ABSTRACT
Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.
Subject(s)
Alzheimer Disease , Cognition , Cyclic Nucleotide Phosphodiesterases, Type 4 , Disease Models, Animal , Mice, Transgenic , Microglia , Phosphodiesterase 4 Inhibitors , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Mice , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Cognition/drug effects , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/therapeutic use , Phosphodiesterase 4 Inhibitors/administration & dosage , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Presenilin-1/genetics , Presenilin-1/metabolism , Humans , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , MaleABSTRACT
The purpose of this retrospective study was to evaluate the outcome of flexor tendon lengthening performed for hammer toes or curly toes in children, after a mean follow up of 31 months. Specific attention was given to postoperative active flexion of the toe. The deformity improved in all patients, but less in the fourth and fifth toe. Active flexion returned and strength was recovered in all patients. We think that open flexor tendon lengthening for hammer and curly toes is a safe and reliable procedure. We recommend a transverse skin incision, Z-lengthening of the flexor digitorum longus in hammer toes and an associated tenotomy of the flexor digitorum brevis in curly toes.
Subject(s)
Hammer Toe Syndrome/surgery , Tendons/surgery , Toes/abnormalities , Adolescent , Child , Child, Preschool , Humans , Infant , Treatment OutcomeABSTRACT
This study illustrates that Plekhm1 is an essential protein for bone resorption, as loss-of-function mutations were found to underlie the osteopetrotic phenotype of the incisors absent rat as well as an intermediate type of human osteopetrosis. Electron and confocal microscopic analysis demonstrated that monocytes from a patient homozygous for the mutation differentiated into osteoclasts normally, but when cultured on dentine discs, the osteoclasts failed to form ruffled borders and showed little evidence of bone resorption. The presence of both RUN and pleckstrin homology domains suggests that Plekhm1 may be linked to small GTPase signaling. We found that Plekhm1 colocalized with Rab7 to late endosomal/lysosomal vesicles in HEK293 and osteoclast-like cells, an effect that was dependent on the prenylation of Rab7. In conclusion, we believe PLEKHM1 to be a novel gene implicated in the development of osteopetrosis, with a putative critical function in vesicular transport in the osteoclast.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Chromosomes, Human, Pair 10 , Membrane Glycoproteins/genetics , Osteopetrosis/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Vesicular Transport/genetics , Animals , Autophagy-Related Proteins , Chromosome Mapping , Female , Gene Expression Regulation , Humans , Kidney/physiology , Kidney/physiopathology , Male , Membrane Glycoproteins/metabolism , Monocytes/physiology , Mutation , Organ Specificity , Pedigree , Rats , rab GTP-Binding Proteins/metabolism , rab7 GTP-Binding ProteinsABSTRACT
In this study, we assessed the functional results after arthroscopic excision of rotator cuff calcifications. Sixty-one shoulders in 57 patients with chronic calcifying tendinitis of the rotator cuff were treated with arthroscopic excision, subacromial bursa debridement and shaving. In patients with fraying or roughness of the coracoacromial ligament, an acromioplasty was also performed. Patients were evaluated after a mean follow-up of 15 months. The modified Constant score and DASH score significantly improved from 33.4 to 66.8 and from 49.7 to 17.3 respectively. Performing an acromioplasty did not influence the final outcome. Frozen shoulder was a frequent complication (18%) without significant effect on the final DASH or Constant score. The presence of residual calcifications after arthroscopic needling did not influence the final outcome. We therefore believe that the presence of residual calcifications can be accepted if this is deemed necessary to preserve the integrity of the tendon.
