Study on the role of maternal sex steroid production and metabolism in the embryotoxicity of para-xylene

CFY rats were exposed to inhalation of clean air or air containing para-xylene (3000 mg/m³) on the 10th, and 9th and 10th days of gestation. Uterine and ovarian venous blood flow, fetal weight, ovarian progesterone and 17β-oestradiol secretion, and the progesterone and 17β-oestradiol level of peripheral blood (uterine and femoral veins) were measured on the 11th day of gestation. Exposure to para-xylene decreased the weight of the fetuses and the progesterone and 17β-oestradiol levels of peripheral blood, but it did not influence the uterine and ovarian venous outflow and the ovarian progesterone and 17β-oestradiol secretion rate. It is concluded that para-xylene, by inducing the hepatic monooxygenase system, facilitates the biotransformation of progesterone and 17β-oestradiol, which is metabolized by this enzyme system. The decrease in the sex hormone level of peripheral blood is supposed to play a role in the embryotoxicity (retarding and lethal effects) of para-xylene.     

Structure-activity relationship studies optimizing the antiproliferative activity of novel cyclic somatostatin analogues containing a restrained cyclic beta-amino acid

The cyclic somatostatin analogue cyclo[Pro(1)-Phe(2)-D-Trp(3)-Lys(4)-Thr(5)-Phe(6)] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural alpha- and beta-amino acids. The N- fluorenylmethoxycarbonyl protected cyclic beta-amino acid [1S, 2S, 5R]-2-amino-3,5-dimethyl-2-cyclohex-3-enecarboxylic acid (cbetaAA), for the replacement of the Phe(6)-Pro(1) moiety of L-363,301, was synthesized in two steps by an enantioselective multicomponent reaction using (-)-8-phenylmenthol as a chiral auxiliary. The resulting peptide cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] (Trt = triphenylmethyl) shows high antiproliferative effects in an in vitro assay with A431 cancer cells. The same peptide without the Trt group does not reveal any biological activity, whereas L-363,301 and closely related hexapeptides show only minor activity. By comparison of the solution structure of cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] with the structure of l-363,301, a nearly perfect match of the betaII'-turn region with d-Trp in the i + 1 position was observed. The cyclic beta-amino acid cbetaAA is likely needed for the bioactive conformation of the peptide.     

Oncogene amplification and overexpression of oncoproteins in thyroid papillary cancer

BACKGROUND: Several oncogene aberrations have been found in papillary thyroid cancer, the incidence of which has increased after the accident in Chernoby. The occurrence and prognostic significance of these aberrations may have importance in therapeutic strategies. MATERIALS AND METHODS: Tumour tissues from 24 patients were investigated by Dot-blot DNA hybridisation for c-myc, Ha-ras amplification and p53 deletion, and by immunohistochemical method for cyclin D1, p53 and p21 overexpression. RESULTS: Overexpression of p53 protein was detected in 66.6%, with p21 expression (25%) without any influence on tumour phenotype. Cyclin D1 overexpression was found in 50% to be associated with p21, in inverse relation to Iymphocytic infiltration. Overexpression of estrogen receptor was shown in 4 cyclin D1-positive samples (17%). CONCLUSION: Our results suggest that cyclin D1 overexpression is associated with poor prognosis. The co-expression of cyclin D1 and p21 causes a CDK-independent, estrogen receptor-mediated effect of the cyclin D1 also described in breast cancer.     

Pharmaceutical and formulation aspects of Petroselinum crispum extract

Parsley (Petroselinum crispum L.) is a very popular spice and vegetable in Europe, it is widely spread and easy to grow. It's herb and fruits are known to be diuretic, smooth muscle relaxant and hepatoprotective. The most important identified active ingredients are flavonoids, cumarins and vitamin C. Apigenin and its glycosides are the main flavonoids in parsley, it can be found relatively large amounts in the leaves. The bioactive flavonoid apigenin has antiinflammatory, antioxidant and anticancer activities. The objectives of this study were the preparation and detemination of the apigenin content of the parsley extract and the formulation using inert pellets by layering the apigenin in fluid-bed process.     

Use of anti‐CD20 antibody in the treatment of post‐transplant glomerulonephritis

Damodar A, Mustafa R, Bhatnagar J, Panesar M, Gundroo A, Zachariah M, Blessios G, Tornatore K, Weber‐Shrikant E, Venuto R. Use of anti‐CD20 antibody in the treatment of post‐transplant glomerulonephritis.
Clin Transplant 2011: 25: 375–379. © 2010 John Wiley & Sons A/S. Abstract: Post‐transplant glomerulonephritis (PTGN) accounts for 4–10% of late graft loss. Six consecutive patients who developed PTGN 3–72 months post‐transplant presented to our center with deteriorating kidney function and proteinuria. Three had focal segmental glomerulosclerosis; one had membranoproliferative glomerulonephritis Type 1; one recurrent membranous nephropathy; and one recurrent immunoglobin A nephropathy. All six were treated with an aggressive immunosuppression regimen including rituximab, pulse steriods and/or maximization of mycophenolic acid and calcineurin inhibitor therapy. Four of the six patients received plasma exchange. The patients were followed for a minimum of nine months after treatment. Proteinuria decreased from 7.2 ± 4.4 to 1.4 ± 1.5 g (p = 0.04), while mean estimated glomerular filtration rate was 31.2 ± 13.1 and 42.5 ± 21.7 mL/min (p = 0.07) at nine months. No adverse events were noted. These observations suggest that immune modulating therapy may be of benefit in the treatment of PTGN.     

Association of systemic and thyroid autoimmune diseases

Objective: There are few large cohort studies available on the association of systemic and thyroid autoimmune diseases. In this study, we wished to determine the association of Hashimotos thyroiditis (HT) and Graves disease (GD) with systemic autoimmune diseases. Methods: One thousand five hundred and seventeen patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögrens syndrome (SS) and polymyositis/dermatomyositis (PM/DM) were included in the study. The HT and GD were diagnosed based on thorough clinical evaluation, imaging and fine-needle aspiration cytology (FNAC). The frequency of HT and GD in these diseases was assessed. In addition, 426 patients with HT or GD were assessed and the incidence of SLE, RA, SSc, MCTD, SS and PM/DM among these patients was determined. Prevalence ratios indicating the prevalences of GD or HT among our autoimmune patients in comparison to prevalences of GD or HT in the general population were calculated. Results: Altogether 8.2% of systemic autoimmune patients had either HT or GD. MCTD and SS most frequently overlapped with autoimmune thyroid diseases (24 and 10%, respectively). HT was more common among MCTD, SS and RA patients (21, 7 and 6%, respectively) than GD (2.5, 3 and 1.6%, respectively). The prevalences of HT in SLE, RA, SSc, MCTD, SS and PM/DM were 90–, 160–, 220–, 556–, 176– and 69-fold higher than in the general population, respectively. The prevalences of GD in the same systemic diseases were 68-, 50-, 102-, 76-, 74- and 37-fold higher than in the general population, respectively. Among all thyroid patients, 30% had associated systemic disease. In particular, 51% of HT and only 16% of GD subjects had any of the systemic disorders. MCTD, SS, SLE, RA, SSc and PM/DM were all more common among HT patients (20, 17, 7, 4, 2 and 2%, respectively) than in GD individuals (2, 5, 5, 1, 2 and 1%, respectively). Conclusion: Systemic and thyroid autoimmune diseases often overlap with each other. HT and GD may be most common among MCTD, SSc and SS patients. On the other hand, these systemic diseases are often present in HT subjects. Therefore it is clinically important to screen patients with systemic autoimmune diseases for the co-existence of thyroid disorders.Take home message: Autoimmune thyroid diseases, such as Hashimotos thyroiditis and Graves disease are often associated with systemic autoimmune diseases, most commonly with Sjögrens syndrome and mixed connective tissue disease.     

Pharmacokinetics and pharmacodynamics of levofloxacin in critically ill patients with ventilator-associated pneumonia

The pharmacokinetics of levofloxacin and outcome of levofloxacin therapy in critically ill patients with ventilator-associated pneumonia (VAP) were assessed. Further theoretical considerations regarding the pharmacokinetic/pharmacodynamic (PK/PD) appropriateness of levofloxacin therapy were made. Twelve patients completed the study, all of whom were treated with a standard intravenous levofloxacin regimen (2x500 mg on Day 1, then 1x500 mg daily). The maximum free plasma levofloxacin concentration (fC(max,ss)) and the area under the free concentration-time curve (fAUC) were 8.13+/-1.64 mg/L and 49.63+/-15.60 mgh/L, respectively. Optimal PK/PD target parameters were achieved in 10 patients; clinical success was attained in 11 of the 12 patients who completed the study. Bacterial eradication was obtained in 9 of the 11 cases with microbiologically confirmed bacteriological aetiology. Intravenous levofloxacin therapy (500 mg/day) was proven to be an effective regimen in this limited number of patients with VAP. However, theoretical considerations based on PK/PD indices predict that, with the current susceptibility breakpoint of 2mg/L, even higher levofloxacin doses (e.g. 1000 mg) could result in treatment failures in infections caused by pathogens labelled as levofloxacin-susceptible in the microbiology report.     

Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease

The objectives of the study is to determine clinical signs and distribution of peripheral T-cell subsets, B cells and T regulatory cells in patients with undifferentiated connective tissue disease (UCTD) and during the development toward well-established connective tissue diseases (CTD). The methods include 46 patients with UCTD were followed and investigated for differentiation into defined CTDs for 2 years. Cell subsets were determined on the basis of cell surface markers, intracellular cytokine production by flow cytometry and serum cytokine levels by ELISA. The results are as follows: 45.6% of UCTD patients developed into a defined CTD. The number and percentage of activated T cells, memory T cells and NKT cells were increased in patients compared with controls. In addition, in patients with UCTD, the percentage of CD4+/IFN gamma+ T(h)1 was significantly higher compared with controls and further increased in patients that developed CTDs. The percentage and absolute number of CD4+CD25+Foxp3+ regulatory T cells (Tregs) were diminished in UCTD patients compared with healthy controls, while the number of CD4+/IL-10+ Tregs increased. The conclusions are Overproduction of IFN gamma and the decrease of natural (Foxp3+) Tregs seem to be characteristic features of UCTD patients. The increased IL-10 production of CD4+ T cells might be a compensatory suppressive mechanism; however, it is probably not able to balance the overproduction of IFN gamma and the observed decrease of Foxp3+ Tregs. The shift toward T(h)1 with increased IFN gamma production in patients with UCTD combined with the degree of immunoregulatory disturbances characterized by the progressive divergent shifts in natural and induced T-regulatory cell populations signify the transition from undifferentiated to definitive CTD.     

Heart transplantation after corrective surgery of a congenital heart disease. Surgical technical problems

Heart transplantation was performed in a 17-year old boy with severe left ventricular failure. Previously a congenital heart disease, tetralogy of Fallot was reconstructed in one and half years old of age. Authors present the different surgical problems complicated this procedure. In Hungary this is the first heart transplantation after a corrective surgical procedure of a complex congenital heart disease.