Treatment of rheumatic musculoskeletal disorders.

Non-medicinal therapies with water, salts, exercise, massage, supportive devices, and electricity have been used for centuries and continue to be of benefit for some people with musculoskeletal disorders. Historical texts refer to the two electuaries mithridatium and theriaca as early therapeutic attempts of man to provide relief of musculoskeletal symptoms and attempt disease cures. For over 200 years, morphine-derived products have been used for musculoskeletal pain. The development of acetyl salicylic acid was a major breakthrough in joint pain management. This was followed by the introduction of nonsteroidal anti-inflammatory agents, paracetamol, and the use of corticosteroids. The gold-based compounds were the initial disease-modifying drugs and have been followed by the highly successful biologics agents. The basic objectives of musculoskeletal pain management include: reduction or elimination of joint pain; improvement or restoration of joint function and mobility; improvement of muscle strength to protect cartilage, ligaments, and joint capsule; prevention and reduction of damage to joint cartilage and supporting structures.

Narcotic analgesics.

There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and by Avicenna (980-1037). Reference to opium like products is made by Paracelsus and by Shakespeare. Charles Louis Derosne and Fredrich Wilhelm Adam Serturner isolated morphine from raw opium in 1802 and 1806 respectively, and it was Sertürner who named the substance morphine, after Morpheus, the Greek God of dreams. By the middle 1800s, Opium and related opioid derived products were the source of a major addiction in USA, and to some extent in the United Kingdom. Opioid products are of major therapeutic value in the treatment of pain from injury, post surgery, intractable pain conditions, and some forms of terminal cancer.

Clinical therapeutic trials.

The term clinical trial implies an investigation of a therapeutic intervention in the pursuit of evidence of benefit, short or sustained, and observations on the possibility of toxicity related to the therapeutic intervention. It is possible that the first clinical trial took place in the court of the Babylonian King Nebuchadnezzar circa 600 BC, as recorded in Chapter 1 of the Book of Daniel, verse 3-20. However, it is in the last 500 years that there has been good written documentation at attempts to interpret therapeutic benefit from the use of treatments. Lind's demonstration on the usefulness of oranges and lemons in the treatment of scurvy in 1747, and the unethical experiment by Edward Jenner (1749-1823) on the inoculation in 1796, of an 8-year-old boy, with cow pox obtained from a milk maid, followed by an attempt to give the young boy smallpox by direct inoculation 18 days later, are striking examples of clinical trials. Human ethics, strict clinical observations, statistics, the governed scientific purity of therapeutic agents, and safety testing of therapeutics, devices, and physical interventions, have created the basis for the modern clinical trial.

Medical aspects of the tour by Martin Martin (c 1660-1719) of the Western and Northern Islands of Scotland, Circa 1695.

This review is based investigations on the Western Isles, Scotland, by Martin Martin, a notable Scottish Highlander, academic and medical doctor, of the 17th-18th century. His extensive observations of the geography and peoples of these Isles were recorded in his books, "On the Description of the Western Islands of Scotland Circa 1695" and "A Late Voyage to St Kilda". In these books and subsequent papers there were some noteworthy observations on the occurrence (and as he says non-occurrence) of "epidemical" diseases and conditions afflicting the peoples of The Isle of Skye and the Western Isles of Scotland in this period, and these are discussed in this review. Martin also gives details of a wide variety of remedies that were observed or reported by inhabitants around that time. Some of these remedies are interesting for their relevance to the period but others are of doubtful merit. These are reviewed here more for their significance in the understanding of the diseases and conditions of humans and even in some cases animals at that time. Introductions by Charles Withers and R.W. Munro, 11 and re-assessments of the contributions of Martin and colleagues of that time have given insight into the health and condition of peoples of the Western Isles of Scotland(the Occidental) (Martin 1695; Martin 1716).

The illness of William Soutar (1898-1943).

William Soutar (1898-1943) was a Scottish poet, but many are unaware of his scholarly work which includes his famous "brain-rhymes". He was born in Perth Scotland in 1898. He was educated at Perth Primary School and Perth Academy and proved to be adept at sport and academics. In 1916, he joined the Royal Navy. In 1918, he had "food poisoning" after which he was hospitalized and developed severe joint pain which became a chronic illness. He had a brief attempt at medical studies at Edinburgh University, but soon switched to the Arts Faculty to study English. Despite various treatments, the joint pain was chronic and disabling. He developed tuberculous lung disease in 1929, and again despite treatments, the problem persisted, and he died in 1943.

Spondyloarthropathies and arthritis post-infection: a historical perspective.

The spondyloarthropathies are a group of conditions characterised by spinal joint pain and have related clinical, epidemiological and genetic-related features. Ankylosing spondylitis, reactive arthritis, the spinal form of psoriatic arthritis and Crohn's and colitis enteropathic arthritis are the major clinical entities of the spondyloarthropathies, and principally occur in HLA-B27 positive individuals. Ankylosing spondylitis is much more common in males than females. Patients are usually seronegative for rheumatoid factor, and extra-articular features including iridocyclitis, mucous membrane and skin lesions: aortitis, may occur in some patients. The reactive arthritis form classically occurs following an infection of the gastrointestinal or genitourinary tract. The Crohn's and colitis enteropathic arthritis forms often have an associated large joint asymmetrical arthritis. Also discussed are acute rheumatic fever and Lyme disease which are conditions where the individual develops arthritis after an infection.

