Systemic Lupus Erythematosus Presenting with Massive Ascites: A Case of Pseudo-Pseudo Meigs Syndrome.

The case presented is consistent with the phenomenon known as Pseudo-Pseudo Meigs Syndrome (PPMS). In it, we describe a young woman with newly diagnosed Systemic Lupus Erythematosus presenting with ascites, pleural effusions, and an elevated CA-125 level. Although rare, and of uncertain etiology, PPMS is becoming increasingly recognized in the literature. It should be considered as a differential diagnosis in such patients, along with the search for malignancy.

Microscopic polyangiitis presenting as idiopathic pulmonary fibrosis: is anti-neutrophilic cytoplasmic antibody testing indicated?

We report a 55-year old woman with microscopic polyangiitis who presented with idiopathic pulmonary fibrosis and 1 year later developed hematuria and proteinuria. She had a high serum level of perinuclear anti-neutrophilic cytoplasmic antibodies. Renal angiogram was normal. The diagnosis of microscopic polyangiitis was confirmed by renal biopsy, which showed pauci-immune crescentic glomerulonephritis. The patient received immunosuppressive therapy and improved markedly. Consideration of small vessel vasculitis is important in the differential diagnosis of idiopathic pulmonary fibrosis.

Clinical evaluation of rhBMP-2/ACS in orthopedic trauma: a progress report.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive protein that plays a pivotal role in bone growth and regeneration. Studies conducted in many mammalian species and, most recently, human clinical studies, have provided definitive evidence of the ability of rhBMP-2 to induce bone. The findings of these studies provide a rationale for investigating whether rhBMP-2 therapy will be clinically useful in orthopedic practice. Consequently, we have initiated a clinical research program to evaluate the safety and efficacy of rhBMP-2 therapy in open tibial fractures. A prospective observational study (involving no rhBMP-2 treatment) was conducted to define an appropriate patient population for rhBMP-2 clinical trials and has provided critical information related to the design and execution of future studies. The rhBMP-2 clinical trials include a small pilot feasibility study and several larger studies. Data from the pilot feasibility study have demonstrated that implantation of rhBMP-2 (combined with an absorbable collagen sponge) is surgically feasible and safe. Larger, multicenter clinical studies are now ongoing in the United States and abroad.

Hidradenitis suppurativa complicated by erosive arthropathy and ulcerative keratitis.

Hidradenitis suppurativa is a chronic suppurative and cicatricial disease of the apocrine glands of the skin. We present a 44-year-old African-American male patient with a history of hidradenitis suppurativa who developed recurrent bilateral peripheral ulcerative keratitis and erosive arthritis of the wrists. These are rare complications of hidradenitis suppurativa. The peripheral ulcerative keratitis responded well to prednisone; immunosuppression with cyclophosphamide was added to attempt to prevent further recurrences. Peripheral ulcerative keratitis probably has an immune mechanism similar to that of the arthritis that may complicate hidradenitis suppurativa and may require aggressive immunosuppressive therapy.

In vitro exposure to sodium fluoride does not modify activity or proliferation of human osteoblastic cells in primary cultures.

The anabolic effects of sodium fluoride (NaF) on trabecular bone mass in osteoporosis is now well established. In vivo histologic studies performed in humans and other animals have shown that fluoride induces an increase in osteoblast number at the tissue level. To determine the mechanisms of action of fluoride on osteoblasts, we studied the effects of NaF on short- and long-term cultures of human osteoblastic cells derived from bone explants obtained from 21 donors. In short-term experiments, bone-derived cells were exposed to NaF for 4 days. At doses ranging from 10(-11) to 10(-5) M, NaF did not modify the alkaline phosphatase (AP) activity or osteocalcin secretion. In long-term experiments, half the bone samples from 15 donors were cultured for 4 months in the presence of 10(-5) M NaF and the other half were maintained in NaF-free medium. Observations by light and electron microscopy disclosed no morphologic modification in bone explants after 4 months of exposure to NaF, despite an increase in the bone fluoride content. After the first month of culture, slight but not significant increases were noted in 6 of 10 cases for AP activity, 4 of 10 for osteocalcin secretion, and 5 of 7 for [3H]thymidine incorporation. After 4 months of culture in the presence of NaF, no change in AP activity or cell proliferation was noted. In contrast, the osteocalcin secretion significantly decreased (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of experimental conditions on osteoblast activity in human primary bone cell cultures.

