Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients

The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly patients, who only normalized their insulin like growth factor (IGF-I) levels with high-dose pegvisomant therapy. We present two cases of a 31 and 44 years old male with gigantism and acromegaly that were controlled subsequently by surgery, radiotherapy, SRIF analogs and daily PEG-V treatment. They were converted to combined treatment of monthly SSA and (twice) weekly PEG-V. High dose SSA treatment was added while the PEG-V dose was decreased during carful monitoring of the IGF-I. After switching from PEG-V monotherapy to SRIF analogs plus pegvisomant combination therapy IGF-I remained normal. However, the necessary PEG-V dose, to normalize IGF-I differed significantly between these two patients. One patient needed twice weekly 100 mg, the second needed 60 mg once weekly on top of their monthly lanreotide Autosolution injections of 120 mg. The weekly dose reduction was 80 and 150 mg. After the introducing of lanreotide, fasting glucose and glycosylated haemoglobin concentrations increased. Diabetic medication had to be introduced or increased. No changes in liver tests or in pituitary adenoma size were observed. In these two patients, PEG-V in combination with long-acting SRIF analogs was as effective as PEG-V monotherapy in normalizing IGF-I levels, although significant dose-reductions in PEG-V could be achieved. However, there seems to be a wide variation in the reduction of PEG-V dose, which can be obtained after conversion to combined treatment

Style, Function and Cultural Transmission

Recent evolutionary approaches to the understanding of lithic variability take us back to long-standing issues in lithic studies to do with the claimed contrast between style and function and the Binford-Bordes debate of the 1960s concerning the factors that affect inter-assemblage variation. In fact, the style and function contrast is an unhelpful one, not least when considering the question of convergence. Taking the definition of style as ‘a way of doing’, all functions are carried out in locally specific ways that have a transmission history, although the extent to which the history of the attributes relevant to the function have been subject to random drift and innovation patterns, as opposed to selection, will vary. Moreover, in a subtractive technology like lithics the extent to which a transmission signal will be visible in an attribute like the angle of a cutting edge is unclear. The contrasting view is that, in the case of lithics, functional requirements will always call into existence the technical innovations to satisfy them, which in any case are not that difficult to find. The paper addresses these and related issues with reference to previous work by Shennan and colleagues on the use of material culture to identify within and between group variation, the extent to which isolation-by-distance in space and time can account for the similarities and differences between assemblages, and the role of phylogenetic methods

Capturing a Flavivirus Pre-Fusion Intermediate

During cell entry of flaviviruses, low endosomal pH triggers the rearrangement of the viral surface glycoproteins to a fusion-active state that allows the release of the infectious RNA into the cytoplasm. In this work, West Nile virus was complexed with Fab fragments of the neutralizing mAb E16 and was subsequently exposed to low pH, trapping the virions in a pre-fusion intermediate state. The structure of the complex was studied by cryo-electron microscopy and provides the first structural glimpse of a flavivirus fusion intermediate near physiological conditions. A radial expansion of the outer protein layer of the virion was observed compared to the structure at pH 8. The resulting ∼60 Å-wide shell of low density between lipid bilayer and outer protein layer is likely traversed by the stem region of the E glycoprotein. By using antibody fragments, we have captured a structural intermediate of a virus that likely occurs during cell entry. The trapping of structural transition states by antibody fragments will be applicable for other processes in the flavivirus life cycle and delineating other cellular events that involve conformational rearrangements

Controlled experiments in lithic technology and function

From the earliest manifestations of tool production, technologies have played a fundamental role in the acquisition of different resources and are representative of daily activities in the lives of ancient humans, such as hunting (stone-tipped spears) and meat processing (chipped stone tools) (Lombard 2005; McPherron et al. 2010; Lombard and Phillipson 2010; Brown et al. 2012; Wilkins et al. 2012; Sahle et al. 2013; Joordens et al. 2015; Ambrose 2001; Stout 2001). Yet many questions remain, such as how and why technological changes took place in earlier populations, and how technological traditions, innovations, and novelties enabled hominins to survive and disperse across the globe (Klein 2000; McBrearty and Brooks 2000; Henshilwood et al. 2001; Marean et al. 2007; Brown et al. 2012; Režek et al. 2018).Projekt DEALinfo:eu-repo/semantics/publishedVersio