Clade extinction appears to balance species diversification in sister lineages of Afro-Oriental passerine birds

Recent analyses suggest that the number of species in a clade often increases rapidly at first, but that diversification subsequently slows, apparently as species fill ecological space. Support for diversity dependence comes largely from the failure of species richness to increase with clade age in some analyses of contemporary diversity. However, clades chosen for analysis generally are named taxa and thus are not selected at random. To avoid this potential bias, we analyzed the numbers of species and estimated ages of 150 pairs of sister clades established by dispersal of ancestral species between the Oriental and African biogeographic regions. The observed positive exponential relationship between clade size and age suggests that species diversify within clades without apparent limit. If this were true, the pattern of accumulation of sister-clade pairs with increasing age would be consistent with the random decline and extinction of entire clades, maintaining an overall balance in species richness. This “pulse” model of diversification is consistent with the fossil record of most groups and reconciles conflicting evidence concerning diversity dependence of clade growth.The close relationship between local species richness and characteristics of the physical environment supports the existence of ecological constraints on species coexistence mediated through competition and other interactions (1–3), although historical influences on diversity sometimes parallel gradients in the physical environment (4–6). If species richness were limited as ecological space filled, one would expect the net rate of species production to slow and the number of species in a clade to level off as species richness approached ecological constraints.Evidence for such “diversity-dependent diversification” consists mostly of (i) nonrandom concentrations of branch points (speciation events) toward the origin of a clade (7–12) and (ii) independence of the number of species and clade age in comparisons among clades (11–14). However, clades included in such analyses often are not randomly chosen. In particular, small clades may be ignored because they do not command interest, and large, older clades are often passed over because of incomplete sampling (15, 16). Moreover, most phylogenetic analyses of diversification include species in named higher taxa rather than clades that have diversified within particular regions.Further support for diversity limits comes from the fossil records of many higher taxa, which exhibit long-term stability in number of species (17–19). It is also clear that species and entire clades continually replace each other through time, and the dynamics of this process appear to include the decline and extinction of evolutionary groups as a component of the local and regional regulation of the number of coexisting species (20–25).We take advantage of the sister relationships of clades of passerine birds in two major biogeographic regions—tropical southern Asia [Oriental (OR)] and the continent of Africa [African (AF)]—to examine the independent diversification of sister clades of known stem ages, selected only because one of the ancestors had dispersed between the two continents at some time in the past. Movement of species between these regions occurred either over water across the Indian Ocean, possibly using island stepping-stones, or through the Arabian Peninsula during periods of suitable environment. Each dispersal event defines the origin of a pair of same-aged sister clades in the two regions.If each diversifying clade filled a certain part of ecological space to a carrying capacity for species, after which diversification slowed, the sizes of clades filling this space would level off over time (26). Furthermore, the number of species per sister clade, particularly among older clades that have filled ecological space, might be correlated between regions, with species richness reflecting the ecological space available to each of the sister lineages (27). Finally, for those dispersal events whose directionality can be inferred, the rate of diversification should be higher, leading to larger clade size compared between sister lineages, in the newly colonized region, which initially would have fewer close (and ecologically similar) relatives of the ancestral species.We include all species of passerine birds (Passeriformes) and, separately, species in nonpasserine orders, of small, terrestrial birds, in the Oriental and African biogeographic regions (SI Appendix, section S1). The passerine avifauna of these regions accumulated from several sources over most of the Cenozoic Era (28, 29), with an old Gondwanan clade of suboscine passerines diversifying in tropical Africa and southern Asia early in the Tertiary, followed by radiations of core corvoid and passerid oscine passerines out of Australia during the early to mid-Cenozoic, through Wallacea to southern Asia, or directly across the Indian Ocean to Africa (30, 31). Thus, the diversification of sister clades in the African and Oriental regions takes place against a background of an increasing number of lineages of modern passerine birds as a whole within the region. Nonpasserine orders of terrestrial birds are likely to have diversified earlier within these regions (32) and perhaps were replaced to some extent by the passerines.Characteristics of a sample of clades include the distribution of node ages and the relationship between clade size and stem age, as well as the distribution of clade sizes regardless of age, including the proportion of clades that contain a single species. Any process-based model of diversification should be judged by how well it reproduces these characteristics. We use these criteria to evaluate simulations in which we attempt to reconstruct the underlying diversification process.     

