Bone loss in rats with aldosteronism

OBJECTIVE: We hypothesized that aldosteronism is accompanied by hypercalciuria and hypermagnesuria that lead to bone loss, which could be rescued by hydrochlorothiazide and spironolactone. METHODS: We monitored 24-hour urinary Ca and Mg excretion; plasma ionized [Ca]o and [Mg]o and plasma K; and bone mineral density of the femur. The following groups (n=5 in each group) were studied: age- and gender-matched, untreated controls; controls + 4 weeks hydrochlorothiazide; 4 weeks aldosterone/salt treatment (ALDOST, 0.75 mug/h and dietary 1% NaCl/0.4% KCl); 4 weeks ALDOST+hydrochlorothiazide (50 mg/kg in prepared food); and 4 weeks ALDOST+hydrochlorothiazide+spironolactone (200 mg/kg day in divided doses by twice-daily gavage). RESULTS: ALDOST increased (P<0.05) urinary Ca and Mg excretion four- and twofold, respectively; hydrochlorothiazide co-treatment attenuated (P<0.05) Ca excretion in controls and during ALDOST without affecting augmented Mg excretion whereas hydrochlorothiazide+spironolactone normalized Ca and reduced Mg excretion (P<0.05). Compared with controls, plasma [Ca]o at 4 weeks of ALDOST was reduced (0.89+/-0.02 versus 0.83+/-0.03 mmol/L; P<0.05) but remained no different from levels in controls with hydrochlorothiazide and hydrochlorothiazide+spironolactone (0.88+/-0.04 and 0.97+/-0.03 mmol/L, respectively). Plasma [Mg]o fell (P<0.05) with ALDOST+hydrochlorothiazide (0.23+/-0.01 versus 0.34+/-0.01 mmol/L) and was prevented with spironolactone co-treatment (0.33+/-0.01 mmol/ dL). Hypokalemia (2.9+/-0.2 mmol/L) occurred in rats with ALDOST+hydrochlorothiazide but not with spironolactone co-treatment. At 4 weeks of ALDOST, plasma parathyroid hormone was increased (30+/-4 versus 11+/-3 pg/mL; P<0.05) and bone mineral density was reduced (0.153+/-0.006 versus 0.170+/-0.002 g/cm; P<0.05). Co-treatments with either hydrochlorothiazide or hydrochlorothiazide+spironolactone each prevented bone loss. CONCLUSIONS: Hypercalciuria and hypermagnesuria accompany aldosteronism and account for a decline in their plasma ionized concentrations and secondary hyperparathyroidism with bone resorption. Attenuation of bone loss in aldosteronism can be achieved with hydrochlorothiazide; however, mono- and divalent cation homeostasis, together with bone integrity, are each preserved with the combination hydrochlorothiazide+spironolactone.     

Carotid revascularization in the presence of contralateral carotid artery occlusion is safe and durable

OBJECTIVE: Complete occlusion of the contralateral carotid artery has been thought to increase the risk of carotid endarterectomy (CEA). This study was conducted to determine whether contralateral occlusion (CO) leads to a higher rate of complications among patients undergoing CEA or alters long-term outcomes. METHODS: All CEAs (N = 221) performed at our institution between September 1997 and June 2002 were reviewed. Patients were divided into two groups, i.e., CO and contralateral patency. Statistical analyses were performed using Fisher's exact test for nominal values and the t test for continuous variables. Life-table analyses were performed for patency and survival. RESULTS: Complete data and follow-up results were available for 170 of the 221 operations performed during the study period. CO was present in 16 cases (9.4%). Preoperative demographic features, indications for surgery, and operative techniques did not vary between study groups; there was increased use of general anesthesia (p = 0.05) in the CO group. No surgical deaths occurred. The perioperative stroke rates were not statistically different between groups (CO group, 6.3%; contralateral patency group, 2.6%; p = 0.39). Long-term patency and stroke-free survival rates at 5 years exceeded 90% and did not vary significantly between groups. CONCLUSION: Patients undergoing CEA with occlusion of the contralateral carotid artery do not have unique preoperative demographic features or indications. Contralateral carotid artery occlusion does not increase risk or alter long-term outcomes after CEA. Carotid revascularization can be safely performed in tertiary military centers.     