Rheumatoid arthritis.

It is difficult to determine from ancient writings, old human specimens, and from Art over the centuries, as to when Rheumatoid Arthritis first appeared. It may be a relatively modern condition, as it was reasonably well described in the seventeenth century. Augustin Jacob Landre-Beauvais (1772-1840), University of Paris is credited, with the first clear description of the disease in his thesis. In 1859 Sir Alfred Baring Garrod (1819-1907), the "father of rheumatology", gave the disease its current name which was finally adapted in Britain by the Ministry of Health in 1922. Some forms of Juvenile Arthritis are related to adult Rheumatoid Arthritis (aka Still's disease). If untreated Rheumatoid arthritis can result in severe destructive joint damage and often there are associated severe systemic complications. Disease modifying agents have benefited the disease management, but it was the discovery of the anti TNF-alpha agents in the 1990s, and subsequently many additional Biologic agents, which have greatly changed the clinical outcome in Rheumatoid Arthritis.

Surgery of joints.

Crude forms of musculoskeletal surgery have been performed through history for the treatment of deformity, pain and the horrors of battle. In more modern times Muller is credited with the first synovectomy in rheumatoid arthritis in 1884, and a Synovectomy was first performed by Richard von Volkmann (1830-1889) for joint tuberculosis. Chemical synovectomy consisting of the intra-articular injection of various agents was popular for a while but is now largely discarded. Joint resection for sepsis and tuberculosis has been documented since the early 1800s, and also joint arthrodesis, and osteotomy. Modern arthroscopic techniques have added the utility of faster intra-joint inspection and treatment while reduced surgical time exposure and often applied with the use of limb regional anaesthetic nerve blocks, to avoid general anaesthetic. Joint arthroplasty has been developed since1800s, with the use of many artificial joint components. There have been many notable pioneers of this work who are documented in this text, among them Austin T. Moore (1899-1963), George McKee (1906-1991) and Sir John Charnley (1911-1982). The success of joint arthroplasty to the hip, knee, shoulder and other joints has resulted in life-changing benefit for hundreds of arthritis and injury sufferers.

Sjögren's syndrome.

Sjögren's syndrome (SS) is characterised as keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth) commonly associated with salivary gland enlargement, and is referred to as Primary Sjögren's syndrome. It is known as Secondary Sjögren's syndrome when it occurs in patients, with connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polyarthritis nodosa, polymyositis, and systemic sclerosis. SS has also been associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation, human immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), chronic biliary cirrhosis, neoplastic and myeloplastic syndromes, fibromyalgia, and chronic fatigue syndrome.

Osteoarthritis.

The clinical appearance and radiological pattern of osteoarthritis have been identified in the skeletons of dinosaurs some 50-70 million years old, and in Egyptian mummies, and in ancient skeletons in England. Osteoarthritis patterns of joint involvement, often referred to as primary osteoarthritis, can be seen in the hands, spinal facet joints, hips, knees and feet, but can also be termed secondary osteoarthritis when seen in any joint that has had trauma, sepsis, surgery or metabolic insult. The prevalence of osteoarthritis increases with age. The histology and pathophysiology both demonstrate an inflammatory process. While there have been studies of genetic predisposition, the basic cause of primary osteoarthritis has not been determined.

John Alexander Mullin (1835-1899): The Canadian Physician who first described Osler's Nodes.

Sir William Osler (1849-1919), who became Regius Professor of Medicine at Oxford in 1905, first drew attention in 1909 to the painful nodes in subacute bacterial endocarditis, which now carry his eponym, and he published an account in the Quarterly Journal of Medicine, which he helped establish. Attention is drawn to the often overlooked fact that it was a Dr John Alexander Mullin (1835-1899) of Hamilton, Ontario, Canada, who first drew the attention of Sir William Oster to their occurrence. Confusion arose over the relationship between Osler's nodes and the skin lesions described by Theodore Caldwell Janeway (1872-1917), which are generally non-tender and found in acute bacterial endocarditis. The evidence is that there is essentially no difference since their pathogenesis and histological findings are identical.

Reactive arthritis: the convoluted history of Reiter's disease.

Reactive arthritis, previously known as Reiter's Syndrome or Disease was a post-dysenteric, asymmetrical acute large joint polyarthritis, with fever, conjunctivitis, iritis, purulent urethral discharge, rash and penile soft tissue swelling. Although the eponym was given to Hans Reiter, various forms of the condition have been recorded in history a few hundred years before Reiter. Two French doctors, Noel Fiessinger (1881-1946) and Edgar Leroy (d. 1965), presented a paper at la Societe des Hopitaux-in Paris on the 8th December 1916 on dysentery in 80 soldiers on the Somme, and four of whom developed a "syndrome conjunctivo-uretro-synovial". Their paper was given 4 days before Reiter's presentation on 12th December 1916 at the Society of Medicine in Berlin, on a German army officer with an illness similar to those described by Fiessinger and Edgar Leroy. It is documented that Hans Reiter was one of a number of University professors who signed an oath of allegiance to Adolf Hitler in 1932. For socio-ethical reasons and for clinical utility, Reiter's syndrome is now known as reactive arthritis.

