cortisone acetate substitution therapy. 11betaHSD2 activity is unaltered or may even be increased. It is unlikely that the bioavailability of conventional doses of cortisone acetate is impaired after GH replacement.

Decreased plasma cholesterol esterification and cholesteryl ester transfer in hypopituitary patients on glucocorticoid replacement therapy.

Cardiovascular risk is increased in hypopituitary patients. No data are available with respect to the effect of glucocorticoid replacement therapy on high density lipoproteins (HDL) metabolism in such patients. Plasma lecithin:cholesterol acyl transferase (LCAT), cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are important determinants of HDL remodelling. The possible influence of conventional glucocorticoid replacement on plasma lipids, plasma LCAT, CETP and PLTP activity levels, as well as on plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) was evaluated in 24 consecutive hypopituitary patients (12 men and 12 women) with untreated growth hormone deficiency of whom 17 had adrenal insufficiency and were treated with cortisone acetate, 25 to 37.5 mg daily. Twenty-three patients were on stable levothyroxin therapy and 22 patients used sex steroids. Urinary excretion of cortisol and cortisone metabolites was higher (p<0.001) in glucocorticoid-treated patients. Body mass index (p<0.08) and fat mass (p<0.12) were not significantly different in patients receiving and not receiving glucocorticoids. Fasting blood glucose, plasma insulin and insulin resistance were similar in the groups. Plasma total (p<0.05) and very low+low density lipoprotein cholesterol (p<0.01) were lower in patients receiving glucocorticoids, whereas HDL cholesterol and plasma triglycerides were not different between patients treated and not treated with glucocorticoids. Plasma LCAT activity was 45% lower (p<0.02) and CETP activity was 34% lower (p<0.05) in patients on glucocorticoid treatment. Multiple regression analysis showed that these effects were independent of gender and fat mass. In glucocorticoid-receiving patients, plasma EST and CET were decreased by 80% (p<0.01) and by 58% (p<0.05), respectively. These changes were at least partly attributable to lower LCAT and CETP activity levels. In contrast, plasma PLTP activity was not different between patients with and without glucocorticoid treatment, suggesting that exogenous glucocorticoids exert a different regulatory effect on plasma CETP compared to PLTP. In conclusion, this preliminary study suggests that conventional glucocorticoid replacement in hypopituitary patients is associated with a decrease in plasma cholesterol esterification and cholesteryl ester transfer, indicating that these steps in HDL metabolism are impaired. Such abnormalities in HDL metabolism could be involved in increased cardiovascular risk in glucocorticoid-treated hypopituitary patients, despite a lack of deterioration in plasma lipids.

Effect of growth hormone replacement therapy on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone-deficient adults.

The effects of growth hormone (GH) replacement on plasma lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP), factors involved in high density lipoprotein (HDL) metabolism, are unknown. We carried out a 6 months study in 24 GH-deficient adults who were randomized to placebo (n = 8), low dose GH (1 U daily, n = 8), and high dose GH (2 U daily, n = 8), followed by a 6 months open extension study with high dose GH (1 drop-out). No significant changes in plasma lipoproteins, LCAT, CETP, and PLTP activities, cholesterol esterification (EST) and cholesteryl ester transfer (CET) were observed after placebo. After 6 months of GH (combined data, n = 24), very low + low density lipoprotein (VLDL + LDL) cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) decreased, whereas HDL cholesterol and HDL cholesteryl ester increased (P < 0. 05). Prolonged treatment showed comparable effects. Plasma apolipoprotein A-I and Lp[a] remained unchanged. Plasma LCAT (P < 0. 01) and CETP activities (P < 0.01), as well as EST (P < 0.01) and CET decreased (P < 0.01) after 12 months of GH (n = 15), but PLTP activity did not significantly change. Changes in EST and CET after 12 months of treatment were independently related to changes in plasma LCAT (P = 0.001 and CETP activity (P = 0.01). In conclusion, GH replacement therapy improves the lipoprotein profile in GH-deficient adults. Chronic GH replacement lowers plasma LCAT and CETP activities, contributing to a decrease in cholesterol esterification and cholesteryl ester transfer. These effects may have consequences for HDL metabolism and reverse cholesterol transport.

One year growth hormone replacement therapy does not alter colonic epithelial cell proliferation in growth hormone deficient adults.

