Development of new osteonecrosis in systemic lupus erythematosus patients in association with long-term corticosteroid therapy after disease recurrence.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients are at high risk of developing osteonecrosis, as they require corticosteroid therapy for life. The purpose of this study was to use periodic MRI analysis to clarify (1) the incidence of new osteonecrosis associated with long-term corticosteroid therapy in SLE patients, and (2) the risk factors for delayed osteonecrosis in SLE patients. METHODS: We prospectively studied 291 joints (134 hips and 157 knees) in 106 SLE patients without osteonecrosis after initial corticosteroid therapy, with a mean follow-up period of 13.6 years and a follow-up rate of 71%. All patients had undergone periodic MRI examination of the hip and knee joints for >10 years. RESULTS: New osteonecrosis developed in 6 joints (3%) and only occurred after SLE recurrence in association with increased corticosteroid doses (to>30 mg/day [p=0.008]). New lesions were delayed for a mean 5.9 years after initial corticosteroid administration. The mean time from SLE recurrence to appearance of new lesions was 6.2 months. SLE recurrence occurred in 131 joints (45%), while SLE was well controlled in 160 joints (55%). CONCLUSIONS: We suggest that with respect to long-term effects, total cumulative dose and duration of corticosteroid therapy do not contribute to osteonecrosis. However, SLE recurrence is a risk factor for new osteonecrosis. We recommend MRI screening for osteonecrosis at SLE recurrence.

Acute effects of antileukotrienes on sinonasal polyposis and sinusitis.

Recently, leukotrienes have been implicated in the mediation of bronchoconstriction and inflammatory changes in asthma. Leukotriene levels have also been shown to be elevated in patients with asthma as well as in those with sinonasal polyposis and sinusitis. The leukotriene synthesis inhibitor zileuton and the leukotriene receptor antagonist zafirlukast have been shown to produce subjective and objective improvements in patients with mild to moderate asthma. Given these findings, we evaluated the efficacy of these two medications in controlling sinonasal polyposis and their associated symptoms. We treated 40 patients diagnosed with sinonasal polyposis and sinusitis with either zileuton or zafirlukast. No other change was made in their standard therapy. Outcome measures included subjective interviews and questionnaire responses, as well as office endoscopic examinations and chart reviews. At study's end, 36 patients were available for evaluation. Twenty-six had taken zafirlukast, five had taken zileuton, and five others had switched from zafirlukast to zileuton. Overall, 26 patients (72%) experienced subjective improvement in their symptomatology after starting their medication. Statistically significant improvement was noted with respect to headache, facial pain and pressure, ear discomfort, dentalgia, purulent nasal discharge, postnasal drip, nasal congestion and obstruction, olfaction, and fever. An objective alleviation, or at least stabilization, of sinonasal polyposis was seen in 50% of the patients. Four patients (11%) discontinued their medication because of side effects. We conclude that antileukotrienes might play a significant role in controlling polyposis and symptoms secondary to sinonasal disease, and they might be a viable alternative to long-term oral steroid therapy and repeated surgical debridement.

Effects of tonsillectomy and/or adenoidectomy on vocal function: laryngeal, supralaryngeal and perceptual characteristics.

A prospective, non-randomized study evaluated the effects of tonsillectomy and/or adenoidectomy (T +/- A) on acoustic and perceptual aspects of vocal function. Thirty-one children, ranging in age from 4 to 15 years participated and measurements were made prior to and 3 months following surgery. Twenty-three children had T +/- A and eight had adenoidectomy alone. Quantitative acoustic measures included: laryngeal (vocal fundamental frequency, FO) and supralaryngeal characteristics of sustained vowels (F1 and F2 formants, formant bandwidths, two-dimensional measures of vowel space) and temporal properties of consonant-vowel productions (diadochokinetic syllable rates). Perceptual measures were based on samples of continuous speech, using the Buffalo voice profile (BVP) and parental interviews/questionnaires were used to evaluate other aspects of surgery (i.e. subjective speech changes, protracted pain, difficulty swallowing, bleeding, etc.). Based on ANOVA, no significant post-surgical changes were detected for the majority of acoustic speech measures studied (vocal F0, formant bandwidths, measures of vowel space or diadochokinetic rates). However, the F2 formant frequency for vowels /i/ and /a/ increased and F1 decreased for /o/ following surgery. These changes had the largest effect on the structure of vowel /i/, which became more acute and diffuse following surgery. Furthermore, of the majority of perceptual measured studied with the BVP, 92% showed no change postoperatively. However, in the category of resonance, a significant decrease in hyponasality was detected. These results demonstrate that removing soft tissue from the oropharynx has only minimal impact on quantitative or qualitative (perceptual) aspects of vocal function, when measurements are made approximately 15 weeks post surgery.

