HIV-1-related Hodgkin lymphoma in the era of combination antiretroviral therapy: incidence and evolution of CD4⁺ T-cell lymphocytes

The risk of Hodgkin lymphoma (HL) is increased in patients infected with HIV-1. We studied the incidence and outcomes of HL, and compared CD4⁺ T-cell trajectories in HL patients and controls matched for duration of combination antiretroviral therapy (cART). A total of 40 168 adult HIV-1-infected patients (median age, 36 years; 70% male; median CD4 cell count, 234 cells/μL) from 16 European cohorts were observed during 159 133 person-years; 78 patients developed HL. The incidence was 49.0 (95% confidence interval [CI], 39.3-61.2) per 100,000 person-years, and similar on cART and not on cART (P = .96). The risk of HL declined as the most recent (time-updated) CD4 count increased: the adjusted hazard ratio comparing more than 350 with less than 50 cells/μL was 0.27 (95% CI, 0.08-0.86). Sixty-one HL cases diagnosed on cART were matched to 1652 controls: during the year before diagnosis, cases lost 98 CD4 cells (95% CI, -159 to -36 cells), whereas controls gained 35 cells (95% CI, 24-46 cells; P < .0001). The incidence of HL is not reduced by cART, and patients whose CD4 cell counts decline despite suppression of HIV-1 replication on cART may harbor HL.

Detrital Zircon Evidence for Mixing of Mazatzal Province Age Detritus With Yavapai Age (ca. 1700-1740 Ma) and Older Detritus in the ca. 1650 Ma Mazatzal Province of Central New Mexico, USA

Preliminary detrital zircon age distributions from Mazatzal crustal province quartzite and schist exposed in the Manzano Mountains and Pedernal Hills of central New Mexico are consistent with a mixture of detritus from Mazatzal age (ca. 1650 Ma), Yavapai age (ca. 1720 Ma.), and older sources. A quartzite sample from the Blue Springs Formation in the Manzano Mountains yielding 67 concordant grain analyses shows two dominant age peaks of 1737 Ma and 1791 Ma with a minimum peak age of 1652 Ma. Quartzite and micaceous quartzite samples from near Pedernal Peak give unimodal peak ages of ca. 1695 Ma and 1738 Ma with minimum detrital zircon ages of ca. 1625 Ma and 1680 Ma, respectively. A schist sample from the southern exposures of the Pedernal Hills area gives a unimodal peak age of 1680 Ma with a minimum age of ca. 1635 Ma. Minor amounts of older detritus (>1800 Ma) possibly reflect Trans-Hudson, Wyoming, Mojave Province, and older Archean sources and aid in locating potential source terrains for these detrital zircon. The Blue Springs Formation metarhyolite from near the top of the Proterozoic section in the Manzano Mountains yields 71 concordant grains that show a preliminary U-Pb zircon crystallization age of 1621 ¿ 5 Ma, which provides a minimum age constraint for deposition in the Manzano Mountains. Normalized probability plots from this study are similar to previously reported age distributions in the Burro and San Andres Mountains in southern New Mexico and suggest that Yavapai Province age detritus was deposited and intermingled with Mazatzal Province age detritus across much of the Mazatzal crustal province in New Mexico. This data shows that the tectonic evolution of southwestern Laurentia is associated with multiple orogenic events. Regional metamorphism and deformation in the area must postdate the Mazatzal Orogeny and ca. 1610 Ma ¿ 1620 Ma rhyolite crystallization and is attributed to the Mesoproterozoic ca. 1400 ¿ 1480 Ma Picuris Orogeny.

p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma

Malignant pleural mesotheliomas (MPMs) are usually wild type for the p53 gene but contain homozygous deletions in the INK4A locus that encodes p14(ARF), an inhibitor of p53-MDM2 interaction. Previous findings suggest that lack of p14(ARF) expression and the presence of SV40 large T antigen (L-Tag) result in p53 inactivation in MPM. We did not detect SV40 L-Tag mRNA in either MPM cell lines or primary cultures, and treatment of p14(ARF)-deficient cells with cisplatin (CDDP) increased both total and phosphorylated p53 and enhanced p53 DNA-binding activity. On incubation with CDDP, levels of positively regulated p53 transcriptional targets p21(WAF), PIG3, MDM2, Bax, and PUMA increased in p14(ARF)-deficient cells, whereas negatively regulated survivin decreased. Significantly, p53-induced apoptosis was activated by CDDP in p14(ARF)-deficient cells, and treatment with p53-specific siRNA rendered them more CDDP-resistant. p53 was also activated by: 1) inhibition of MDM2 (using nutlin-3); 2) transient overexpression of p14(ARF); and 3) targeting of survivin using antisense oligonucleotides. However, it is noteworthy that only survivin downregulation sensitized cells to CDDP-induced apoptosis. These results suggest that p53 is functional in the absence of p14(ARF) in MPM and that targeting of the downstream apoptosis inhibitor survivin can sensitize to CDDP-induced apoptosis.

