Síndrome de hipermovilidad articular / Joint hypermobility syndrome

Resumen: El síndrome de hipermovilidad articular es un desorden hereditario con patrón autosómico dominante; se caracteriza por hiperlaxitud articular y dolores musculoesqueléticos. El término hipermovilidad se refiere al incremento en los movimientos activos o pasivos de las articulaciones con base en sus rangos normales. El síndrome de hipermovilidad articular presenta además síntomas gastrointestinales, trastornos de sueño, fibromialgia, trastornos sicológicos, cefalea migrañosa, oftálmicos, autonómicos, entre otros. Para diagnosticar el síndrome de hipermovilidad, en general son aceptados los criterios de Brighton, los cuales fueron publicados en 1998. También se le conoce como síndrome de hipermovilidad articular benigno. El término benigno se utiliza para distinguirlo de otras condiciones más severas como Ehler-Danlos (tipo clásico o vascular), síndrome de Marfan y osteogénesis imperfecta. El tratamiento con fisioterapia y medidas farmacológicas ayudan a mejorar la calidad de vida de los pacientes.

Abstract: Joint hypermobility syndrome is an inherited disorder with autosomal dominant pattern; is characterized by joint hyperlaxity and musculoskeletal pains. Thermal hypermobility refers to the increase in active or passive movements of joints based on their normal ranges. Joint hypermobility syndrome also has gastrointestinal symptoms, sleep disorders, fibromyalgia, psychological disorders, migraine headache, ophthalmic, autonomic, among others. To diagnose hypermobility syndrome, Brighton's criteria are generally accepted and published in 1998. This criteria also known as benign joint hypermobility syndrome. The term benign is used to distinguish it from other more severe conditions such as Ehler-Danlos (classic or vascular type), Marfan syndrome, and imperfect osteogenesis. Treatment with physiotherapy and pharmacological means help improve patients' quality of life.

[Joint hypermobility syndrome]. / Síndrome de hipermovilidad articular.

Joint hypermobility syndrome is an inherited disorder with autosomal dominant pattern; is characterized by joint hyperlaxity and musculoskeletal pains. Thermal hypermobility refers to the increase in active or passive movements of joints based on their normal ranges. Joint hypermobility syndrome also has gastrointestinal symptoms, sleep disorders, fibromyalgia, psychological disorders, migraine headache, ophthalmic, autonomic, among others. To diagnose hypermobility syndrome, Brighton's criteria are generally accepted and published in 1998. This criteria also known as benign joint hypermobility syndrome. The term benign is used to distinguish it from other more severe conditions such as Ehler-Danlos (classic or vascular type), Marfan syndrome, and imperfect osteogenesis. Treatment with physiotherapy and pharmacological means help improve patients' quality of life.

El síndrome de hipermovilidad articular es un desorden hereditario con patrón autosómico dominante; se caracteriza por hiperlaxitud articular y dolores musculoesqueléticos. El término hipermovilidad se refiere al incremento en los movimientos activos o pasivos de las articulaciones con base en sus rangos normales. El síndrome de hipermovilidad articular presenta además síntomas gastrointestinales, trastornos de sueño, fibromialgia, trastornos sicológicos, cefalea migrañosa, oftálmicos, autonómicos, entre otros. Para diagnosticar el síndrome de hipermovilidad, en general son aceptados los criterios de Brighton, los cuales fueron publicados en 1998. También se le conoce como síndrome de hipermovilidad articular benigno. El término benigno se utiliza para distinguirlo de otras condiciones más severas como Ehler-Danlos (tipo clásico o vascular), síndrome de Marfan y osteogénesis imperfecta. El tratamiento con fisioterapia y medidas farmacológicas ayudan a mejorar la calidad de vida de los pacientes.

Changes in milk composition in obese rats consuming a high-fat diet.

Maternal obesity programmes offspring development. We addressed maternal obesity effects induced by high-fat diets on maternal mammary gland (MG) structure and function and offspring brain, liver and fat outcomes. Mothers were fed control (C, n 5) or obesogenic (MO, n 5) diet from the time they were weaned through pregnancy beginning at 120 d, through lactation. At offspring postnatal day (PND) 20, milk leptin and nutrients were determined. At the end of lactation, maternal liver and MG fatty acid profile were measured. Desaturase (Δ6D and Δ5D) and elongase (ELOVL 5 and ELOVL 2) protein was measured by immunohistochemistry and Western blotting (WB) in the liver and WB in the MG. In mothers, liver, MG and milk fat content were higher in MO than in C. Liver arachidonic acid (AA) and EPA and MG EPA were lower in MO than in C. Liver desaturases were higher in MO. The MG was heavier in MO than in C, with decreased Δ5D expression in MO. Desaturases and elongases were immunolocalised in parenchymal cells of both groups. Milk yield, water, carbohydrate content, EPA and DHA were lower, whereas milk leptin and AA were higher in MO than in C. At PND 21 and 36, brain weight was less and fat depots were greater in MO offspring than in C. MO decreased male absolute brain weight but not female absolute brain weight. In conclusion, maternal obesity induced by an obesogenic diet negatively affects maternal liver and MG function with the production of significant changes in milk composition. Maternal obesity adversely affects offspring metabolism and development.

Thiazide-sensitive cotransporter mRNA expression is not altered in three models of hypertension.

BACKGROUND/AIMS: Several lines of evidence support that the kidney is involved in the increase of arterial blood pressure, and some genetic studies suggest that the thiazide-sensitive Na+:Cl- cotransporter could be implicated in the development of hypertension. In the present study, we analyzed the Na+:Cl- cotransporter mRNA levels in the kidney during the development of hypertension in three experimental models. METHODS: The first model included 18 spontaneously hypertensive rats studied at 4, 10, and 16 weeks of age. The second model included 28 Wistar rats with two-kidney, one-clip Goldblatt hypertension studied at 7, 14, 21, and 28 days. The third model included 6 Wistar rats treated with N(G)-nitro-L-arginine methyl ester during 10 days. Respective controls were studied for all models. At the end of each experimental period, the systolic blood pressure was measured in the tail by plethysmography. Individual renal cortex total RNA was extracted, and the mRNA levels of the thiazide-sensitive Na+:Cl- cotransporter were assessed following a semiquantitative RT-PCR strategy. RESULTS: All experimental models developed systemic hypertension. However, the level of mRNA expression of the Na+:Cl- cotransporter did not change in any of the models studied as compared with their respective controls. CONCLUSION: Our results suggest that a change in mRNA levels of the thiazide-sensitive Na+:Cl- cotransporter is not associated with the development of hypertension in spontaneously hypertensive rats, in rats with renovascular hypertension, nor in rats with hypertension induced by nitric oxide synthesis inhibition.

Nifedipine prevents changes in nitric oxide synthase mRNA levels induced by cyclosporine.

Cyclosporine toxicity mainly affects kidney and liver function. We have previously shown that cyclosporine nephrotoxicity alters kidney nitric oxide synthase mRNA pattern of expression. To determine if nitric oxide synthase expression changes are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if these effects are tissue specific and if nifedipine-induced vasodilation prevents these alterations. Uninephrectomized Wistar rats treated for 7 days with olive oil, cyclosporine (30 mg/kg), nifedipine (3 mg/kg), and nifedipine+cyclosporine were studied. In vehicle and cyclosporine groups, the gene expression of the neuronal, inducible, and endothelial nitric oxide synthases in cerebellum, heart, intestine, liver, renal cortex, and medulla was evaluated. The administration of cyclosporine was associated with nephrotoxicity and hepatotoxicity, increased endothelial nitric oxide synthase mRNA levels in renal cortex and liver, and a decrease in inducible nitric oxide synthase and neuronal nitric oxide synthase in renal medulla. The mRNA levels of the 3 nitric oxide synthase isoforms were not affected in any other tissue. Nifedipine did not alter nitric oxide synthase expression in the control group but prevented changes associated with cyclosporine. These results suggest that cyclosporine-induced changes in the pattern of expression of the nitric oxide synthases may be secondary to its hemodynamic effects.

Na(+):K(+):ATPase mRNA expression in the kidney during adaptation to sodium intake and furosemide treatment.

