Early osteoarthritis and microdialysis: a novel in vivo approach for measurements of biochemical markers in the perisynovium and intraarticularly.

The microdialysis technique was evaluated as a possible method to obtain local measurements of biochemical markers from knee joints with degenerative changes. Seven patients scheduled for arthroscopy of the knee due to minor to moderate degenerative changes had microdialysis catheters inserted under ultrasonographic guidance, intraarticularly and in the synovium-close tissue. Catheters were perfused at a rate of 2 µl/min for approximately 100 min with a Ringer solution containing radioactively labeled glucose, and the positions of the catheters were later visualized during arthroscopy. All intraarticular catheters and 6/7 subsynovial catheters were positioned correctly. Relative recovery (RR) was intraarticularly 0.64 ± 0.02 (mean ± SEM) and synovium-close 0.54 ± 0.06. Mean values of cartilage oligomeric matrix protein (COMP), aggrecan and glucosyl-galactosyl-pyridinoline in the intraarticular dialysates were 18.1 ± 7.0 U/l, 243.6 ± 108.6 ng/ml and 108.0 ± 29.0 pmol/ml, respectively. COMP and glucosyl-galactosyl-pyridinoline concentrations were significantly higher intraarticularly compared to perisynovial tissue (P < 0.05), whereas for aggrecan, no significant difference was found (P = 0.06). The microdialysis method can be used for intraarticular and subsynovial determination of metabolites in human knees at these sites. The present methodology displays a potential for future studies of simultaneous biochemical changes within and around joints.

Swallowing function and medical diagnoses in infants suspected of Dysphagia.

OBJECTIVE: There has been an increase in infant swallowing disorders as a result of improved survival for infants born prematurely or with life-threatening medical disorders. These infants often have multiple health issues and an increased risk of respiratory complications. However, there is little understanding of the biomechanics of infant swallowing disorders. Therefore, the objectives of this study were to determine 1) the percentage of dysphagic infants who experience laryngeal penetration, aspiration, or nasopharyngeal backflow; 2) reasons for laryngeal penetration/aspiration; 3) whether infants with laryngeal penetration/aspiration clear their airway; and 4) the relationship between swallowing disorders and medical diagnoses. METHODS: Patients included 43 infants who were referred for videofluoroscopic swallowing studies in a university-affiliated pediatric medical center. Medical charts were reviewed. The videofluoroscopic swallowing studies were recorded on videotape, and each swallow was analyzed for laryngeal penetration, aspiration, nasopharyngeal backflow, cough, airway clearance, and reason for penetration/aspiration. Statistics included chi2 for nonparametric data and measures of central tendency for numeric/timing data. RESULTS: More than half of the infants experienced laryngeal penetration, aspiration, or nasopharyngeal backflow; however, the first occurrence of these events was after multiple swallows. Only 3 infants experienced laryngeal penetration and aspiration on the first swallow and all 3 had an absent pharyngeal response. Premature infants experienced significantly more nasopharyngeal backflow. Material in the pyriform sinuses before pharyngeal swallowing was associated with penetration/aspiration. In episodes of laryngeal penetration, all patients were able to clear their airway during the swallow without a cough. Almost all infants (8 of 9) who aspirated did not cough or clear their airway. CONCLUSIONS: This study demonstrated that most infants suspected of dysphagia showed overt abnormalities: laryngeal penetration, aspiration, and/or nasopharyngeal backflow on the videofluoroscopic swallowing study. Most of these infants did not demonstrate abnormalities in the first few swallows but displayed deterioration in swallowing function as they continued to feed. Thus, radiographic assessments in infants must examine multiple swallows. The high incidence of silent aspiration demonstrates the necessity of a videofluoroscopic assessment to evaluate swallowing function in these infants.

Advances in prevention and treatment of cerebral palsy.

In recent years there have been a number of advances in understanding of predisposing and protective factors in the development of cerebral palsy in infants. Multiple gestation births, maternal infection, and maternal and fetal thrombophilic conditions all predispose to the development of CP in the infant. Opportunities for prevention of CP may develop from an improved understanding of these factors and their mechanisms of operation. Similar progress has been made in the evaluation of treatments for CP and the effects of these treatments on the individual's impairment, function, and disability. Selective posterior rhizotomy and Botulinum toxin A are now widely used in the treatment of spasticity. The challenge remains to determine how effectively these promising interventions can alter long-term function and quality of life outcomes in children and adults with CP.

CAT/CLAMS: its use in detecting early childhood cognitive impairment.

The Cognitive Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS), a neurodevelopmental tool for the cognitive assessment of infants and toddlers, correlates well with the Bayley Scales of Infant Development. In 1993 the Bayley Scales were revised and the second edition published (BSID-II). This study was designed to determine how well the CAT/CLAMS correlates with the BSID-II and its utility in identifying mild and severe cognitive impairment. Sixty-eight infants and toddlers (age range = 14-48 months), referred for suspected developmental delays, were administered the CAT/CLAMS and BSID-II and the results compared. The correlation between the two instruments was strong (r = 0.89, P<0.0001). The CAT/CLAMS was sensitive (81%) and specific (85%) for detecting overall cognitive impairment (BSID-II less than 70) and was even more sensitive (100%) and specific (96%) in detecting severe cognitive impairment (BSID-II less than 50). The physician using the CAT/CLAMS formulated a clinical impression of cognitive impairment that was sensitive (95%) and specific (84%) compared with formal psychologic testing. The CAT/CLAMS correlates well with the BSID-II. It is useful for detecting and quantifying mild and severe cognitive impairment. It permits the physician to formulate an accurate clinical impression of cognitive impairment consistent with possible mental retardation.