OBJECTIVE: Increased colonic epithelial cell proliferation has been found in various conditions associated with increased risk of colorectal cancer including acromegaly. In a placebo-controlled study we determined the effect of growth hormone (GH) replacement therapy in GH deficient adults on the colonic epithelial proliferation rate. PATIENTS AND DESIGN: Sixteen GH deficient adults were randomised to low dose GH therapy (1 U (0.5 mg) subcutaneously per day, n = 5), high dose GH therapy (2 U daily, n = 5) or placebo (n = 6) during 6 months. Thereafter, all patients were treated with 2 U of GH daily during a 6-months open extension period. MEASUREMENTS: Plasma Insulin-like growth hormone I (IGF-I) and IGF binding protein 3 (IGF BP3) concentrations were measured using commercial RIA kits. The colonic epithelial proliferation rate, expressed as overall crypt labelling index (LI) using 5-bromo-2'-deoxyuridine (BrdU) immunostaining, was determined at baseline, after 6 months treatment and at the end of the 6 months open extension period. RESULTS: IGF-I rose from 8.9 +/- 6.7 to 34.6 +/- 20.0 nmol/l after 6 months in 8 GH treated patients (P < 0.01 from baseline; P < 0.01 from change with placebo). In the extension study, plasma IGF-I was also increased in the patients who previously received placebo (P < 0.02, n = 5). LI was evaluable in 14 biopsies at baseline, in 16 after 6 months and in 14 after 12 months. Overall crypt LI did not change in 8 GH treated patients after 6 months (P > 0.40 from baseline; P > 0.80 from change with placebo). In the extension study, overall crypt LI was also unchanged in those patients who received GH after placebo (n = 5, P > 0.40) and in those who continued GH replacement (n = 9, P > 0.60; P > 0.80 from change in initially placebo treated patients). Separate evaluation of the LI at the basal, mid and luminal portions of the colonic crypts also did not reveal any effect of GH treatment on BrdU labelling. CONCLUSIONS: Six to 12 months of GH replacement therapy, aimed to increase plasma IGF-I into the (high) physiological range, does not adversely affect colonic epithelial cell proliferation as a biomarker for the risk of development of colorectal cancer.

Catecholamine dependency in a polytrauma patient: relative adrenal insufficiency?

A 65-year-old polytrauma patient was admitted post-operatively to the intensive care unit. His situation deteriorated with hemodynamic instability and continuous high fever. An infectious focus could not be found and repeated cultures remained negative. Empirical administration of antibiotics and changing of lines did not have any effect on the clinical picture. It was impossible to lower the dose of catecholamines because of repeated occurrence of hypotension, despite optimal hydration state and filling pressures. On the 15th day of admission intravenous hydrocortisone was started on suspicion of relative adrenal insufficiency. This action resulted in rapid hemodynamic recovery, disappearance of fever and enabled rapid tapering of the dose of noradrenaline. Incidence of relative adrenal insufficiency and diagnostic strategies are discussed in the population of critically intensive care patients.

Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation?

A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. HUM PATHOL 31:1522-1527.

Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins.

Growth hormone (GH) deficiency and acromegaly may be associated with increased cardiovascular risk. Little is known about alterations in high density lipoproteins (HDL) in these conditions. Lecithin:cholesterol acyl transferase (LCAT) has the ability to esterify free cholesterol (FC) in HDL. Cholesteryl ester transfer protein (CETP) is able to transfer cholesteryl esters (CE) from HDL to very low and low density lipoproteins (VLDL and LDL). During phospholipid transfer protein (PLTP)-mediated HDL remodelling, small pre beta-HDL particles are generated which serve as acceptors for cellular cholesterol and provide the initial LCAT-substrate. We documented plasma lipids, LCAT, CETP and PLTP activity levels as well as plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) in 12 adult men with acquired GH deficiency, 12 acromegalic men and 24 healthy male subjects. All GH deficient and acromegalic patients received conventional hormonal replacement therapy if necessary. VLDL + LDL cholesterol and plasma triglycerides were higher in GH deficient (P < 0.01 and P < 0.05) and acromegalic patients (P < 0.05 and P < 0.01) than in healthy subjects. HDL cholesterol and HDL CE were lower (P < 0.05 for both) and the HDL FC/CE ratio was higher (P < 0.01) in these patient groups compared to healthy subjects. Plasma LCAT, CETP and PLTP activity levels were lower in acromegalic patients (P < 0.01 for all) and CETP activity was lower in GH deficient patients (P < 0.01) compared to healthy subjects. Plasma EST and CET were decreased in both acromegalic (P < 0.01 for both) and GH deficient patients (P < 0.05 for both). Multiple regression analysis demonstrated independent negative relationships of plasma insulin-like growth factor I with plasma LCAT (P = 0.0001), CETP (P = 0.009) and PLTP activity levels (P = 0.021). Plasma LCAT (P = 0.0001) and CETP activity (P = 0.0001) were also negatively associated with (substitution therapy for) adrenal insufficiency. In conclusion, GH deficient and acromegalic patients show abnormalities in HDL, consistent with impaired LCAT action. Decreases in plasma EST and CET in such patients, as well as a low PLTP activity in acromegaly suggest that reverse cholesterol transport may be impaired, contributing to increased cardiovascular risk.

Evaluation of adrenal function in patients with hypothalamic and pituitary disorders: comparison of serum cortisol, urinary free cortisol and the human-corticotrophin releasing hormone test with the insulin tolerance test.

OBJECTIVE: This study aimed to evaluate the performance of screening tests (serum cortisol and 24-h urinary free cortisol) and the human-corticotrophin releasing hormone (h-CRH) test in the assessment of adrenal function in patients with hypothalamic-pituitary disorders. DESIGN: Summary receiver operating characteristics (SROC) curve analysis was applied with the insulin tolerance test (ITT) as reference test. A peak serum cortisol response to ITT > or = 500 nmol/l indicated adrenal sufficiency. The sensitivity at the intersect of the diagonal between sensitivity = 1 and (1-specificity) = 1 with the SROC curve, where sensitivity and specificity are equal, and the corresponding weighted kappa, an estimate of agreement with the ITT, served as parameters of test performance. The diagnostic yield, representing the proportion of tests obviating the need for an ITT, was also calculated. MEASUREMENTS: Serum cortisol at 0800 h (n = 122), at 1600 h (n = 116), 24-h urinary free cortisol (n = 115) and the peak serum cortisol to h-CRH (n = 129) were compared with the peak serum cortisol to ITT. PATIENTS: Eighty patients with hypothalamic-pituitary disorders in whom 75 ITT's were performed pre- and 57 post-operatively. RESULTS: Sensitivity at the intersect and weighted kappa were higher for 0800 h serum cortisol (0.873 and 0.763 respectively) than for 1600 h serum cortisol (0.769 and 0.561) and 24-h urinary free cortisol (0.777 and 0.576). These parameters were 0.868 and 0.756 for the h-CRH test. The diagnostic yield was 63.9% for 0800 h serum cortisol compared to 25.9% for 1600 h serum cortisol (P < 10(-8)), 23.5% for 24-h urinary free cortisol (P < 10(-8)) and 60.5% for the h-CRH test (NS). CONCLUSIONS: Serum cortisol measurement at 0800 h is better than 1600 h and 24-h urinary free cortisol to evaluate adrenal function in this patient category. The diagnostic applicability of the h-CRH test is not superior to 0800 h serum cortisol measurement.

Divergence between growth hormone responses to insulin-induced hypoglycaemia and growth hormone-releasing hormone in patients with non-functioning pituitary macroadenomas and hyperprolactinaemia.

