Blood-brain barrier unlocked.

The brain is protected by a physiological blood-brain barrier (BBB) against toxins and some metabolites circulating in the blood. At the same time, the BBB limits penetration into the brain of many neuroactive drugs. Efficient ways to increase BBB permeability for delivery of drugs of different chemical nature into the brain are unknown. This work deals with delivery into the brain of 10(-2) M dopamine, a substance that does not penetrate the BBB under normal circumstances. It was studied in two independent experiments: (i) penetration of (3)H-labeled dopamine from its mixture with 10(-5) M H2O2 into hypothalamus and striatum structures of intact rat brain, and (ii) effect of unlabeled dopamine from a mixture with H(2)O(2) on the rat motor activity in a haloperidol catalepsy model. It was shown that (i) at the third minute after nasal application of the dopamine + H(2)O(2) mixture, the dopamine level increases 45-fold in the hypothalamus and almost 30-fold in the striatum and (ii) motility of animals in the catalepsy haloperidol model is recovered 90 sec after intranasal introduction of dopamine. No such effects were observed after replacement of H(2)O(2) by 0.9% NaCl solution. Thus, it was shown on the example of dopamine that its introduction into the nasal cavity simultaneously with H(2)O(2) provides for rapid delivery of the drug into the brain. These results expand our knowledge concerning the biological role of exoROS in modulating BBB permeability and may contribute to the development of a new therapeutic strategy for neurological diseases.

Influence of co-morbidity on renal function assessment by Cockcroft-Gault calculation in lung cancer and mesothelioma patients receiving platinum-based chemotherapy.

BACKGROUND: Creatinine clearance (CrCl) estimation by Cockcroft-Gault calculation (CG) often replaces measurement of glomerular filtration rate (GFR) by [(51)Cr]-ethylenediaminetetraacetic acid clearance (EDTA). Co-morbidity, age, and renal impairment influence the accuracy of CG, whilst the relationship between CG and EDTA has been poorly assessed in lung cancer patients, a population significantly affected by these covariates. METHODS: Retrospective analysis of co-morbidity, nephrotoxic drug use, chemotherapy toxicity, and correlation between paired CG and EDTA, in 388 lung cancer and mesothelioma patients receiving platinum-based chemotherapy. RESULTS: Potentially nephrotoxic co-morbidity or medication use occurred in 47% of patients, and was twice as likely in those aged >70 years (OR=2.07; 95%CI: 1.25-3.44, p=0.003). Patients with co-morbidity or nephrotoxic medication use had a lower EDTA compared to those without these baseline factors (p=0.02), but were not significantly more likely to experience chemotherapy toxicity. CG and EDTA correlation was high (r(2)=0.68), but reduced in patients with ETDA<50 ml/min (r(2)=0.26, p=0.02) or >120 ml/min (r(2)=0.32, p=0.09), and in those with CG>120 ml/min (r(2)=0.20, p=0.01). The correlation between CG and EDTA was not significantly altered in patients with co-morbidity or nephrotoxic medication use. CG bias (mean percentage error) and precision (mean absolute percentage error, MAPE) were 7% and 26%, respectively, and precision was impaired in patients with abnormally raised serum creatinine (MAPE 65%, p<0.0001). CONCLUSION: CG estimation of CrCl is accurate and safe in lung cancer patients with potentially nephrotoxic co-morbidity or concomitant medication, but should not be used when values are outside the range 50-120 ml/min, or with abnormally elevated serum creatinine.

2010 ACVIM small animal consensus statement on leptospirosis: diagnosis, epidemiology, treatment, and prevention.

This report offers a consensus opinion on the diagnosis, epidemiology, treatment, and prevention of leptospirosis in dogs, an important zoonosis. Clinical signs of leptospirosis in dogs relate to development of renal disease, hepatic disease, uveitis, and pulmonary hemorrhage. Disease may follow periods of high rainfall, and can occur in dogs roaming in proximity to water sources, farm animals, or wildlife, or dogs residing in suburban environments. Diagnosis is based on acute and convalescent phase antibody titers by the microscopic agglutination test (MAT), with or without use of polymerase chain reaction assays. There is considerable interlaboratory variation in MAT results, and the MAT does not accurately predict the infecting serogroup. The recommended treatment for optimal clearance of the organism from renal tubules is doxycycline, 5 mg/kg p.o. q12h, for 14 days. Annual vaccination can prevent leptospirosis caused by serovars included in the vaccine and is recommended for dogs at risk of infection.

