Standardization and validation of a novel and simple method to assess lumbar dural sac size.

AIM: To develop and validate a simple, reproducible method to assess dural sac size using standard imaging technology. MATERIALS AND METHODS: This study was institutional review board-approved. Two readers, blinded to the diagnoses, measured anterior-posterior (AP) and transverse (TR) dural sac diameter (DSD), and AP vertebral body diameter (VBD) of the lumbar vertebrae using MRI images from 53 control patients with pre-existing MRI examinations, 19 prospectively MRI-imaged healthy controls, and 24 patients with Marfan syndrome with prior MRI or CT lumbar spine imaging. Statistical analysis utilized linear and logistic regression, Pearson correlation, and receiver operating characteristic (ROC) curves. RESULTS: AP-DSD and TR-DSD measurements were reproducible between two readers (r = 0.91 and 0.87, respectively). DSD (L1-L5) was not different between male and female controls in the AP or TR plane (p = 0.43; p = 0.40, respectively), and did not vary by age (p = 0.62; p = 0.25) or height (p = 0.64; p = 0.32). AP-VBD was greater in males versus females (p = 1.5 × 10(-8)), resulting in a smaller dural sac ratio (DSR) (DSD/VBD) in males (p = 5.8 × 10(-6)). Marfan patients had larger AP-DSDs and TR-DSDs than controls (p = 5.9 × 10(-9); p = 6.5 × 10(-9), respectively). Compared to DSR, AP-DSD and TR-DSD better discriminate Marfan from control subjects based on area under the curve (AUC) values from unadjusted ROCs (AP-DSD p < 0.01; TR-DSD p = 0.04). CONCLUSION: Individual vertebrae and L1-L5 (average) AP-DSD and TR-DSD measurements are simple, reliable, and reproducible for quantitating dural sac size without needing to control for gender, age, or height.

Functional connectivity in the developing brain: a longitudinal study from 4 to 9months of age.

We characterize the development of intrinsic connectivity networks (ICNs) from 4 to 9months of age with resting state magnetic resonance imaging performed on sleeping infants without sedative medication. Data is analyzed with independent component analysis (ICA). Using both low (30 components) and high (100 components) ICA model order decompositions, we find that the functional network connectivity (FNC) map is largely similar at both 4 and 9months. However at 9months the connectivity strength decreases within local networks and increases between more distant networks. The connectivity within the default-mode network, which contains both local and more distant nodes, also increases in strength with age. The low frequency power spectrum increases with age only in the posterior cingulate cortex and posterior default mode network. These findings are consistent with a general developmental pattern of increasing longer distance functional connectivity over the first year of life and raise questions regarding the developmental importance of the posterior cingulate at this age.

Use of the Ages and Stages Questionnaire and Bayley Scales of Infant Development-II in neurodevelopmental follow-up of extremely low birth weight infants.

OBJECTIVE: For infants born with extremely low birth weight (ELBW), we examined the (1) correlation between results on the Ages and Stages Questionnaire (ASQ) and the Bayley Scales of Infant Development-II (BSID-II) at 18 to 22 months corrected age; (2) degree to which earlier ASQ assessments predict later BSID-II results; (3) impact of ASQ use on follow-up study return rates. STUDY DESIGN: ASQ data were collected at 4, 8, 12 and 18 to 22 months corrected age. The BSID-II was completed at 18 to 22 months corrected age. ASQ and BSID-II 18 to 22 month sensitivity and specificity were examined. Ability of earlier ASQs to predict later BSID-II scores was examined through linear regression analyses. RESULT: ASQ sensitivity and specificity at 18 to 22 months were 73 and 65%, respectively. Moderate correlation existed between earlier ASQ and later BSID-II results. CONCLUSION: For extremely low birth weight infant assessment, the ASQ cannot substitute for the BSID-II, but seems to improve tracking success.

Temperature effects in cyanolysis using elemental sulfur.

As part of our studies directed at new treatments for cyanide poisoning we examined the effect of temperature on both the non-catalyzed and the albumin-catalyzed reactions of cyanide with a colloidal suspension of elemental sulfur (CSES). Using saturated sulfur solutions prepared in two solvents, pyridine (PY) and methyl cellosolve (MC), the reactions were studied at 15.0, 25.0, 30.0 and 37.5 degrees C. For all the cyanolysis reactions (non-catalyzed and albumin-catalyzed) there is an enhancement of reaction rate when the organic solvent for the sulfur is MC. Irrespective of the solvent for the CSES, the non-catalyzed reactions gave linear Arrhenius plots (PY, correlation coefficient = 0.998; MC, correlation coefficient = 0.997). In each case the entropy of activation was positive (14.1 cal K-1 mol-1 for PY and 56.4 cal K-1 mol-1 for MC). In contrast with these results the albumin-catalyzed reactions generated non-linear Arrhenius plots and negative entropies of activation. Non-linear plots were observed with the three albumins studied: human serum albumin, heat-shock bovine serum albumin and fatty acid-free bovine serum albumin. The non-linear plots are the result of a more complex reaction sequence than a simple cyanolysis reaction.

The development and assessment of DNA and oligonucleotide probes for the specific detection of Bacillus anthracis.

Two DNA probes and a number of oligonucleotide probes were designed from the virulence factor genes of Bacillus anthracis. These probes were tested for specificity against 52 B. anthracis strains and 233 Bacillus strains encompassing 23 other species. A rapid slot blotting technique was used for screening the large numbers of isolates involved. All probes tested appeared to be specific for B. anthracis under high stringency conditions. These probes could differentiate between virulent and avirulent strains. The probes were also applied to the detection of B. anthracis in routine environmental and clinical samples. A non-radioactive hybridization and detection system based on digoxigenin-11-dUTP was developed.

Postexposure prophylaxis against experimental inhalation anthrax.

Inhalation anthrax is a rare disease that is almost invariably fatal. This study determined whether a prolonged course of postexposure antibiotics with or without vaccination would protect monkeys exposed to a lethal aerosol dose of Bacillus anthracis when the antibiotic was discontinued. Beginning 1 day after exposure, groups of 10 animals were given penicillin, ciprofloxacin, doxycycline, doxycycline plus vaccination, vaccination alone, or saline. Antibiotics were administered for 30 days and then discontinued. Vaccine was given on days 1 and 15. Two animals died of causes other than anthrax and were not included in the statistical analysis. Nine of 10 controls and 8 of 10 animals given only vaccine died. Each antibiotic regimen completely protected animals while on therapy and provided significant long-term protection upon discontinuance of the drug (penicillin, 7 of 10 survived, P < .02; ciprofloxacin, 8 of 9 survived, P < .002; doxycycline, 9 of 10 survived, P < .002; doxycycline plus vaccination, 9 of 9 survived, P < .0002). Protection against rechallenge was provided by combining postexposure antibiotic treatment with vaccination.

NICU infants born at developmental risk and the Individualized Family Service Plan/Process (IFSP).

In summary, newborn intensive care is a rapidly changing field serving a heterogeneous population of infants and families. A family-centered/developmental perspective needs to be incorporated as a part of basic nursery care. Some infants and families have developmental needs beyond this baseline. The ability to respond to these needs is supported by PL 99-457. A way to sort out which infants and families might benefit from entering the IFSP process has been described. The IFSP process and plan have been presented and a framework for integrating this continuum of care into the NICU has been proposed. Implementing the IFSP process in the hospital setting needs to be approached gradually and with caution, recognizing the lack of correspondence between early risk factors and ultimate outcome.

Location of receptor-binding region of protective antigen from Bacillus anthracis.

The pag gene, which codes for protective antigen (PA), a common component of the lethal and edema toxins of Bacillus anthracis, was cloned and expressed in Escherichia coli. Nested deletions of pag were generated into the C-terminus coding region. Recombinant proteins were analyzed by Western blot with either an anti-PA polyclonal antisera or two monoclonal antibodies that neutralized lethal toxin and edema toxin activities by inhibiting the binding of PA to cell receptors. Localization of the receptor binding domain within the C-terminal region of PA was suggested by the inability of the monoclonal antibodies 3B6 and 14B7 to recognize the recombinant proteins expressed by C-terminal deletions of the pag gene.