Effect of simvastatin on coronary lesion site remodeling: a serial intravascular ultrasound study

BACKGROUND: Direct evidence of coronary artery remodeling can be derived only from serial changes in the external elastic membrane (EEM) and plaque area. The aim of the study was to assess the effect of simvastatin on coronary remodeling in serial intravascular ultrasound (IVUS) studies. METHODS: In 39 male patients ECG-triggered transducer pullback IVUS was performed at baseline, after 3 months on a lipid-lowering diet (control period), and after another 12 months of simvastatin 40 mg/day. The lesion site was the image slice with maximum plaque burden at 3 months. RESULTS: Absolute changes in the EEM area correlated significantly with changes in plaque area during the control period [B = 0.966, r = 0.792 (95% CI 0.71-1.22); p < 0.001] and during simvastatin treatment [B = 0.945, r = 0.822 (95% CI 0.73-1.16); p < 0.001], but there was no significant difference in the slope (delta EEM/delta plaque) between the two time intervals. After 12 months of simvastatin, there was a significant reduction in the lesion EEM area of 4.6% (p = 0.006) and in the lesion plaque area of 5.9% (p < 0.001), but there was no change in reference measurements. As a result, the remodeling index was reduced by simvastatin from 1.01 +/- 0.12 to 0.95 +/- 0.09 (p < 0.001). CONCLUSION: Simvastatin decreases the remodeling index by reducing lesion, but not reference plaque and EEM area. However, simvastatin does not affect direct evidence of remodeling (delta EEM/delta plaque) obtained using serial IVUS studies.     

Reasons for treating secondary AML as de novo AML

In a Danish bi‐regional registry‐based study, we conducted an analysis of the incidence and clinical importance of secondary acute myeloid leukaemia (AML). In a total of 630 cases of AML, we found 157 (25%) cases of secondary AML. The secondary leukaemia arose from MDS (myelodysplastic syndrome) in 77 cases (49%), CMPD (chronic myeloproliferative disorder) in 43 cases (27%) and was therapy‐related AML (t‐AML) in 37 cases (24%). Median age at diagnosis of AML was 69 yr in secondary cases when compared to 66 yr in de novo cases (P = 0.006). In univariate analyses, secondary AML was associated with an inferior complete remission (CR) rate (P = 0.008) and poorer overall survival (OS, P = 0.003) whereas in complete remitters, disease‐free survival (DFS) of secondary cases was equal to that of de novo cases. Interestingly, in all further analyses of CR‐rates, OS and DFS, when correcting for the influence of age, cytogenetic abnormalities, performance status and leucocyte count (WBC), presence of secondary AML completely lost prognostic significance. We conclude that the presence of secondary AML does not per se convey an unfavourable prognosis and that patients with secondary AML should be offered the chance of benefiting from treatment according to current frontline AML protocols.     

High-resolution SNP mapping by denaturing HPLC

With the availability of complete genome sequences, new rapid and reliable strategies for positional cloning become possible. Single-nucleotide polymorphisms (SNPs) permit the mapping of mutations at a resolution not amenable to classical genetics. Here we describe a SNP mapping procedure that relies on resolving polymorphisms by denaturing HPLC without the necessity of determining the nature of the SNPs. With the example of mapping mutations to the Drosophila nicastrin locus, we discuss the benefits of this method, evaluate the frequency of closely linked and potentially misleading second site mutations, and demonstrate the use of denaturing high-performance liquid chromatography to identify mutations in the candidate genes and to fine-map chromosomal breakpoints. Furthermore, we show that recombination events are not uniformly dispersed over the investigated region but rather occur at hot spots.     

Epidermal growth factor-mediated activation of the map kinase cascade results in altered expression and function of ABCG2 (BCRP).

