Does Sex Speed Up Evolutionary Rate and Increase Biodiversity?

Most empirical and theoretical studies have shown that sex increases the rate of evolution, although evidence of sex constraining genomic and epigenetic variation and slowing down evolution also exists. Faster rates with sex have been attributed to new gene combinations, removal of deleterious mutations, and adaptation to heterogeneous environments. Slower rates with sex have been attributed to removal of major genetic rearrangements, the cost of finding a mate, vulnerability to predation, and exposure to sexually transmitted diseases. Whether sex speeds or slows evolution, the connection between reproductive mode, the evolutionary rate, and species diversity remains largely unexplored. Here we present a spatially explicit model of ecological and evolutionary dynamics based on DNA sequence change to study the connection between mutation, speciation, and the resulting biodiversity in sexual and asexual populations. We show that faster speciation can decrease the abundance of newly formed species and thus decrease long-term biodiversity. In this way, sex can reduce diversity relative to asexual populations, because it leads to a higher rate of production of new species, but with lower abundances. Our results show that reproductive mode and the mechanisms underlying it can alter the link between mutation, evolutionary rate, speciation and biodiversity and we suggest that a high rate of evolution may not be required to yield high biodiversity.

Failure Rate and Conductor Externalization of the Biotronik Linox / Sorin Vigila Implantable Cardioverter Defibrillator Lead

BACKGROUND We observed a case of conductor externalization in a Biotronik Linox lead. OBJECTIVE To investigate lead performance of the Linox and identical Sorin Vigila lead and prevalence of conductor externalization. METHODS We compared lead performance of all Linox and Vigila leads implanted at our center (BL group; n=93) with all Boston Scientific Endotak Reliance leads (ER group; n=190) and Medtronic Sprint Quattro leads (SQ group; n=202) implanted during the same period. We screened all BL group patients for conductor externalization. RESULTS We identified 8 cases of lead failures in the BL group (index case of conductor externalization; 6 cases of non-physiological high rate sensing; one case of high voltage conductor fracture). Prospective, fluoroscopic screening of 98% of all active BL group cases revealed one additional case of conductor externalization. Median follow-up was 41, 27 and 29 months for the BL group, ER group and SQ group, respectively, lead survival 94.9%, 99.2% and 100% at 3 years, and 88%, 97.5% and 100% at 5 years (p=0.038 for BL group vs. ER group, and p=0.007 for BL group vs. SQ group by the log-rank test). Younger age at implant was an independent predictor for lead failure in the BL group (adjusted HR 0.85 [95% confidence interval 0.77-0.94]; p=0.001). CONCLUSION At our center, survival of the Linox lead is 88% at five years and significantly worse than its comparators. Conductor externalization is present in a minority of failed Linox leads. Younger age at implant is an independent predictor of Linox lead failure.

Treatment of slipped capital femoral epiphysis with a modified Dunn procedure

Surgical procedures with use of traditional techniques to reposition the proximal femoral epiphysis in the treatment of slipped capital femoral epiphysis are associated with a high rate of femoral head osteonecrosis. Therefore, most surgeons advocate in situ fixation of the slipped epiphysis with acceptance of any persistent deformity in the proximal part of the femur. This residual deformity can lead to secondary osteoarthritis resulting from femoroacetabular cam impingement.

Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia

Patients with critical limb ischaemia have a high rate of amputation and mortality. We tested the hypothesis that non-viral 1 fibroblast growth factor (NV1FGF) would improve amputation-free survival.

Hysteroscopic findings in women with two and with more than two first-trimester miscarriages are not significantly different

The purpose of this study was to analyse hysteroscopic results in patients with recurrent miscarriages and to compare the frequency of uterine anomalies in women with a history of exactly two and with more than two consecutive miscarriages. A retrospective analysis of 206 patients undergoing hysteroscopy for repeated early pregnancy losses was performed at two university centres. Late miscarriages were excluded, terminations of pregnancy were not counted. Eighty-seven patients had suffered from exactly two early miscarriages and 119 from more than two. Both groups were comparable with respect to age at admission (32.95+/-4.46 versus 34.06+/-5.02 years) and at first miscarriage (30.43+/-4.24 versus 29.08+/-5.38 years). The prevalence of acquired (adhesions, polyps, fibroids) and congenital uterine anomalies (septate or bicornuate uterus, etc.) did not differ significantly (acquired: 28.7 versus 27.7%; congenital: 9.2 versus 16.8%). The rates of uterine anomalies did not differ significantly overall (36.8 versus 42.9%). In conclusion, uterine anomalies are frequently found in patients with two and with more than two early miscarriages. Due to the high rate of anomalies, their risk for adverse pregnancy outcome and a possible therapeutic approach, hysteroscopy might be a diagnostic option even after two early miscarriages.

Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia

Patients with critical limb ischaemia (CLI) unsuitable for revascularisation have a high rate of amputation and mortality (30% and 25% at 1 year, respectively). Localised gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pecaplasmid) has showed an increased amputation-free survival in a phase II trial. This article provides the rationale, design and baseline characteristics of CLI patients enrolled in the pivotal phase III trial (EFC6145/TAMARIS).

Chapter I: Definitions, epidemiology, clinical presentation and prognosis

The concept of chronic critical limb ischaemia (CLI) emerged late in the history of peripheral arterial occlusive disease (PAOD). The historical background and changing definitions of CLI over the last decades are important to know in order to understand why epidemiologic data are so difficult to compare between articles and over time. The prevalence of CLI is probably very high and largely underestimated, and significant differences exist between population studies and clinical series. The extremely high costs associated with management of these patients make CLI a real public health issue for the future. In the era of emerging vascular surgery in the 1950s, the initial classification of PAOD by Fontaine, with stages III and IV corresponding to CLI, was based only on clinical symptoms. Later, with increasing access to non-invasive haemodynamic measurements (ankle pressure, toe pressure), the need to prove a causal relationship between PAOD and clinical findings suggestive of CLI became a real concern, and the Rutherford classification published in 1986 included objective haemodynamic criteria. The first consensus document on CLI was published in 1991 and included clinical criteria associated with ankle and toe pressure and transcutaneous oxygen pressure (TcPO(2)) cut-off levels <50 mmHg, <30 mmHg and <10 mmHg respectively). This rigorous definition reflects an arterial insufficiency that is so severe as to cause microcirculatory changes and compromise tissue integrity, with a high rate of major amputation and mortality. The TASC I consensus document published in 2000 used less severe pressure cut-offs (≤ 50-70 mmHg, ≤ 30-50 mmHg and ≤ 30-50 mmHg respectively). The thresholds for toe pressure and especially TcPO(2) (which will be also included in TASC II consensus document) are however just below the lower limit of normality. It is therefore easy to infer that patients qualifying as CLI based on TASC criteria can suffer from far less severe disease than those qualifying as CLI in the initial 1991 consensus document. Furthermore, inclusion criteria of many recent interventional studies have even shifted further from the efforts of definition standardisation with objective criteria, by including patients as CLI based merely on Fontaine classification (stage III and IV) without haemodynamic criteria. The differences in the natural history of patients with CLI, including prognosis of the limb and the patient, are thus difficult to compare between studies in this context. Overall, CLI as defined by clinical and haemodynamic criteria remains a severe condition with poor prognosis, high medical costs and a major impact in terms of public health and patients' loss of functional capacity. The major progresses in best medical therapy of arterial disease and revascularisation procedures will certainly improve the outcome of CLI patients. In the future, an effort to apply a standardised definition with clinical and objective haemodynamic criteria will be needed to better demonstrate and compare the advances in management of these patients.

Recent developments for surgical aortic valve replacement: the concept of sutureless valve technology

Aortic stenosis has become the most frequent type of valvular heart disease in Europe and North America and presents in the large majority of patients as calcified aortic stenosis in adults of advanced age. Surgical aortic valve replacement has been recognized to be the definitive therapy which improves considerably survival for severe aortic stenosis since more than 40 years. In the most recent period, operative mortality of isolated aortic valve replacement for aortic stenosis varies between 1–3% in low-risk patients younger than 70 years and between 4 and 8% in selected older adults. Long-term survival following aortic valve replacement is close to that observed in a control population of similar age. Numerous observational studies have consistently demonstrated that corrective surgery in symptomatic patients is invariably followed by a subjective improvement in quality of life and a substantial increase in survival rates. More recently, transcatheter aortic valve implantation (TAVI) has been demonstrated to be feasible in patients with high surgical risk using either a retrograde transfemoral or transsubclavian approach or an antegrade, transapical access. Reported 30-day mortality ranges between 5 and 15%) and is acceptable when compared to the risk predicted by the logistic EuroSCORE (varying between 20 and 35%) and the STS Score, although the EuroScore has been shown to markedly overestimate the effective operative risk. One major concern remains the high rate of paravalvular regurgitation which is observed in up to 85% of the patients and which requires further follow-up and critical evaluation. In addition, long-term durability of these valves with a focus on the effects of crimping remains to be addressed, although 3-5 year results are promising. Sutureless biological valves were designed to simplify and significantly accelerate the surgical replacement of a diseased valve and allow complete excision of the calcified native valve. Until now, there are 3 different sutureless prostheses that have been approved. The 3f Enable valve from ATS-Medtronic received CE market approval in 2010, the Perceval S from Sorin during Q1 of 2011 and the intuity sutureless prosthesis from Edwards in 2012. All these devices aim to facilitate valve surgery and therefore have the potential to decrease the invasivness and to shorten the conventional procedure without compromise in term of excision of the diseased valve. This review summarizes the history and the current knowledge of sutureless valve technology.

Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic β emitters (90)Y and (177)Lu. (90)Y- and/or (177)Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using (111)In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of (90)Y-/(177)Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach.

Ungual melanoma - controversies in diagnosis and treatment

Ungual melanomas are considered rare, being difficult to diagnose, and having a poor prognosis. The aim of the present study was to discuss the epidemiology, potential causes, treatment options, and outcome of ungual melanomas. In contrast to assumptions in many articles, ungual melanomas are not rare when calculated for the cumulative size of the nail apparatus of both the fingers and toes. The prognosis is not worse than that of melanomas with the same thickness, mitotic rate, or presence of ulceration on other sites. Melanomas of the nail apparatus behave similar to melanomas in other localizations. What makes them enigmatic is the high rate of misdiagnoses and very late diagnoses.

Determinants of hepatitis A vaccine immunity in a cohort of human immunodeficiency virus-infected children living in Switzerland

Vaccination in HIV-infected children is often less effective than in healthy children. The goal of this study was to assess vaccine responses to hepatitis A virus (HAV) in HIV-infected children. Children of the Swiss Mother and Child HIV Cohort Study (MoCHiV) were enrolled prospectively. Recommendations for initial, catch-up, and additional HAV immunizations were based upon baseline antibody concentrations and vaccine history. HAV IgG was assessed by enzyme-linked immunosorbent assay (ELISA) with a protective cutoff value defined as ≥10 mIU/ml. Eighty-seven patients were included (median age, 11 years; range, 3.4 to 21.2 years). Forty-two patients were seropositive (48.3%) for HAV. Among 45 (51.7%) seronegative patients, 36 had not received any HAV vaccine dose and were considered naïve. Vaccine responses were assessed after the first dose in 29/35 naïve patients and after the second dose in 33/39 children (25 initially naïve patients, 4 seronegative patients, and 4 seropositive patients that had already received 1 dose of vaccine). Seroconversion was 86% after 1 dose and 97% after 2 doses, with a geometric mean concentration of 962 mIU/ml after the second dose. A baseline CD4(+) T cell count below 750 cells/μl significantly reduced the post-2nd-dose response (P = 0.005). Despite a high rate of seroconversion, patients with CD4(+) T cell counts of <750/μl had lower anti-HAV antibody concentrations. This may translate into a shorter protection time. Hence, monitoring humoral immunity may be necessary to provide supplementary doses as needed.