Fulminant liver failure due to usnic acid for weight loss.

The use of complementary and alternative medicine (CAM) in developed countries has increased significantly over the years. Among the most popular are the weight loss supplements or "fat burners." Liver failure due to these popular remedies has been widely recognized. Usnic acid has been an ingredient of dietary supplements that cause liver failure. Its hepatotoxicity has not been recognized because it is usually mixed with other ingredients that are presumably hepatotoxic. We describe a case of a 28-yr-old woman who presented with fulminant liver failure requiring orthotopic liver transplantation, after taking pure usnic acid for weight loss. This is the first report on fulminant liver failure associated with the ingestion of pure usnic acid. A discussion about hepatotoxicity of the different compounds of dietary supplements is presented. This is a reminder for the clinicians about the potential side effects of CAM.

Percutaneous ultrasound-guided chemical parathyroid ablation for treatment of primary hyperparathyroidism in dogs.

OBJECTIVE: To evaluate the efficacy, feasibility, and safety of ultrasound-guided chemical ablation of parathyroid masses in dogs with primary hyperparathyroidism. DESIGN: Prospective clinical trial. ANIMALS: 8 dogs. PROCEDURE: In all dogs, a solitary parathyroid mass was evident ultrasonographically. Dogs were anesthetized with propofol, and a 27-gauge needle was directed into the parathyroid mass under ultrasound guidance. Ethanol (96%) was injected into the mass until there was evidence of diffusion of fluid throughout the mass. Serum total calcium, ionized calcium, phosphorus, and parathyroid hormone (PTH) concentrations were monitored daily for 5 to 7 days after the ablation procedure and again 1, 3, and 6 months after the procedure. Dogs were also monitored for adverse effects. Follow-up ultrasonography was performed 5 days and 1 month after the ablation procedure. RESULTS: One injection was required in 7 dogs, and 2 injections were required in 1. Serum total and ionized calcium concentrations were within reference ranges within 24 hours after treatment in 7 dogs and within 5 days in 1 dog. Serum PTH concentration decreased and serum phosphorus concentration increased within 24 hours after treatment in all 8 dogs. Transient hypocalcemia developed in 4 dogs during the first 5 days after treatment, but only 1 dog required treatment for hypocalcemic tetany. Hypercalcemia recurred in 1 dog 1 month after the procedure and surgical removal of the parathyroid mass was required. Other adverse effects were not reported. CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasound-guided chemical ablation of parathyroid masses is a safe and effective alternative to surgery for dogs with primary hyperparathyroidism.

Pulmonary rehabilitation programs in Canada: national survey.

OBJECTIVE: To characterize pulmonary rehabilitation (PR) programs in terms of their type, size, duration, patient population, content and staffing. DESIGN: Surveys were sent to members of the Rehabilitation Committee of the Canadian Thoracic Society, as well as any program identified by members of the Canadian Physiotherapy Cardio-Respiratory Society, by provincial lung associations or by the respondents. PARTICIPANTS: Of 51 surveys sent, responses were received from 44 facilities (86% response rate). In-patient or out-patient pulmonary rehabilitation programs were offered by 36 facilities. RESULTS: Most programs (97%) admitted out-patients, and 22% had an in-patient capability. Out-patient programs enrolled 13 patients (median 11; range five to 48) at a given time for a duration of 8.3 weeks (range two to 26). In-patient programs enrolled nine patients at a given time (range two to 26) for 4.6 weeks (range one to eight). Programs included patients with chronic obstructive pulmonary disorder (100%), restrictive disease (93%), asthma (82%), adults with cystic fibrosis (46%), patients pre- or postlung transplantation (45%) and patients receiving mechanical ventilatory support (18%). Breathing retraining, education and upper extremity training were incorporated in more than 90% of all programs. Only one-third of programs offered smoking cessation as part of the rehabilitation. Education sessions on medications and inhaler usage were included in most programs, but sexuality was addressed in only half the programs. CONCLUSIONS: This first comprehensive national survey of PR programs in Canada shows that there are similarities in the format, content and staffing of PR programs. Programs are only able to service a small percentage of patients with chronic respiratory conditions.

The components of a respiratory rehabilitation program: a systematic overview.