Methylsulphasalazine in rheumatoid arthritis.

Methylsulphasalazine, which differs from sulphasalazine by the addition of one methyl group, may provide the benefits of the parent drug with fewer side-effects in rheumatoid arthritis (RA). We describe the outcome of its use in RA. Of 21 patients entered into the study, 10 successfully completed 6 months of therapy; five developed adverse effects, four withdrew for reasons unrelated to drug treatment and two stopped because of inefficacy. No serious adverse effects were reported. A statistically significant improvement in most clinical assessments was observed from weeks 8-12 onwards. Significant improvement in plasma viscosity was observed and there was a trend towards improvement in serum CRP, histidine and IgM concentrations. There was a good correlation between mean serial changes in clinical and biochemical assessments indicating that the drug may exhibit the properties of a second-line agent. Median steady-state serum concentrations of methylsulphasalazine and methylsulphapyridine were 26.6 micrograms/ml and 2.85 micrograms/ml respectively.

Sequence and analysis of the DNA encoding protective antigen of Bacillus anthracis.

The nucleotide sequence of the protective antigen (PA) gene from Bacillus anthracis and the 5' and 3' flanking sequences were determined. PA is one of three proteins comprising anthrax toxin; and its nucleotide sequence is the first to be reported from B. anthracis. The open reading frame (ORF) is 2319 bp long, of which 2205 bp encode the 735 amino acids of the secreted protein. This region is preceded by 29 codons, which appear to encode a signal peptide having characteristics in common with those of other secreted proteins. A consensus TATAAT sequence was located at the putative -10 promoter site. A Shine-Dalgarno site similar to that found in genes of other Bacillus sp. was located 7 bp upstream from the ATG start codon. The codon usage for the PA gene reflected its high A + T (69%) base composition and differed from those of genes for bacterial proteins from most other sequences examined. The TAA translation stop codon was followed by an inverted repeat forming a potential termination signal. In addition, a 192-codon ORF of unknown significance, theoretically encoding a 21.6-kDa protein, preceded the 5' end of the PA gene.

The effect of indomethacin on the psychomotor function of patients with rheumatic diseases.

We have compared the effect of single and multiple doses of indomethacin and placebo on objective measurements of psychomotor impairment in patients. Following a single 50 mg dose (n = 8), indomethacin produced psychomotor disturbance in only those patients who had no recent history of NSAID exposure. After multiple doses of indomethacin (25 and 50 mg tid for 5 days), significant psychomotor impairment was observed. We conclude that other NSAIDs may induce cross-tolerance to the psychomotor effects of indomethacin. Tachyphylaxis may develop to the psychomotor disturbance caused by indomethacin.

The effect of allopurinol on the steady-state pharmacokinetics of indomethacin.

The effect of 5 days treatment with allopurinol (300 mg) on the pharmacokinetics of indomethacin at steady-state was investigated in eight patients. Allopurinol produced no significant effect on the indomethacin serum concentration-time curve. Allopurinol did not alter significantly the amounts of indomethacin excreted in the urine within 8 h. However, the urinary ratio of N-deschlorobenzoylindomethacin to indomethacin was reduced significantly by allopurinol administration (P less than 0.05).

Caeruloplasmin concentration and oxidase activity in polyarthritis.

Caeruloplasmin (Cp) concentration and oxidase activity have been shown to be elevated in rheumatoid arthritis (RA) and psoriatic arthritis, but normal in Reiter's syndrome, Behcet's syndrome and juvenile seronegative polyarthritis. Synovial fluid Cp was significantly depressed in comparison with serum Cp in RA. During second-line therapy in RA, Cp concentration and activity fell significantly (P less than 0.001), but the change in Cp did not correlate with plasma viscosity.

Serum and synovial fluid levels of angiotensin converting enzyme in polyarthritis.

