A morphometric study of nucleolar organiser regions in cervical intraepithelial neoplasia

The study sought a correlation between the number of AgNOR granules and the degree of cervical intraepithelial neoplasia (CIN). Thirty-five sections (5 normal, 10 CIN1, 10 CIN2 and 10 CIN3) were subjected to retrospective analysis. The percentage of cells with 1, 2, 3, 4 and more AgNORs was calculated and the number of granules per 100 cells was counted. The number of cells containing single granules decreases. However, the number increases with CIN level when the cells contain 4 and more AgNORs. The number of granules per 100 cells also increases with the degree of CIN. It can be thus concluded that the number of cells with 4 and more AgNOR granules can serve as a CIN differentiation exponent

The influence of doxycycline on articular cartilage in experimental osteoarthrosis induced by iodoacetate

The experiment was performed on 36 Wistar rats. On the first day of the experiment iodoacetate was administered to the left posterior knee joint of the 18 rats which composed Group I. The second group of 18 rats received additionally doxycycline (doxy) through the gastric tube in doses comparable with those of doxycycline used in humans. The experiment lasted 21 days. The animals were sacrificed after 7, 14 and 21 days in groups of 6 rats each. In sections stained with Safranin 0 semiquantitative histochemical intensity tests were performed on articular cartilage glycosaminoglycans (GAG) using a four-point scale (0–3). In the first group examined destructive lesions in the articular cartilage and weak reactivity on GAG were noted at all stages of the experiment. The intensity of GAG staining was higher in the second group after 14 and especially after 21 days, which may suggest a protective action of doxy on articular cartilage

Hepatic profile analyses of tipranavir in Phase II and III clinical trials

<p>Abstract</p> <p>Background</p> <p>The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.</p> <p>Methods</p> <p>Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.</p> <p>Results</p> <p>Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.</p> <p>Conclusion</p> <p>Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4⁺> 200 cells/mm³at baseline.</p> <p>Trial registration</p> <p>US-NIH Trial registration number: NCT00144170</p

Instantons on ALE spaces and orbifold partitions

We consider N=4 theories on ALE spaces of $A_{k-1}$ type. As is well known, their partition functions coincide with $A_{k-1}$ affine characters. We show that these partition functions are equal to the generating functions of some peculiar classes of partitions which we introduce under the name 'orbifold partitions'. These orbifold partitions turn out to be related to the generalized Frobenius partitions introduced by G. E. Andrews some years ago. We relate the orbifold partitions to the blended partitions and interpret explicitly in terms of a free fermion system.Comment: 28 pages, 10 figures; reference adde

Expression of the apoptotic markers in normal breast epithelium, benign mammary dysplasia and in breast cancer

Apoptosis and proliferation are processes associated with the development and progression of breast cancer. The sensitivity of tumour cells to the induction of apoptosis depends on the balance between pro- and anti-apoptotic proteins. The expression of Bak and Bcl-2 was examined using an immunohistochemical method in 71 primary breast cancers. Furthermore, Bcl-2 and Bak were assessed in the normal mammary gland as well as in benign mammary dysplasia adjacent to breast cancer. Positive immunostaining for Bcl-2 was observed in 77.8% of cases of normal breast epithelium (NBE), 93% of benign dysplasia without intraductal proliferation (BBD) as well as in 94% of intraductal proliferative lesions of the breast (BIPL). Expression of Bak was detected in 39% of cases of NBE, 45% of BBD and in 67% of BIPL. In breast cancer Bcl-2 and Bak expression was found in 83% and 70% of the cases studied, respectively. Increased Bcl-2 expression in primary tumours significantly correlated with favourable prognostic factors, namely pT1, G2 and lack of metastases to the regional lymph nodes (p < 0.01, p < 0.03, p < 0.02, respectively). There were no relationships between Bak and the clinicopathological features studied, but our results indicate changes in the expression of Bak during breast cancer development and progression. It would appear to be important to assess and compare pro- and anti-apoptotic proteins between normal mammary gland, benign mammary dysplasia and the primary tumours of breast cancer. This knowledge should be helpful in understanding breast cancer development and progression

Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli

PURPOSE: Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesity-related stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions. EXPERIMENTAL DESIGN: The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines. RESULTS: Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231 cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231 cells. CONCLUSIONS: Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol

Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review

Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection