Fibrin glue for fistula–in–ano: the evidence reviewed

Fibrin glue is increasingly used in the treatment of anal fistulae. This review aims to establish its longterm efficacy and clarify its role in this setting. A search of Medline and Pubmed databases was performed from 1966 to 2004. Data were collated regarding the type of study, fistula aetiology and complexity, technical aspects of glue application, and short– and long–term healing rates. The majority of studies comprised prospective series with fistulae of mixed aetiology. The overall healing rate was 53% with a wide variation between studies (10%–78%). The only factor that could account for this diversity was fistula complexity, with series including a high proportion of complex fistulae reporting worse outcomes. The quality of data to assess the efficacy of fibrin glue in the treatment of anal fistulae is poor and further clinical trials are needed. Fistula complexity is the main factor that adversely influences long–term healing rates.     

Fossil evidence for a hyperdiverse sclerophyll flora under a non–Mediterranean-type climate

The spectacular diversity of sclerophyll plants in the Cape Floristic Region in South Africa and Australia’s Southwest Floristic Region has been attributed to either explosive radiation on infertile soils under fire-prone, summer-dry climates or sustained accretion of species under inferred stable climate regimes. However, the very poor fossil record of these regions has made these ideas difficult to test. Here, we reconstruct ecological-scale plant species richness from an exceptionally well-preserved fossil flora. We show that a hyperdiverse sclerophyll flora existed under high-rainfall, summer-wet climates in the Early Pleistocene in southeastern Australia. The sclerophyll flora of this region must, therefore, have suffered subsequent extinctions to result in its current relatively low diversity. This regional loss of sclerophyll diversity occurred at the same time as a loss of rainforest diversity and cannot be explained by ecological substitution of species of one ecological type by another type. We show that sclerophyll hyperdiversity has developed in distinctly non-Mediterranean climates, and this diversity is, therefore, more likely a response to long-term climate stability. Climate stability may have both reduced the intensity of extinctions associated with the Pleistocene climate cycles and promoted the accumulation of species richness by encouraging genetic divergence between populations and discouraging plant dispersal.     

Genome-wide evidence of Austronesian–Bantu admixture and cultural reversion in a hunter-gatherer group of Madagascar

Linguistic and cultural evidence suggest that Madagascar was the final point of two major dispersals of Austronesian- and Bantu-speaking populations. Today, the Mikea are described as the last-known Malagasy population reported to be still practicing a hunter-gatherer lifestyle. It is unclear, however, whether the Mikea descend from a remnant population that existed before the arrival of Austronesian and Bantu agriculturalists or whether it is only their lifestyle that separates them from the other contemporary populations of South Madagascar. To address these questions we have performed a genome-wide analysis of >700,000 SNP markers on 21 Mikea, 24 Vezo, and 24 Temoro individuals, together with 50 individuals from Bajo and Lebbo populations from Indonesia. Our analyses of these data in the context of data available from other Southeast Asian and African populations reveal that all three Malagasy populations are derived from the same admixture event involving Austronesian and Bantu sources. In contrast to the fact that most of the vocabulary of the Malagasy speakers is derived from the Barito group of the Austronesian language family, we observe that only one-third of their genetic ancestry is related to the populations of the Java-Kalimantan-Sulawesi area. Because no additional ancestry components distinctive for the Mikea were found, it is likely that they have adopted their hunter-gatherer way of life through cultural reversion, and selection signals suggest a genetic adaptation to their new lifestyle.Located 400 km of the East African coast, Madagascar has been referred to as “the single most astonishing fact of human geography” (1, 2). Despite its proximity to Africa, less than 10% of the vocabulary of the Malagasy language is from African languages (mainly Sabaki, a branch of Bantu) (3–5). In contrast, 90% of Malagasy vocabulary belongs to the Barito (6) or other subgroups of Austronesian languages of Island Southeast Asia (7–9). Although being less specific, genetic studies have generally confirmed the dual ancestry of the Malagasy population (10–14).Low genetic differentiation of the Malagasy mtDNA and Y chromosome lineages from related lineages observed in present day Bantu and Austronesian populations support a model drawn from linguistic evidence that the Malagasy gene pool has been derived predominantly from these two dispersals of agriculturalist populations. As shown by linguistic and phylogenetic studies on cattle and crop names and their genetic diversity, both agricultural populations have apparently brought their way of life once they had settled in Madagascar (15, 16).Although one archaeological report claims the presence of anthropic artifacts as early as 4,000 y ago (17), most research points to first human impact on the Malagasy environment around 2,400 y ago (18), which would still be before the Bantu expansion reached the East African coast (19). In addition, European traveler reports and putative archaeological artifacts support hunter-gatherers living in the south of the island until the 16th century (20–23). It has been speculated that these hunter-gatherer groups were the remnants of a pre-Bantu settlement of Madagascar (24). The cause of disappearance of the hunter-gatherers after the 16th century is unknown, but the two most likely scenarios that can be contemplated involve either a cultural shift or population replacement.Traditions concerning the dispersal of a sedentary way of life and agriculture in the south of the island relate to the Sakalava expansion (25). These traditions recount that in the 17th century, leaders, soothsayers, and migrants from the arabo-islamized Temoro population from the southeastern coast of Madagascar colonized the southern regions of Madagascar with the intention of creating new cities and kingdoms, such as Maroserana and Andrevola (25, 26). A few decades later, new Sakalava kingdoms emerge on the southeast coast and gradually spread throughout southern Madagascar, which coincides with the disappearance of hunter-gatherer populations (25).The survival in Madagascar of a modern hunter-gatherer population was believed to be a myth (24, 25). However, there are a variety of hunter-gatherer groups scattered across the island that have been studied and mapped since the 1920s, particularly in the Tsiribihina region (southwest Madagascar) under the names Vazimba and Beosi (27). In the Mikea forest (south of the Mangoky River, southern Madagascar) one population, the Mikea, still live as hunter-gatherers. Earlier writers thought the Mikea were descended from ancient forager groups who have maintained their way of life up to the present (24, 25, 27, 28), but most modern scholarship argues the Mikea reverted back to the forest for political or economical reasons, such as Sakalava royalty pressure or French colonization (29–31).We address here the question of whether and to what extent the Mikea share their genetic ancestry with their neighboring Malagasy populations with a sedentary lifestyle. Specifically, we aim to detect in the Mikea patterns of genetic diversity assignable to a population that would predate Austronesian and Bantu incursions. Alternatively, we consider the scenario by which it is only their subsistence strategy that separates the Mikea from other contemporary populations in southern Madagascar.To answer these questions, we performed a genome-wide analysis of 21 Mikea individuals, 24 individuals from a nearby Vezo population, and 24 individuals of the Temoro population, using Illumina HumanOmniExpress BeadChips, and compared the data with Southeast Asian and African populations. Based on this dataset, we have: (i) studied the genetic distance between the three Malagasy populations; (ii) tested the existence and age of admixture patterns; and (iii) tested the Mikea genome for any adaptive signal that may be associated with the hunter-gather way of life.     

Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus α-hemolysin–mediated cellular injury

Staphylococcus aureus α-hemolysin (Hla), a potent cytotoxin, plays an important role in the pathogenesis of staphylococcal diseases, including those caused by methicillin-resistant epidemic strains. Hla is secreted as a water-soluble monomer that undergoes a series of conformational changes to generate a heptameric, β-barrel structure in host membranes. Structural maturation of Hla depends on its interaction with a previously unknown proteinaceous receptor in the context of the cell membrane. It is reported here that a disintegrin and metalloprotease 10 (ADAM10) interacts with Hla and is required to initiate the sequence of events whereby the toxin is transformed into a cytolytic pore. Hla binding to the eukaryotic cell requires ADAM10 expression. Further, ADAM10 is required for Hla-mediated cytotoxicity, most notably when the toxin is present at low concentrations. These data thus implicate ADAM10 as the probable high-affinity toxin receptor. Upon Hla binding, ADAM10 relocalizes to caveolin 1-enriched lipid rafts that serve as a platform for the clustering of signaling molecules. It is demonstrated that the Hla–ADAM10 complex initiates intracellular signaling events that culminate in the disruption of focal adhesions.     

Lifetime Risk of Stage 3–5 CKD in a Community-Based Sample in Iceland

Background and objectives

Lifetime risk estimates of CKD can be used effectively in public education campaigns. This study sought to estimate lifetime risk of incident CKD stage 3 and higher in Iceland for people without CKD by the age of 45 years.

Design, setting, participants, & measurements

This was a prospective cohort study with longitudinal creatinine measurements of residents in Reykjavik, Iceland, from 1967 to 2005. CKD was ascertained by two consecutive eGFR measurements <60 ml/min per 1.73 m², development of treated kidney failure, one eGFR<60 ml/min per 1.73 m² if the participant died before the next evaluation, or one eGFR<45 ml/min per 1.73 m² if it was the last eGFR.

Results

Mean follow-up was 25 (SD 10) years. Of the study participants, 727 (19%) developed the outcome and 942 (24%) died first. By age 85 years, the lifetime risks for 45-year-old women and men without prevalent CKD were 35.8% (95% confidence interval [95% CI], 32.7 to 38.9) and 21.3% (95% CI, 18.7 to 23.8), respectively. Risk was higher in individuals with a lower eGFR, hypertension, and a higher body mass index. Lifetime risk for higher stages of CKD 3b and 4 were less common than stage 3a; by age 85 years, the lifetime risks for CKD stages 3a, 3b, and 4 in women were 38.5% (95% CI, 25.8 to 51.1), 19.4% (95% CI, 8.9 to 29.9), and 3.6% (95% CI, 2.2 to 5.0), respectively.

