High-calcium vs high-phosphate intake and small artery tone in advanced experimental renal insufficiency

Background. Disturbed calcium–phosphorus balance significantlycontributes to uraemic changes in large arteries. We examinedthe influences of high-calcium and high-phosphate intake onsmall artery tone in experimental renal insufficiency. Methods. Sixty-five rats were assigned to 5/6 nephrectomy (NTX)or sham operation. After 15 week disease progression, NTX ratswere given high-calcium (3%), high-phosphate (1.5%) or controldiet (0.3% calcium, 0.5% phosphate) for 12 weeks. Then isolatedsegments of small mesenteric arteries were studied using wireand pressure myographs. Results. Subtotal nephrectomy reduced creatinine clearance by60% and increased parathyroid hormone (PTH) and phosphate 12-foldand 2.7-fold, respectively. High-phosphate intake further elevatedPTH and phosphate (33-fold and 5.5-fold, respectively), whilethe calcium diet suppressed them (to 3.5 and 62% vs sham, respectively).Ventricular B-type natriuretic peptide synthesis was increased,and blood pressure was 27 and 18 mmHg higher in NTX rats oncontrol and phosphate diet, respectively, than in calcium-fedrats. Vasorelaxation to acetylcholine was impaired by 50% inuraemic rats, and was further deteriorated by high-phosphateintake, whereas the calcium diet improved endothelium-mediatedrelaxation via nitric oxide and potassium channels. Small arteriesof all NTX groups featured eutrophic inward remodelling: wall-to-lumenratio was increased 1.3-fold without change in cross-sectionalarea. Conclusion. High-phosphate intake had a detrimental influenceon secondary hyperparathyroidism and vasodilatation, whereashigh-calcium intake reduced blood pressure and PTH, alleviatedvolume overload and improved vasorelaxation in experimentalrenal insufficiency. Therefore, alterations in the calcium–phosphorusbalance can significantly modulate small artery tone duringimpaired kidney function.     

Feasibility of the use of a novel soft tissue stiffness meter

Simple but objective measurement of soft tissue consistency would be advantageous in the assessment of many neurological, lymphostatic and venous disorders. The aim of the present study was to evaluate the feasibility of using a novel hand-held computerized soft tissue stiffness meter (STSM). The STSM describes the soft tissue stiffness (STS) in the form of the instantaneous force (N) by which the tissue resists the constant deformation produced by a cylindrical intender. Firstly, the STSM was used to test elastomer samples with known mechanical properties. In the in vivo assessment, 12 healthy, nondisabled adults (age range, 24-57 years) and 16 subjects with chronic myofascial neck pain syndrome (age range, 27-55 years) were studied. To study the reproducibility (coefficient of variation (CV(%))) of the method, the measurement sites were either marked with a marker pen (marked points) or localized anatomically (unmarked points). Measurements were made from the dorsal forearm (Arm), trapezius (Tra), levator scapulae (Lev), infraspinatus (Inf) and deltoideus (Del) muscle areas. STS in the forearm was studied during different types of short-term relative isometric loading of the muscle as well as during venous occlusion. STS values of the myofascial trigger points in the Lev muscles were evaluated bilaterally. A linear, positive relationship was found between the indenter force (N) and the dynamic compressive modulus (MPa) of elastomer stiffness (r(2) = 0.90, n = 9). Intra- and interrater CVs of marked and unmarked sites varied between 4.31% and 12.06%. STS increased linearly along the relative muscle load (r(2) = 0.96) and nonlinearly during the venous occlusion (r(2) = 0.97). Statistically significant regional variation of STS was found between the different measurement sites (p < 0.05). In conclusion, STSM can evaluate tissue stiffness quantitatively and yield reproducible data.     

Antioxidant and neuroprotective activity of the extract from the seaweed, Halimeda incrassata (Ellis) Lamouroux, against in vitro and in vivo toxicity induced by methyl-mercury

A growing body of evidence suggests oxidative stress as part of the toxicity mechanism of methyl-mercury (MeHg) in cell cultures and animal models and so justifies the use of natural antioxidants as therapeutic alternatives. This research examines the effect of an aqueous extract from the marine seaweed Halimeda incrassata (Hi) against the oxidative stress induced by MeHg on in vitro and in vivo models. In GT1-7 mouse hypothalamic cell cultures, the extract of Hi increased cell viability and reduced ROS production after 24-h exposure to MeHgCl. Wistar rats, acutely intoxicated with MeHgCl, had reduced levels of serum and brain thiobarbituric reactive substances when treated with the Hi extract. Similarly, animals exposed to repeated doses of MeHgCl were protected by the seaweed extract from variations in body weight, food consumption and the appearance of neurological effects. This research supports the notion that oxidative stress is directly involved in MeHg intoxication, so that natural antioxidants, particularly those in the extract of Hi, can be useful therapeutic alternatives.     