Structural scoliosis model in dogs with experimentally induced syringomyelia.

STUDY DESIGN: Animal scoliosis model associated with syringomyelia. OBJECTIVE: To investigate the pathogenesis of scoliosis produced in dogs with kaolin-induced syringomyelia. SUMMARY OF BACKGROUND DATA: Kaolin injected into the cisterna magna produces basilar arachnoiditis, leading to hydrocephalus and syringomyelia. There have been no reports on scoliosis associated with kaolin-induced syringomyelia. METHODS: Kaolin was injected percutaneously into the cisterna magna of 11 beagles 6-8 weeks after birth. Roentgenograms, computed tomography, and magnetic resonance imaging were obtained. The spinal cord and the paraspinal muscles were examined histologically. Structural changes of the vertebral column were analyzed with calcein and tetracycline labeling. RESULTS: Hydrocephalus occurred in nine dogs. A communicating syringomyelia appeared in five dogs. Mild scoliosis developed in two dogs, and severe cervical scoliosis in one dog. In the syringomyelia cases, acute or subacute inflammatory changes were found in the spinal cord. Damage of the anterior and posterior horn cells was more marked in the scoliotic animals than in the nonscoliotic animals. In three of the syringomyelia cases, including two scoliosis cases, the paraspinal muscles revealed neurogenic changes. The deformed vertebrae appeared to diminish rather than to increase the deformity in severe scoliosis. CONCLUSION: The exact mechanism of the development of scoliosis could not be identified, although an etiologic relation with malfunction of the central nervous system was noted. This model may be useful to study scoliosis experimentally.

Sera from habitual aborters induce monocyte procoagulant activity: a lymphocyte-dependent event.

Placental thrombosis is a prominent feature in patients with unexplained recurrent fetal loss. To determine whether induction of monocyte procoagulant activity might be a relevant mechanism for unexplained recurrent fetal loss, peripheral blood mononuclear cells isolated from normal healthy controls were cocultured with (a) sera from normal healthy controls (n = 16), (b) sera from habitual aborters (n = 41), and (c) lipopolysaccharide as a positive control. Sera from three patients were fractionated on Sephracryl S-300 and the inducing molecule(s) characterized. Sera from normal healthy controls failed to induce procoagulant activity above basal levels of 21 +/- 4.6 mU/10(5) peripheral blood mononuclear cells. Of the sera from 41 habitual aborters examined 26 (63%) induced procoagulant to a mean value of 410 +/- 48 mU/10(5) peripheral blood mononuclear cells (P < 0.01). Sera from 15 patients failed to augment procoagulant activity. The induction of procoagulant activity was maximal after 6 hr of incubation and was lymphocyte dependent. Fractionation of serum from the three patients on Sepharcryl S300 revealed the procoagulant activity (PCA)-inducing factor(s) to have a molecular weight of between 300,000 and 800,000 Da. The serum factor was found to be heat, alkaline, and acid sensitive. Both anti-IgM and anti-IgA immunoabsorbents reduced the PCA-inducing factor. We conclude that IgM and IgA from some patients with unexplained recurrent fetal loss are capable of inducing procoagulant activity and could contribute to the development of placental microthrombi and infarction, prominent features of this syndrome.

Metastasizing neuroendocrine tumor of unknown origin found in cervical lymph nodes: a case report.

Neuroendocrine tumors are a diverse category of tumors that have been known to produce biologically active amines and ectopic hormones of various types. Numerous metastasizing primary lesions have been identified, however, the head and neck region is not a common site for them. Even less common than these are head and neck metastatic sites without an identifiable primary lesion. We report a case of a metastatic neuroendocrine tumor, where the primary site eluded detection despite an extensive battery of investigations.

Transforming growth factor beta and follicle-stimulating hormone promote rat granulosa cell proliferation.