OBJECTIVE: The GH responses to the insulin tolerance test (ITT) and growth hormone-releasing hormone (GHRH) may yield different results in patients with pituitary lesions. The GH responses to these stimuli were compared in patients with untreated non-functioning pituitary macroadenomas, who represent an important cause of GH deficiency. DESIGN: Analysis of peak GH to ITT and to 100 micrograms GHRH in relation to an elevated PRL level (> 200 mIU/l for males and > 600 mIU/l for females) as an indication of hypothalamic-pituitary dysregulation, as well as in relation to other anterior pituitary hormone deficiencies. A peak GH < 5 micrograms/l in either test indicated GH deficiency. PATIENTS: Twenty females and 14 males (median age 52 (23-77) years) evaluated preoperatively in a university hospital setting. RESULTS: In the whole group the median peak GH to GHRH (3.6 (0.9-26.3) micrograms/l) was higher than to ITT (1.6 (0.2-7.8) micrograms/l, P < 0.001). This difference was seen only in 19 patients with concomitant hyperprolactinaemia (P < 0.001). When hyperprolactinaemia was present, an insufficient GH peak was demonstrated by ITT in 16 cases and by GHRH stimulation in 7 cases (P < 0.01). The frequency of an insufficient GH peak by ITT (13 cases) and by GHRH (14 cases) was similar in the normoprolactinaemic patients. In addition, 9 of 10 patients with an impaired response to ITT and a normal response to GHRH were hyperprolactinaemic compared to 7 of 19 patients with GH deficiency as assessed by both stimuli (P < 0.02). Peak GH to ITT was lower in 24 patients with, compared to 10 patients without, other hormonal deficiencies (1.4 (0.2-5.6) vs 3.0 (1.0-7.8) micrograms/l, P < 0.02), but was not related to elevated PRL. In contrast, GHRH-stimulated GH was higher in hyperprolactinaemic than in normoprolactinaemic patients (5.9 (1.6-26.3) vs 2.9 (0.9-5.4) micrograms/l, P < 0.001) and was not related to the presence of other pituitary hormone deficiencies. Analysis of covariance confirmed that peak GH to ITT was negatively associated with the presence of other pituitary hormone deficiencies (P < 0.01), whereas peak GH to GHRH was positively related to an elevated PRL level (P < 0.02). Basal GH was positively correlated with PRL (R(s) = 0.36, P < 0.05). CONCLUSIONS: This study demonstrates that ITT and GHRH tests cannot be used interchangeably in diagnosing GH deficiency in patients with non-functioning pituitary macroadenoma and hyperprolactinaemia. If the ITT is considered to be the reference test, GH deficiency as assessed by GHRH can be missed in patients with hyperprolactinaemia. This disparity is probably due to a different mechanism of action of these stimuli. Hyperprolactinaemia may be associated with a diminished somatostatin tone, leading to a higher basal and GHRH-stimulated GH, without having an effect on peak GH to ITT.

Erythroid progenitors in polycythemia vera demonstrate a different response pattern to IL-4 compared to the normal BFU-E from peripheral blood.

Human recombinant interleukin 4 (IL-4) was studied for its effects on erythroid burst-forming units (BFU-E) from normal peripheral blood and from patients with polycythemia vera (PV). IL-4 enhanced the proliferation of normal peripheral blood BFU-E (183% +/- 20% enhancement), whereas in the presence of interleukin 3 (IL-3) no further augmentation was noticed. The IL-4-mediated effects were independent of the absence or presence of adherent cells, B cells, or T cells. These data are in contrast with results obtained from normal human bone marrow cells, in which IL-4 antagonized the enhancing effects of IL-3. In PV a different response pattern was observed. The effects of IL-4 on the erythropoietin (Epo)-independent BFU-E were variable. In five PV patients no suppressive or enhancing effects of IL-4 were observed, whereas in two additional patients a significant decline in the Epo-independent BFU-E was noted. In the presence of IL-3, IL-4 significantly antagonized the IL-3-supported Epo-independent BFU-E in all patients (272% +/- 57% vs 187% +/- 49% enhancement, p less than 0.05). In contrast, IL-4 did not modify the IL-3-supported Epo-dependent BFU-E. In summary, these data suggest a difference between the normal and PV peripheral blood BFU-E. The Epo-dependent erythroid progenitors in PV patients showed a response pattern with IL-3 and IL-4 comparable to that of normal peripheral blood BFU-E, whereas the Epo-independent erythroid progenitors behaved like normal human bone marrow BFU-E, suggesting a shift in the stem cell compartment in PV. This is further supported by the finding that erythroid colony-forming units (CFU-E), normally only present in the bone marrow, could be cultured from the peripheral blood of PV patients in the presence or absence of Epo.

Detection, prevalence, and prognosis of asymptomatic carcinoma of the cervix.

