Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds

STATEMENT OF PROBLEM: There are discrepancies among researchers concerning the reliability and use of temporomandibular joint sounds. PURPOSE: This study examined the reliability of mandibular movements and sounds and determined the correlation between movements and sounds. MATERIAL AND METHODS: The mandibular movements of 35 subjects diagnosed with temporomandibular disorders were recorded with 2 CCD cameras, and sounds were recorded bilaterally with Panasonic electret condenser microphones in the ear canal. Subjects performed 3 movements, each repeated 5 times. RESULTS: Reliability of maximum movements across the 5 trials was good to excellent, with Intraclass Correlation Coefficients (ICC) between 0.76 and 0.91 for all movements except protrusion. Temporomandibular sound event counts were reliable for most movements, including vertical opening, protrusion, and right and left laterotrusion (ICCs between 0.41 and 0.81). Most subjects produced sound events either in 100% or in none of the trials. Reliability for sound events was better during protrusion (ICCs between 0.56 and 0.81) than vertical opening (ICCs 0.41 to 0.64). Subjects with sound events during vertical opening (followed by closing) were significantly more likely to have sound events during protrusion (followed immediately by vertical opening and closing) (P <.01). CONCLUSION: Temporomandibular sound events are generally reliable and warrant study regarding their use in classifying and diagnosing patients with temporomandibular disorders. Condylar translation, which occurs during both vertical opening and protrusion, appears to have a strong influence on the production of temporomandibular sound events.     

Levels of urinary beta-core fragment, total oestriol, and the ratio of the two in second-trimester screening for Down syndrome

Levels of beta-core fragment and total oestriol in second-trimester maternal urine samples were measured in 32 Down syndrome pregnancies and 206 control pregnancies. Beta-core fragment and total oestriol values were corrected for the urinary creatinine level and expressed as multiples of the control medians (MOM). In addition, the ratio of the beta-core fragment level to the total oestriol level, without creatinine correction, was calculated, and expressed as MOM values. The median beta-core fragment, total oestriol, and ratio levels in Down syndrome cases were 5.42, 0.64, and 9.32 MOM, respectively. In the Down syndrome pregnancies, 66 per cent of the beta-core fragment levels were above the 95th centile of control levels, while 22 per cent of the total oestriol levels were below the fifth centile of control levels. In combination with maternal age, measurement of beta-core fragment and total oestriol levels in Down syndrome pregnancy resulted in an 80 per cent detection rate at a 5 per cent false-positive rate. Use of the ratio resulted in a univariate detection rate of 72 per cent. In combination with maternal age, the ratio resulted in a detection rate of 81 per cent at a 5 per cent false-positive rate. Based on this unmatched study, the measurement of a ratio of beta-core fragment to total oestriol levels, without the need for creatinine correction, may be useful in screening for fetal Down syndrome in second-trimester urine.     

Use of the Fourier series window protocol with a zig-zag surface coil in 31P NMR human skin spectroscopy. A theoretical study

The use of a zig-zag surface coil with a three-pulse Fourier Series Window (FSW) has been suggested as a means by which in vivo NMR spectroscopic studies of human skin can be performed. Using direct numerical simulations of the magnetic field profile of a 10 limb zig-zag surface coil, the role of the FSW in reducing NMR signals originating from the deeper skeletal muscle layers is examined theoretically. The extent of muscle signal contamination is determined for different coil inter-limb spacings and pulse width settings. The optimum inter-limb spacing for studying living human skin, that which minimizes signal contamination and maximizes skin signal collected, is shown to be between 4 and 6 mm. These calculations demonstrate that the FSW and zig-zag surface coil offer a protocol for investigating the metabolism of large areas of surface tissue while keeping signal contamination from the deeper skeletal muscle layers down to an acceptable level.     

Evaluation of carborane-containing porphyrins as tumour targeting agents for boron neutron capture therapy

A number of carborane-containing porphyrins were administered to mice bearing subcutaneously transplanted mammary carcinomas. Administration was via serial intraperitoneal (i.p.) injections to assess their relative toxicities and tumour affinities. Three analogues of the natural porphyrin heme and four tetraphenylporphyrins (TPPs) were given at total doses of 78-245 micrograms g-1 body weight. The water-insoluble TPPs were less toxic to mice, and delivered greater amounts of boron to tumour than did the water-soluble TPPS and the heme analogues. One such compound, NiTCP-H, delivered more than 100 micrograms B g-1 to tumour tissue with a tumour:blood boron concentration ratio greater than 500:1 and a tumour: brain boron concentration ratio greater than 50:1, 4 days after the last of six i.p. injections given over 2 days. Another TPP analogue, NiTCP, delivered approximately 50 micrograms B g-1 to tumour with similar boron concentrations in normal tissues. Neither compound was toxic to mice at total doses of approximately 200 micrograms g-1 body weight. In contrast, the heme analogues were toxic and, with the exception of VCDP, delivered less boron to tumour than NiTCP and NiTCP-H. The two porphyrins with the greatest potential for application to boron neutron capture therapy (BNCT), NiTCP and NiTCP-H, yielded higher tumour:blood and tumour:brain boron concentration ratios in mice than could be achieved with p-boronophenylalanine (BPA) and sodium mercaptoundecahydrododecaborate (BSH), the compounds which are currently being used in clinical trials of BNCT in the treatment of glioblastoma. The boron delivered by each of the porphyrins tested remained in tumour tissue longer than did boron delivered by either BPA or BSH. The copper and nickel chelates of these porphyrins behave identically in vivo. The former offer the potential for imaging by 67Cu-mediated single photon emission computed tomography (SPECT) to aid BNCT treatment planning.     