OBJECTIVE: To determine the contribution of the various components of a rehabilitation program to the improvement of exercise capacity and health-related quality of life (HRQL) in patients with COPD. DATA SOURCES: MEDLINE (1966 to April 1996) was searched. Abstracts presented at international conferences were also hand searched for additional relevant trials. Bibliographies of the retrieved articles were reviewed. Experts in rehabilitation were consulted to uncover unpublished trials. STUDY SELECTION: Randomized controlled trials (RCTs) of exercise training, breathing exercises, education, and psychosocial support in patients with COPD were primarily included if (1) the treatment effect of a specific component of a rehabilitation program could be isolated, and (2) exercise capacity, HRQL, compliance with medical therapy, and/or knowledge about the disease were measured. DATA SYNTHESIS: A best-evidence synthesis was conducted; 22 RCTs contributed to the analysis. We found the following: (1) the patients exposed to interventions that included exercise training improved their functional exercise capacity and HRQL; (2) exercise training was muscle specific; (3) the evidence to support inspiratory muscle training and other breathing exercises as an adjunct to exercise training in COPD remains equivocal; (4) the contribution of education has not been well addressed; and (5) psychosocial support reduced dyspnea acutely and, when used as an adjunct to rehabilitation, promoted compliance with an exercise regimen and improved HRQL. CONCLUSION: Respiratory rehabilitation is likely to improve functional exercise capacity and HRQL if it includes exercise training and psychosocial support. Further research is required to better define the types and intensity of exercise as well as the influence of respiratory muscle training and patient education.

Using air-abrasive technology to diagnose and restore pit and fissure caries.

National Institute of Dental Research surveys indicate that the incidence of pit and fissure caries constitutes a higher proportion of the total caries incidence among U.S. teens and children than in the past. Air-abrasive technology may provide a more conservative alternative in the diagnosis and treatment of pit and fissure caries than traditional techniques using handpieces. The authors review characteristics of pit and fissure lesions and discuss methods for diagnosing and treating these lesions using air-abrasive technology.

Air-abrasive technology: its new role in restorative dentistry.

Air-abrasive technology has re-emerged in dentistry. The history, characteristics and clinical applications of this approach are reviewed, including advantages and limitations for the removal of stain, enamel, dentin and decay. Air-abrasive technology may be especially suited for use in bonded restorations.

Studies of the HLA class II alleles involved in human responses to ragweed allergens Ambrosia artemisiifolia V (Ra5S) and Ambrosia trifida V (Ra5G)

Previous studies have associated skin test sensitivity and specific IgE response to Ambrosia artemisiifolia V (Amb a V) with HLA-DR2, and to Ambrosia trifida V (Amb t V) with HLA-DRw52 haplotypes in atopic individuals. Using HLA class II typing by restriction fragment length polymorphism (RFLP) analysis with DRB, DQB and DQA DNA probes to define the HLA-D alleles, we have demonstrated the association of the DQw6 in 16 out of 16 (100%) Amb a V-responsive individuals, compared to 3 out of 18 (17%) ragweed-sensitive but Amb a V-nonresponsive individuals (p = 5.7 x 10(-6), RR greater than 75). We suggest that the DQw6 association with Amb a V sensitivity may be a reflection of an association with the DQA*0102 allele. This suggests an association of a particular HLA class II allele with an immune response to a well-characterized antigen (Amb a V). The HLA-DRw52 haplotypes in the Amb t V-sensitive individuals are not of one particular subtype. The HLA-DRw52 association with Amb t V sensitivity may reside in homologous DRB1 alleles linked on HLA-DRw52-bearing haplotypes.

Characterization of the renal effects and renal elimination of sulotroban in the dog.

The renal effects and renal handling of the nonprostanoid thromboxane receptor antagonist, sulotroban (4-[2-(phenylsulfonylamino)ethyl]phenoxyacetic acid), were characterized in dogs. Sulotroban was infused i.v. at 0.06, 0.2, 0.6 and 1.0 mg kg-1 min-1 (plus prime) for 180 min. Arterial blood pressure was reduced significantly during infusion of the 1.0 mg kg-1 min-1 dosage only. Diuresis, characterized by increases in both fractional and absolute urinary excretion of sodium, potassium, chloride and calcium, and decreases in urine osmolality occurred at each of the sulotroban dosages tested. The renal clearance of sulotroban exceeded the glomerular filtration rate, suggesting renal secretion of sulotroban. The transport maximum for sulotroban secretion was approximately 160 micrograms kg-1 min-1. Renal cortical slices from naive dogs accumulated [14C]sulotroban against a concentration gradient. Sulotroban accumulation was blocked by metabolic inhibitors (dinitrophenol and sodium azide) and inhibitors of organic anion transport (probenecid and p-aminohippurate), but not by inhibitors of organic cation transport (cyanine and tetraethylammonium), suggesting that tubular secretion of sulotroban is mediated by an organic anion transport system. It was concluded that: 1) decreases in blood pressure occurred only after high dosages and were associated with high plasma sulotroban concentrations; 2) diuresis occurred at all dosages and may represent a separate pharmacological action unrelated to thromboxane receptor antagonism; and 3) renal excretion of sulotroban in the dog occurs by both filtration and tubular secretion with secretion occurring via an organic acid transporter.