Conclusions

The lifetime risk of developing CKD stage 3 or higher is substantial, emphasizing the importance of strategies to prevent development of CKD throughout the course of life. Estimates are lower than reported using single estimates of GFR, emphasizing the importance of confirming estimates of reduced GFR in studies of CKD.     

What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium?

Microalbuminuria is an important risk factor for cardiovascular disease and progressive renal impairment. This holds true in the general population and particularly in those with diabetes, in whom it is common and marks out those likely to develop macrovascular disease and progressive renal impairment. Understanding the pathophysiological mechanisms through which microalbuminuria occurs holds the key to designing therapies to arrest its development and prevent these later manifestations. Microalbuminuria arises from the increased passage of albumin through the glomerular filtration barrier. This requires ultrastructural changes rather than alterations in glomerular pressure or filtration rate alone. Compromise of selective glomerular permeability can be confirmed in early diabetic nephropathy but does not correlate well with reported glomerular structural changes. The loss of systemic endothelial glycocalyx—a protein-rich surface layer on the endothelium—in diabetes suggests that damage to this layer represents this missing link. The epidemiology of microalbuminuria reveals a close association with systemic endothelial dysfunction and with vascular disease, also implicating glomerular endothelial dysfunction in microalbuminuria. Our understanding of the metabolic and hormonal sequelae of hyperglycaemia is increasing, and we consider these in the context of damage to the glomerular filtration barrier. Reactive oxygen species, inflammatory cytokines and growth factors are key players in this respect. Taken together with the above observations and the presence of generalised endothelial dysfunction, these considerations lead to the conclusion that glomerular endothelial dysfunction, and in particular damage to its glycocalyx, represents the most likely initiating step in diabetic microalbuminuria.     

Indications for 5-aminosalicylate in inflammatory bowel disease： IS the body of evidence complete？

INTRODUCTION In the late 1970s, elegant studies revealed that 5-aminosalicylate is the active moiety of sulphasalazine in patients suffering from ulcerative colitis (UC) and Crohn’s disease (CD)[1,2]. Since then, 5-aminosalicylate has become the gold standard first line therapy for patients with UC, although its use in CD remains controversial. After 25 years, discussion of monocomponent 5-aminosalicylate with regard to its efficacy in comparison with sulphasalazine[3,4], drug profile…     

Is there a place for cardiovascular magnetic resonance imaging in the evaluation of cardiovascular involvement in rheumatic diseases?

Cardiovascular magnetic resonance (CMR) is a noninvasive, nonradiating imaging technique, which provides novel information for the evaluation of cardiovascular diseases. Until now it has been successfully used for the evaluation of congenital and acquired heart diseases, cardiac tumors-mass, iron overload, and myocardial fibrosis detection. Recently, its diagnostic capabilities have been extended to the evaluation of myocardial inflammation and myocardial perfusion. Currently, it is considered the gold standard for the evaluation of volumes, mass, ejection fraction of atriums and ventricles, quantification of iron overload in different organs, detection and follow-up of myocardial inflammation, myocardial infarction and its complications, evaluation of the aorta, detection of anomalous coronary arteries, and ectatic or aneurysmatic coronary arteries. All the above applications and mainly the CMR ability to detect myocardial inflammation, perfusion defects, fibrosis, coronary and great arteries aneurysms make it a valuable tool for cardiovascular system assessment, commonly affected during the course of rheumatic diseases. The technique has been already successfully used in the evaluation of vasculitides, systemic lupus erythematosus, myositis, and scleroderma. However, further studies are needed to evaluate its usefulness as a diagnostic and monitoring tool of cardiovascular involvement in rheumatic patients.     

Molecular basis for SH3 domain regulation of F-BAR–mediated membrane deformation

Members of the Bin/amphiphysin/Rvs (BAR) domain protein superfamily are involved in membrane remodeling in various cellular pathways ranging from endocytic vesicle and T-tubule formation to cell migration and neuromorphogenesis. Membrane curvature induction and stabilization are encoded within the BAR or Fer-CIP4 homology-BAR (F-BAR) domains, α-helical coiled coils that dimerize into membrane-binding modules. BAR/F-BAR domain proteins often contain an SH3 domain, which recruits binding partners such as the oligomeric membrane-fissioning GTPase dynamin. How precisely BAR/F-BAR domain-mediated membrane deformation is regulated at the cellular level is unknown. Here we present the crystal structures of full-length syndapin 1 and its F-BAR domain. Our data show that syndapin 1 F-BAR-mediated membrane deformation is subject to autoinhibition by its SH3 domain. Release from the clamped conformation is driven by association of syndapin 1 SH3 with the proline-rich domain of dynamin 1, thereby unlocking its potent membrane-bending activity. We hypothesize that this mechanism might be commonly used to regulate BAR/F-BAR domain-induced membrane deformation and to potentially couple this process to dynamin-mediated fission. Our data thus suggest a structure-based model for SH3-mediated regulation of BAR/F-BAR domain function.     

