There are over 100 different types of arthritis and each can differ greatly in their aetiology and pathophysiology; however, one characteristic that is common to all arthritic conditions is joint pain. Musculoskeletal pain is the leading cause of disability in the world, and the number one reason arthritis patients visit their primary care physician. Despite the prevalence and burden of arthritis pain, current analgesics lack sufficient efficacy and are plagued by multiple adverse side effects. In this review, we outline the current landscape of research concerning joint pain, drawing from both preclinical and clinical studies. Specifically, this review is a discussion of the different neurophysiological processes that occur during joint disease and how inflammatory and neuropathic aspects contribute to the development of arthritis pain.

Cardiac fibrosis, a known risk factor for heart disease, is typically caused by uncontrolled proliferation of fibroblasts and excessive deposition of extracellular matrix proteins in the myocardium. Cyclin-dependent kinase 1 (CDK1) is involved in the control of G2/M transit phase of the cell cycle. Here, we showed that isoproterenol (ISO)-induced cardiac fibrosis is associated with increased levels of CDK1 exclusively in fibroblasts in the adult mouse heart. Treatment of primary embryonic ventricular cell cultures with ISO (a nonselective β-adrenergic receptor agonist) increased CDK1 protein expression in fibroblasts and promoted their cell cycle activity. Quantitative PCR analysis confirmed that ISO increases CDK1 transcription in a transient manner. Further, the ISO-responsive element was mapped to the proximal -100-bp sequence of the CDK1 promoter region using various 5'-flanking sequence deletion constructs. Sequence analysis of the -100-bp CDK1 minimal promoter region revealed two putative nuclear factor-Y (NF-Y) binding elements. Overexpression of the NF-YA subunit in primary ventricular cultures significantly increased the basal activation of the -100-bp CDK1 promoter construct but not the ISO-induced transcription of the minimal promoter construct. In contrast, dominant negative NF-YA expression decreased the basal activity of the minimal promoter construct and ISO treatment fully rescued the dominant negative effects. Furthermore, site-directed mutagenesis of the distal NF-Y binding site in the -100-bp CDK1 promoter region completely abolished both basal and ISO-induced promoter activation of the CDK1 gene. Collectively, our results raise an exciting possibility that targeting CDK1 or NF-Y in the diseased heart may inhibit fibrosis and subsequently confer cardioprotection.

No abstract

We studied a 26-year-old Type 1 diabetic patient who experienced recurrent episodes of ketoacidosis and who was unresponsive to subcutaneous insulin, but normally responsive to intravenous insulin as demonstrated by insulin challenge test. Attempts at intravenous and intraperitoneal insulin administration were complicated by recurrent septicaemia. We therefore investigated the hypoglycaemic effect of intramuscular insulin administration in this patient. After intramuscular injection of NPH and Ultralente human insulin (0.1 U kg-1), the lowest plasma glucose levels occurred 1 and 7 h later, respectively; the hypoglycaemic effect lasted approximately 2 and 12 h, respectively. We based insulin therapy on intramuscular NPH as a fast-acting insulin and Ultralente as an intermediate-acting insulin using four injections a day. During the next 24 months, the patient was hospitalized for 4 weeks versus 56 weeks in the 20 months preceding intramuscular insulin administration, and was able to resume full-time work. HbAlC decreased from 11.7% to 8.7% (normal range: 4.2-5.9%). Thus, long-term intramuscular insulin therapy is a feasible alternative to intravenous or intraperitoneal insulin in patients with well-demonstrated resistance to subcutaneous insulin.

There are sex differences in degenerative disease prevalence in humans. Most models of degenerative disease use male animals. Examining female and male responses to stress may give insight into disease prevalence. Heat shock proteins are chaperones linked to damaged proteins in degenerative diseases and may be expressed differentially in females and males. We have characterized the induced expression of Hsp27 and Hsp70 in the brain and the heart of female and male rats. Rats were heat shocked, brains were removed 24 h after, and western analyses were done to quantify the expression of these proteins. Immunofl uorescence was used to localize Hsp70 and Hsp27 in the hippocampus. Overall, male rats have signifi cantly greater induced expression of both Hsp27 and Hsp70 in the brain. In the hippocampus, Hsp27 was localized in astrocytes, and Hsp70 was localized in blood vessels and microglia, following heat shock. Therefore, the difference in expression of heat shock proteins seen in the brain of male and female rats following heat shock suggests that sex hormones may have an impact on degenerative disease prevalence.