Synthesis,crystal structure and initial biological evaluation of the new enantiomerically pure chiral palladium(II) complex trans-bis[endo-(1R)-1,7,7-trimethylbicyclo[2.2.1]-heptan-2-amino]palladium(II)dichloride

The palladium(II) complex trans-bis[(R)-(+)-bornylamino]palladium(II) dichloride was synthesised and characterised. The solid state structure of the complex was determined by X-ray structure analysis. The compound crystallises in the monoclinic space group P2(1) with a=12.383(2), b=23.689(5), c=12.769(3) A, beta=93.25(3) degrees, and V=3739.6(13) A(3). The complex was tested for its cytotoxicity against L(929), K(562) and HeLa cell lines using the MTT assay technique. It is also tested for its anticomplementary activity using a test that detects complement proteins inhibition. These activities were compared with those of the reference standards, cisplatin, carboplatin and oxaliplatin. The significance of these results is given and discussed.     

Locally advanced breast cancer in Saudi Arabia: high frequency of stage III in a young population

In the Kingdom of Saudi Arabia (KSA), breast cancer constitutes 18% of all cancers in Saudi women. Whilst locally advanced breast cancer disease is unusual in Western countries, it constitutes more than 40% of all non-metastatic breast cancer in KSA. The relative frequency of locally advanced disease among our breast cancer population and the lack of a uniform consensus in the literature about its optimal management have prompted this retrospective analysis of the medical records of patients with Stage III breast cancer patients seen at King Faisal Specialist Hospital and Research Center between 1981 and 1991. In all, 315 patients were identified. Their median age ±SD was 46±11.6 years which is distinctly different from the 60–65 years median age in industrial Western nations. Most patients were younger than 50 years (64%) and premenopausal (62%). Patients were approximately equally divided between Stage III A and Stage III B Patients received multimodality treatment, including surgery., adjuvant chemotherapy, tamoxifen, and adjuvant radiotherapy. Sixty-one patients were excluded from survival analysis as they were considered lost to follow-up. Of the remaining 254 patients, 73 (29%) were alive and disease free, and 18 patients (7%) were alive but, with evidence of the disease. The remaining 163 (64%) had died from breast cancer or its related complications. Their median overall survival (OS) was 54 months, (95%, Cl, 27 to 121 months) and the median progression-free survival (PFS) was 28.8 months (95% Cl, 14.2 to 113 months). Cox proportional hazard, model identified Stage III B and the number of positive axillary lymph nodes as poor predictors of OS and PFS. Radiotherapy was the only adjuvant modality that affected survival favourably. The prognosis of patients with Stage III disease remains poor despite the use of a multimodality approach. The overall young age of our patients may have contributed to the poor outcome. Moreover, the adverse effect of Stage III B disease (as compared with Stage III A) and axillary nodal status was evident. Whilst the favourable effect of radiotherapy on survival was demonstrated, the lack of independent efficacy of other modalities (adjuvant chemotherapy and tamoxifen) or the apparent deleterious effect of neoadjuvant chemotherapy should be addressed with discretion in such retrospective analysis. Optimal management of patients with locally advanced breast cancer disease should be appraised in well designed, prospective, randomised studies.     

Pulmonary tuberculosis presenting as mass lesions and simulating neoplasms in adults

In a review of the chest X-rays and medical records of 597 cases of culture- or biopsy-proven pulmonary tuberculosis (PTB; age range 1.5-72 years), seen over a period of 6 years (1991-97), 26 patients had radiographic patterns unusual for PTB. These patterns were mass-like densities simulating neoplasms, chronic lower lobe airspace opacities without adenopathy, mediastinal adenopathy without parenchymal airspace opacities and bronchopleural fistula without other radiographic abnormalities. The most common of these unusual radiographic patterns was mass-like densities, most of which were initially and mistakenly diagnosed as neoplasms. These masses, seen in 11 adult patients, form the basis of this report. Two children aged 1.5 and 2 years also had tuberculous mass densities initially diagnosed as neurogenic tumour and round pneumonia, respectively. They have been excluded from the present series, and form the subject of another report. The masses were lower lobe predominant and were not usually associated with fibro-productive satellite lesions or with calcification or cavitation. In view of the recent resurgence of PTB and the importance of chest X-rays in its diagnosis and management, this rare radiographic pattern needs to be emphasized.     

