Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system

In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood--brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase- 1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.     

COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia

The skeletal dysplasias are a clinically and genetically heterogeneous group of conditions affecting the development of the osseous skeleton and fall into the category of rare genetic diseases in which the diagnosis can be difficult for the nonexpert. Two such diseases are pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), which result in varying degrees of short stature, joint pain and stiffness and often resulting in early onset osteoarthritis. PSACH and some forms of MED result from mutations in the cartilage oligomeric matrix protein (COMP) gene and to aid the clinical diagnosis and counselling of patients with a suspected diagnosis of PSACH or MED, we developed an efficient and accurate molecular diagnostic service for the COMP gene. In a 36-month period, 100 families were screened for a mutation in COMP and we identified disease-causing mutations in 78% of PSACH families and 36% of MED families. Furthermore, in several of these families, the identification of a disease-causing mutation provided information that was immediately used to direct reproductive decision-making.     

Clinical, biochemical and immunoelectron microscopical evidence of dual hormone production in a mammosomatotroph cell adenoma

This paper reports the occurrence of a rare, yet distinct pituitary adenoma which was surgically removed from a 42-year-old male with both clinical and biochemical evidence of acromegaly and mild hyperprolactinaemia. The monomorphic adenoma consisted of mature cells which were ultrastructurally indistinguishable from those of a prolactinoma. Electron immunocytochemistry, including a series of double-labelling techniques using selected colloidal gold particles as markers, indicated the presence of a pituitary adenoma in which the cells were capable of simultaneously producing growth hormone and prolactin and packaging them within the same secretory granule. This is thought to represent a mammosomatotroph cell adenoma.     

Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease?

An unstable CAG triplet repeat expansion encoding a polyglutamine stretch within the ubiquitously expressed protein huntingtin is responsible for causing Huntington's disease (HD). By quantifying the repeat sizes of individual mutant alleles in tissues derived from an accurate genetic mouse model of HD we show that the mutation becomes very unstable in striatal tissue. The expansion-biased changes increase with age, such that some striatal cells from old HD mice contain mutations that have tripled in size. If this pattern of repeat instability is recapitulated in human striatal tissue, the concomitant increased polyglutamine load may contribute to the patterns of selective neuronal cell death in HD. Our findings also suggest that trinucleotide repeat instability can occur by mechanisms that are not replication-based.     

The diagnosis of major depression in renal dialysis patients

Controversy exists regarding the frequency of depression in renal dialysis patients. We have assessed an unselected sample of 99 dialysis patients using the Diagnostic Interview Schedule (DIS). A current Major Depressive Episode (MDE) was diagnosed in 8.1% of the sample, one-half of whom had a past history of MDE. An additional 12.1% had only a past history of depression. In contrast to patients with no affective disorder, characteristics of patients with a current MDE included the following: a history of previous MDE; female sex; duration of dialysis less than or equal to 24 months; a younger mean age; solitary living arrangements; and unemployment. The following DSM-III criteria distinguished patients with MDE from those with no affective disorder: depressed mood or loss of interest; feelings of worthlessness or excessive guilt; anorexia and weight loss; and slowed or mixed-up thoughts. DSM-III criteria that were common in the entire sample but not useful in distinguishing patients with MDE included loss of energy, insomnia, and decreased sexual interest. These results indicate that some DSM-III criteria are common in dialysis patients and therefore do not distinguish major depression, whereas other DSM-III criteria are more specific for MDE. Further, it is possible that the prevalence of MDE is greater in dialysis patients than in the general population.     

Experimental mechanical and histologic evaluation of the Kennedy ligament augmentation device

Reconstruction of the knee with a chronic injury to the anterior cruciate ligament is an unsolved problem. Biologic graft substitutes have failed to maintain knee stability in the longer postreconstruction intervals. In an attempt to overcome the limitations in graft performance, synthetic materials have been proposed to augment the biologic tissue. In this study, a 6-mm polypropylene braid Ligament Augmentation Device (LAD) possessing a tensile strength of 1500 N and excellent fatigue and creep properties was investigated as an adjunct to the MacIntosh/Marshall Over-the-Top repair. A two-year animal study of 54 adult goats was conducted in which experimental ACL defects were created and reconstructed with a transplant consisting of a portion of the rectus femoris tendon, prepatellar tissue, and the central one-third of the patellar tendon. The goats were equally divided between nonaugmented and LAD-augmented groups and sacrificed at three, six, 12, and 24 months after surgery. Mechanically, the augmented transplants were substantially stronger at the time of initial implantation (364N versus 26N) and again at two years (841N versus 528N). Intermediate times did not demonstrate a difference in strength. Histologically, the augmented transplants consisted of a loosely organized fibrous capsule surrounding the LAD. At 24 months, "insertion fibers" were noted to provide continuity between the fibrous tissue and bone on both the tibia and femur.     

Behavioral trait associated with conditioned immunity

Inbred strains of mice were tested for their activity in an open field. Animals selected for high or low activity ("tails" of the normal distribution) were further inbred through nine generations (brother x sister) with further selection at each generation. Reciprocal skin grafts between the two groups were performed to ensure that little/no genetic drift occurred. Using a cyclophosphamide:saccharin conditioning paradigm (R. Ader & N. Cohen (1975) Psychosom. Med. 37, 333-342) we show that mice preselected for high activity in an open field were those in which it was most easy to demonstrate conditioned immunosuppression. There was no difference in the conditionability of the two groups as assessed by taste aversion. By use of a cross-fostering design we conclude that immunological conditioning (in adult mice) can be affected by a characteristic of the nursing mother which is associated with activity in an open-field trial.     

Does Perceived Quality of Care Moderate Postpartum Depression? A Secondary Analysis of a Two-Stage Survey

Maternal and Child Health Journal - The purpose of this study was to examine if women’s perceptions of the quality of hospital care during childbirth moderate their risks for symptoms of...     

Efficacy of Unfocused Medium-Intensity Extracorporeal Shock Wave Therapy (MI-ESWT) for Plantar Fasciitis

Extracorporeal shock wave therapy (ESWT) is a promising treatment for plantar fasciitis (PF), however, treatment results have varied due to inconsistencies among types of shock wave treatment and devices used. This retrospective chart review includes patients who underwent ESWT using the OrthoGold 100? shock wave device (MTS, Konstanz, Germany) for PF between January, 2013 and September, 2018. There were 108 patients (119 heels) identified, with a mean age of 51.7 ± 16.5 (Range 21-83) years. Patients were treated weekly for 3 weeks, with 2000 impulses per session at an energy flux density between 0.10 and 0.17 mJ/mm². Mean follow-up duration was 11.5 ± 9.7 (Range 3-51) months. Mean pre-ESWT pain visual assessment scale improved from 6.7 ± 1.7 to 2.6 ± 2.7 (p < .001). The Foot and Ankle Outcome Score subscales: pain, function of daily living, function of sports and recreational activities and quality of life domains improved from 53.7 ± 14.9 to 75.7 ± 16.7 (p < .001), from 38 ± 15.2 to 71.8 ± 23 (p < .001), from 55.8 ± 16.4 to 71.4 ± 18 (p < .001), from 42.4 ± 21.5 to 59.4 ± 20.3 (p < .001) and from 44.9 ± 16.4 to 69 ± 23.9 (p < .001), respectively. Eighty-eight (81.5%) patients were satisfied with the procedure at final follow-up. Treatment of PF with unfocused shock waves was well tolerated and led to significant pain reduction, functional improvement, and patient satisfaction.