Epidermal growth factor (EGF) is a multifunctional growth factor known to play a major role in proliferation and differentiation processes. EGF-induced differentiation is a prerequisite for function of various cell types, among them cytotrophoblasts, a functionally important cellular fraction in human placenta. Stimulation of cytotrophoblasts with EGF results in formation of a multinuclear syncytium representing the feto-maternal interface, which protects the fetus against exogenous substances. It is well established that part of this protection system is based on ATP-binding cassette (ABC) transporters such as ABCG2 (breast cancer resistance protein, BCRP). However, little is known about regulation of transport proteins in the framework of EGF-mediated cellular differentiation. In the present work we show a significant increase of ABCG2 expression by EGF in cytotrophoblasts, BeWo, and MCF-7 cells on both mRNA and protein levels. This increase resulted in decreased sensitivity to the ABCG2 substrates mitoxantrone and topotecan. In each cell type, EGF increases expression of ABCG2 by activation of mitogen-activated protein kinase cascade via phosphorylation of extracellular regulated kinase (ERK)1/2 and c-jun NH-terminal kinase/stress-activated protein kinase (JNK/SAPK). Consequently, the increase of ABCG2 by EGF was abolished by pretreatment of cells with the tyrosine kinase inhibitor 4-(3-chloroanillino)-6,7-dimethoxyquinazoline (AG1478) or the mitogen-activated protein kinase kinase inhibitor 2'-amino-3'methoxyflavone (PD 98059), thereby reestablishing sensitivity toward mitoxantrone. Moreover, analysis of ABCG2 expression during placental development revealed a significant increase in preterm versus term placenta. Taken together, our data show regulation of ABCG2 expression by EGF. In view of EGF signal transduction as a target for drugs (e.g., gefitinib), which are in turn substrates and/or inhibitors of ABCG2, this regulation has therapeutic consequences.     

Morphological abnormalities of the terminal neuromuscular apparatus in recent juvenile diabetes

Summary Muscle biopsies from eight cases of acute juvenile diabetes (a few weeks after the beginning of the disease) revealed well marked degenerative changes combined with vigorous regeneration of the terminal neuromuscular apparatus. This observation is in accordance with previous demonstrations of neurophysiological disturbances at this early stage of diabetes.

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Morphologische Anomalien der neuromuskulären Endplatte bei frisch entdeckten juvenilen Diabetikern

Zusammenfassung Muskelbiopsien von 8 Patienten mit akutem juvenilem Diabetes (einige Wochen nach Krankheitsausbruch) zeigten ausgeprägte degenerative Veränderungen mit kräftigen Regenerationserscheinungen an der neuromuskulären Endplatte. Diese Befunde stimmen mit früher mitgeteilten Beobachtungen neurophysiologischer Störungen dieses Frühstadiums des Diabetes überein.

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Anomalies morphologiques de l'appareil neuro-musculaire terminal dans le diabète juvénile récent

Résumé Dans huit cas de diabete juvénile aigu (quelques semaines après le début de la maladie) des biopsies musculaires ont révélé des modifications dégénératives bien marquées, associées á une puissante régénération de l'appareil neuro-musculaire terminal. Cette observation est en accord avec les démonstrations précédentes de troubles neurophysiologiques à ce stade précoce du diabète.

     

The supra-additive natriuretic effect addition of bendroflumethiazide and bumetanide in congestive heart failure: Permutation trial tests in patients in long-term treatment with bumetanide

The additive natriuretic effect of a single dose of bendroflumethiazide, 5 mg., has been studied in patients with advanced congestive heart failure in long-term treatment with bumetanide, 4 mg., daily. Three permutation trial tests were performed including six patients each. In the first trial, the response to supplementary bendroflumethiazide, 5 mg., was definitely superior to that of additional bumetanide, 4 mg., in terms of renal output of sodium, chloride, potassium, water, and osmolal clearance. In the second trial, a similar pattern was found in patients receiving a combination of bumetanide, 4 mg., and spironolactone, 100 mg., daily. The third trial compared the effects of bendroflumethiazide, 5 mg., plus bumetanide, 4 mg.; of bendroflumethiazide, 5 mg.; and of bumetanide, 4 mg. In terms of natriuresis and chloruresis, the response to the combination of two drugs was significantly larger than the sum of the effects of other treatments.It is concluded that the combined effects of the drugs represent a supra-additive effect addition for sodium and chloride. A tentative explanation of the mechanism of interaction in terms of inhibition of renal tubular sodium transport is given.Since the combined effects of the two drugs, independent of supplementary spironolactone, involve a tendency to development of hypokalemia, hypochloremia, and alkalosis, it is recommended that supplementary use of bendroflumethiazide in this setting is combined with the administration of potassium chloride or potassium-saving diuretics.