A novel protocol allowing oral delivery of a protein complement inhibitor that subsequently targets to inflamed colon mucosa and ameliorates murine colitis.

While there is evidence of a pathogenic role for complement in inflammatory bowel disease, there is also evidence for a protective role that relates to host defence and protection from endotoxaemia. There is thus concern regarding the use of systemic complement inhibition as a therapeutic strategy. Local delivery of a complement inhibitor to the colon by oral administration would ameliorate such concerns, but while formulations exist for oral delivery of low molecular weight drugs to the colon, they have not been used successfully for oral delivery of proteins. We describe a novel pellet formulation consisting of cross-linked dextran coated with an acrylic co-polymer that protects the complement inhibitor CR2-Crry from destruction in the gastrointestinal tract. CR2-Crry containing pellets administered by gavage, were characterized using a therapeutic protocol in a mouse model of dextran sulphate sodium (DSS)-induced colitis. Oral treatment of established colitis over a 5-day period significantly reduced mucosal inflammation and injury, with similar therapeutic benefit whether or not the proton pump inhibitor, omeprazole, was co-administered. Reduction in injury was associated with the targeting of CR2-Crry to the mucosal surface and reduced local complement activation. Treatment had no effect on systemic complement activity. This novel method for oral delivery of a targeted protein complement inhibitor will reduce systemic effects, thereby decreasing the risk of opportunistic infection, as well as lowering the required dose and treatment cost and improving patient compliance. Furthermore, the novel delivery system described here may provide similar benefits for administration of other protein-based drugs, such as anti-tumour necrosis factor-α antibodies.

Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women.

OBJECTIVE: To determine the effects of dietary inclusion of soy foods on clinical markers for cardiovascular disease (CVD) and osteoporosis in normal postmenopausal women. DESIGN: This was a single open-group prospective clinical intervention. Forty-two normal postmenopausal women consumed three daily servings for 12 consecutive weeks of whole soy foods containing approximately 60 mg/d of isoflavones. Blood and urine specimens were obtained at baseline and after 12 weeks of dietary intervention. RESULTS: Serum and urine levels of individual and total isoflavones increased significantly (7-19 fold, p < 0.001) from baseline. A significant increase (9.3%, p < 0.05) in the mean lag-time of low-density lipoprotein cholesterol oxidation was seen and was positively correlated with serum phytoestrogens (p < 0.05). Significant increases were found in mean levels of high-density lipoprotein cholesterol (HDLc) (3.7%, p < 0.05) and serum osteocalcin (10.2%, p < 0.025). Significant decreases were observed in total cholesterol:HDLc ratios (5.5%, p < 0.006) and mean urinary N-telopeptide excretion (13.9%, p < 0.02). Urinary excretion of total isoflavones was negatively correlated with very-low-density lipoprotein cholesterol, triglycerides, and total cholesterol:HDLc ratios (p < 0.04). No significant changes from baseline in HDLc peroxidation, total cholesterol, triglycerides, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, bone-specific alkaline phosphatase, follicle-stimulating hormone, or estradiol levels were observed. CONCLUSIONS: Dietary inclusion of whole soy foods containing 60 mg/d of isoflavones results in significant serum levels of phytoestrogens and reductions in several key clinical risk factors for CVD and osteoporosis in normal postmenopausal women. Long-term, placebo-controlled clinical trials are needed to evaluate the effect of phytoestrogens on the clinical endpoints of CVD and osteoporosis in this population.

Racial and economic demographics of couples seeking infertility treatment.

OBJECTIVE: We characterized new infertility patients on the basis of race and economic factors. STUDY DESIGN: A retrospective chart review was performed of all patients seeking infertility evaluation from 1998 to 1999 at two infertility centers in Cincinnati, Ohio. Patients were categorized by race (white, black, or other). Statistics were analyzed by chi2 and logistic regression. RESULTS: Of 756 patients, 85.2% were white, 10.2% were black, and 4.4% were other. Infertility diagnoses were placed into the following 7 categories: ovarian, salpingitis, surgical sterilization, male factor, endometriosis, unexplained, and other. Black women had significantly more salpingitis than did nonblack women (P <.001) regardless of insurance status. However, surgical sterilization was more prevalent in patients without insurance regardless of race (P <.001). CONCLUSIONS: Our findings are consistent with previous studies showing that black women have more risk factors for salpingitis. Surgical sterilization risk factors were concordant with those of the National Center for Health Statistics.

