Some new aryl-sydnones: effects on murine tumours.

The effects of new aryl-sydnones: 3-[4-X-3-nitrophenyl]-1,2,3-oxadiazolium-5-olates, where X = Cl (SYD-1); pyrrolidino (SYD-2); piperidino (SYD-3) and morpholino (SYD-4) on the survival of mice bearing Sarcoma 180, Ehrlich carcinoma, B10MCII (Fibrous histiocytoma) and L1210 leukemia ascitic tumours, on the proliferation of cultured tumour cells and on the synthesis of DNA in L1210 leukemia were determined. SYD-1 and SYD-2 in vivo significantly enhanced the survival of S180, Ehrilich and B10MCII tumour-bearing mice. Furthermore, SYD-2 showed significant activity against L1210. SYD-3 and SYD-4 did not show antitumour activity. SYD-1, in vitro was the most cytotoxic against all the above tumour cells. All of the drugs tested inhibited thymidine uptake by L1210 cells, SYD-4 being the least active.     

Ultrasonographic evaluation of acute appendicitis.

Twenty-one patients with a clinical diagnosis of acute appendicitis underwent graded compression ultrasonography as an ongoing clinical study. The findings at surgery were compared with the ultrasonographic findings. There were no false-positive, 8 false-negative, 9 true-positive, and 11 true-negative results. The specificity was 100% and sensitivity, 52.9% The findings of this study, in contrast to findings of other recently reported studies, demonstrates that ultrasonography is a poor modality with which to evaluate acute appendicitis.     

Antibodies to lipid A in pauciarticular juvenile arthritis: clinical studies.

IgG antibodies to monophosphoryl lipid A (MPL) are more concentrated in synovial fluids than in the blood of children with pauciarticular juvenile arthritis. Correlations between IgG anti-MPL levels and numbers of inflamed joints were highly significant in 2 of 10 patients followed for 8 years and suggestive in 2 patients followed for shorter periods. A fifth patient had a correlation between IgM anti-MPL and joint count.     

Corticotrophin-releasing factor immunostaining is present in placenta and fetal membranes from the first trimester onwards and is not affected by labour or administration of mifepristone

BACKGROUND AND OBJECTIVES Corticotrophin releasing factor (CRF) is present in the human placenta and fetal membranes. Placental CRF content and plasma CRF concentrations rise throughout gestation and fail rapidly after delivery. The regulation of CRF production from the placenta is poorly understood. The objective of this study was to use the antiprogestin, mifepristone, to determine whether progesterone has a regulatory effect on CRF production in the first trimester of pregnancy. PATIENTS Women undergoing first trimester (gestation 5-12 weeks) therapeutic abortion (by suction curettage with and without the synthetic PGE, analogue, gemeprost (16,16-dimethyl-trans- Δ²-PGE₁ methyl ester) vaginally 2-4 hours prior to the procedure; or with 600 mg mifepristone 48 hours prior to receiving 1 mg gemeprost vaginally), second trimester therapeutic abortion (600 mg mifepristone, 1 mg gemeprost), In association with pre-term delivery (gestation 25-34 weeks) and at term (gestation 35-42 weeks) by spontaneous delivery, induced labour or elective Caesarean section. MEASUREMENTS immunohistochemical localization Of CRF and quantification of CRF content by radioimmunoassay of tissue extracts, in human placenta and fetal membranes. RESULTS CRF was Immunolocalized to the syncytlo-trophoblast cells of the placenta at ail stages of gestation from 5 to 42 weeks. In the fetal membranes CRF immunoreactlvity was localized in the epithelial and subepithelial cells of the amnion, some cells of the reticular and cellular layers of the chorion, and in decidual stroma. This pattern was seen in all tissues studied. Pretreatment with prostaglandins, mifepristone or both during the first trimester did not alter the distribution or the intensity of the CRF Immunostaining. Placental CRF content rose throughout gestation but, consistent with the Lmmunostaining results, was unaffected by the administration of mifepristone or by labour. CONCLUSIONS CRF is localized in the syncitlotropho-blast cells of the placenta and is clearly present early in the first trimester of pregnancy. The lack of an effect of mifepristone or mode of delivery suggests that syncytlo-trophoblast produces CRF constitutively throughout pregnancy.     

Effect of FK-506 on xenografted human Graves' thyroid tissue in severe combined immunodeficient mice

