Twenty-five-year outcomes after multiple internal thoracic artery bypass

ObjectiveCoronary artery bypass grafting with multiple internal thoracic artery grafts is currently controversial. This study assessed single institutional outcomes with multiple internal thoracic artery grafting for guidance with future clinical decisions.MethodsIn 19,482 patients undergoing multivessel coronary artery bypass grafting (1984-2009), baseline characteristics were recorded in a prospective databank, and follow-up was obtained by questionnaires, phone contact, or National Death Index. Outcomes examined were subsequent myocardial infarction, percutaneous coronary intervention, reoperative coronary artery bypass grafting, all-cause death, and a composite of the 4. Three groups were defined: (1) no internal thoracic artery graft (1874/19,482 or 9%); (2) single internal thoracic artery grafts and adjunctive venous conduits (single internal thoracic artery; 16,881/19,482 or 87%); and (3) multiple internal thoracic artery grafts (728/19,482 or 4%). Multivariable Cox modeling adjusted for differences in baseline characteristics, and comparisons were performed using area under the curve analysis.ResultsDifferences in baseline characteristics for the no internal thoracic artery graft, single internal thoracic artery, and multiple internal thoracic artery groups were as follows: median age 66, 64, and 59 years, respectively; congestive heart failure 22%, 18%, and 13%, respectively; ejection fraction 0.50, 0.52, and 0.51, respectively; reoperation 10%, 3%, and 7%, respectively; diabetes 27%, 30%, and 15%, respectively; and female gender 33%, 28%, and 20%, respectively. No differences existed in the median number of diseased vessels (3, 3, and 3, respectively) or number of grafts per patient (3, 3, and 3, respectively). Composite outcome improved with increasing internal thoracic artery grafts, whether assessing unadjusted or risk-adjusted data. Compared with no internal thoracic artery graft, the adjusted hazard ratio was 0.79 (confidence interval, 0.74-0.83) for single internal thoracic artery grafting and 0.70 (confidence interval, 0.62-0.80) for multiple internal thoracic artery grafting (both P < .001), reducing risk by 21% and 30%, respectively.ConclusionsThis study confirms improved patient outcomes with multiple internal thoracic artery grafting, achieving half again as much benefit as single internal thoracic artery grafting alone. The data suggest that increasing application of multiple internal thoracic artery grafting should be encouraged to mitigate the inherent risks and costs of long-term cardiac events

Mythical numbers and the proceeds of organised crime: estimating mafia proceeds in Italy

Organised crime is a field vulnerable to mythical numbers, i.e. exaggerated estimates lacking empirical support, but acquiring acceptance through repetition. The figures on mafia proceeds in Italy are a striking example of this problem. This study proposes an estimation of mafia proceeds in Italy from nine criminal activities (sexual exploitation of women, illicit firearms trafficking, drug trafficking, counterfeiting, the illicit cigarette trade, illicit gambling, illicit waste disposal, loan sharking, and extortion racketeering) by region and type of mafia (Cosa Nostra, Camorra,\u2018Ndrangheta, Apulian mafias, and other mafias). The results estimate yearly mafia proceeds at approximately \u20ac10.7 bn (0.7% of the Italian GDP), discussing the impact on the regional and national economies and the differences among the types of mafias as to their geographical sources of revenue

Spider conservation in Europe : a review

Despite their ecological importance and diversity, spiders (Arachnida: Araneae) are underrepresented in conservation policies in comparison to other groups. We review all extant conservation tools focusing on spiders in Europe, highlighting general patterns, limitations, gaps, and future directions. We assembled a comprehensive online database reporting all available information concerning the legal protection and conservation status of 4,154 spider species. Existing international legislation has limited coverage, with only one species listed in the Bern Convention and EU Habitats Directive. At the national and subnational levels, 178 species are formally mentioned in the legislation of 19 European countries. Moreover, the International Union for Conservation of Nature (IUCN) includes assessments for 301 species worldwide, 164 of these threatened and eight native to Europe. In addition, spiders are mentioned in Regional Red Lists and Red Books in 28 out of 42 European countries considered in this review. Northern and Central European countries have the highest percentage of species assessed at the regional level in Red Lists and Red Books. The Mediterranean basin has the highest spider diversities in Europe but conservation efforts are lacking, both in terms of assessments and national or subnational legislation. Among European species, Dolomedes plantarius, Argyroneta aquatica and Eresus kollari are the most frequently mentioned in European conservation measures, possibly due to their ecological traits and their strict association with declining habitats. Considering the current threats to spiders in Europe, the protection of large areas of suitable habitat should be considered as the most effective approach to spider conservation.Peer reviewe

Intestinal Ischemia-Reperfusion Injury Alters Purinergic Receptor Expression in Clinically Relevant Extraintestinal Organs

Intestinal ischemia-reperfusion (IIR) injury is known to initiate the systemic inflammatory response syndrome which often progresses to multiple organ failure. We investigated changes in purinoceptor expression in clinically relevant extra-intestinal organs following IIR injury

A mutation in the endonuclease domain of mouse MLH3 reveals novel roles for MutLγ during crossover formation in meiotic prophase I