Evidence for the role of high density lipoproteins in mediating the antioxidant effect of estrogens.

Estrogens possess strong antioxidant effects in vitro, but in vivo studies in humans have yielded conflicting results. Little is known regarding factors that mediate the antioxidant effect of estrogens in vivo. In this study the potential role of high density lipoprotein (HDL) was examined. The antioxidant effect of estradiol-17beta (E2) added to low density lipoprotein (LDL) was lost after dialysis. In contrast, the antioxidant effect of E2 added to HDL was conserved after dialysis, suggesting that E2 was bound to HDL. Binding of E2 to LDL increased after esterification (especially to long chain fatty acids). In the presence of HDL, an increased amount of E2 was transferred to LDL. E2-17 ester was as potent as E2 in preventing LDL oxidation in vitro, but 3,17-diesters were not as effective (E2=E2-17 ester>E2-3 ester>E2-3,17 diester). This was also supported by experiments which showed that estrogens with masked 3-OH groups were not effective as antioxidants. These studies provide evidence that HDL could facilitate the antioxidant effect of E2 through initial association, esterification and eventual transfer of E2 esters to LDL. Therefore it is critical that HDL peroxidation parameters be evaluated in subjects receiving estrogen replacement therapy.

Isoflavones and postmenopausal bone health: a viable alternative to estrogen therapy?

OBJECTIVE: The rapidly growing postmenopausal population in the United States, and this population's high incidence and prevalence of osteoporosis and related morbidity and mortality herald an enormous public health burden for the coming decades. Estrogen replacement has been the mainstay of therapy for the prevention and treatment of osteoporosis in this estrogen-deficient population. However, long-term compliance with estrogen therapy generally is poor, and there are numerous concerns regarding its safety. The phytoestrogens are nonsteroidal plant-derived compounds that exhibit estrogenic activity at several sites. The isoflavones are one class of phytoestrogens derived largely from soy-based products. International popularity for menopausal therapy regimens containing isoflavones is growing rapidly. In this article, we review the existing data on isoflavones and postmenopausal bone health. DESIGN: A review of interventional trials examining isoflavones and bone in animals and humans. RESULTS: The data point to a reduction in bone resorption resulting from isoflavone/ipriflavone intake. CONCLUSIONS: The data on naturally occurring isoflavones are very limited but suggest that including them in the diet results in reduction in bone resorption caused by estrogen deficiency. The extensive data on ipriflavone, a synthetic isoflavone derivative, suggest that it is a useful and safe alternative to estrogen therapy in treating existing low bone mass or osteoporosis in postmenopausal women. Further studies are warranted to examine the utility of ipriflavone as a preventive agent, as well as the clinical efficacy of the naturally occurring isoflavones.

Successful non-surgical management of a heterotopic abdominal pregnancy following embryo transfer with cryopreserved-thawed embryos.

Heterotopic pregnancy is an increasingly common complication of assisted reproductive technology. Abdominal pregnancy is a rare and life-threatening form of ectopic pregnancy that can present as the extrauterine portion of a heterotopic pregnancy. We present the case of a cryopreserved-thawed embryo transfer that resulted in a simultaneous intrauterine and abdominal pregnancy first recognized at 10 weeks gestation. Ultrasound-guided transvaginal injection of potassium chloride into the abdominal pregnancy resulted in asystole and spontaneous resorption of the ectopic fetus, while the intrauterine pregnancy continued and resulted in a liveborn vaginal delivery at full term. Selective embryo reduction using a non-surgical approach in a haemodynamically stable patient can therefore be considered in the management of heterotopic abdominal pregnancy if diagnosed relatively early.