Functional characterisation of the human cloned 5-HT7 receptor (long form); antagonist profile of SB-258719

1. The functional profile of the long form of the human cloned 5-HT7 receptor (designated h5-HT7(a)) was investigated using a number of 5-HT receptor agonists and antagonists and compared with its binding profile. Receptor function was measured using adenylyl cyclase activity in washed membranes from HEK293 cells stably expressing the recombinant h5-HT7(a) receptor. 2. The receptor binding profile, determined by competition with [3H]-5-CT, was consistent with that previously reported for the h5-HT7(a) receptor. The selective 5-HT7 receptor antagonist SB-258719 ((R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]ben zene sulfonamide) displayed high affinity (pKi 7.5) for the receptor. 3. In the adenylyl cyclase functional assay, 5-CT and 8-OH-DPAT were both full agonists compared to 5-HT and the rank order of potency for agonists (5-CT > 5-HT > 8-OH-DPAT) was the same in functional and binding studies. 4. Risperidone, methiothepin, mesulergine, clozapine, olanzapine, ketanserin and SB-258719 antagonised surmountably 5-CT-stimulated adenylyl cyclase activity. Schild analysis of the antagonism by SB-258719 gave a pA2 of 7.2+/-0.2 and slope not significantly different from 1, consistent with competitive antagonism. 5. The same antagonists also inhibited basal adenylyl cyclase activity with a rank order of potency in agreement with those for antagonist potency and binding affinity. Both SB-258719 and mesulergine displayed apparent partial inverse agonist profiles compared to the other antagonists tested. These inhibitory effects of antagonists appear to be 5-HT7 receptor-mediated and to reflect inverse agonism. 6. It is concluded that in this expression system, the h5-HT7(a) receptor shows the expected binding and functional profile and displays constitutive activity, revealing inverse agonist activity for a range of antagonists.     

Calcium and vitamin D status of pregnant teenagers in Maiduguri, Nigeria

This study investigates parameters related to calcium and bone metabolism by determining the concentrations of total calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, parathyroid hormone, and phosphorous in young pregnant women. The patient population was 30 pregnant Nigerian teenage women grouped by trimester (10 per group), 10 women immediately following delivery, and 21 healthy age-matched controls. On the basis of serum prealbumin levels, the general nutrition of the pregnant women was found to be significantly below that of the more privileged and better-educated nonpregnant controls. The mean total calcium concentration in sera of the third-trimester women was 8.83 mg/dL, which was significantly below that of the controls (9.77 mg/dL) and the first-trimester group (9.30 mg/dL). Despite the 10% to 15% decline in the serum level of total calcium during pregnancy, the parathyroid hormone level decreased markedly from 0.60 to 0.61 ng/mL in the first and second trimesters to 0.41 ng/mL in the third trimester. Serum vitamin D and 1,25-dihydroxyvitamin D levels in the second and third trimesters were within the normal range. These data indicate that toward the end of gestation, pregnant teenagers in northern Nigeria appear to become calcium deficient and do not exhibit the expected increase in serum parathyroid hormone levels normally seen in pregnant women.     

Characterization of the binding of [3H]-SB-204269, a radiolabelled form of the new anticonvulsant SB-204269, to a novel binding site in rat brain membranes

1. SB-204269 (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3, 4-dihydro-2,2-dimethyl-2H-benzol[b]pyran-3R-ol, hemihydrate) shows potent anticonvulsant activity in a range of animal seizure models, with a lack of neurological or cardiovascular side-effects. The profile of the compound suggests that it may have a novel mechanism of action. This study describes the characteristics of a binding site for [3H]-SB-204269 in rat forebrain membranes. 2. Specific [3H]-SB-204269 binding was saturable and analysis indicated binding to a homogenoeous population of non-interacting binding sites with a dissociation constant (KD) of 32 +/- 1 nM and a maximum binding capacity (Bmax) of 253 +/- 18 fmol mg-1 protein. Kinetic studies indicated monophasic association and dissociation. Binding was similar in HEPES or Tris-HCl buffers and was unaffected by Na+, K+, Ca2+ or Mg2+ ions. Specific binding was widely distributed in brain, but was minimal in a range of peripheral tissues. 3. Specific [3H]-SB-204269 binding was highly stereoselective, with a 1000 fold difference between the affinities of SB-204269 and its enantiomer SB-204268 for the binding site. The affinities of analogues of SB-204269 for binding can be related to their activities in the mouse maximal electroshock seizure threshold (MEST) test of anticonvulsant action. 4. None of the standard anticonvulsant drugs, phenobarbitone, phenytoin, sodium valproate, carbamazepine, diazepam and ethosuximide, or the newer anticonvulsants, lamotrigine, vigabatrin, gabapentin and levetiracetam, showed any affinity for the [3H]-SB-204269 binding site. A wide range of drugs active at amino acid receptors, Na+ or K+ channels or various other receptors did not demonstrate any affinity for the binding site. 5. These studies indicate that SB-204269 possesses a specific CNS binding site which may mediate its anticonvulsant activity. This binding site does not appear to be directly related to the sites of action of other known anticonvulsant agents, but may have an important role in regulating neuronal excitability.