Fish oil treatment of hyperlipidemia in children and adolescents receiving renal replacement therapy.

The effect of 8 weeks of daily oral fish oil supplementation in a dose of 3 to 8 g/d on serum lipid levels was studied in 16 patients, 7 to 8 years of age, who had end-stage renal disease and were receiving renal replacement therapy. Fasting serum cholesterol (CHOL), triglyceride (TG) levels, and lipoprotein profiles were measured before therapy, 8 weeks after fish oil supplementation, and 4 weeks after its cessation. During 8 weeks of treatment the mean serum CHOL level did not change. The mean serum TG level, however, decreased significantly (P less than .01) from 236 +/- 31 mg/dL to 171 +/- 21 mg/dL (27.5%). Four weeks after treatment was stopped, the mean serum TG level returned to a value not significantly different from the pretreatment level (208 +/- 30 mg/dL). In a subgroup of 11 excessively hyperlipidemic patients, with serum CHOL and TG levels greater than or equal to 50% of the 90th percentile for age and sex, the mean serum TG level decreased even more (30.8%), from 286 +/- 35 mg/dL to 198 +/- 24 mg/dL (P less than .01), and the mean CHOL/high-density lipoprotein CHOL ratio decreased from 8.4 +/- 1.2 to 7.4 +/- 1.3 (P less than .05). Blood pressure and platelet counts remained stable during the entire study period. Side effects of the treatment were minimal. These results show that dietary fish oil supplementation reduces serum TG levels in young patients receiving renal replacement therapy and improves their "atherogenic" serum lipoprotein profile.

Metabolic fate of chylomicrons obtained from rats maintained on diets varying in fatty acid composition.

The importance of the fatty acid component in the metabolism of chylomicrons was demonstrated by feeding diets varying in fatty acid composition which resulted in chylomicrons of different sizes. On a diet rich in polyunsaturated fatty acids (PUFA) from safflower oil, chylomicrons of diameter 1853 +/- 192 A were harvested from the mesenteric lymph, whereas on coconut oil and medium-chain triglyceride diets the chylomicron size was 1403 +/- 83 and 604 +/- 40 A, respectively. When the isolated chylomicrons were injected into recipient rats maintained on a regular diet, their half-life (t1/2) decreased from 5.4 +/- 0.4 to 1.8 +/- 0.3 min with the increase in particle size. No significant difference in the apolipoprotein profile of chylomicrons of various sizes was noted, indicating that alterations of chylomicron removal are not related to apolipoprotein composition. Rats maintained on PUFA diets showed a marked increase in their adipose tissue lipoprotein lipase activity. The fast removal of large chylomicrons and increased tissue lipoprotein lipase activity, together with suppression of hepatic lipogenesis on this diet, apparently explains the low plasma triglyceride level in rats maintained on diets rich in PUFAs.

Applicability of a threshold loading device for inspiratory muscle testing and training in patients with COPD.

We evaluated application of a Pth device for testing inspiratory muscle endurance among patients with severe but stable COPD. Endurance time in five patients was reproducible. Magnitude of variability was +/- 1.26 minutes with a range of +/- 0.19 to +/- 2.28 minutes. Eleven inpatients completed inspiratory muscle training twice daily for four weeks in addition to their usual program of respiratory rehabilitation. The mean age of our experimental cohort was 65 years; FEV1, 33 +/- 12 percent predicted; and Dsb, 42 +/- 7 percent predicted. Baseline measurements showed no significant differences in pulmonary function, exercise tolerance, inspiratory muscle strength or inspiratory muscle endurance between control and study groups. Following training, the study group significantly improved inspiratory muscle endurance as evidenced by an increase in endurance time while breathing against the same absolute external Pth load used during baseline assessments. There were no associated changes in lung mechanics, muscle strength or exercise tolerance.

Reasons for possible failure of inoculation to enhance biodegradation.

Pseudomonas strains capable of mineralizing 2,4-dichlorophenol (DCP) and p-nitrophenol (PNP) in culture media were isolated from soil. One DCP-metabolizing strain mineralized 1.0 and 10 micrograms of DCP but not 2.0 to 300 ng/ml in culture. When added to lake water containing 10 micrograms of DCP per ml, the bacterium did not mineralize the compound, and only after 6 days did it cause the degradation of 1.0 microgram of DCP per ml. The organism did not grow or metabolize DCP when inoculated into sterile lake water, but it multiplied in sterile lake water amended with glucose or with DCP and supplemental nutrients. Its population density declined and DCP was not mineralized when the pseudomonad was added to nonsterile sewage, but the bacterium grew in sterile DCP-amended sewage, although not causing appreciable mineralization of the test compound. Addition of the bacterium to nonsterile soil did not result in the mineralization of 10 micrograms of DCP per g, although mineralization was evident if the inoculum was added to sterile soil. A second DCP-utilizing pseudomonad failed to mineralize DCP when added to the surface of sterile soil, although activity was evident if the inoculum was mixed with the soil. A pseudomonad able to mineralize 5.0 micrograms of PNP per ml in culture did not mineralize the compound in sterile or nonsterile lake water. The bacterium destroyed PNP in sterile sewage and enhanced PNP mineralization in nonsterile sewage. When added to the surface of sterile soil, the bacterium mineralized little of the PNP present at 5.0 micrograms/g, but it was active if mixed well with the sterile soil.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasotocin-like activity of cerebrospinal fluid induced by habenular lesions in cats.

The cisternal cerebrospinal fluid (CSF) samples, taken at 30, 60, 120 and 180 minutes after multiple electrolitic lesions of lateral habenular (LHB) lesions or of thalamus, performed in urethane anesthetized cats, were assayed for their antidiuretic and hydroosmotic activities before and after trypsine or thioglycollate incubation. LHB but not thalamic lesions, specifically induced the appearance of antidiuretic and hydroosmotic activities at 60 and 120 minutes. The activities decreased under the bioassays sensibilities at 180 minutes. The biological activities of the CSF samples, their ratio as well as their susceptibility to tryptic digestion and thioglycollate incubation suggest that LHB lesions induce the release of a basic peptide with a disulfide bound, indistinguishable from arginine vasotocin (AVT). Since it was previously argued that there is a pineal-habenula circuit with AVT as neuromudulator, it is advanced the hypothesis that LHB lesions interfere with an inhibitory feed-back loop between habenula and the pineal gland.

Effects of calcium entry blockers on coronary constriction and myocardial ischemia due to leukotriene D4.

Recent studies show that leukotrienes (LTs) produce profound coronary artery constriction. Although calcium entry blockers are commonly used to remedy coronary vasospasm, their capacity to interfere with LT-mediated coronary constriction is unknown. Therefore, we compared effects of intracoronary LTD4 before and during treatment with calcium entry blockers in the in situ, blood-perfused hearts of domestic pigs. Intravenous administration of verapamil (0.1-1.6 mg/kg), nifedipine (10 or 100 micrograms/kg) or diltiazem (0.6-2.0 mg/kg) sufficient to increase base-line coronary blood flow (CBF) and decrease mean arterial pressure did not change decrement in CBF after LTD4. Infusion of verapamil (0.01-0.04 mg/min) into the left anterior descending coronary artery raised pre-LTD4 CBF almost 2-fold without alteration in mean arterial pressure, heart rate or left ventricular end-diastolic pressure. Intracoronary boluses of LTD4 (0.3, 1.0 and 3.0 micrograms) during verapamil infusion into the same vessel caused dose-dependent decreases in CBF identical to those observed when LTD4 was injected during control infusion. ECGs showed myocardial ischemia during severe flow reduction after high dose intracoronary LTD4 (3.0 or 10.0 micrograms). When the same LTD4 doses were injected during intracoronary verapamil, electrocardiographic changes did not occur despite similar decreases in CBF. The capacity of verapamil to prevent LTD4-induced ischemia may be caused by higher residual CBF after LTD4 even though the magnitude of LTD4-induced CBF decrement was unaltered. LTD4-induced coronary constriction seems to be mediated by a mechanism unrelated to calcium entry channels blocked by verapamil, nifedipine or diltiazem.