Primary bone cell cultures were derived from human bone explants. Cellular activity was characterized by the alkaline phosphatase (AP) activity, osteocalcin, and type I and III collagen secretions in the supernatant. The determination of bone cell activity was performed in three different wells. No significant difference was noted between wells: the coefficient of variation was 8.0 +/- 2.9% for AP activity, 18.3 +/- 1.9% for osteocalcin secretion, and 22.5 +/- 14.3% for collagen. The AP activity and osteocalcin secretion significantly decreased with the number of passages: they were the highest after the first passage. Between each subject, the coefficient of variation was 85% for AP activity and osteocalcin secretion and 63 and 57% for type I and III collagen secretion, respectively. The AP activity did not differ with the age or sex of the donor. In contrast, osteocalcin secretion was significantly lower in females than in males. In males, osteocalcin significantly decreased with the age of the donor (r = -0.61; p less than 0.05). Cellular activity did not depend on the site of the biopsy. When bone explants from one donor were cultured in two different petri dishes, the activity of cells was similar in both dishes, except in one case. Primary cell cultures derived from human bone explants are the only model providing untransformed osteoblastlike cells of human origin. Because of the experimental conditions, some factors may have influenced the cellular activity and they must be taken into account to validate further in vitro studies.

Insulin like growth factor I hormonal regulation by growth hormone and by 1,25(OH)2D3 and activity on human osteoblast-like cells in short-term cultures.

IGF-1 has been shown to be locally produced in several tissues and to play a role in the regulation of cellular activity. We have investigated its production in short-term cultures of human bone derived cells, and the regulation of this production by growth hormone (GH) and by 1,25 dihydroxyvitamin D3 (1,25(OH)2D3). Bone cells obtained from surgical bone biopsies produced and secreted IGF-1 in their culture media. In four days cultures of bone-derived cells recombinant human r-IGF-1 at 20 ng/mL increased the alkaline phosphatase activity and the osteocalcin (bone gla protein) secretion, two specific markers of bone formation. This stimulation occurred only in the presence of 1,25(OH)2D3. Human bone cells exposed to GH increased their alkaline phosphatase activity, but no osteocalcin was detectable. However, in the presence of 1,25(OH)2D3 (1 nM), GH in concentrations of 8 to 40 nM increased by 30-50% the alkaline phosphatase activity and by 50 to 100% the osteocalcin secretion of human bone cells. At the same concentrations, GH also increased by 140% endogenous IGF-1 levels in cell culture supernatants, 1,25(OH)2D3 (10 nM) also increased time- and dose-dependently, IGF-1 levels in human bone cell supernatants, and stimulated dose-dependently alkaline phosphatase activity and osteocalcin secretion. It is therefore suggested that by regulating local production of growth factors such as IGF-1, GH and 1,25(OH)2D3 may modulate the metabolism of human bone cells.

The potential role of platelet-derived growth factor as an autocrine or paracrine factor for human bone cells.

Platelet-derived growth factor, PDGF, is a potent mitogen for cells of mesenchymal origin such as fibroblasts, smooth muscle cells and glial cells. PDGF is thought to have the potential to act as both a paracrine and an autocrine factor. Studies described here extend these observations to human bone-derived cells. Exogenous PDGF induces biologic activity in two human osteogenic sarcoma cell lines and in one of these, the two PDGF genes, PDGF-1 and PDGF-2/c-sis are expressed. In addition, PDGF stimulates proliferation of normal osteoblastic cells derived from adult human cancellous bone. The expression of the PDGF-1 gene but not the PDGF-2/c-sis gene is demonstrated in normal human adult bone-derived cells by Northern blot analysis and synthesis of PDGF is shown by immunoprecipitation with PDGF antisera. These studies indicate that PDGF has the potential to act as a paracrine or autocrine regulator of bone cells.