Immunizing California's children. Effects of current policies on immunization levels.

Data collected by the Immunization Unit of the California Department of Health Services from 1979 to 1987 were analyzed to determine the effects of changes in state policy on the immunization levels of children in California. By December 1986, 90% of all children entering kindergarten in California were adequately immunized, representing a 15% increase from 1979. Although California has shown substantial improvements, it still lags behind the national weighted average. Even with high levels of immunization at kindergarten entry, many toddlers of 7 months and 2 years old remain inadequately immunized. Children immunized solely in the private sector were more adequately immunized than those served by public health clinics; the public-private difference for infants aged 7 months was nearly twofold.

Stereotaxic fine needle aspiration cytology of clinically occult malignant and premalignant breast lesions.

Stereotaxic fine needle aspiration (FNA) cytology was used to study clinically occult (nonpalpable) breast lesions in 114 consecutive patients with mammographically suspicious findings prior to excisional biopsy. The aspirate contained insufficient material for cytologic evaluation in 15 cases (13.2%), which were histologically diagnosed as benign (7 cases), atypical hyperplasia (7 cases) or carcinoma in situ (1 case). The cytologic findings indicated a benign lesion in 77 cases (67.5%), which were histologically diagnosed as benign (71 cases) or atypical ductal hyperplasia (6 cases). The cytologic sample showed atypia in eight cases (7.0%), which were histologically diagnosed as severe atypical ductal hyperplasia (three cases), carcinoma in situ (one case) or proliferative fibrocystic disease (four cases). In the eight cases (7.0%) cytologically interpreted as probably malignant, histology confirmed six invasive carcinomas, one carcinoma in situ and one fibrocystic disease. Of six cases (4.4%) cytologically reported as malignant, five were histologically diagnosed as invasive carcinoma and one as carcinoma in situ. Overall, stereotaxic FNA cytology reported as malignant or probably malignant 14 of the 15 cases with a histologic confirmation of malignancy, for a sensitivity of 93.3%. Cytology correctly identified 78 of the 83 histologically negative cases, for a specificity of 94.0%. The 16 cases histologically diagnosed as ductal hyperplasia, which carries a high risk for subsequent malignancy, were studied in detail in an effort to define histologic and cytologic criteria for this entity. Using selected histologic criteria, 11 of these cases were graded as showing mild-to-moderate atypical hyperplasia and 5 as showing severe atypical hyperplasia. Three of the latter cases were similarly identified by an analogous cytologic grading; the other two cases had insufficient cytologic samples. The total results in this series of 114 cases support the use of stereotaxic FNA cytology in the diagnosis of these nonpalpable breast lesions, examples of which are illustrated. In particular, it may help to raise the low specificity yielded by mammography alone, which would represent a significant advance for the patient in terms of the accuracy, expediency and reduced cost of diagnosing these lesions.

Suprascapular neuropathy related to the use of crutches.

A 41-year-old man with shoulder pain was found to have a suprascapular neuropathy. The nerve injury was believed to be secondary to improper crutch usage. The pathophysiology of this unusual cause of suprascapular neuropathy involves injury to the nerve due to exaggerated movements around the shoulder joint. Suprascapular entrapment neuropathy is another potential hazard of improper crutch usage. Therefore, properly fitted crutches and adequate crutch training are essential for the prevention of additional disability.

Cytologic findings in stage I adenocarcinoma of the lung: implications for the detection of early lung cancer.

Preoperative cytologic examinations were performed on bronchial material from 92 patients with postsurgical (pathologic) stage I (American Joint Committee) adenocarcinoma of the lung. All patients were followed up for at least 5 years or until death; thus, cases of adenocarcinoma metastatic to the lungs were virtually excluded. Only 22 patients (24%) had abnormal preoperative cytologic findings. This low cytologic sensitivity is ascribed to the small size and peripheral location of the tumors. Large lesions of high histologic grades were more likely to have positive preoperative cytologic findings than small, well-differentiated ones.