IgE antibody quantification and the probability of wheeze in preschool children

BACKGROUND: IgE-mediated sensitization is usually considered a dichotomous variable (either sensitized or not). Quantitative IgE antibody analysis may better predict the expression of wheeze. OBJECTIVE: Within the context of a population-based birth cohort, we investigated the association among wheeze, lung function, and specific IgE antibody levels. METHODS: Children (n = 521) were followed to age 5 years with repeated questionnaires, skin testing, and measurement of lung function (specific airway resistance) and specific serum IgE (ImmunoCAP). RESULTS: Using specific IgE as a continuous variable, the risk of current wheeze increased significantly with increasing IgE to mite, cat, and dog (P < .0001). When IgE levels to these 3 allergens were summed, the probability of current wheeze increased 1.33-fold (95% CI, 1.21-1.47; P < .0001) per logarithmic unit increase, corresponding to an odds ratio of 3.1 at 10 and 4.25 at 30 kU(A)/L (kilo units of Allergen per liter). Similarly, increasing sum of mite-specific, cat-specific, and dog-specific IgE was associated with reduced lung function (P = .004). Among sensitized children (n = 184), the sum of mite, cat, and dog IgE was the strongest associate of current wheeze (odds ratio, 1.28; 95% CI, 1.13-1.46; P < .001), corresponding to an odds ratio of 2.56 at 10 and 3.32 at 30 kU(A)/L. There was no association between current wheeze and the size of skin test wheal. Furthermore, the sum of IgE to mite, cat, and dog at age 3 years increased the risk of persistent wheeze by age 5 years (2.15-fold/logarithmic unit increase in the specific IgE). CONCLUSION: IgE-mediated sensitization is not an all or nothing phenomenon. The probability of wheeze and reduced lung function increases with increasing specific IgE antibody levels.     

CD86 (B7-2), but Not CD80 (B7-1), Expression in the Epidermis of Transgenic Mice Enhances the Immunogenicity of Primary Cutaneous Candida albicans Infections

Transgenic (Tg) mice whose epidermal keratinocytes constitutively overexpress either B7-1 (CD80) or B7-2 (CD86) exhibited exaggerated cutaneous delayed type hypersensitivity (DTH) to haptens compared to non-Tg mice. To determine whether enhanced DTH in these Tg mice is seen in response to cutaneous fungal infections, a primary infection with Candida albicans was established by inoculating this organism on the occluded skin of Tg and non-Tg mice. These infections resolved 7 days after removal of occlusive dressing in all three groups of mice, without evidence of exaggerated inflammation in either the Tg or non-Tg mice. Only B7-2 Tg mice developed enhanced Th1-lymphocyte-mediated immune responses to C. albicans antigens after resolving this infection: enhanced footpad swelling in response to intradermal C. albicans antigens, enhanced production of mRNA encoding Th1 lymphokines in draining lymph nodes, and increased gamma interferon secreted into culture supernatants by lymph node T lymphocytes stimulated with Candida antigens in vitro. Lastly, Western blotting of sera from mice that had resolved this fungal infection indicated that only B7-2 Tg mice recognized a wide range of Candida-associated antigens. These data suggest that these two costimulatory molecules, when expressed by keratinocytes, do not deliver identical signals to C. albicans antigen-reactive Th1 lymphocytes. The enhanced immune response in B7-2 Tg mice to a cutaneous C. albicans infection demonstrates the importance of antigen presentation and costimulation in immune reactivity to fungi. Furthermore, B7-2 Tg mice may be useful in identification of protective Candida antigens.     

Controlling indoor allergens.