Androgens increase osteoblast-stimulating activity of human breast cancer cells in vitro.

Bone metastases of breast cancers produce not only osteolytic but also osteosclerotic lesions. The latter are often observed after androgenic treatment of the tumor. Potential production of osteoblast stimulating activity (ObSA) in breast cancer cell lines, and possible androgen control of this activity have been investigated. Conditioned media (CM) collected from 4 breast cancer cell lines (MCF-7, ZR75, MDA-MB 231, BT20) was tested in vitro on ROS 17/2,8 osteoblast-like cells and on osteoblasts derived from human bone biopsies. The parameters monitored in osteoblasts were [3H]thymidine incorporation, alkaline phosphatase activity, and osteocalcin secretion. Serum-free media conditioned during 24 h by MCF-7 cells presented the highest ObSA. CM decreased thymidine incorporation in DNA and increased alkaline phosphatase activity in a dose-dependent manner. Bone GLA protein (osteocalcin) secretion by human osteoblasts was not increased however in the presence of CM. MCF-7 cells were cultured in the presence of dihydrotestosterone (DHT) [1-100 nM] for 5 days. Serum-free, DHT-free CM collected after an additional 24 h, contained alkaline-phosphatase stimulating activity which was DHT dose-dependent. Estradiol and 1,25(OH)2D3 failed to elicit a comparable increase of the ObSA in the CM. In conclusion, MCF-7 cells product factor(s) that interfere with bone remodeling. The DHT modulation of ObSA parallels the estradiol control of MCF-7 cells osteolytic lesions in relation with Prostaglandin E secretion. Sex hormones at physiological and pharmacological levels might thus control both osteosclerotic and osteolytic lesions observed in bone deposits of hormone dependent cancers.

Estrogens and antiestrogens stimulate release of bone resorbing activity by cultured human breast cancer cells.

Patients with advanced breast cancer may develop acute, severe hypercalcemia when treated with estrogens or antiestrogens. In this study, we examined the effects of estrogens and related compounds on the release of bone resorbing activity by cultured human breast cancer cells in vitro. We found that the estrogen receptor positive breast cancer cell line MCF-7 releases bone resorbing activity in response to low concentrations of 17 beta-estradiol. Bone resorbing activity was also released in response to the antiestrogen nafoxidine. Other steroidal compounds had no effect on the release of bone resorbing activity. Estrogen-stimulated release of bone resorbing activity occurred with live bone cultures, but not with devitalized bones, indicating that the effect was bone cell mediated. The breast cancer cell line MDA-231, which does not have estrogen receptors, did not release bone resorbing activity in response to 17 beta-estradiol or nafoxidine. Release of the bone resorbing activity by MCF-7 cells incubated with 17 beta-estradiol was inhibited by indomethacin (10 microM) and flufenamic acid (50 microM), two structurally unrelated compounds that inhibit prostaglandin synthesis. Concentrations of 17 beta-estradiol and nafoxidine that caused increased release of bone resorbing activity by the breast cancer cells caused a four- to fivefold increase in release of prostaglandins of the E series by MCF-7 cells. These data may explain why some patients with advanced breast cancer develop acute hypercalcemia when treated with estrogens or antiestrogens, and why bone metastases are more common in patients with estrogen receptor positive tumors.

[Resorption and formation in metastatic bone]. / Résorption et formation dans l'os métastatique.

Bony metastases are a source of numerous complications and remain a difficult therapeutic target. Malignant cells implant in bony tissue where they can secrete factors which stimulate resorption and/or bone formation. The nature of these factors is now being discovered, even though their mode of action is better understood: the osteolytic action of prostaglandin E2 secreted in breast cancer, or the osteogenesis stimulating action of "transforming growth factor" in prostatic cancer. Progress in these areas of research is soon forthcoming due to new techniques in molecular biology.

[Myelomatous bone. Histomorphometric study and therapeutic effects]. / L'os myélomateux. Etude histomorphométrique et incidences thérapeutiques.