Self-inflicted burns fatalities in Manipal, India

Death due to burns is an important public health problem. Suicide by burning is uncommon in the Western world compared with Asian countries. This study presents retrospective research carried out in the tertiary care teaching hospital of Kasturba Medical College, Manipal, Southern India, between January 1993 to December 2003 (11 years). Out of a total of 343 burns deaths during the above-mentioned period, 39 were victims of suicide. The majority of deaths (46.1%) occurred in the 21-30 years age group, with a preponderance of the female sex (79.5%). Most of the victims belonged to the Hindu religion and the incident occurred mostly during the daytime. In the overwhelming majority of cases, the incident occurred at home (97.4%). In all cases kerosene was the accelerant and flame was the causative agent. In more than fifty per cent of cases, the total body surface area (TBSA) involved was more than 80%. Dowry demands and harassment were the reasons for committng suicide in 12 cases. More stringent laws and empowering female independence, both mentally and economically, will reduce suicidal burns in young women.     

19F: a versatile reporter for non-invasive physiology and pharmacology using magnetic resonance

The fluorine atom provides an exciting tool for diverse spectroscopic and imaging applications using Magnetic Resonance. The organic chemistry of fluorine is widely established and it can provide a stable moiety for interrogating many aspects of physiology and pharmacology in vivo. Strong NMR signal, minimal background signal and exquisite sensitivity to changes in the microenvironment have been exploited to design and apply diverse reporter molecules. Classes of agents are presented to investigate gene activity, pH, metal ion concentrations (e.g., Ca(2+), Mg(2+), Na(+)), oxygen tension, hypoxia, vascular flow and vascular volume. In addition to interrogating speciality reporter molecules, (19)F NMR may be used to trace the fate of fluorinated drugs, such as chemotherapeutics (e.g., 5-fluorouracil, gemcitabine), anesthetics (e.g., isoflurane, methoxyflurane) and neuroleptics. NMR can provide useful information through multiple parameters, including chemical shift, scalar coupling, chemical exchange and relaxation processes (R1 and R2). Indeed, the large chemical shift range (approximately 300 ppm) can allow multiple agents to be examined, simultaneously, using NMR spectroscopy or chemical shift selective imaging.     

Brain permeability of inhaled corticosteroids

The aim of this study was to evaluate if the permeability of inhaled corticosteroids entering the brain is reduced and if P-glycoprotein (P-gp) transporters are involved. Currently employed inhaled corticosteroids were given intravenously and intratracheally to rats at a dose of 100 microg kg-1. An ex-vivo receptor binding assay was used to monitor over 12 h the glucocorticoid receptor occupancy in the brain and a systemic reference organ (kidney). The involvement of P-gp in the brain permeability of triamcinolone acetonide was assessed in wild-type mice and mdr1a(-/-) knockout mice (mice lacking the gene for expressing P-gp). After both forms of administration, the average brain receptor occupancies were 20-56% of those of the reference organ, with the more lipophilic drugs showing a more pronounced receptor occupation. While the receptor occupancies in the liver of wild-type and mdr1a(-/-) mice were similar after administration of triamcinolone acetonide, brain receptor occupancies in mdr1a(-/-) mice were significantly greater (mdr1a(-/-): 47.6%, 40.2-55.0%, n=14; 2; wild-type: 11.5+/-33.0%, n=14; 3). Penetration into the brain for inhaled corticosteroids (especially those of lower lipophilicity) is reduced. Experiments in mdr1a(-/-) mice confirmed the involvement of P-gp transporters. Further studies are needed to assess whether potential drug interactions at the transporter level are of pharmacological significance.     

Renal humoral modulation of skeletal muscle tone in mice: implications for 'the pulmonary-renal cascade'

The pulmonary-renal cascade may regulate the respiration and skeletal muscle contractility. To evaluate this working hypothetical model, we conducted experiments to ascertain the skeletal muscle tone of the Swiss mice (20-35 g). The animals were evaluated for their skeletal muscle tone via several techniques i.e. inclined plane test, grip strength test and swim test. Groups of mice (n=6) were pre-treated with mefenamic acid (60 mg/kg, i.p), carbenoxolone (100 mg/kg i.p) or vehicle only 15 minutes before the treatment with heparin (500 U/kg, i.v), urokinase (5500 U/kg, i.v) and erythropoietin (150 U/kg, i.v). Heparin potentiated the loss of skeletal muscle tone induced by mefenamic acid and carbenoxolone while urokinase & erythropoietin significantly enhanced the skeletal muscle tone as evaluated by all or one of the tests. Other groups of mice (n=6) were pretreated with mefenamic acid (1 mg i.c.v), carbenoxolone (160 microg i.c.v) or minoxidil (30 microg i.c.v) and the effects of heparin & urokinase and erythropoietin on skeletal muscle tone were evaluated. To study the effects of heparin and urokinase on nerve regeneration, two groups of mice underwent a sham and sciatic nerve crush procedure. The mice treated with urokinase recovered much faster as compared to those treated with heparin or saline. These experimental results suggest that gap junction blockers and potassium channel openers interact with heparin, urokinase and erythropoietin to control the skeletal muscle tone.