OBJECTIVES: Reading of this article reinforces the reader's knowledge of the role of allergen exposure in relation to asthma and its severity, as well as the relevance of allergen avoidance in the treatment of asthma. DATA SOURCES: Initial literature search for existing evidence-based guidelines, reviews, and meta-analyses was carried out, and further literature searches were performed to review individual randomized controlled trials. Evidence level was graded according to the Scottish Intercollegiate Guidelines Network recommendations. RESULTS: There is good evidence for the link between mite and cockroach allergen exposure and sensitization, and between sensitization and asthma. For pet allergens, some studies found that exposure to pets in early life was associated with specific immunoglobulin E sensitization and allergic disease later in childhood, whereas others reported a protective effect. The effectiveness of allergen reduction in the treatment of asthma is suggested by studies in which the patients improve substantially when moved into the low-allergen environment of hospitals or high-altitude sanatoria. Because of limitations in the design of the most clinical of studies, we do not yet have a conclusive answer on the effectiveness of domestic aeroallergen avoidance. CONCLUSIONS: Minimizing the impact of identified environmental risk factors is an important first step to reduce the severity of asthma. Although environmental control is difficult, it should be an integral part of the overall management of sensitized patients. However, what is unclear is which patients would benefit and by how much, and whether the intervention is cost-effective. These questions will be answered satisfactorily only by large randomized trials.     

The impact of c-kit and ki-67 expression on patients prognosis in advanced ovarian serous carcinoma.

The transmembrane-tyrosine-kinase receptor, c-kit, is involved in cell differentiation and has been found to be expressed in normal human cell types and solid tumors. This study was designed to investigate the effects of c-kit expression on: 1) tumor proliferation and apoptosis, and 2) survival in patients with high-grade advanced stage ovarian serous carcinoma (OSC). We identified 118 patients with high-grade advanced stage OSC from our files. Clinical data, including demographics and overall survival, were collected. Immunohistochemical panel consisting of c-kit, ki-67, p53, and bcl-2 was performed. C-kit was categorized as positive if any cytoplasmic or membranous staining pattern was identified. Correlation between c-kit expression and the other markers was performed. Survival analysis was performed using COX proportional hazards regression and Kaplan-Meier test. Of 118 cases, 25 (21.2%) expressed c-kit. Of 93 c-kit-negative tumors, 87.1% had a high proliferation index. High p53 and bcl-2 expression was identified in 96 (81.4%) and 59 (50%) cases respectively. No significant statistical correlation was identified between c-kit and apoptosis markers. Tumors lacking c-kit expression showed a trend toward having high proliferation index, but this did not achieve statistical significance (p = 0.07). Of the seven variables included in the multivariate survival analysis, only c-kit (odds ratio, 2.12; 95% confidence interval, 08-4.17; p = 0.02) and ki-67 (odds ratio, 1.9; 95% confidence interval, 1.1-3.1; p = 0.03) showed an independent statistically significant impact on survival. High-grade advanced stage OSC lacking c-kit expression correlates with poor outcome. Interestingly, cases lacking c-kit expression also showed a trend to have high proliferation index.     

Species and tissue differences in the toxicity of 3-butene-1,2-diol in male Sprague-Dawley rats and B6C3F1 mice.

3-Butene-1,2-diol (BDD) is a major metabolite of 1,3-butadiene (BD), but the role of BDD in BD toxicity and carcinogenicity remains unclear. In this study, the acute toxicity of BDD was investigated in male Sprague-Dawley rats and B6C3F1 mice. Of the rats given 250 mg/kg BDD, 2 out of 4 died within 24 h; rats experienced hypoglycemia, significant alterations of liver integrity tests, and had lesions in the liver 4 h after treatment, but no lesions were detected in extrahepatic tissues. Rat hepatic GSH and GSSG levels were significantly depleted at both 1 and 4 h after the BDD treatment. Rats administered 200 mg/kg BDD also had liver lesions but no death or hypoglycemia was observed four or 24 h after treatment; these rats had depleted hepatic GSH and GSSG levels at 1 h but not at 4 or 24 h after treatment. Mice administered 250 mg/kg BDD exhibited modest alterations of liver integrity tests, but no death, hypoglycemia, or lesions in any tissue, and hepatic GSH and GSSG levels were depleted at 1 h but not at 4 h. The plasma half-life of BDD was four times longer in rats than in mice. Additional studies in rats showed the depletion of hepatic GSH and GSSG preceded the BDD-induced hypoglycemia and hepatotoxicity. Thus, the long half-life of BDD in rat plasma and the sustained depletion of hepatic GSH and GSSG may in part explain the higher sensitivity of the rat to BDD-induced hepatotoxicity. Furthermore, the results indicate that BDD may play a role in BD-induced toxicity.