In order to evaluate quantitatively the bony changes in multiple myeloma, 118 transiliac bone biopsies in non decalcified bone were made in patients with multiple myeloma and studied histologically. Areas of osteoclastic resorption were increased when compared to normal controls and the number of osteoclasts/mm2 in spongy bone was significantly more elevated in zones massively invaded by plasmocytes than in non-invaded zones. The binding of tetracycline to osteoid was increased, indicating active bone formation. However, the reduced thickness of the osteoid and the rate of calcification measured by double labeling with tetracycline showed reduced osteoblastic activity at the cellular level. The volume of trabecular bone was not significantly reduced when compared to controls but plasmocyte infiltration was quite variable in distribution. In invaded zones, there was no noteworthy difference in the different parameters analyzed between patients receiving chemotherapy and those untreated. This shows that if chemotherapy can reduce the tumoral mass of plasmocytes, it does not change the increased osteoclastic activity of these areas. These histological findings justify the usage of antiosteoclastic agents such as the diphosphonates.

[Treatment of hypercalcemia of myelomatous origin with intravenous diphosphonates]. / Traitement de l'hypercalcémie d'origine myélomateuse par les diphosphonates intraveineux.

Diphosphonates were administered intravenously to 4 patients with myeloma-induced hypercalcaemia. All patients received EHDP 4.3 mg/kg/day for 3 to 8 days. One of them, whose hypercalcaemia recurred, was later treated with Cl 2 MDP 5 mg/kg i.v. for 8 days. In 2 patients EHDP infusions were followed by EHDP administered orally (5 mg/kg/d) for 3 weeks, after which transiliac bone biopsy was performed. In all patients calcemia fell from 130 +/- 14 to 99 +/- 4 mg/l at the end of the intravenous treatment, with parallel decrease in calciuria. Histomorphometric analysis of the bone biopsies showed few osteoclasts but massive infiltration with plasmocytes. In one case, EHDP probably induced a deficit in mineralization. Intravenous diphosphonates therefore proved to be rapidly effective in the treatment of hypercalcaemia due to malignancy. However prolonged administration of EHDP in high doses is not recommended, as it may result in osteomalacia.

Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia.

Transiliac undecalcified bone biopsy specimens were taken after tetracycline double labeling from 14 patients with radiologic evidence of osteosclerotic metastases from prostatic carcinoma. The histomorphometric analysis showed an increased trabecular bone volume in all patients, and in seven morphologic and dynamic evidence of osteomalacia (Group 1). The seven other patients demonstrated an extension of apposition surfaces without evidence of osteomalacia (Group 2). Group 1 was different from Group 2 in terms of a greater increase in serum alkaline phosphatase and a lower urinary calcium. In four Group 1 patients, a second bone sample taken after two to six months of treatment with vitamin D and calcium provided evidence of improving osteomalacia. The high incidence of osteomalacia in osteosclerotic metastases of prostatic origin appears to be the result of the increase in bone formation induced by prostatic cells, and the unability to satisfy the high calcium demand for new bone.

Quantitative histology of myeloma-induced bone changes.

In order to quantify bone changes which occur in multiple myeloma, undecalcified transiliac bone biopsies from 118 myelomatous patients were analysed by histomorphometric methods. Osteoclastic resorption surfaces were increased compared with controls, and the number of osteoclasts/mm2 of bone section was significantly greater in the areas massively invaded by plasma cells than in less invaded areas. The osteoid surfaces were also increased and the percentage of trabeculae that exhibited tetracycline labelling was also greater, indicating increased formation surfaces. However, reduced thickness of the osteoid seams and a low calcification rate, measured after tetracycline double labelling, suggests a reduced activity for each osteoblast. The mean trabecular bone volume was not reduced as compared with controls, but the biopsies showed a heterogeneous distribution of osteolytic and osteosclerotic areas. In the invaded areas, no major histomorphometric difference was found between patients receiving chemotherapy and untreated patients, demonstrating that if usual chemotherapies reduce the tumour mass, they do not improve histological bone lesions in areas still invaded by plasma cells.