Increased salt retention and hypertension from non-steroidal agents in the elderly

We studied blood pressure and natriuretic responses to acute salt loading, and the effect of non-steroidal anti-inflammatory agents on these responses, in five healthy normotensive women aged 65 to 71 years. Five women aged 25 to 31 years acted as controls. Intravenous saline loading, with and without prior ingestion of ibuprofen, was 15 ml/kg/h for 3 h. Baseline blood pressures were higher in the elderly. Saline infusion without ibuprofen raised systolic blood pressure (SBP) by about 25 mmHg in the older group only. Ibuprofen increased baseline SBP in the elderly (129 +/- 6 vs. 116 +/- 5 mmHg, p < 0.05). Saline loading after ibuprofen again raised blood pressure by about 25 mmHg in the elderly only. The elderly group showed markedly increased sodium excretion during saline loading, but this was reduced by ibuprofen. Ibuprofen had no effect on SBP or sodium excretion in controls. Ageing appears to increase susceptibility to salt retention and hypertension from non-steroidal anti-inflammatory agents.      

Imaging of thoracic aortic dissection

Acute thoracic aortic dissection has a high mortality if untreated, so the diagnosis must be rapidly made if mortality is to be lowered significantly. Multiple imaging techniques are often used. This retrospective study from 1988 to 1993 assesses the usefulness in diagnosis of chest X-rays, computed tomography (CT) scanning, aortography, magnetic resonance imaging (MRI), trans-thoracic (TTE) and trans-oesophageal (TOE) echocardiography. Forty-two patients with a final clinical diagnosis of dissection were studied. The diagnosis was confirmed in 16 (13 at surgery and three at autopsy). Three died with dissection given as the only cause for death. Chest X-ray abnormalities were seen in all 19 patients with surgery or death from dissection, with a widened mediastinum and/or dilated aorta being present in 17. In the group of 16 patients with surgery or autopsy proof, CT scans found dissections in 9 of 12 patients studied and correctly classified the type in only five. Aortography was performed in five, with accurate depiction of dissection and type in all. TTE found dissections in three of eight patients imaged by this method. MRI and TOE were performed each on two patients, with accurate depiction of dissection and type in each. Because of the relatively low sensitivity of CT scanning in defining aortic dissections Westmead Hospital is currently assessing the use of TOE as the prime imaging modality prior to surgical intervention.     

Crystalloids, colloids and kids: a review of paediatric burns in intensive care

This is a retrospective review of all burns patients admitted to a paediatric intensive care unit (PICU) over a 7 year period. Resuscitation fluid therapy and clinical course are presented. Ninety-eight new burns victims were admitted with a mortality rate of 10.2%, all in burns of greater than 25% body surface area (BSA). The incidence of ARDS was 20%, with an 18% mortality rate. Of 85 patients with burns greater than 5% BSA, 33 received the hospital-recommended colloid-based resuscitation formula, 46 received a combination of crystalloids and colloids and in 6 patients the resuscitation regimen was not able to be determined. The aetiology, age distribution, sex ratio, severity of burns and length of stay in hospital did not alter significantly over the study period. The number of burns admissions to PICU increased, as did their duration of intubation and ICU stay. The hospital-recommended resuscitation formula consistently underestimated the fluid volume required for adequate resuscitation. No statistically significant difference in adverse effects was found between the resuscitation groups. This study is unable to recommend a definitive approach to the fluid resuscitation of burns shock in paediatrics and the best approach is one of meticulous fluid resuscitation titrated on clinical effect.     

A double mutant [N543H+2393del9] allele in the LDL receptor gene in familial hypercholesterolemia: effect on plasma cholesterol levels and cardiovascular disease

Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDL receptor gene. During a survey of mutations of LDL receptor gene in Spanish FH patients we found two mutations in the same allele: a missense N543H mutation in exon 11 and a 9bp inframe deletion (2393del9) located in exon 17. This double mutant allele was founded in 10 out of 458 unrelated patients: one homozygous FH [N543H+2393del9] + [N543H+2393del9], one compound heterozygote [N543H+2393del9] + [W-18X+E256K] and 8 heterozygotes. Flow cytometric analysis showed a defective LDL binding (20% of normal value) and internalization (23%) in lymphocytes from the homozygous patient; furthermore, studies of mitogen-stimulated lymphocytes demonstrated that the ability of LDL to support cell proliferation was impaired. Unexpectedly, not all carriers of the double mutant allele develop hypercholesterolemia and, furthermore, cholesterol-lowering treatment of the homozygous patient resulted in a 58% LDL cholesterol reduction. In conclusion, the phenotypic expression in the homozygous and heterozygous patients presented here, as well as the LDL-receptor residual activity, allowed the classification of this mutation as mild extending the group of mild mutations found at homozygosity.     

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.      

Evidence that mechanisms dependent and independent of nitric oxide mediate endothelium-dependent relaxation to bradykinin in human small resistance-like coronary arteries

1. The effects of the nitric oxide (NO) synthase inhibitor, N^G-nitro-L-arginine (L-NOARG), the NO scavenger, oxyhaemoglobin (HbO) and high extracellular K⁺ upon endothelium-dependent relaxation to bradykinin were investigated in human isolated small coronary arteries.
2. Endothelium-dependent relaxations to bradykinin were compared in vessels contracted to ∼50% of their maximum contraction to 124 mM KCl Krebs solution, regardless of treatments, with the thromboxane A₂ mimetic, U46619 and acetylcholine. All relaxations were expressed as percentage reversal of the initial level of active force.
3. L-NOARG (100 μM) caused a small but significant, 12% (P<0.01), decrease in the maximum relaxation (R_max: 91.5±5.4%) to bradykinin but did not significantly affect the sensitivity (pEC₅₀: 8.08±0.17). Increasing the concentration of L-NOARG to 300 μM had no further effect on the pEC₅₀ or R_max to bradykinin. HbO (20 μM) and a combination of HbO (20 μM) and L-NOARG (100 μM) reduced R_max to bradykinin by 58% (P<0.05) and 54% (P<0.05), respectively. HbO (20 μM) and L-NOARG (100 μM, combined but not HbO (20 μM) alone, caused a significant 11 fold (P<0.05) decrease in sensitivitiy to bradykinin. HbO (20 μM) decreased the sensitivity to the endothelium-independent NO donor, S-nitroso-N-acetylpenicillamine (SNAP), approximately 17 fold (P<0.05).
4. Raising the extracellular concentration of K⁺ isotonically to 30 mM, reduced the R_max to bradykinin from 96.6±3.1% to 43.9±10.1% (P<0.01) with no significant change in sensitivity. A combination of HbO, L-NOARG and high K⁺ (30 mM) abolished the response to bradykinin. High K⁺ did not change either the sensitivity or maximum relaxation to SNAP.
5. In conclusion, L-NOARG does not completely inhibit endothelial cell NO synthesis in human isolated small coronary arteries. By comparison, HbO appeared to block all the effects of NO in this tissue and revealed that most of the relaxation to bradykinin was due to NO. The non-NO -dependent relaxation to bradykinin in the human isolated small coronary arteries appeared to be mediated by a K⁺-sensitive vasodilator mechanism, possibly endothelium-derived hyperpolarizing factor (EDHF).

     

Recent developments in SWL physics research

Two projects in our laboratory highlight some recent developments in shockwave lithotripsy (SWL) physics research. In the first project, we developed a prototype of a piezoelectric annular array (PEAA) shockwave generator that can be retrofitted on a Dornier HM-3 lithotripter for active control of cavitation during SWL. The PEAA generator, operating at 15 kV, produces a peak positive pressure of approximately 8 MPa with a -6-dB beam diameter of 5 mm. The shockwave generated by the PEAA was used to control and force the collapse of cavitation bubbles induced by a laboratory electrohydraulic shockwave lithotripter with a truncated HM-3 reflector. With optimal time delay between the lithotripter pulse and the PEAA-generated shockwave, the collapse of cavitation bubbles near the stone surface could be intensified, and the resultant stone fragmentation in vitro could be significantly improved. In the second project, high-speed shadowgraph imaging was used to visualize the dynamics of lithotripter-induced bubble oscillation in a vascular phantom. Compared with the free bubble oscillation in water, the expansion of cavitation bubble(s) produced in silicone tubes and a 200-microm cellulose hollow fiber by either a Nortech EHL or a Dornier XL-1 lithotripter was found to be significantly constrained. Rupture of the cellulose hollow fiber was observed consistently after about 20 shocks from the XL-1 lithotripter at an output voltage of 20 kV. These results confirm experimentally that SWL-induced cavitation in vivo can be significantly constrained by the surrounding tissue, and large intraluminal bubble expansions could cause rupture of capillaries and small blood vessels.