Serum levels of angiotensin converting enzyme (ACE) activity in patients with rheumatoid arthritis (RA) (n = 48), osteoarthritis (OA) (n = 11), ankylosing spondylitis (n = 24), psoriatic arthritis (n = 12), and Behçet's syndrome (n = 20) were not significantly different from those of normal controls (n = 26). Synovial fluid ACE activity was lower in OA than in RA but was similar when corrected for protein levels. An increase in serum ACE concentration in patients with RA receiving captopril therapy is in agreement with previous results. There was some correlation of ACE with erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) but not with clinical indices in captopril treated patients. It is suggested that the beneficial actions of captopril in the treatment of RA are not due to its activity as an ACE inhibitor, but more probably a result of captopril being an aliphatic thiol.

The effects of food and of antacid on the single oral dose pharmacokinetics of tenoxicam.

A single oral dose (40 mg) of tenoxicam (Ro12-0068) was administered to six normal male volunteers pre- and post-prandially and to a further six volunteers with and without antacid to determine the effect of food and and of antacid on absorption. The rate of absorption was slower with post-prandial than with pre-prandial administration, resulting in a significantly later time for peak plasma drug levels (4.1 h compared to 1.3 h). No effect was evident on the extent of absorption or other pharmacokinetic parameters. Similarly, the rate of absorption was significantly slower after concurrent antacid than without antacid (t1/2 0.47 h compared to 0.18 h) resulting in a later peak time (4.7 h compared to 2.3 h) and significantly lower peak level (4.2 micrograms X ml-1 compared to 5.1 micrograms X ml-1) of parent drug in plasma. Again, no effect was evident on the extent of absorption or other pharmacokinetic parameters. It is concluded that food and antacids both tend to reduce the rate of absorption of tenoxicam, but that the extent of absorption is essentially unchanged. The influence on the overall kinetic profile is relatively minor, and thus unlikely to affect the therapeutic response.

A double-blind comparison of tenoxicam (Tilcotil, Mobiflex) at two doses against ibuprofen in rheumatoid arthritis.

Tenoxicam (Tilcotil, Mobiflex), a new non-steroidal anti-inflammatory agent of the oxicam group, has been compared at two dose levels (20 mg/day and 4 mg/day) to ibuprofen 800 mg t.d.s. in a double-blind parallel group study of four weeks duration in rheumatoid arthritis. Efficacy results showed no significant difference between the three treatments at two or four weeks though clinical assessments slightly favoured groups treated with tenoxicam in this 30 patient study. No patients withdrew from tenoxicam because of side-effects and there were no withdrawals because of inefficacy. The higher dose (40 mg) of tenoxicam was as well tolerated as the lower dose (20 mg) though plasma levels of tenoxicam suggested that at the lower dose this drug had barely reached optimum plasma levels in a study of relatively short duration.

A clinical and biochemical evaluation of Clozic, a novel disease modifying drug in rheumatoid arthritis.

We have compared two dose levels of Clozic, a novel agent with potential anti-rheumatoid activity, to D-penicillamine and aspirin in an observer blind randomised parallel group study of 56 patients with active rheumatoid arthritis. Eight clinical assessments and 26 laboratory assessments were performed on each patient at each visit over a six month period. Results were analysed by conventional methods and also by correlation matrices constructed between clinical and laboratory variables. Patients treated with D-penicillamine (500 mg/day) responded adequately and the control group on aspirin (up to 3.6 g of enteric coated formulation/day) performed well, though the withdrawal rate from this latter group was high, predominantly because of continued disease activity. Patients receiving Clozic (100 mg/day or 300 mg/day) improved more than patients receiving penicillamine, particularly at the higher dose. Comparison of methods of analysis validates the use of correlation matrices both for detecting anti-rheumatoid activity and for determining the optimum dose of a novel compound. This trial illustrates the problems of a study of this nature, with the powerful effect on patients of being enrolled in such a closely monitored investigation. It emphasises the greater value of biochemical changes in following disease changes.