Treatment of secondary hyperparathyroidism by high calcium diet is associated with enhanced resistance artery relaxation in experimental renal failure

Background. Vasorelaxation is impaired in renal failure (RF)and hypertension. A high calcium diet enhances vasodilatationand reduces blood pressure in experimental hypertension. Oralcalcium salts are used as phosphate binders in RF. However,the effect of increased calcium intake on arterial tone in RFis unknown. Methods. We investigated the influence of an 8-week high calciumdiet (0.3 vs 3.0%) on resistance artery tone in 5/6 nephrectomized(NTX) rats. Calcium was supplemented as carbonate salt, bloodpressure measured by tail-cuff, urine collected in metaboliccages, and samples taken for blood chemistry and parathyroidhormone (PTH). Functional studies of isolated third-order branchesof the mesenteric artery in vitro were performed using the Mulvanymultimyograph. Results. Plasma urea was elevated 1.6-fold and systolic bloodpressure by 10 mmHg after NTX, while increased calcium intakewas without effect on these variables. Plasma PTH and phosphatewere raised following NTX, and suppressed by high calcium diet.Vasorelaxations induced by K⁺ channel agonists 11,12-epoxyeicosatrienoicacid and levcromakalim were impaired after NTX. Vasorelaxationinduced by acetylcholine was also reduced following NTX, andexperiments with N^G-nitro-L-arginine methyl ester, diclofenacand charybdotoxin + apamin suggested that the K⁺ channel-mediatedcomponent of endothelium-dependent relaxation was deficientafter NTX. Increased calcium intake corrected all impairmentsof vasodilatation in NTX rats. Conclusions. Deficient vasorelaxation via K⁺ channels was normalizedby high calcium diet in experimental RF. This effect was independentof the degree of renal impairment and blood pressure, but wasassociated with improved calcium metabolism: plasma levels ofPTH and phosphate were decreased and ionized calcium was increased.     

Cytochrome P450-activated prodrugs: targeted drug delivery

Cytochrome P450 (CYP) enzymes are a superfamily of heme containing proteins that catalyze xenobiotic metabolism phase I reactions. Oxidation reactions are the most common CYP-catalyzed reactions for both endogenous substrates and exogenous compounds, including drugs, although CYP enzymes are capable also to catalyze reduction reactions. Whereas the majority of clinically used drugs are inactivated by CYPs, several prodrugs are bioconverted to their active species by these enzymes. Therefore, this mechanism could be exploited to a greater extend, e.g. by taking advantage of the different CYP enzymes to achieve targeted drug delivery, to improve efficacy or to decrease the unwanted adverse effects of existing and novel drug molecules. This review describes the potential of CYP enzymes in prodrug design and summarizes a wide variety of CYP-activated prodrug structures, which are on the market or under the development. The bioactivation mechanisms of each CYP-activated prodrug structure are described and the specificity for the different forms of CYP enzymes is discussed.     

How readily does ketorolac penetrate cerebrospinal fluid in children?

Ketorolac is a potent nonsteroidal anti-inflammatory analgesic used in postoperative pain management. Ketorolac elicits its analgesic action by inhibiting the cyclo-oxygenase enzyme in peripheral tissues and in the spinal cord. Central nervous system penetration of parenteral ketorolac has been evaluated in adults but not in children. In the present study we investigated ketorolac cerebrospinal fluid penetration via spinal anesthesia in 30 healthy children undergoing surgery in the lower part of the body. A single cerebrospinal fluid and blood sample was obtained between 11 minutes and 6 hours after receiving ketorolac 0.5 mg x kg(-1) IV. Ketorolac concentrations were determined by gas chromatography with mass spectrometric detection. Ketorolac was detected from 22 of the 30 cerebrospinal fluid samples, and the concentrations ranged between 0.2 and 7.6 microg x L(-1) (median, 0.6 microg x L(-1)). The cerebrospinal fluid to unbound plasma concentration-ratio ranged between 0.01 and 0.69 (median, 0.08). These low concentrations indicate that ketorolac does not readily penetrate cerebrospinal fluid in children.     

Increases in local pressure pain thresholds after muscle exertion in women with chronic shoulder pain

OBJECTIVE: To examine the relation between muscular tenderness and local muscular fatigue. DESIGN: Before-after trial, measuring pressure pain thresholds and signs of local muscular fatigue by using surface electromyography before, after, 10 minutes after, and 20 minutes after intervention. SETTING: University rehabilitation department in Sweden. PARTICIPANTS: Nineteen female hospital cleaners with unilateral chronic shoulder pain for 1 year. No previous trauma, surgery, or signs of systemic or neurologic disease. INTERVENTION: Static abduction endurance test with submaximal unilateral activation of the trapezius and deltoid muscles. MAIN OUTCOME MEASURES: Pressure pain thresholds and electromyographic fatigue parameters (root mean square [RMS]; mean power frequency [MPF]). RESULTS: Mean normalized pressure pain threshold values increased significantly (95% confidence interval [CI]) and lasted for 20 minutes: in the trapezius, threshold values increased to 115% to 120% (95% CI, 100%-140%; P=.04-.05); and in the deltoid, the threshold increased to 112% to 115% (95% CI, 100%-130%; P=.02-.05). Development of significant electromyographically defined fatigue was seen: in the trapezius, the RMS increased to 130% (95% CI, 119%-141%), and in the deltoid, the MPF decreased to 78% (95% CI, 74%-82%), but normalized within 15 seconds to 10 minutes. CONCLUSION: Lasting bilateral increases in pressure pain thresholds but transient local muscular fatigue were seen after a unilateral static endurance test. The sensitivity of the sensory nervous system may change during a static muscle contraction and sometimes contributes to a localized sensation of numbness.     

Mortality of patients with acute coronary syndromes still remains high: a follow-up study of 1188 consecutive patients admitted to a university hospital

BACKGROUND: Based on randomized clinical trials, mortality of acute coronary syndrome (ACS) has been considered to be relatively low. The prognosis of clinical presentations of ACS in real-life patient cohorts has not been well documented. AIM: The aim of this study was to evaluate actual clinical outcome across the whole spectrum of ACS in a series of unselected prospectively collected consecutive patients from a defined geographical region, all admitted to one university hospital. METHODS: A total of 1188 patients with ST-elevation myocardial infarction (STEMI), non-ST-elevation MI (NSTEMI) or unstable angina pectoris (UA) were included. Results. In-hospital mortality was 9.6%, 13% and 2.6% (P<0.001) and mortality at a median follow-up of 10 months 19%, 27% and 12% (P<0.001), for the three ACS categories, respectively. In multivariate Cox regression analysis age, diabetes mellitus type 1, diuretic use at admission, creatinine level, lower systolic blood pressure, STEMI and NSTEMI ACS category were associated with higher mortality during follow-up. CONCLUSIONS: In an unselected patient cohort, short-term mortality of MI patients, especially those classified as NSTEMI, still was high despite increasing use of proven treatment modalities.     

Contraction-induced [18F]-fluoro-deoxy-glucose uptake can be measured in human calf muscle using high-resolution PET

Contraction-induced glucose uptake can be imaged and quantified by the use of positron emission tomography (PET). In the human extremities, such data may reveal important information regarding the in vivo mechanical function of e.g. the force transmitting tissues such as tendons. However, to investigate structures of limited size, a PET scanner with high resolution is required. We tested the potential of the recently developed high-resolution brain PET scanner (ECAT HRRT) for imaging of human lower extremities. [18F]-fluoro-deoxy-glucose uptake following voluntary and stimulated isometric muscle contractions was studied in a 30-year-old male. The results showed that the activated muscle or muscles are clearly delineated in the high-resolution PET images. Furthermore, the load-induced gain in tendon uptake was clearly visualized. In conclusion, the HRRT scanner is an appropriate tool for investigating physiological processes within the human extremities, and the very high resolution yields a potential for more accurate conclusions when target tissues are limited in size.     