Nephron tubular epithelium possesses the capacity of adaptation to any salt ingestion condition. The mechanism of adaptation is due in part to an increase in the activity of Na(+):K(+):ATPase at the basolateral membrane. The goal of the present study was to analyze the long-term regulation of the Na(+):K(+):ATPase alpha(1)-subunit mRNA expression during changes in NaCl metabolism. Male Wistar rats given a normal, high, or low NaCl diet, and intraperitoneal administration of the loop diuretic furosemide from 12 h to 7 days were studied. Rats were kept in metabolic cages 4 days before and throughout the study to determine daily urinary electrolyte excretion and osmolarity. At the end of each experimental period, creatinine clearance and serum electrolytes were also measured. Total RNA was extracted from each individual cortex or outer medulla and from pooled inner medullas using the guanidine/cesium chloride method. Na(+):K(+):ATPase alpha(1)-subunit mRNA expression was assessed by nonradioactive dot-blot analysis. Experimental maneuvers were well tolerated and all groups developed the appropriate renal response to each experimental condition. Urinary sodium excretion was significantly higher in rats administered a high sodium diet or furosemide and lower in rats treated with a low sodium diet after 7 days of treatment. Glomerular filtration rate was similar among all groups. However, the level of expression of the Na(+):K(+):ATPase alpha(1)-subunit did not change in any model. Nephron adaptation to the modification in NaCl intake or furosemide administration over 7 days did not include changes in Na(+):K(+):ATPase alpha(1)-subunit mRNA levels.

Pentosan polysulfate treatment reduces cyclosporine-induced nephropathy in salt-depleted rats.

BACKGROUND: Long-term cyclosporine (CsA) treatment leads to a decreased glomerular filtration rate, hyalinosis of afferent arterioles, and striped cortical tubulo-interstitial fibrosis. We showed previously that pentosan polysulfate (SP54) prevented the development of microvascular and interstitial lesions in mouse models of progressive glomerulosclerosis. In this study, we examined the effect of pentosan polysulfate on the development of CsA nephropathy. METHODS: Pair-fed Sprague-Dawley rats were fed a low-sodium (0.03%) diet and received CsA (15 mg/kg, subcutaneously, in olive oil)/5% glucose, pentosan polysulfate (10 mg/kg, subcutaneously in 5% glucose) plus CsA, olive oil/pentosan polysulfate, or olive oil/5% glucose for 30 days. Creatinine clearance (CrCl) was determined at three time points. Afferent arteriolar lesions, glomerular volume, and tubulo-interstitial lesions were quantitated. RNA was extracted from cortex. RESULTS: Severe lesions were found in the CsA group. A reduction in the number of affected arterioles (32%) and the degree of chronic tubulo-interstitial lesions (44%) was found in pentosan polysulfate/CsA-treated rats. A 20% decrease in glomerular volume was found in CsA rats, but not in pentosan polysulfate/CsA-treated rats. Pentosan polysulfate treatment did not prevent the CsA-induced decrease in CrCl (approximately 30%) at 4 weeks. CsA did not affect cortical endothelial or neuronal nitric-oxide synthase or mRNA levels, but there was small increase in neuronal nitric-oxide synthase mRNA levels in the pentosan polysulfate/CsA-treated group. CONCLUSIONS: Pentosan polysulfate reduced structural renal lesions in CsA-treated, salt-depleted Sprague-Dawley rats.

Dexamethasone increases eNOS gene expression and prevents renal vasoconstriction induced by cyclosporin.

Cyclosporin A (CsA)-induced renal vasoconstriction (RV) is attributed to an imbalance in vasoactive factors release. Dexamethasone (Dex) exerts a renal vasodilatory effect by a mechanism not yet characterized. This study evaluates whether the effect of Dex is mediated by NO and whether it prevents CsA-induced RV. Micropuncture studies were performed in six groups of uninephrectomized rats treated for 7 days with the following: vehicle (Veh); Veh + 4 mg/kg dexamethasone (Veh+Dex); 30 mg/kg CsA; CsA+Dex; vehicle + 10 mg/kg nitro-L-arginine methyl ester (Veh+L-NAME); and Veh+Dex+L-NAME. NO synthase (NOS) isoform mRNA levels were evaluated in renal cortex and medulla by semiquantitative RT-PCR analysis in the first four groups. Dex produced renal vasodilation, which was blocked by concomitant L-NAME administration, and the effect of Dex was associated with higher cortical and medullary endothelial NOS (eNOS) and cortical inducible NOS (iNOS) mRNA levels. In the CsA group, Dex prevented RV, restoring glomerular hemodynamics to control values. These changes were associated with further enhancement of eNOS and restoration of medullary iNOS and neuronal NOS (nNOS) expression. We conclude that Dex prevents CsA-induced RV, and its vasodilator effect could be mediated by increased intrarenal generation of NO, secondary to enhanced expression of eNOS and iNOS.