Between 1979-1986, 82 of 407 patients (20%) treated for infiltrative carcinoma of the cervix were asymptomatic at the time of diagnosis. Sixteen (20%) of these 82 patients had stage IA, 60 (73%) had stage IB, and six (7%) had stage IIA disease. Asymptomatic patients represented 16 of 23 (70%) of stage IA, 60 of 196 (31%) of stage IB, and six of 77 (8%) of stage IIA. In the Netherlands, population screening for cervical carcinoma is conducted on women aged 35-55 years. To examine the prevalence of asymptomatic cervical carcinoma and the way in which it was detected in different age groups, we studied the patients referred to our department. Among the patients younger than 35 years with cervical carcinoma, 20 of 70 (29%) were asymptomatic with disease detected by incidental screening, whereas eight of 177 (5%) in the group 55 years or older had been detected by incidental screening. In the age category 35-55 years, 54 of 160 (34%) were asymptomatic. Patients aged 35-55 years had undergone population screening or incidental screening. In the patients 55 years or older, asymptomatic disease was significantly less prevalent than in younger patients. Only one of the 66 asymptomatic patients in stage IB or higher suffered tumor recurrence. Among symptomatic patients, 25 of 136 (18%) with stage IB and 17 of 71 (24%) with stage IIA had tumor recurrence. Despite the favorable prognosis of patients with asymptomatic carcinoma, asymptomatic presentation could not be shown to be a significant prognostic factor, as were tumor diameter and lymph node status.

Interleukin-4 suppresses the interleukin-3 dependent erythroid colony formation from normal human bone marrow cells.

Human recombinant interleukin 4 (IL-4) was studied for its effects on the erythroid burst forming unit (BFU-E) from human bone marrow cells. IL-4 alone neither supports nor suppresses the erythropoietin (Epo)-dependent colony formation. Different results were obtained when IL-4 was combined with interleukin-3 (IL-3) in the presence of Epo. IL-4 suppressed the IL-3 supported erythroid colony formation in all cases (an increase of 58 +/- 8% with IL-3 versus an increase of 14 +/- 7% with IL-3 plus IL-4, n = 8). This antagonizing effect was dependent on the continuous presence of IL-4 in the culture medium, but was independent of adherent cells, B-, T-cells, or the presence of serum in the culture medium. Finally, the effects of IL-4 and IL-3 were studied on the 'Epo-independent' BFU-E by adding Epo on day 3. A decline of the IL-3 supported BFU-E was observed in the presence of IL-4 but the degree of reduction was equivalent to the results obtained when Epo was supplied at day 0. These findings indicate that IL-4 acts as suppressive growth factor for the IL-3 supported erythroid colony formation from human bone marrow cells.

Divergent effects of interleukin-4 (IL-4) on the granulocyte colony-stimulating factor and IL-3-supported myeloid colony formation from normal and leukemic bone marrow cells.

Human recombinant interleukin-4 (IL-4) was studied for its effects on myeloid progenitor cells from normal and leukemic bone marrow cells in the presence and absence of additional growth factors. IL-4 itself did not support myeloid cluster or colony formation (CFU-GM). However, cultures supplied with IL-4 (300 U/mL) and IL-3 demonstrated a significant decline in myeloid colony numbers (CFU-GM) compared with the effects of IL-3 alone: (48 +/- 27 v 88 +/- 27 CFU-GM/10(5) MNC). In contrast, IL-4 augmented the G-CSF-supported CFU-GM: (80 +/- 31 v 148 +/- 52 CFU-GM/10(5) MNC). The effects of IL-4 were not mediated by accessory cells because similar results were obtained with and without T-cell, B-cell, or adherent depleted cell fractions. Morphologic analysis of clusters (day 7) and the colonies (day 14) demonstrated that IL-4 enhanced myeloid colony formation in the presence of G-CSF, whereas the cultures supplied with IL-3 and IL-4 did not show a lineage-restricted decline of CFU-GM. A heterogeneity in growth response was observed in the leukemic counterpart. With the 3H-thymidine proliferation assay, IL-4 augmented the G-CSF-induced proliferation of acute myeloid leukemic (AML) cells in 4 of the 12 cases, while the IL-3-supported proliferation was antagonized in 3 of the 12 cases. In the blast colony assay, IL-4 suppressed the IL-3-supported AML-CFU in the majority of cases, but enhanced the G-CSF stimulated AML-CFU in 3 of 6 cases. These data demonstrate divergent effects of IL-4 on the normal myeloid progenitor cell in the presence of IL-3 or G-CSF, while a variability in responsiveness is observed in the leukemic counterpart.