Catheter-based treatment of ilio-femoral deep vein thrombosis - an update on current evidence

Ilio-femoral deep vein thrombosis (DVT) has a high rate of long-term morbidity in the form of the postthrombotic syndrome (PTS). Therefore, management of acute thrombosis should not only focus on the prevention of acute complications such as propagation or embolisation of the initial clot but also on preventing PTS and recurrent thrombosis. Contemporary catheter-based treatments of deep vein thrombosis have proven to be safe and effective in selected patients. Current guidelines recommend medical therapy with anticoagulation alone for all but the most severe, limb-threatening thrombosis. They additionally allow for consideration of catheter-based treatment in patients with acute DVT and low risk of bleeding complications to prevent PTS. Recent studies favoring interventional therapy have not been included in these guidelines. Data on long-term outcome is expected to be published soon, clarifying and very likely strengthening the role of catheter-based treatments in the management of acute ilio-femoral DVT.

Globally dispersed Y chromosomal haplotypes in wild and domestic sheep

To date, investigations of genetic diversity and the origins of domestication in sheep have utilised autosomal microsatellites and variation in the mitochondrial genome. We present the first analysis of both domestic and wild sheep using genetic markers residing on the ovine Y chromosome. Analysis of a single nucleotide polymorphism (oY1) in the SRY promoter region revealed that allele A-oY1 was present in all wild bighorn sheep (Ovis canadensis), two subspecies of thinhorn sheep (Ovis dalli), European Mouflon (Ovis musimon) and the Barbary (Ammontragis lervia). A-oY1 also had the highest frequency (71.4%) within 458 domestic sheep drawn from 65 breeds sampled from Africa, Asia, Australia, the Caribbean, Europe, the Middle East and Central Asia. Sequence analysis of a second locus, microsatellite SRYM18, revealed a compound repeat array displaying fixed differences, which identified bighorn and thinhorn sheep as distinct from the European Mouflon and domestic animals. Combined genotypic data identified 11 male-specific haplotypes that represented at least two separate lineages. Investigation of the geographical distribution of each haplotype revealed that one (H6) was both very common and widespread in the global sample of domestic breeds. The remaining haplotypes each displayed more restricted and informative distributions. For example, H5 was likely founded following the domestication of European breeds and was used to trace the recent transportation of animals to both the Caribbean and Australia. A high rate of Y chromosomal dispersal appears to have taken place during the development of domestic sheep as only 12.9% of the total observed variation was partitioned between major geographical regions.

Tyrosine kinase modulation of protein kinase C activity regulates G protein-linked Ca2+ signaling in leukemic hematopoietic cells

We have used a recombinant mouse pre-B cell line (TonB210.1, expressing Bcr/Abl under the control of an inducible promoter) and several human leukemia cell lines to study the effect of high tyrosine kinase activity on G protein-coupled receptor (GPCR) agonist-stimulated cellular Ca(2+) release and store-operated Ca(2+) entry (SOCE). After induction of Bcr/Abl expression, GPCR-linked SOCE increased. The effect was reverted in the presence of the specific Abl inhibitor imatinib (1microM) and the Src inhibitor PP2 (10microM). In leukemic cell lines constitutively expressing high tyrosine kinase activity, Ca(2+) transients were reduced by imatinib and/or PP2. Ca(2+) transients were enhanced by specific inhibitors of PKC subtypes and this effect was amplified by tyrosine kinase inhibition in Bcr/Abl expressing TonB210.1 and K562 cells. Under all conditions Ca(2+) transients were essentially blocked by the PKC activator PMA. In Bcr/Abl expressing (but not in native) TonB210.1 cells, tyrosine kinase inhibitors enhanced PKCalpha catalytic activity and PKCalpha co-immunoprecipitated with Bcr/Abl. Unlike native TonB210.1 cells, Bcr/Abl expressing cells showed a high rate of cell death if Ca(2+) influx was reduced by complexing extracellular Ca(2+) with BAPTA. Our data suggest that tonic inhibition of PKC represents a mechanism by which high tyrosine kinase activity can enhance cellular Ca(2+) transients and thus exert profound effects on the proliferation, apoptosis and chemotaxis of leukemic cells.