Role of NO in cyclosporin nephrotoxicity: effects of chronic NO inhibition and NO synthases gene expression.

The role of nitric oxide (NO) during cyclosporin renal vasoconstriction was evaluated by glomerular hemodynamic and histological changes produced by chronic NO synthesis inhibition and neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) NO syntheses mRNA expression in renal cortex and medulla. Uninephrectomized rats treated during 7 days with vehicle (Veh), cyclosporin A (CsA) 30 mg/kg, CsA + nitro-L-arginine methyl ester (L-NAME), and Veh + L-NAME (10 mg/dl) in the drinking water were studied. Increase in arterial pressure and afferent and efferent resistances, as well as decrease in glomerular plasma flow, ultrafiltration coefficient, and single-nephron glomerular filtration rate were significantly greater with CsA + L-NAME than with CsA alone. The increase in afferent resistance was higher with CsA + L-NAME than with Veh + L-NAME. In addition, glomerular thrombosis, proximal tubular vacuolization, and arteriolar thickening were more prominent. In renal cortex, eNOS mRNA expression exhibited a 2.7-fold increase in CsA, whereas, in medulla, nNOS and iNOs expression were lower in CsA than in Veh, while eNOS tended to increase. Our results support the hypothesis that NO synthesis is enhanced at cortical level during CsA nephrotoxicity, counterbalancing predominantly preglomerular vasoconstriction. Higher NO production could be the result of increased eNOS mRNA expression.

Semi-quantitative PCR: a tool to study low abundance messages in the kidney.

Some specific functions are often localized to unique cellular types or structures in organs such as kidney, brain, blood, and endocrine glands. As a result, it is not uncommon that gene products, although heavily expressed in some cell types within these organs, ultimately appear as low abundance products when total RNA is probed, resulting in decreased power of the conventional Northern blot analysis. To study gene expression in these circumstances, more sensitive techniques like RNAse protection assay and quantitative or semi-quantitative PCR strategies have been developed. In the present study, we provide a detailed description of the semi-quantitative PCR strategy in our laboratory. Using specific primers to amplify fragments from the neuronal isoform of the nitric oxide synthase and the thiazide-sensitive Na+:Cl- cotransporter (low abundance messages in the kidney), we show that the semi-quantitative PCR strategy is a valuable tool when low abundance messages are to be studied.

Participation of adenosine in the renal hemodynamic abnormalities of hypothyroidism.

To investigate the participation of adenosine (ADO) in the abnormalities of renal function associated with hypothyroidism, glomerular hemodynamics were evaluated in normal (Nl) and 2-wk thyroidectomized (Htx) rats. Studies were performed before and during intravenous infusion of the ADO blocker 1,3-dipropyl-8-p-sulfophenyl xanthine (PSPX, 20 mM, 1.2 ml/h), intra-aortic ADO (100 nmol.kg-1.min-1), or vehicle. In addition, single-nephron glomerular filtration rate (SNGFR) was measured during the infusion of different intrarenal ADO doses (1, 10, and 35 nmol.kg-1.min-1); plasma and renal content of ADO were measured by high-performance liquid chromatography in additional groups. Decreased SNGFR, glomerular blood flow (QA), and ultrafiltration coefficient (Kf) were found in Htx rats. PSPX did not modify glomerular hemodynamics in Nl rats; in contrast, in Htx rats, the antagonist increased SNGFR, QA, and Kf, with a fall in afferent (RA) and efferent (RE) resistances. ADO infusion in Nl rats produced renal vasoconstriction characterized by a fall in SNGFR, QA, and Kf, with an increased RA and RE. Paradoxically, in Htx rats, ADO increased SNGFR, QA, and Kf, decreasing RA and RE. However, when ADO was infused through the renal artery, it induced a 20% reduction of SNGFR at 1 nmol.kg-1.min-1 that rose to control values at 10 nmol.kg-1.min-1 and increased to 38.3% to 35.kg-1.min-1. Renal ADO content was markedly low in Htx rats (4.37 +/- 0.79 and 115.46 +/- 14.9 nmol/g wet wt for Htx and Nl rats, respectively). Renal vasodilation induced by PSPX in Htx rats suggests predominant activation of A1 receptors in this condition. The vasodilatory response to exogenous ADO suggests additional activation of A2 receptors.