Salsalate: a pleotropic anti-inflammatory drug in the treatment of diabetes, obesity, and metabolic diseases.

Type two Diabetes Mellitus (T2DM) is a rising epidemic. Available therapeutic strategies have provided glycaemic control via HbA1c reduction but fail to provide clinically meaningful reduction in microvascular and macrovascular (cardiac, renal, ophthalmological, and neurological) complications. Inflammation is strongly linked to the pathogenesis of T2DM. Underlying inflammatory mechanisms include oxidative stress, endoplasmic reticulum stress amyloid deposition in the pancreas, lipotoxicity, and glucotoxicity. Molecular signalling mechanisms in chronic inflammation linked to obesity and diabetes include JANK, NF-kB, and AMPK pathways. These activated pathways lead to a production of various inflammatory cytokines, such as Interleukin (IL-6), tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP), which create a chronic low-grade inflammation and ultimately dysregulation of glucose homeostasis in the liver, skeletal muscle, and smooth muscle. Anti-inflammatory agents are being tested as anti-diabetic agents such as the IL-1b antagonist, Anakinra, the IL-1b inhibitor, Canakinuma, the IL-6 antagonists such as Tocilizumab, Rapamycin (Everolimus), and the IKK-beta kinase inhibitor, Salsalate. Salsalate is a century old safe anti-inflammatory drug used in the treatment of arthritis. Long-term safety and efficacy of Salsalate in the treatment of T2DM have been evaluated, which showed improved fasting plasma glucose and reduced HbA1C levels as well as reduced pro-inflammatory markers in T2DM patients. Current publication summarizes the literature review of pathophysiology of role of inflammation in T2DM and clinical efficacy and safety of Salsalate in the treatment of T2DM.

Selenium, selenoprotein P, and oxidative stress levels in SARS-CoV-2 patients during illness and recovery.

BACKGROUND: This study aimed to assess tendency of oxidative stress in COVID-19 patients depending on severity. METHODS: The study was conducted with 80 post-COVID-19 disease patients and 40 acutely ill patients. Content of selenium in blood plasma was detected by a fluorimetric method with di-amino-naphthalene using acidic hydrolysis. Selenoprotein P, malondialdehyde and 4-hydroxynonenal and their metabolite adducts were evaluated by spectrophotometric methods using commercial assay kits. RESULTS: Obtained results showed that selenium content in blood for post-COVID-19 disease patients was of a similar lower norm for Latvian inhabitants. Selenium and seleno-protein P contents for acute patients were significantly decreased compared with post-COVID-19 disease patients. CONCLUSION: In conclusion, COVID-19 involves induction of antioxidant systems-in case of severe disease, patients have significantly low concentration of selenium, seleno-protein P and higher level of oxidative stress, which, in turn, confirms the more intense formation of free radicals in the body.

Effects of nitro-butoxyl- and butyl-esters of non-steroidal anti-inflammatory drugs compared with parent compounds on the contractility of digital arterial smooth muscle from the fallow deer (Dama dama).

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are a major cause of upper gastro-intestinal (GI) ulceration and bleeding as well as cardiovascular (CV) diseases (e.g., myocardial infarction and stroke). A feature common to both these adverse events is a variety of vascular reactions. One approach to overcome these side effects has been the development of nitric-oxide (NO)-donating NSAIDs. The NO is considered to overcome some of these vascular reactions caused by NSAIDs. Unfortunately, the NO-NSAIDs developed so far have not had the expected benefits compared with NSAIDs alone. OBJECTIVES: Using in vitro preparations it is hoped to gain insight into the vascular and smooth muscle reactions induced by NO-NSAIDs compared with NSAIDs as a basis for improving the protective responses attributed to the NO-donating properties of these drugs. METHODS: A range of NO-NSAIDs was synthesized based on the esterification of NSAIDs with the nitro-butoxylate as a prototype of an NO-donor. These compounds, as well as NO-donor agents and NSAIDS, were examined for their possible effects on isolated segments of digital arteries of fallow deer, which provide a robust model for determining the effects of vasodilator and vasoconstrictor activities, in comparison with those of standard pharmacological agents. RESULTS: The NO-NSAIDs were found to antagonise the smooth muscle contractions produced by 5-hydroxytryptamine (serotonin, 5-HT). However, while almost all their parent NSAIDs had little or no effect, with the exception of the R-(-)-isomers of both ibuprofen and flurbiprofen, which caused vasodilatation, all the NO-NSAIDs tested antagonised the increase in tension produced by 5-HT. CONCLUSIONS: R-(-)-ibuprofen and R-(-)-flurbiprofen, along with the nitro-butoxyl esters of the NSAIDs examined, produce relaxation of segments of deer digital artery smooth muscle in vitro. The evidence presented suggests that their mechanism involves the release of NO or its products.