A cyclopent-2-enecarbonyl group mimics proline at the P2 position of prolyl oligopeptidase inhibitors

With the aim to replace the natural amino acid proline by a proline mimetic structure, a cyclopent-2-enecarbonyl moiety was studied at the P2 position of prolyl oligopeptidase (POP) inhibitors. The cyclopent-2-enecarbonyl moiety proved to be an excellent proline mimetic at the P2 position of POP inhibitors. The replacement is particularly useful when increased lipophilicity is needed.     

Hepatotoxicity in patients with juvenile idiopathic arthritis receiving longterm methotrexate therapy

OBJECTIVE: To evaluate hepatotoxicity in patients with juvenile idiopathic arthritis (JIA) receiving methotrexate (MTX) therapy with doses of 20-30 mg/m2 of body surface area. METHODS: We graded the histology of percutaneous liver biopsies from 34 patients with JIA receiving longterm (> 2.4 years) MTX therapy at the Rheumatism Foundation Hospital, Heinola, Finland, using the Roenigk classification scale. Medical records of the patients with JIA were retrospectively analyzed. RESULTS: Of 10 patients with MTX doses >/= 20 mg/m2, 4 had grade II, 5 had grade I histology, and one specimen with extensive steatosis as the only pathologic finding could not be classified. All 24 patients treated with low dose MTX had grade I histology. No specimen showed fibrosis or cirrhosis. In 2 patients with grade II histology, extensive portal tract inflammation resolved when MTX was discontinued for 6 months. CONCLUSION: Aggressive medical treatment of JIA with MTX at 20-30 mg/m2 with concomitant disease modifying antirheumatic drugs and corticosteroids may contribute to minor liver abnormalities that seem to be reversible.     

An endothelial laminin isoform, laminin 8 (alpha4beta1gamma1), is secreted by blood neutrophils, promotes neutrophil migration and extravasation, and protects neutrophils from apoptosis

During extravasation, neutrophils migrate through the perivascular basement membrane (BM), a specialized extracellular matrix rich in laminins. Laminins 8 (LN-8) (alpha4beta1gamma1) and 10 (LN-10) (alpha5beta1gamma1) are major components of the endothelial BM, but expression, recognition, and use of these laminin isoforms by neutrophils are poorly understood. In the present study, we provide evidence, using a panel of novel monoclonal antibodies against human laminin alpha4 (LNalpha4) chain, that neutrophils contain and secrete LN-8, and that this endogenous laminin contributes to chemoattractant-induced, alphaMbeta2-integrin-dependent neutrophil migration through albumin-coated filters. Phorbol ester-stimulated neutrophils adhered to recombinant human (rh) LN-8, rhLN-10, and mouse LN-1 (mLN-1) (alpha1beta1gamma1) via alphaMbeta2-integrin, and these laminin isoforms strongly promoted chemoattractant-induced neutrophil migration via the same integrin. However, only rhLN-8 enhanced the spontaneous migration. In addition, recruitment of neutrophils into the peritoneum following an inflammatory stimulus was impaired in LNalpha4-deficient mice. rhLN-8 also protected isolated neutrophils from spontaneous apoptosis. This study is the first to identify a specific laminin isoform in neutrophils and provides evidence for the role of LN-8 in the adhesion, migration, extravasation, and survival of these cells.     

Status Epilepticus Causes Selective Regional Damage and Loss of GABAergic Neurons in the Rat Amygdaloid Complex

In human epilepsy, the amygdala is often a primary focus for seizures. To analyse the status epilepticus-induced alterations in the amygdaloid circuitries which may later underlie epileptogenesis, we studied the amygdaloid damage in kainic acid and perforant pathway stimulation models of status epilepticus in the rat. We also studied the damage to inhibitory GABAergic neurons. In both models, the medial division of the lateral nucleus, the parvicellular division of the basal nucleus and portions of the anterior cortical and medial nuclei were damaged. In the kainate model, where the seizure activity was more severe, the accessory basal nucleus, amygdalohippocampal area, posterior cortical nucleus and periamygdaloid cortex were also damaged. Two weeks after kainate-induced seizures, 56% of the GABA-immunoreactive neurons remained in the lateral nucleus ( P < 0.05) and 25% in the basal nucleus ( P < 0.01). Further analysis showed that one subpopulation of damaged GABAergic neurons was immunoreactive for somatostatin (48% remaining in the lateral nucleus, P < 0.01; 33% in the basal nucleus, P < 0.01). In the perforant pathway stimulation model, the damage to somatostatin neurons was milder. According to our data, the initial insult, such as status epilepticus, selectively damages amygdaloid nuclei. The loss of inhibition may underlie the spontaneous generation of seizures and epileptogenesis. On the other hand, many amygdaloid output nuclei (magnocellular and intermediate division of the basal nucleus, the central nucleus) remained relatively undamaged, providing pathways for seizure spread and generation of seizure-related behavioural manifestations such as motor convulsions and fear response.