The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review.

Destruction of articular cartilage is a key feature of a number of arthritides, osteoarthritis prominent among them. Aggrecan degradation, caused by increased activity of proteolytic enzymes that degrade macromolecules in the cartilage extracellular matrix, is followed by irreversible collagen degradation. The degradation of aggrecan is mediated by various matrix proteinases, mainly the aggrecanases, multidomain metalloproteinases belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. There has been much interest in the possible role of these aggrecanases, mainly ADAMTS4 and ADAMTS5, as therapeutic targets in osteoarthritis. There is still debate which of them is the major aggrecanase in osteoarthritis, however, as well as major issues concerning how they are regulated, with possible discrepancies between murine models and results obtained using human osteoarthritis tissue. This review discusses some recent data regarding the regulation of ADAMTS4 and ADAMTS5 gene expression in osteoarthritis, with emphasis on the role of proinflammatory cytokines in driving these enzymes, and of the transcription factor NFkappaB in mediating their expression.

Promotion of acid-induced membrane fusion by basic peptides. Amino acid and phospholipid specificities.

The ability of oligo- and polymers of the basic amino acids L-lysine, L-arginine, L-histidine and L-ornithine to induce lipid intermixing and membrane fusion among vesicles containing various anionic phospholipids has been investigated. Among vesicle consisting of either phosphatidylinositol or mixtures of phosphatidic acid and phosphatidylethanolamine rapid and extensive lipid intermixing, but not complete fusion, was induced at neutral pH by poly-L-ornithine or L-lysine peptides of five or more residues. When phosphatidylcholine was included in the vesicles, the lipid intermixing was severely inhibited. Such lipid intermixing was also much less pronounced among phosphatidylserine vesicles. Poly-L-arginine provoked considerable leakage from the various anionic vesicles and caused significantly less lipid intermixing than L-lysine peptides at neutral pH. When the addition of basic amino acid polymer was followed by acidification to pH 5-6, vesicle fusion was induced. Fusion was more pronounced among vesicles containing phosphatidylserine or phosphatidic acid than among those containing phosphatidylinositol, and occurred also with vesicles whose composition resembles that of cellular membranes (i.e., phosphatidylcholine/phosphatidylethanolamine/phosphatidylserine, 50:30:20, by mol). Liposomes with this composition are resistant to fusion by Ca2+ or by acidification after lectin-mediated contact. The tight interaction among vesicles at neutral pH, resulting in lipid intermixing, does not seem to be necessary for the fusion occurring after acidification, but the basic peptides nevertheless appear to play a more active role in the fusion process than simply bringing the vesicles in contact. However, protonation of the polymer side chains and transformation of the polymer into a polycation does not explain the need for acidification, since the pH-dependence was quite similar for poly(L-histidine)- and poly(L-lysine)-mediated fusion.

Phosphatidylethanol counteracts calcium-induced membrane fusion but promotes proton-induced fusion.

The susceptibility of phosphatidylethanol-containing lipid vesicles towards Ca2+- and proton-induced fusion has been investigated, using a system of interacting vesicles. The results show that phosphatidylethanol-rich vesicles are quite resistant to Ca2+-induced fusion while being highly sensitive to proton-induced fusion. Inclusion of phosphatidylethanol was also found to promote and inhibit, respectively, the proton-induced and Ca2+-induced fusion of bilayer vesicles containing also phosphatidylethanolamine and either phosphatidylserine or phosphatidic acid. Thus, phosphatidylethanol affected Ca2+- and proton-induced fusion in opposite directions, in contrast to the naturally occurring anionic phospholipids phosphatidic acid, phosphatidylserine and phosphatidylinositol, which affect the sensitivity to Ca2+- and H+-induced fusion in the same direction. However, the fusion competence of phosphatidylethanol vesicles in response to both Ca2+ and H+ was inversely related to the apparent thickness of the polar headgroup layer, determined by using lectin-glycolipid interaction as a steric probe, as previously found for vesicles containing naturally occurring anionic phospholipids.

Proton-induced membrane fusion. Role of phospholipid composition and protein-mediated intermembrane contact.

Glycolipid-phospholipid vesicles containing phosphatidate and phosphatidylethanolamine were found to undergo proton-induced fusion upon acidification of the suspending medium from pH 7.4 to pH 6.5 or lower, as determined by an assay for lipid intermixing based on fluorescence resonance energy transfer. Lectin-mediated contact between the vesicles was required for fusion. Incorporation of phosphatidylcholine in the vesicles inhibited proton-induced fusion. Vesicles in which phosphatidate was replaced by phosphatidylserine underwent fusion only when pH was reduced below 4.5, while no significant fusion occurred (pH greater than or equal to 3.5) when the anionic phospholipid was phosphatidylinositol. It is suggested that partial protonation of the polar headgroup of phosphatidate and phosphatidylserine, respectively, causes a sufficient reduction in the polarity and hydration of the vesicle surface to trigger fusion at sites of intermembrane contact.

Antirheumatic gold compounds and penicillamine enhance protein kinase C-mediated activation of the arachidonate-mobilizing phospholipase A2 in mouse macrophages.

The effects of antirheumatic gold compounds and D-penicillamine on protein kinase C- and Ca(2+)-mediated activation of arachidonate mobilization and the formation of eicosanoids in mouse macrophages have been investigated. Auranofin (0.2-2 microM) enhanced the response to phorbol ester two- to three-fold, and similar enhancement was caused by aurothiomalate, aurothioglucose, and penicillamine, but only after pretreatment for 1-4 h. The enhanced mobilization of arachidonate was accompanied by increased formation and release of prostaglandin E2 and 6-keto prostaglandin F1 alpha, but not of lipoxygenase metabolites. No such enhancement occurred when the arachidonate-mobilizing phospholipase A2 was activated directly (calcium ionophore A23187). Instead, auranofin caused selective inhibition of calcium ionophore-induced formation of leukotriene C4. Treatment of macrophages with 4 beta-phorbol 12-myristate 13-acetate causes a rapid increase in the phosphorylation and a 1.4-1.8-fold increase in the activity of the 85-kd arachidonate-mobilizing phospholipase A2 as determined in an in vitro assay. The increase in activity was further enhanced by both the gold compounds and penicillamine. These findings indicate that the target for the enhancing effect of the antirheumatic drugs is located between protein kinase C and phospholipase A2 in the signal chain leading to activation of the latter enzyme.

Wegener's granulomatosis mimicking a parotid abscess.

We present the case of a previously healthy 59-year-old man who was under treatment for scleritis and episcleritis when he developed a parotid-gland swelling and pus-producing sinus. On surgical exploration, the features were those of a parotid abscess, but the lesion not only failed to heal post-operatively but increased in size very significantly. There was also severe necrotizing keratitis of the eyes. Due to clinical suspicion and a positive antineutrophil cytoplasmic antibodies test, Wegener's granulomatosis was diagnosed and the patient successfully treated with cyclophosphamide and steroids. Previously, a number of cases of Wegener's granulomatosis causing salivary-gland swelling have been reported in the literature; this is the first case in which the disease has masqueraded as a parotid abscess.

Historical analysis of Newfoundland dog fur colour genetics.

This article makes use of digitized historic newspapers to analyze Newfoundland dog fur colour genetics, and fur colour variations over time. The results indicate that contrary to the accepted view, the 'Solid' gene was introduced into the British population of Newfoundland dogs in the 1840s. Prior to that time, the dogs were white and black (Landseer) or white and brown, and thus spotted/spotted homozygotes. Due to 'Solid' being dominant over 'spotted', and selective breeding, today the majority of Newfoundland dogs are solid black. Whereas small white marks on the chest and/or paw appears to be a random event, the historical data supports the existence of an 'Irish spotted' fur colour pattern, with white head blaze, breast, paws and tail tip, in spotted/spotted homozygotes.

Effects of tenidap on Ca(2+)- and protein kinase C-mediated protein phosphorylation, activation of the arachidonate-mobilizing phospholipase A2 and subsequent eicosanoid formation in macrophages.

Tenidap is a novel antirheumatic drug which combines non-steroidal antiinflammatory drug-like cyclooxygenase inhibition with cytokine modulating qualities in rheumatoid arthritis. We show herein that tenidap (5-20 microM) inhibited protein kinase C-mediated signalling leading to release of arachidonate in mouse macrophages by interfering with the up-regulation of the 85 kDa arachidonate-mobilizing phospholipase A2, although it did not inhibit this enzyme directly. The Ca(2+)-mediated activation of arachidonate mobilization was inhibited only at higher concentrations (20-40 microM). Studies of protein phosphorylation indicated that tenidap in itself was capable of inducing the phosphorylation of several protein bands through interaction with intracellular protein kinases and/or phosphatases. Importantly, tenidap inhibited both arachidonate release and the increase in intracellular protein phosphorylation when the cells were stimulated with zymosan. We propose that the main inhibitory influence of tenidap on the macrophage signalling investigated here is exerted at some level between protein kinase C and the 85 kDa phospholipase A2 and quite possibly also at the receptor-linked activation of phospholipase C.

Auranofin inhibits the induction of interleukin 1 beta and tumor necrosis factor alpha mRNA in macrophages.

Gold compounds are widely used in the treatment of rheumatoid arthritis, but their mechanisms of action remain unclear. We demonstrate here that auranofin (AF) (0.1-3 microM), but neither the hydrophilic gold compounds aurothiomalate (ATM) and aurothioglucose nor methotrexate or D-penicillamine, inhibits the induction of interleukin 1 beta and tumor necrosis factor (TNF) alpha mRNA and protein by either zymosan, lipopolysaccharide (LPS), or various bacteria in mouse macrophages. The auranofin-mediated inhibition of the induction of TNF-alpha mRNA was stronger than that of interleukin (IL) 1 beta mRNA. AF, but not the other drugs, also inhibited zymosan-induced mobilization of arachidonate. The fact that AF inhibited the induction of mRNA for both these proinflammatory cytokines, irrespective of which stimulus was used, may indicate that it affects some common signal transduction step vital to their induction.

Differential effects of tenidap on the zymosan- and lipopolysaccharide-induced expression of mRNA for proinflammatory cytokines in macrophages.

Tenidap is a novel antirheumatic drug that combines cyclooxygenase inhibition with cytokine modulating qualities. We demonstrate here that tenidap inhibits the zymosan-induced expression of both interleukin 1 and tumor necrosis factor alpha in macrophages, at the mRNA and protein levels. The concentration-dependence of the tenidap-induced inhibition of the expression of mRNA for these proinflammatory cytokines agrees with that of its inhibitory effects on zymosan-induced arachidonate mobilization and changes in phosphoprotein pattern. The effects of tenidap on the lipopolysaccharide-induced expression of these cytokines are more complex. Tenidap inhibits the induction of interleukin 1 by lipopolysaccharide or bacteria, but less potently than the interleukin 1-response induced by zymosan. In contrast, the drug markedly potentiates the lipopolysaccharide-induced expression of tumor necrosis factor alpha at both the mRNA and protein levels. The latter effect is demonstrated to be due to cyclooxygenase inhibition and is reversed by prostaglandin E2.

Caroline Crachami, the Sicilian Fairy: a case of bird-headed dwarfism.

One of the most remarkable cases of extreme dwarfism on record is Caroline Crachami, the Sicilian Fairy. She was born in 1815, and was taken to London to be exhibited for money in 1824. Due to her proportional dwarfism, severe intrauterine growth retardation, and typical "bird-headed" profile, Caroline Crachami has by some been diagnosed as a case of the autosomal recessive Seckel syndrome. In this historical vignette, the Sicilian Fairy's life and death are presented in some detail using new material, and the problem of her correct diagnosis is discussed.

Julia Pastrana, the nondescript: an example of congenital, generalized hypertrichosis terminalis with gingival hyperplasia.

Julia Pastrana (1834-1860) has gained immortality as one of the most extreme cases of generalized hypertrichosis upon record. When she was exhibited for money in the United States and Europe during the years 1855-1860, people thronged to see her, and she was several times described in the medical press of the day. After Julia Pastrana's death in childbirth, her corpse was embalmed in a very life-like manner, and exhibited all over Europe for several decades. Later, the mummy was believed to be lost, but in 1990 it was discovered at the Oslo Forensic Institute. Some writers have included Julia Pastrana among the cases of congenital hypertrichosis languinosa. However, a microscopic examination of hair samples from the mummy shows that her hairy growth is unmistakably terminal in character, and we propose that she instead was an example of congenital, generalized hypertrichosis terminalis with associated gingival hyperplasia. While many earlier writers have asserted that Julia Pastrana's dentition was abnormal, a radiographic examination of the mummy has shown that she had a complete permanent dentition.

Reversible scleroderma, fasciitis and perimyositis.