OBJECTIVE We studied the macrolide antibiotic FK-506, an immunosuppressive agent, in an attempt to ameliorate the lesion of autoimmune thyroid disease in human thyroid tissue xenografted into severe combined immunodeficient (SCID) mice. It was not felt appropriate to employ this agent directly in patients with autoimmune thyroid disease because adequate therapeutic modalities are available and the introduction of new, experimental agents could not be justified. Moreover, the study of the tissue before and after treatment could not have been undertaken directly in patients. DESIGN Human thyroid xenografts from four patients with Graves' disease and two normal persons were xenografted into SCID mice. Two weeks after xenograft-ing, human immunoglobulin G (IgG) was detectable in all SCID mice xenografted with Graves' thyroid tissue. Mice were divided into two groups with human IgG levels similar to each other. Mice in the first group were treated with FK-506 daily for 6 weeks; mice in the second (similar) group were given phosphate-buffered saline (PBS) only (control group). MEASUREMENTS Blood samples were taken every 2 weeks from the tail veins for human IgG, thyroid stimulating antibody, thyroperoxidase antibodies, thyroglobulin antibodies, and interferon-gamma (IFN-7). After 8 weeks treatment, animals were sacrificed; thyroid tissue was examined histologically and for thyrocyte HLA-DR expression. FK-506 was also added to thyrocytes in in-vitro tissue culture conditions. RESULTS After 4–6 weeks of FK-506 therapy, human IgG, all thyroid antibodies and IFN-7 were suppressed, while the levels remained elevated in the control group. Lymphocytic infiltration virtually disappeared in the human thyroid tissue of the FK-506-treated mice and thyrocyte HLA-DR expression markedly declined; in the control mice, lymphocytic infiltration remained heavy and HLA-DR expression remained high. On the other hand, FK-506 added directly to thyrocytes in vitro (without lymphocytes) did not reduce thyrocyte HLA-DR expression. CONCLUSIONS FK-506 appears to suppress the activation of intrathyroidal lymphocytes, but not thyrocytes. From these observations, it is concluded that this agent, by its action on intrathyroidal lymphocytes, is able to ameliorate the immunologically mediated histological and serological disturbance in human autoimmune thyroid disease, at least under these circumstances.     

A markedly diminished pleiotropic response to phenobarbital and structurally-related xenobiotics in Zucker rats in comparison with F344/NCr or DA rats.

Phenobarbital (PB) and certain structurally-related compounds induce a variety of hepatic drug-metabolizing enzymes in many strains of rats. Thus, following administration of PB (300, 500 ppm), barbital (BB, 1500 ppm) or 5-ethyl-5-phenylhydantoin (EPH, 500 ppm), CYP2B1-mediated benzyloxyresorufin O-dealkylase activity and epoxide hydrolase activity were profoundly induced in female DA and F344/NCr rats. In contrast, outbred female lean and obese Zucker rats showed markedly reduced CYP2B1 responses (less than 15% and less than 5% of those observed in the female DA or F344/NCr rat) to PB (doses less than or equal to 300 ppm), BB (1500 ppm) or EPH (500 ppm). In parallel studies, profound increases in RNA levels coding for CYP2B1, glutathione S-transferases Ya/Yc (alpha subclass), or epoxide hydrolase were detected in the female F344/NCr rat following treatment with PB (300 ppm), BB (1500 ppm) or EPH (500 ppm). In contrast, lean Zucker rats showed a strong response only to the highest dose of PB (500 ppm), implying that the diminished response in the Zucker rats may occur at some pretranslational level. Similar studies with lower doses of PB, EPH or BB in male lean Zucker rats showed a decreased response, relative to that in male F344/NCr rats. However, this insensitivity was not as profound as that observed in the female Zucker rats. In fact, the response to PB-type inducers in male or female Zucker rats is probably most clearly explained as a shift of the dose-response curve sharply to the right (decreased responsiveness, compared to F344/NCr or DA rats of the same sex). This decreased responsiveness of female lean Zucker rats to induction of CYP2B1, relative to that of F344/NCr rats, was also observed with the structurally-diverse PB-type inducers clonazepam, clotrimazole and 2-hexanone. In contrast, the female Zucker rat (obese or lean) displayed a pronounced response to induction of CYP1A-mediated ethoxyresorufin O-deethylase activity by beta-naphthoflavone, a prototype inducer of CYP1A1 and CYP1A2. The Zucker rat would thus appear to represent a potentially exploitable genetic model for examining the mechanism of enzyme induction by the myriad xenobiotics which induce a PB-type response.     

Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Initial steps taken by nine primary care practices to implement alcohol screening guidelines with hypertensive patients: the AA-TRIP project.

Many medical conditions are caused or exacerbated by heavy drinking, necessitating alcohol screening and discussion in primary care practices. This is particularly true of hypertension, the most common primary diagnosis in the United States, which has been linked to the regular consumption of 3 or more standard alcoholic beverages a day. The Accelerating Alcohol Screening-Translating Research into Practice (AA-TRIP) project was designed to improve detection and management of alcohol problems in primary care patients with hypertension. Medical providers are being trained using the Practice Partner Research Network's- Translating Research into Practice (PPRNet-TRIP) quality improvement model. This includes a multi-method intervention (electronic medical records, on-site academic detailing, practice feedback reports and annual network meetings) to help practices increase adherence to clinical guidelines. Qualitative analyses of initial steps taken by nine primary care practices toward the routine implementation of alcohol screening guidelines are presented. Organizational factors and provider and patient characteristics all influenced the method and consistency of alcohol screening and intervention. Perceived time constraints, patient sensitivity to questions about alcohol, and possible stigma associated with a diagnosis of alcoholism were also relevant barriers requiring problem solving.