Amaurosis fugax mit erhöhten Akutphasenproteinen

Case report of a 66-year-old woman with episodes of amaurosis fugax and hemicranic headache with otherwise normal ophthalmologic and neurological examinations and normal imaging. While ESR was in the normal range for patient's age, acute phase proteins (C-reactive protein and fibrinogen) were elevated. Giant cell arteritis was proved by temporal artery biopsy. Giant cell arteritis should be considered as an important differential diagnosis of amaurosis fugax even in patients with normal ESR. Acute phase protein testing can give relevant diagnostic information.

Multi-vessel stenting during primary percutaneous coronary intervention for acute myocardial infarction. A single-center experience

BACKGROUND: Recanalization of the culprit lesion is the main goal of primary angioplasty for acute ST-segment elevation myocardial infarction (STEMI). Patients presenting with acute myocardial infarction and multivessel disease are, therefore, usually subjected to staged procedures, with the primary percutaneous coronary intervention (PCI) confined to recanalization of the infarct-related artery (IRA). Theoretically at least, early relief of stenoses of non-infarct-related arteries could promote collateral circulation, which could help to limit the infarct size. However, the safety and feasibility of such an approach has not been adequately established. METHODS: In this single-center prospective study we examined 73 consecutive patients who had an acute STEMI and at least one or more lesions > or = 70% in a major epicardial vessel other than the infarct-related artery. In the first 28 patients, forming the multi-vessel (MV) PCI group, all lesions were treated during the primary procedure. In the following 45 patients, forming the culprit-only (CO) PCI group, only the culprit lesion was treated during the initial procedure, followed by either planned-staged or ischemia-driven revascularization of the non-culprit lesions. Fluoroscopy time and contrast dye amount were compared between both groups, and patients were followed up for one year for major adverse cardiac events (MACE) and other significant clinical events. RESULTS: The two groups were well balanced in terms of clinical characteristics, number of diseased vessels and angiographic characteristics of the culprit lesion. In the MV-PCI group, 2.51 lesions per patient were treated using 2.96 +/- 1.34 stents (1.00 lesions and 1.76 +/- 1.17 stents in the CO-PCI group, both p < 0.001). The fluoroscopy time increased from 10.3 (7.2-16.9) min in the CO-PCI group to 12.5 (8.5-19.3) min in the MV-PCI group (p = 0.22), and the amount of contrast used from 200 (180-250) ml to 250 (200-300) ml, respectively (p = 0.16). Peak CK and CK-MB were significantly lower in patients of the MV-PCI group (843 +/- 845 and 135 +/- 125 vs 1652 +/- 1550 and 207 +/- 155 U/l, p < 0.001 and 0.01, respectively). Similar rates of major adverse cardiac events at one year were observed in the two groups (24% and 28% in multi-vessel and culprit treatment groups, p = 0.73). The incidence of new revascularization in both infarct- and non-infarct-related arteries was also similar (24% and 28%, respectively, p = 0.73). CONCLUSION: We may state from this limited experience that a multi-vessel stenting approach for patients with acute STEMI and multi-vessel disease is feasible and probably safe during routine clinical practice. Our data suggest that this approach may help to limit the infarct size. However, larger studies, perhaps using drug-eluting stents, are still needed to further evaluate the safety and efficiency of this procedure, and whether it is associated with a lower need of subsequent revascularization and lower costs.

[Stem-cell-based approaches for treating inner ear diseases]

The capacity of stem cells to regenerate lost tissue cells has gained recognition among physicians. Despite the successful use of blood stem cells for treating blood cancers, other stem cell types have not yet been widely introduced into clinical practice. Therapy options involving stem cells for inner ear diseases consequently have not been implemented. Nonetheless, several reports have recently been published describing the generation of morphologically and immunologically distinctive inner ear cell types-such as hair cells, supporting cells, and spiral ganglion neurons-from stem cells. Although promising, all of these studies still lack functional results regarding hearing restoration or vestibular function.

Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK

In adults, glioblastomas are the most lethal and most frequent malignant brain tumors, and the poor prognosis despite aggressive treatment indicates the need to establish novel targets for molecular intervention. The secreted growth factor pleiotrophin (PTN, HB-GAM, HBNF, OSF-1) shows mitogenic, chemotactic, and transforming activity. Whereas PTN expression is tightly regulated during embryogenesis and is very limited in normal adult tissues, a marked PTN up-regulation is seen in tumors including glioblastomas. Likewise, the PTN receptor anaplastic lymphoma kinase (ALK) has been shown previously to be upregulated and functionally relevant in glioblastoma. In this study, we explore the antitumorigenic effects of the simultaneous ribozyme-mediated knockdown of both receptor and ligand. Various glioblastoma cell lines are analyzed for PTN and ALK expression. Beyond the individual efficacies of several specific ribozymes against PTN or ALK, respectively, antiproliferative and proapoptotic effects of a single gene targeting approach are strongly enhanced on double knockdown of both genes in vitro. More importantly, this results in the abolishment of tumor growth in an in vivo subcutaneous tumor xenograft model. Finally, the analysis of various downstream signaling pathways by antibody arrays reveals a distinct pattern of changes in the activation of signal transduction molecules on PTN/ALK double knockdown. Beyond the already known ones, it identifies additional pathways relevant for PTN/ALK signaling. We conclude that double targeting of PTN and ALK leads to enhanced antitumorigenic effects over single knockdown approaches, which offers novel therapeutic options owing to increased efficacy also after prolonged knockdown.

Physiologic cold shock increases adherence of Moraxella catarrhalis to and secretion of interleukin 8 in human upper respiratory tract epithelial cells

Moraxella catarrhalis, a major nasopharyngeal pathogen of the human respiratory tract, is exposed to rapid and prolonged downshifts of environmental temperature when humans breathe cold air. In the present study, we show that a 26 degrees C cold shock up-regulates the expression of UspA1, a major adhesin and putative virulence factor of M. catarrhalis, by prolonging messenger RNA half-life. Cold shock promotes M. catarrhalis adherence to upper respiratory tract cells via enhanced binding to fibronectin, an extracellular matrix component that mediates bacterial attachment. Exposure of M. catarrhalis to 26 degrees C increases the outer membrane protein-mediated release of the proinflammatory cytokine interleukin 8 in pharyngeal epithelial cells. Furthermore, cold shock at 26 degrees C enhances the binding of salivary immunoglobulin A on the surface of M. catarrhalis. These data indicate that cold shock at a physiologically relevant temperature of 26 degrees C affects the nasopharyngeal host-pathogen interaction and may contribute to M. catarrhalis virulence.

Insider Trading in Germany - Do Corporate Insiders Exploit Inside Information?

Our study focuses on the question whether corporate insiders in Germany exploit inside information while trading in their company’s stock. In contrast to prior international studies, which are not able to link insider transactions to a formal definition of inside information, we relate insider transactions to subsequent releases of inside information via ad-hoc news disclosures. We find evidence that corporate insiders as a group seem to trade on inside information. Moreover, members of the supervisory board seem to be most active in exploiting inside information, since they realize exceptionally high profits with their frequent front-running transactions.

Right ventricle best predicts the race performance in amateur ironman athletes

PURPOSE The ironman (IM) triathlon is a popular ultraendurance competition, consisting of 3.8 km of swimming, 180.2 km of cycling, and 42.2 km of running. The aim of this study was to investigate the predictors of IM race time, comparing echocardiographic findings, anthropometric measures, and training characteristics. METHODS Amateur IM athletes (ATHL) participating in the Zurich IM race in 2010 were included. Participants were examined the day before the race by a comprehensive echocardiographic examination. Moreover, anthropometric measurements were obtained the same day. During the 3 months before the race, each IM-ATHL maintained a detailed training diary. Recorded data were related to total IM race time. RESULTS Thirty-eight IM finishers (mean ± SD age = 38 ± 9 yr, 32 men [84%]) were evaluated. Total race time was 684 ± 89 min (mean ± SD). For right ventricular fractional area change (45% ± 7%, Spearman ρ = -0.33, P = 0.05), a weak correlation with race time was observed. Race performance exhibited stronger associations with percent body fat (15.2 ± 5.6%, ρ = 0.56, P = 0.001), speed in running training (11.7 ± 1.2 km · h(-1), ρ = -0.52, P = 0.002), and left ventricular myocardial mass index (98 ± 24 g · m(-2), ρ = -0.42, P = 0.009). The strongest association was found between race time and right ventricular end-diastolic area (22 ± 4 cm2, ρ = -0.64, P < 0.0001). In multivariate analysis, right ventricular end-diastolic area (β = -16.7, 95% confidence interval = -27.3 to -6.1, P = 0.003) and percent body fat (β = 6.8, 95% confidence interval = 1.1-12.6, P = 0.02) were independently predictive of IM race time. CONCLUSIONS In amateur IM-ATHL, RV end-diastolic area and percent body fat were independently related to race performance. RV end-diastolic area was the strongest predictor of race time. The role of the RV in endurance exercise may thus be more important than previously thought and needs to be further studied.