During meiotic prophase I, double-strand breaks (DSBs) initiate homologous recombination leading to non-crossovers (NCOs) and crossovers (COs). In mouse, 10% of DSBs are designated to become COs, primarily through a pathway dependent on the MLH1-MLH3 heterodimer (MutLγ). Mlh3 contains an endonuclease domain that is critical for resolving COs in yeast. We generated a mouse (Mlh3DN/DN) harboring a mutation within this conserved domain that is predicted to generate a protein that is catalytically inert. Mlh3DN/DN males, like fully null Mlh3-/- males, have no spermatozoa and are infertile, yet spermatocytes have grossly normal DSBs and synapsis events in early prophase I. Unlike Mlh3-/- males, mutation of the endonuclease domain within MLH3 permits normal loading and frequency of MutLγ in pachynema. However, key DSB repair factors (RAD51) and mediators of CO pathway choice (BLM helicase) persist into pachynema in Mlh3DN/DN males, indicating a temporal delay in repair events and revealing a mechanism by which alternative DSB repair pathways may be selected. While Mlh3DN/DN spermatocytes retain only 22% of wildtype chiasmata counts, this frequency is greater than observed in Mlh3-/- males (10%), suggesting that the allele may permit partial endonuclease activity, or that other pathways can generate COs from these MutLγ-defined repair intermediates in Mlh3DN/DN males. Double mutant mice homozygous for the Mlh3DN/DN and Mus81-/- mutations show losses in chiasmata close to those observed in Mlh3-/- males, indicating that the MUS81-EME1-regulated crossover pathway can only partially account for the increased residual chiasmata in Mlh3DN/DN spermatocytes. Our data demonstrate that mouse spermatocytes bearing the MLH1-MLH3DN/DN complex display the proper loading of factors essential for CO resolution (MutSγ, CDK2, HEI10, MutLγ). Despite these functions, mice bearing the Mlh3DN/DN allele show defects in the repair of meiotic recombination intermediates and a loss of most chiasmata

Phase II study of helical tomotherapy in the multidisciplinary treatment of oligometastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Complete metastasectomy provides a real chance for long-term survival in patients with oligometastatic colorectal cancer (CRC). For inoperable patients, we evaluated in this study intensity-modulated and image-guided radiotherapy (IMRT-IGRT) by helical tomotherapy.</p> <p>Methods</p> <p>Twenty-four CRC patients with ≤ 5 metastases were enrolled, receiving a dose of 50 Gy in fractions of 5 Gy. No limitations concerning dimension or localization of the metastases were imposed. Whole body PET-CT was performed at baseline and 3 months after the initiation of RT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST) version 1.0.</p> <p>Results</p> <p>A total of 53 metastases were treated. Seventeen patients (71%) received previously ≥ 1 line of chemotherapy for metastatic disease, displaying residual (n = 7) or progressive (n = 10) metabolic active oligometastatic disease at time of inclusion. Most common sites were the lung, liver and lymphnodes. One patient (4%) experienced grade 3 dysphagia. Twenty-two patients were evaluated by post-treatment PET-CT. Twelve patients achieved a complete (n = 6) or partial (n = 6) metabolic response, resulting in an overall metabolic response rate of 55%. At a median follow-up of 10 months, 7 patients (29%) are in remission, of which 5 received previous chemotherapy with residual oligometastatic disease at time of inclusion. The actuarial 1-year local control, progression-free survival, and overall survival were 54%, 14% and 78%.</p> <p>Conclusions</p> <p>Helical tomotherapy delivering 10 fractions of 5 Gy resulted in a metabolic response rate of 55%, and appeared to be attractive as consolidation of inoperable oligometastatic disease after effective chemotherapy.</p> <p>Trial registration</p> <p>Eudract 2008-008300-40; <a href="http://www.clinicaltrials.gov/ct2/show/NCT00807313">NCT00807313</a></p

Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

Vitamin-D receptor (VDR) mRNA is overexpressed in neuroblastoma and carcinomas of lung, pancreas, and ovaries and predicts poor prognoses. VDR antagonists may be able to inhibit tumors that overexpress VDR. However, the current antagonists are arduous to synthesize and are only partial antagonists, limiting their use. Here, we show that the VDR antagonist MeTC7 (5), which can be synthesized from 7-dehydrocholesterol (6) in two steps, inhibits VDR selectively, suppresses the viability of cancer cell-lines, and reduces the growth of the spontaneous transgenic TH-MYCN neuroblastoma and xenografts in vivo. The VDR selectivity of 5 against RXRα and PPAR-γ was confirmed, and docking studies using VDR-LBD indicated that 5 induces major changes in the binding motifs, which potentially result in VDR antagonistic effects. These data highlight the therapeutic benefits of targeting VDR for the treatment of malignancies and demonstrate the creation of selective VDR antagonists that are easy to synthesize

Co-circulation of Four Human Coronaviruses (HCoVs) in Queensland Children with Acute Respiratory Tract Illnesses in 2004

Acute respiratory illnesses (ARIs) with unconfirmed infectious aetiologies peak at different times of the year. Molecular diagnostic assays reduce the number of unconfirmed ARIs compared to serology- or culture-based techniques. Screening of 888 inpatient and outpatient respiratory specimens spanning late autumn through to early spring, 2004, identified the presence of a human coronavirus (HCoV) on 74 occasions (8.3% of all specimens and 26.3% of all respiratory virus detections). Prevalence peaked in August (late winter in the southern hemisphere) when they were detected in 21.9% of specimens tested. HCoV-HKU1 and HCoV-OC43 comprised 82.4% of all HCoVs detected. Positive specimens were used to develop novel reverse transcriptase real-time PCRs (RT-rtPCRs) for HCoV detection. An objective clinical severity score was assigned to each positive HCoV patient. Severity scores were similar to those from a random selection of young children who were positive for respiratory syncytial virus at a different time but from the same specimen population. During the cooler months of 2004, sensitive and specific RT-rtPCRs identified the concurrent circulation of all four HCoVs, a quarter of which co-occurred with another virus and most of which were from children under the age of two years

Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study

Purpose: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis. Experimental design: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days. Results: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime. Conclusion: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies