The differential diagnosis of children with joint hypermobility: a review of the literature

<p>Abstract</p> <p>Background</p> <p>In this study we aimed to identify and review publications relating to the diagnosis of joint hypermobility and instability and develop an evidence based approach to the diagnosis of children presenting with joint hypermobility and related symptoms.</p> <p>Methods</p> <p>We searched Medline for papers with an emphasis on the diagnosis of joint hypermobility, including Heritable Disorders of Connective Tissue (HDCT).</p> <p>Results</p> <p>3330 papers were identified: 1534 pertained to instability of a particular joint; 1666 related to the diagnosis of Ehlers Danlos syndromes and 330 related to joint hypermobility.</p> <p>There are inconsistencies in the literature on joint hypermobility and how it relates to and overlaps with milder forms of HDCT. There is no reliable method of differentiating between Joint Hypermobility Syndrome, familial articular hypermobility and Ehlers-Danlos syndrome (hypermobile type), suggesting these three disorders may be different manifestations of the same spectrum of disorders. We describe our approach to children presenting with joint hypermobility and the published evidence and expert opinion on which this is based.</p> <p>Conclusion</p> <p>There is value in identifying both the underlying genetic cause of joint hypermobility in an individual child and those hypermobile children who have symptoms such as pain and fatigue and might benefit from multidisciplinary rehabilitation management.</p> <p>Every effort should be made to diagnose the underlying disorder responsible for joint hypermobility which may only become apparent over time. We recommend that the term "Joint Hypermobility Syndrome" is used for children with symptomatic joint hypermobility resulting from any underlying HDCT and that these children are best described using <b>both </b>the term Joint Hypermobility Syndrome <b>and </b>their HDCT diagnosis.</p

Automated mass spectrometric analysis of urinary and plasma serotonin

Serotonin emerges as crucial neurotransmitter and hormone in a growing number of different physiologic processes. Besides extensive serotonin production previously noted in patients with metastatic carcinoid tumors, serotonin now is implicated in liver cell regeneration and bone formation. The aim was to develop a rapid, sensitive, and highly selective automated on-line solid-phase extraction method coupled to high-performance liquid chromatography–tandem mass spectrometry (XLC-MS/MS) to quantify low serotonin concentrations in matrices such as platelet-poor plasma and urine. Fifty microliters plasma or 2.5 μL urine equivalent were pre-purified by automated on-line solid-phase extraction, using weak cation exchange. Chromatography of serotonin and its deuterated internal standard was performed with hydrophilic interaction chromatography. Mass spectrometric detection was operated in multiple reaction monitoring mode using a quadrupole tandem mass spectrometer with positive electrospray ionization. Serotonin concentrations were determined in platelet-poor plasma of metastatic carcinoid patients (n = 23) and healthy controls (n = 22). Urinary reference intervals were set by analyzing 24-h urine collections of 120 healthy subjects. Total run-time was 6 min. Intra- and inter-assay analytical variation were <10%. Linearity in the 0–7300 μmol/L calibration range was excellent (R2 > 0.99). Quantification limits were 30 and 0.9 nmol/L in urine and plasma, respectively. Platelet-poor serotonin concentrations in metastatic carcinoid patients were significantly higher than in controls. The urinary reference interval was 10–78 μmol/mol creatinine. Serotonin analysis with sensitive and specific XLC-MS/MS overcomes limitations of conventional HPLC. This enables accurate quantification of serotonin for both routine diagnostic procedures and research in serotonin-related disorders

Individualizing therapy – in search of approaches to maximize the benefit of drug treatment (II)

Adjusting drug therapy to the individual, a common approach in clinical practice, has evolved from 1) dose adjustments based on clinical effects to 2) dose adjustments made in response to drug levels and, more recently, to 3) dose adjustments based on deoxyribonucleic acid (DNA) sequencing of drug-metabolizing enzyme genes, suggesting a slow drug metabolism phenotype. This development dates back to the middle of the 20(th )century, when several different drugs were administered on the basis of individual plasma concentration measurements. Genetic control of drug metabolism was well established by the 1960s, and pharmakokinetic-based individualized therapy was in use by 1973

Release of tryptophan and serotonin into the portal vein of the isolated perfused rat small intestine

To investigate the release of serotonin from intestinal enterochromaffin cells, we used an in vitro technique which allows studies excluding overlapping influences from outside the gut. The entire small intestine of rats fed a standard or tryptophan-enriched (3% of total) diet was totally isolated by ligatures with the exception of the superior mesentric artery and portal vein that supply and drain the intestine. Simultaneously to the vascular perfusion (Krebs-Ringer bicarbonate buffer, 0,4% human albumin, 5 m M glucose, 0.6 m M glutamine) the gut lumen was infused (buffer or 0.1 N HCL). Acidification of the gut lumen resulted in an increment of venously released tryptophan and serotonin. After feeding tryptophan-enriched food the release of tryptophan was increased. However, the total amount of released serotonin after tryptophan diet did not differ as compared to that after standard diet. Addition of a monoamino-oxidase inhibitor (pargyline) to the arterial perfusate enhanced the released amount of serotonin 3-fold in the portal venous effluent (at a concentration of 1 m M but not 0.1 m M ). Recovery studies done by arterial infusions of serotonin (1 µ M , 10µ M ) and evaluation of the amounts venously released revealed a high loss of infused serotonin (40%–70%). Our data suggest gut-born serotonin to more likely play a paracrine role than a role as a classical hormone.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47538/1/433_2005_Article_BF01852260.pd

The effects of a low extracellular concentration of potassium on the activity and numbers of Na+/K+ pumps in an EB-virus transformed human lymphocyte cell line.

The BM1A EB-virus transformed human lymphocyte cell line contains approximately 950,000 Na+/K(+)-ATPase sites per cell. The turnover number of each site is approx. 2240 molecules of rubidium per min. When cells are exposed to a low extracellular concentration of potassium the intracellular concentration of sodium rises, and the cells respond in the short term by increasing the Vmax of 86Rb+ uptake. In the longer term the cells respond by increasing both the Vmax of 86Rb+ uptake and the Bmax of [3H]ouabain binding. The suggestion that increases in the intracellular concentration of sodium is responsible for these changes is supported by the finding that monensin, which increases intracellular sodium without affecting intracellular potassium, is capable of inducing both the short- and long-term changes associated with a low external concentration of potassium

The effects of gepirone on neuroendocrine function and temperature in humans.

The effects of the selective 5-HT1A receptor agonist gepirone (10 and 20 mg orally) on neuroendocrine function and temperature were assessed using a single-blind cross-over design in 12 healthy male volunteers. Gepirone significantly increased plasma levels of ACTH, beta-endorphin, cortisol, prolactin and growth hormone. Following gepirone there was a significant decrease in body temperature and moderate increases in subjective reports of light-headedness, nausea and drowsiness. Our results are consistent with studies in rodents suggesting that 5-HT1A receptor agonists increase ACTH and prolactin secretion and decrease body temperature. Further investigations are needed to determine if the neuroendocrine and temperature effects of gepirone in humans are mediated by 5-HT1A receptors

Techniques for studying the pharmacodynamic effects of cardiac glycosides on patients' own erythrocytes during glycoside therapy.

We have measured the effects of digoxin on the cation transport mechanisms of patients' erythrocytes during treatment with digoxin for atrial fibrillation and cardiac failure in sinus rhythm. The results show that during short-term treatment with digoxin there is occupation of erythrocytic cardiac glycoside receptors by digoxin with resultant inhibition of active cation transport. These effects correlate well with the patients' clinical responses to treatment. During long-term treatment, however, these effects are not seen, suggesting that there is pharmacological tolerance to the effects of digoxin. The clinical implications of these results are discussed

Monitoring digoxin therapy. The use of plasma digoxin concentration measurements in the diagnosis of digoxin toxicity.

The usefulness of measuring plasma digoxin concentrations in the diagnosis of digoxin toxicity has been assessed in 83 in-patients. The mean plasma digoxin concentration in clinically toxic patients was significantly higher than the mean concentration in non-toxic patients. The overlap between the groups, however, was extensive and could partly be accounted for by hypokalaemia in those toxic patients whose plasma digoxin concentration was less than 3 ng/ml. There was, in addition, a higher incidence of hyperkalaemia, without obvious cause, in toxic patients than in non-toxic patients. Consideration of the incidence of various non-cardiac factors, specifically plasma potassium concentration greater than 5.0 mmol/l, plasma creatinine concentration greater than 150 mumol/l, daily maintenance dose greater than 6 microgram/kg, and age greater than 60 years, led to the development of guidelines to aid in the diagnosis of digoxin toxicity. Patients with plasma digoxin concentration greater than 3 ng/ml or with hypokalaemia should be considered probably toxic and those with plasma digoxin concentration greater than or equal to 3 ng/ml in the absence of hypokalaemia should only be considered toxic if they have at least two of the non-cardiac factors outlined above. Plasma digoxin concentrations could not be predicted with more than 31 per cent certainty by considering the magnitude of those non-cardiac factors