A patient with reversible scleroderma, fasciitis (without blood or tissue eosinophilia) and perimyositis is described. This case is of interest because it might be considered as an overlap between progressive systemic sclerosis and eosinophilic fasciitis.

Polymyositis associated with asymptomatic primary biliary cirrhosis.

We here describe a case of polymyositis associated with asymptomatic primary biliary cirrhosis and a high titer of antimitochondrial antibodies. The patient had remarkable multiorgan engagement: polyarthritis, pericarditis, pleuritis and tachyarrythmia. Atypical changes, suggestive of mitochondrial damage, were observed in a muscle biopsy specimen. Under treatment with azathioprine and steroids, the disease had a favourable outcome.

Craniopagus parasiticus. Everard Home's Two-Headed Boy of Bengal and some other cases.

Craniopagus parasiticus, or épicome, is a rare teratological type, of which only six cases have been recorded in the medical literature. It differs from craniopagus conjoined twins in that the body and limbs of the parasitic twin are underdeveloped, leaving in some cases only a parasitic head, inserted on the crown of the autositic twin. The first case of this malformation was Everard Home's famous Twin-Headed Boy of Bengal, whose skull is preserved at the Hunterian Museum. In this historical review, Home's case is presented in some detail, and the later cases are used to explain further some of its particulars.

Cytokine blockade in rheumatoid arthritis.

As we enter the 2000's it is clear that cytokine blockade is an effective therapeutic strategy for rheumatoid arthritis. In this brief review, we will review the rationale for anti TNFalpha therapy, the current status of therapy and focus on the regulation of TNFalpha production in rheumatoid synovium. New approaches to studying TNF regulation in RA and of elucidating the controversial role of T cells in this complex disease will be described.

Dicephalus conjoined twins: a historical review with emphasis on viability.

Dicephalus conjoined twins (2 heads on 1 body) form a distinct subgroup. They are often stillborn because of cardiopulmonary malformations. This article describes 17 historical cases with particular emphasis on viability. There are reliable reports of unseparated dicephali reaching maturity; 1 pair (the Tocci brothers) reached at least 34 years of age. In the absence of concomitant cardiac, pulmonary, and intestinal malformations, dicephalus conjoined twins may well attain adulthood. This appears to be unrelated to whether they have 4 (dicephalus tetrabrachius) or 3 (dicephalus tribrachius) arms at birth.

The earliest known case of a lithopaedion.

A lithopaedion, or stone-child, is a dead fetus, usually the result of a primary or secondary abdominal pregnancy, that has been retained by the mother and subsequently calcified. This paper describes the earliest known case of this phenomenon. It was discovered in 1582, at the autopsy of a 68-year-old woman in the French city of Sens, and described in a thesis by the physician Jean d'Ailleboust. The woman had carried her lithopaedion for 28 years. In this historical vignette, the lithopaedion of Sens is compared to later instances of this phenomenon. The ultimate fate of the lithopaedion specimen, which was widely traded throughout Europe in the 1600s before finally ending up in Copenhagen, is traced.

The Countess Margaret of Henneberg and her 365 children.

According to an obscure medieval legend, the Countess Margaret of Henneberg, a notable Dutch noblewoman, gave birth to 365 children in the year 1276. The haughty Countess had insulted a poor beggar woman carrying twins, since she believed that a pair of twins must have different fathers, and that their mother must be an adultress. She was punished by God, and gave birth to 365 minute children on Good Friday, 1276. The Countess died shortly after, together with her offspring, in the village of Loosduinen near The Hague. The Countess and her numerous brood were frequently described in historical and obstetrical works. To this day, a memorial tablet and two basins, representing those in which the 365 children were baptized, are to be seen in the church of Loosduinen.

The hairy family of Burma: a four generation pedigree of congenital hypertrichosis lanuginosa.

A Burmese family with congenital hypertrichosis lanuginosa had an eventful history in the nineteenth century. The earlier members of this family were employed at the court of Ava, but the later ones spent their lives in show business, being widely exhibited for money in the 1880s. Their extraordinary hairiness attracted much curiosity, and they were photographed several times. The hairy Burmese are the only example of a four-generation pedigree of congenital hypertrichosis lanuginosa, which is consistent with an autosomal dominant mode of inheritance. There is good evidence that, when the members of this family were hairy, their dentition was also deficient.