Rat granulosa cells isolated from the ovaries of diethylstilbestrol-primed immature rats were treated with estrogen, FSH, and growth factors to determine those factors that were required to promote DNA synthesis. Estrogen and FSH, previously shown to stimulate the incorporation of [3H]thymidine into rat granulosa cell DNA in vivo, were ineffective in vitro. Epidermal growth factor, insulin-like growth factor 1 (IGF1), and fibroblast growth factor did not influence DNA synthesis whereas transforming growth factor beta (TGF beta) alone had a significant effect. Neither estradiol-17 beta (5 X 10(-8)-5 X 10(-6) M) nor IGF1 augmented the actions of TGF beta and FSH. FSH did not influence the actions of epidermal growth factor or IGF1 but dramatically augmented the effect of TGF beta on DNA synthesis. FSH and TGF beta also stimulated [3H]thymidine incorporation into the DNA of granulosa cells isolated from immature rats not treated with diethylstilbestrol. The increase in [3H]thymidine incorporation into DNA stimulated by TGF beta and FSH resulted subsequently in an increase in cell number. The response of the cells to TGF beta in the presence of a constant level of FSH (10 ng/ml) was dose dependent, 2.5 ng/ml being the minimal effective concentration. In the presence of antibody specific for TGF beta the bioactivity of the TGF beta was neutralized indicating that the growth promoting activity was due to TGF beta and not due to contaminants. In this paper, we have shown that the combined actions of FSH and TGF beta influence DNA synthesis and the proliferation of rat granulosa cells. Interactions between FSH and TGF beta may be important in regulating aspects of rat granulosa cell growth in addition to exerting pronounced effects on cytodifferentiation.

Bovine thecal cells secrete factor(s) that promote granulosa cell proliferation.

To determine if soluble factors (other than steroids) secreted by bovine thecal cells may be involved in local regulation of follicular development, we examined the effects of thecal cell secretory products on the growth of granulosa cells obtained from the same follicles. DNA synthesis (assessed by the incorporation of 3H-thymidine) by granulosa cells plated on coverslips and cocultured with, but not directly in contact with, thecal cells in organ culture dishes in a serum-free medium was 5-fold greater than controls. The effect of the thecal cell-secreted products on DNA synthesis by granulosa cells was significantly higher than the maximum response produced by epidermal growth factor (EGF). Thecal cell-conditioned medium stimulated 3H-thymidine incorporation into the DNA of granulosa cells and a normal rat kidney cell line in a dose-dependent manner. The increases in 3H-thymidine incorporation into granulosa cell DNA subsequently lead to an increase in cell number. Preliminary characterization studies using ultrafiltration membranes indicated that the mitogenic factor was retained in the greater than 10,000 molecular weight fraction. The activity was stable to heating at 90 degrees C for 5 min and was not extracted in ether. The thecal cell-generated growth factor may act as a paracrine regulator of granulosa cell growth, thus providing the dominant follicle with autonomy over other follicles in the cohort.

Actions of growth factors in the follicle.

In this paper we have examined the possibility that soluble factors produced by the thecal and granulosa cells may be essential local modulators of follicular development. The observations that insulin could influence both the growth and the differentiation of granulosa cells were important in establishing the concept that peptides could act as amplifiers of the actions of gonadotrophins. Insulin alone did not influence aromatase activity significantly but acted synergistically with FSH to augment aromatase activity in rat granulosa cells. Unlike aromatase activity, insulin alone was able to significantly stimulate 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity, the maximum level achieved approaching that obtained with high concentrations of FSH. To determine if insulin could influence other parameters of granulosa cell function in addition to steroidogenesis, we measured a component of extracellular matrix, fibronectin, previously shown to be inhibited by FSH. Treatment with insulin independently inhibited the increase in fibronectin secretion observed in control cultures. Also, insulin alone was able to stimulate quiescent bovine granulosa cells to incorporate [3H]thymidine into DNA under serum-conditions. The concentration of insulin required in these experiments was higher than physiological levels suggesting that other insulin-like growth factors may be involved. Our work and that of others has shown that IGF1 can mimic the actions of insulin and is effective at lower concentrations. A possible source of IGF1 production in the follicle was sought initially by collecting rat granulosa cell conditioned medium, and assessing biological activity and immunoreactivity. Conditioned medium augmented the actions of FSH on aromatase activity and alone stimulated 3 beta-HSD, indicating the presence of insulin-like bioactivity. A positive reaction on immunoblots using specific antiserum confirmed the presence of immunoreactive IGF1. Conditioned medium from thecal cells contained a growth-promoting activity (TcGF) that did not augment FSH-induced aromatase activity. The production of growth factors locally within the follicle may represent the self-amplifying mechanism that enables the dominant follicle to complete its developmental program and ovulate.