Role of nitric oxide in renal hemodynamic abnormalities of cyclosporin nephrotoxicity.

To evaluate the participation of nitric oxide (NO) in chronic cyclosporin A (CsA) nephrotoxicity, the glomerular hemodynamic response to NO inhibition with N-nitro-L-arginine-methyl-ester (NAME) and stimulation of NO production with L-arginine was studied in uninephrectomized rats. Chronic CsA administration produced renal vasoconstriction, characterized by increased afferent (AR) and efferent (ER) resistances, decrease of glomerular plasma flow (QA) and ultrafiltration coefficient (Kf) that resulted in a 53% fall of single-nephron glomerular filtration rate (SNGFR). NAME infusion in vehicle group (V) elevated mean arterial pressure (MAP), AR and ER, reduced qA and Kf, and increased glomerular capillary pressure (PGC), resulting in a 28.9% fall of SNGFR. In the CsA group, NAME also increased MAP, but renal vasoconstriction was more intense; a greater rise of AR lowered PGC (P < 0.05 vs. V) further decreasing SNGFR by 38.9%. In control rats, L-arginine infusion induced a vasodilatory response of AR and ER, and elevation of QA and Kf, which resulted in a 72.6% increase in SNGFR. In the CsA group, greater vasodilation was observed and SNGFR rose by 114.9%. NO2-/NO3- urinary excretion was similar in CsA and V groups, and it was not modified by NAME in either group, but it increased five- to sixfold during L-arginine infusion in both groups. In conclusion, in CsA nephrotoxicity NO production seems to be normal and the ability of the renal endothelium to produce NO is maintained. Therefore renal vasoconstriction associated with CsA is not mediated by NO deficiency, although NO appears to attenuate it.

Mechanisms involved in the progression to glomerular sclerosis induced by systemic hypertension during mild puromycin aminonucleoside nephrosis.

To evaluate the contribution of systemic hypertension in the progression of nephropathies to glomerular sclerosis, a mild form of puromycin aminonucleoside (PAN) nephrosis was associated with Goldblatt hypertension and studied after 18 weeks. We studied four groups: Group I, controls; Group II, Goldblatt hypertension; Group III, PAN nephrosis; and Group IV, both conditions. Systolic blood pressure, 24-h proteinuria, serum cholesterol, triglycerides, glomerular hemodynamics, and histological studies were compared among the groups. Rats in groups II and IV developed systemic hypertension, but only group IV rats showed persistent proteinuria. No alterations in lipid metabolism were present in any of the groups. The most striking findings in the micropuncture studies were a significant increase of glomerular capillary pressure in group IV rats (63.15 +/- 1.34 mm Hg) as compared to controls (48.74 +/- 0.97 mm Hg) and to groups II and III (55.31 +/- 2.11 and 48.17 +/- 1.23 mm Hg, respectively), and a marked fall in Kf in groups III and IV. Only group IV showed significant histological alterations such as glomerular sclerosis, interstitial damage, and increased glomerular area. These results suggest that, in the presence of an underlying nephropathy, a greater fraction of systemic pressure is transmitted to the glomerular capillaries when systemic hypertension is present; the resulting elevation in glomerular pressure and proteinuria seems to be responsible for the progression to glomerular sclerosis.

Ischemia-reperfusion induced acute renal failure in the rat is ameliorated by the spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN).

The spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN) reduced the ischemia-reperfusion induced acute renal failure in the rat. Renal ischemia was produced in unilateral nephrectomized rats by complete occlusion of the left renal artery for 60 min. Perfusion of the kidney was then reestablished, and the rats were sacrificed 48 h later. PBN (100 mg/kg i.p.) administered 30 min prior to renal artery occlusion significantly reduced the increase in serum creatinine and urea and renal failure index, as well as the decrease in urine/plasma creatinine ratio and creatinine clearance compared to saline-injected ischemic rats. PBN injected to control rats had no effect on these parameters. These data support the hypothesis of an involvement of reactive free radicals in the pathogenesis of ischemia-reperfusion induced acute renal failure in the rat and suggest that PBN may be a useful agent for the prevention of renal ischemia-reperfusion damage.

Effect of circulating factors on vascular smooth muscle contraction and its calcium uptake in uremia.

Uremia is often associated with alterations in calcium metabolism and vascular smooth muscle function in hypertension and atherosclerosis. The ways in which these conditions inter-relate are not clearly understood. In order to study the possibility that circulating factors might influence smooth muscle function, experiments were performed on rat aortic strips. The serum from both uremic patients and rats enhanced the norepinephrine-induced contraction (NEIC) and net 45-calcium uptake in rat aortic strips. In a similar manner, the serum of parathyroidectomized uremic rats also increased the NEIC, whereas verapamil reduced the aortic response to levels below those of the control, in the presence of uremic serum. These findings suggest that in both chronic (patients) and early (rats) stages of uremia, there is a circulating factor, different from parathyroid hormone, that affects calcium uptake and vascular smooth muscle contraction.

Evaluating hyperfiltration with glycine in hypertensive rats with renal ablation.

Hypertension-induced renal damage is mediated by increased glomerular pressure and flow. These alterations have been evaluated by the renal response to protein or amino acids. To test this assumption, we studied glomerular hemodynamic responses to glycine infusion in rats with reduced renal mass, with and without Goldblatt hypertension. The left kidney was ablated by two thirds in 12 rats, and in 5, hypertension was induced by clipping the right renal artery. Seven normal, unmanipulated rats served as controls. Micropuncture was performed in the left kidney during control and 15% glycine infusion periods, 45 days after surgery. Arterial pressure was higher in hypertensive rats (160.3 mm Hg) than in controls (103.8 mm Hg) and rats with renal ablation (125 mm Hg; p less than 0.05). Higher values of single-nephron glomerular filtration rate and single-nephron plasma flow in rats with renal ablation (63.0, 223.7 nl/min) and hypertension (46.1, 239.7 nl/min) than in controls (28.8, 94.9; p less than 0.05) demonstrated the presence of hyperfiltration. However, glomerular pressure was elevated only in hypertensive rats (40.1 mm Hg), when compared to controls (32.7 mm Hg; p less than 0.05) and rats with renal ablation (33.4 mm Hg; p less than 0.05). Glycine increased single-nephron glomerular filtration rate and single-nephron plasma flow in control rats by 76 and 65%; rats with renal ablation had only partial responses, 35% and 23%, respectively, whereas in hypertensive rats the response was completely abolished. Glycine detected hyperfiltration and unmasked a dysfunction of preglomerular vessels that was greater in hypertensive rats and could contribute to the rise in glomerular pressure and flow and thereby to glomerular damage.

Effect of captopril and hydrochlorothiazide on glomerular haemodynamics and histological damage in Goldblatt hypertension with partial renal ablation.

Increased glomerular capillary pressure (GCP) mediates glomerular damage in hypertension. The efficacy of captopril, an angiotensin converting enzyme (ACE) inhibitor, and captopril-hydrochlorothiazide (captopril-TZ) in lowering GCP and preventing glomerular damage was evaluated in rats with two-kidney, one clip (2K, 1C) Goldblatt hypertension and partial ablation of the unclipped kidney. Thirty days after surgery nine rats received captopril, 11 received captopril-TZ and eight served as untreated control rats. Sixty days later systemic hypertension was associated with increased GCP and severe structural damage in the unclipped kidney of C rats. Captopril lowered arterial pressure (AP), and prevented the rise in GCP and structural lesion. Captopril-TZ decreased AP and GCP to a greater extent, but did not reduce structural damage further. Captopril lowered GCP, preventing structural damage; greater reduction of GCP with captopril-TZ did not provide further protection.