Direct acting inhibitors of ammoniagenesis: a role in post-TIPS encephalopathy?

A limited number of medications are typically considered for the management of hepatic encephalopathy occurring as a complication of transjugular intrahepatic portosystemic shunt (TIPS) placement. Multiple alternative compounds aimed at disrupting ammoniagenesis are or will soon be available, though their use tends to be limited by a lack of large data sets and of clinical awareness. In this review, we provide a targeted overview of the mechanisms and availability of five anti-ammoniagenic compounds (sodium phenylbutyrate, glycerol phenylbutyrate, sodium benzoate, L-ornithine L-aspartate, and ornithine phenylacetate) identified as possibly useful alternative therapeutic agents for cirrhotic encephalopathy. Three of these medications have been FDA approved for use in congenital urea cycle disorders only, while two are under active investigation for use in cirrhotic patients. In spite of limitations posed by cost and comorbidities, familiarity with these options may prove beneficial in cases refractory to conventional management.     

VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism and serves as a marker of poor prognosis for cancer patients

The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A–null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk^−/− mice and mice treated with anti–VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.Although genetic alterations of malignant cells govern the intrinsic features of invasiveness, host-derived cellular and molecular components may play predominant roles in cancer invasion and metastasis (1). For example, the tumor vasculature is essential for tumor growth and metastasis (2), and blocking tumor angiogenesis has been used successfully for treatment of animal and human cancers (3–5). Similarly, targeting other nonvascular host components, including inflammatory cells and stromal cells, also provides effective therapeutic options for treatment of cancer (6). Hematogenous metastasis is a complex process that involves intimate interactions between malignant cells and various host cells. At the primary tumor site, tumor cells must intravasate through the vessel wall into the circulation, and intravasation requires cooperative and coordinated interactions between tumor cells, perivascular cells such as pericytes, endothelial cells, and possibly inflammatory cells (7–9). In addition to their physical interactions, tumor cells and host cells produce various signaling molecules that modulate cell morphology, migration, proliferation, production of proteases, and adhesion molecules. Consequently, the vascular endothelium within and surrounding primary tumors undergoes structural changes that permit tumor cell invasion. After arriving at distal organs, tumor cells need to extravasate from the circulation. Again, circulating tumor cells interact closely with endothelial cells and perivascular cells to manipulate vascular structures for extravasation (10). The subsequent formation of metastatic niches and regrowth of metastatic nodules to clinically detectable masses are dependent on angiogenesis and vascular remodeling.Tumors often express angiogenic factors at high levels to induce neovascularization (11). Multiple growth factors/cytokines and their signaling receptors often coexist in the same tumor microenvironment and collectively modulate tumor growth, invasiveness and metastasis (12). Among all known angiogenic factors, vascular endothelial growth factor A (VEGF-A), which modulates angiogenesis, vascular permeability, vessel survival, and vascular remodeling, is probably the best characterized (13, 14). Although VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2, two tyrosine kinase receptors, it is believed that VEGFR2 mediates most of these VEGF-A–triggered vascular functions (15). Unlike VEGF-A, VEGF-B binds only to VEGFR1, which also is considered a decoy receptor that transduces negative signals for angiogenesis (16, 17). Despite its early discovery, the biological functions, and especially the vascular functions, of VEGF-B remain an enigma (18, 19). Initially, VEGF-B was shown to stimulate endothelial cell activity and angiogenesis (18). However, later studies do not support these claims, and opposing results that VEGF-B inhibits tumor angiogenesis have been reported (20, 21). The roles of VEGF-B in tumor invasion and metastasis have not been studied.In this work, we report, for the first time to our knowledge, the crucial role of VEGF-B in modulating the vascular remodeling that facilitates tumor metastasis in human and mouse tumor models. Surprisingly, VEGF-B expression is reversely correlated with primary tumor growth, demonstrating that it negatively regulates tumor angiogenesis. Despite retarded growth rates of primary tumors, VEGF-B markedly promotes metastasis. Thus, primary tumor growth and metastasis are separate events, and the latter process is dependent on vascular alterations that become permissive for tumor invasion. Our present work provides compelling experimental evidence that VEGF-B is a metastatic factor and that targeting VEGF-B may be an important approach for the treatment of cancer invasion and metastasis.