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Aim Custom-made foot orthoses reduce plantar pressure, ulceration and amputation in patients with diabetes mellitus. There is limited evidence of their effect on foot pain. In a randomized, single-blind, sham-controlled trial, the efficacy of custom orthoses on foot pain and plantar pressure in diabetic patients with peripheral arterial disease was investigated. Methods Sixty-one participants were randomly assigned to either custom foot orthoses ( n = 30) or sham insoles ( n = 31). Both groups also received standardized walking footwear. Outcomes included foot pain and function, mean pressure, toe-brachial index, average daily steps, disability, comfort, quality of life, adherence and adverse events. A multivariate predictive model was constructed to explore factors contributing to pain relief during the trial. Results At 8 weeks, 95% of participants provided follow-up data, adherence was high and there were few adverse events. Foot pain and function scores significantly improved at 8 weeks with both custom orthoses and the sham, but there was no significant difference between groups. Custom orthoses reduced pressure significantly more than the sham. There were no significant differences between groups for toe-brachial index, daily steps, disability, comfort or quality of life. Regression modelling identified inappropriate pre-trial footwear as the strongest predictor of foot pain relief during the trial. Conclusions Custom foot orthoses significantly reduced plantar pressure compared with the sham, but there were no significant differences between groups for pain or function. The high-quality walking footwear provided to both groups may explain this finding. Footwear should have greater emphasis as the clinical intervention. [ABSTRACT FROM AUTHOR]

The perennial grass Dupontia fisheri is an important forage for reindeer (Rangifer tarandus platyrhynchus) in Svalbard. In a growth chamber experiment, biomass and tillering responses to different clipping frequencies and clipping heights, simulating different reindeer grazing pressures, were measured at two nutrition levels during two growthperiods. Total accumulated biomass was reduced by clipping at high frequency, low height, or both in the first growth period, but was unaffected by clipping in the second growth period. Moreover, the reducing effect of clipping on total biomass was present at low nutrition level only; i.e. plants compensated for high simulated grazing pressure when sufficient nutrients were available. Aboveground biomass was reduced 36% by high clipping frequency in the first growth period, but, due to a 61% reduction in aboveground biomass with time in unclipped plants, clipped groups appeared to have higher mean aboveground biomass than unclipped during the second growth period. This observationcould be explained by increased self-shading in the unclipped control plants over time. Although the interactions between nutrition and clipping treatments indicate that regrowth of D. fisheri is resource dependent, these results also suggest that grazing by reindeer is important for the maintenance of a high net aboveground production in D. fisheri in Svalbard. [ABSTRACT FROM AUTHOR]

The small ventrolateral neurons (sLNvs) are key components of the central clock in the Drosophila brain. They signal via the neuropeptide pigment-dispersing factor (PDF) to align the molecular clockwork of different central clock neurons and to modulate downstream circuits. The dorsal terminals of the sLNvs undergo daily morphological changes that affect presynaptic sites organised by the active zone protein Bruchpilot (BRP), a homolog of mammalian ELKS proteins. However, the role of these presynaptic sites for PDF release is ill-defined. Here, we combined expansion microscopy with labelling of active zones by endogenously tagged BRP to examine the spatial correlation between PDF-containing dense-core vesicles and BRP-labelled active zones. We found that the number of BRP-labelled puncta in the sLNv terminals was similar while their density differed between Zeitgeber time (ZT) 2 and 14. The relative distance between BRP- and PDF-labelled puncta was increased in the morning, around the reported time of PDF release. Spontaneous dense-core vesicle release profiles of sLNvs in a publicly available ssTEM dataset (FAFB) consistently lacked spatial correlation to BRP-organised active zones. RNAi-mediated downregulation of brp and other active zone proteins expressed by the sLNvs did not affect PDF-dependent locomotor rhythmicity. In contrast, down-regulation of genes encoding proteins of the canonical vesicle release machinery, the dense-core vesicle-related protein CADPS, as well as PDF impaired locomotor rhythmicity. Taken together, our study suggests that PDF release from the sLNvs is independent of BRP-organised active zones, while BRP may be redistributed to active zones in a time-dependent manner., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Neuropeptides are processed from larger preproproteins by a dedicated set of enzymes. The molecular and biochemical mechanisms underlying preproprotein processing and the functional importance of processing enzymes are well-characterised in mammals, but little studied outside this group. In contrast to mammals, Drosophila melanogaster lacks a gene for carboxypeptidase E (CPE), a key enzyme for mammalian peptide processing. By combining peptidomics and neurogenetics, we addressed the role of carboxypeptidase D (dCPD) in global neuropeptide processing and selected peptide-regulated behaviours in Drosophila. We found that a deficiency in dCPD results in C-terminally extended peptides across the peptidome, suggesting that dCPD took over CPE function in the fruit fly. dCPD is widely expressed throughout the nervous system, including peptidergic neurons in the mushroom body and neuroendocrine cells expressing adipokinetic hormone. Conditional hypomorphic mutation in the dCPD-encoding gene silver in the larva causes lethality, and leads to deficits in starvation-induced hyperactivity and appetitive gustatory preference, as well as to reduced viability and activity levels in adults. A phylogenomic analysis suggests that loss of CPE is not common to insects, but only occurred in Hymenoptera and Diptera. Our results show that dCPD is a key enzyme for neuropeptide processing and peptide-regulated behaviour in Drosophila. dCPD thus appears as a suitable target to genetically shut down total neuropeptide production in peptidergic neurons. The persistent occurrence of CPD in insect genomes may point to important further CPD functions beyond neuropeptide processing which cannot be fulfilled by CPE., (© 2019 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)