Evaluating Picture Exchange and the iPad™ as a Speech Generating Device to Teach Communication to Young Children with Autism

The purpose of the study was to compare picture exchange (PE) and an iPad? –based speech generating device (SGD) in teaching mands to five preschool boys diagnosed with autism. Participants’ preferences for each device were assessed following training. Three participants met mastery criterion for mands using the SGD more quickly, while two participants met mastery criterion for mands using PE more readily. However, the overall rate of independent manding across training and maintenance was higher for four participants using the SGD. Four participants demonstrated a clear preference for the SGD device and one for PE. Results are consistent with previous research showing that acquisition of alternative communication modalities varies across children with autism, and supports the use of assessment to determine modality preference.     

Cytosolic phospholipase A(2)α protects against ischemia/reperfusion injury in the heart

Studies with sPLA(2) Group X, and cPLA(2) α gene-targeted mice suggest that absence of sPLA(2) Group X results in protection from ischemia/reperfusion (I/R) injury in the heart, and absence of cPLA(2) α Group IV is protective in the brain. Although latter studies might suggest a similar deleterious role for cPLA(2) α in I/R injury in the heart, the pathophysiology of stroke is intricately related to excitotoxicity and cannot necessarily be extrapolated to the heart. We report here that unlike findings in the brain, cPLA(2) α((-/-)) mice have exaggerated injury following I/R in vivo. In contrast, there is no difference in injury induced by simulated ischemia in cardiomyocytes isolated from cPLA(2) α((-/-)) versus cPLA(2) α((+/+)) mice. This suggests that cPLA(2) α does not have an important cardiomyocyte autonomous effect on ischemic injury. Prostaglandin E(2) (PGE(2) ) levels are significantly reduced in the hearts of the cPLA(2) α((-/-)) mice, and the enhanced injury is ameliorated by treatment with the PGE analog, misoprostol. We demonstrate that cPLA(2) α is cardioprotective in vivo, and this is likely via cPLA(2) α-mediated production of cardioprotective eicosanoids. These studies are the first to identify a protective role for cPLA(2) in I/R injury in any organ and raise concerns over long-term inhibition of cPLA(2).     

Cross-validation of Input Functions Obtained by H2 15O PET Imaging of Rat Heart and a Blood Flow-through Detector

Purpose

Positron emission tomography (PET) with ¹⁵O-labeled water (H₂ ¹⁵O) facilitates the visualization and quantification of blood flow in clinical investigations and also in small animals. The quantification of blood flow requires an input function, which is generally obtained by measuring radioactivity in arterial blood withdrawn during PET scanning. However, this approach is not always feasible, because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop and cross-validate two methods, namely, a blood- and an image-based method for obtaining the input function for blood flow studies from rat H₂ ¹⁵O PET.

Methods

The study material consisted of two separate groups of rats. Group 1 rats were imaged twice by a high-resolution research tomograph PET camera at resting condition for a test?Cretest study (n?=?4), and group 2 rats were imaged with and without adenosine infusion for a rest?Cstress study (n?=?4). In group 1, radioactivity concentration in arterial blood was measured with a new flow-through detector during imaging and a blood-based input function was obtained. The image-based input function was estimated using time-activity curves from the left ventricle and myocardial regions. To validate the two input function methods, myocardial blood flow (MBF) and cerebral blood flow (CBF) were computed, and the methods were tested for reproducibility (test?Cretest study) and changes (rest?Cstress study).

Results

The blood- and image-based input functions were similar, and the corresponding CBF values differed only by ?6.9?±?8.1%. In the test?Cretest study, both MBF and CBF showed good reproducibility, and in the rest?Cstress study, adenosine significantly increased both MBF (P?=?0.035) and CBF (P?=?0.029), compared with the resting condition.

Conclusion

It is possible both to measure the input function from rat arteria femoralis during H₂ ¹⁵O PET imaging and to estimate the input function from rat H₂ ¹⁵O PET images, thereby facilitating the assessment of blood flow in organs visible in PET images.