Classification of developmental delays.

Developmental delay is frequently used to identify children with delay in meeting developmental milestones in one or more streams of development. There is no consensus on the specific definition. Developmental delay is best viewed generically as a chief complaint rather than a diagnosis. A child suspected to have delays should always be assessed in each of the major streams of development: expressive and receptive language, including social communication; visual problem solving (nonverbal cognition); motor development; neurobehavioral development; and social-emotional development. A model developed by the National Center for Medical Rehabilitation Research is used to compare existing classifications of developmental delays. This model defines the five domains in the disability process: pathophysiology, impairment, functional limitation, disability, and societal limitation. An etiology domain is added. This model is used to illustrate how existing classification systems of cerebral palsy, mental retardation, autism, and language delay draw on information from one or more domains. The model illustrates some of the conflicts between different systems. For example, most classification systems for cerebral palsy emphasize only impairment (spasticity, dyskinesias, and topography). The current definition and classification system for mental retardation focuses on functional limitations (IQ), disability, and societal limitations, ignoring pathophysiology and details of impairment. Given the complexity of neurodevelopmental disabilities, it is unlikely that a single classification system will fit all needs.

Abnormalities in control of ventilation in newborn infants with myelomeningocele.

OBJECTIVE: The objective of this study was to assess respiratory responses of newborn infants with myelomeningocele through pneumograms and carbon dioxide challenge, and to evaluate the possibility of predicting which patients with myelomeningocele acquired respiratory symptoms related to the Arnold-Chiari deformity and brain-stem dysfunction. METHODS: All surviving infants with spina bifida who were born at the University of Iowa Hospitals and Clinics (UIHC) or were transferred there on the first day of life between January 1987 and January 1991 were assessed with a pneumogram and CO2 challenge once they were medically stable, and were followed for a mean of 30 months (10 to 53 months). RESULTS: Thirty patients met the inclusion criteria for this study; four died before being studied. Of the 26 remaining patients, 12 were born at the UIHC and 14 were transferred to the UIHC on the first day of life. Of the 26 infants studied, 12 (46%) had abnormalities on the pneumogram, including 2 with significant periodic breathing and 10 with episodes of desaturation below 87%. Of the 26 infants studied, 4 had no detectable response to an increasing fraction of CO2 in inspired air on the CO2 challenge and 12 had an increase in exhaled minute ventilation per increase in the alveolar fraction of CO2 in exhaled air more than 2 SD below the mean. Only 10 patients (38.5%) had normal ventilatory responses to the increasing fraction of CO2 in inspired air. On follow-up, only one study patient had symptoms related to Arnold-Chiari deformity and brain-stem dysfunction (bilateral vocal cord paralysis). His neonatal CO2 challenge results and his pneumogram were normal. CONCLUSION: We conclude that these two tests are not useful in predicting which patients will have symptoms related to Arnold-Chiari deformity. Specificity for the pneumogram and the CO2 challenge was 0.52 and 0.36, respectively. Sensitivity was zero for both tests, although this result is limited by the low incidence of symptomatic Arnold-Chiari deformity in this sample. As previous investigators have found, a significant number of patients with meningomyelocele had abnormal ventilatory patterns. These ventilatory abnormalities indicate that even in the absence of severe symptoms, the control of the ventilatory response is somewhat impaired in many patients with meningomyelocele. This alteration in ventilatory control is probably related to abnormalities in the development of the brain stem.

Tethered cord syndrome in myelodysplasia: correlation between level of lesion and height at time of presentation.

The purpose of this study was to determine whether the onset of tethered cord syndrome is related to the level of the myelomeningocele (MMC) (sacral, low lumbar, high lumbar or thoracic) and the height and age of the patient at time of presentation. Of 163 patients followed, 18 underwent corrective surgery for symptomatic tethered cord syndrome. The level of lesion at time of presentation correlated highly with height and age. The mean height and age for each level at the time of surgery were: sacral 134.5cm, 9.3 years; low lumbar: 124cm, 9.9 years; high lumbar: 108cm, 4.9 years; thoracic: 92.4cm, 4.7 years. The author concludes that the sensorimotor level of patients with MMC is a useful clue in predicting the onset of symptoms related to tethered cord syndrome.

Disposition of betamethasone in parturient women after intramuscular administration.

When betamethasone phosphate equivalent to 8 mg betamethasone was administered intramuscularly in solution (Celestone Injection) to pregnant women, a large proportion of this ester was absorbed unchanged. Bioavailability of betamethasone from the phosphate ester was as high as after intravenous injection. When pregnant patients received the equivalent of either 6 or 12 mg betamethasone in a formulation containing 3.1 mg/ml betamethasone acetate suspended in a solution of 4 mg/ml betamethasone phosphate (Celestone Chronodose), much of the phosphate ester was absorbed intact but betamethasone acetate was not detected in plasma. Availability of betamethasone from Celestone Chronodose was much lower than from Celestone Injection. After administration of either formulation, maternal plasma cortisol concentrations fell towards a basal level but were rising again within 2 to 3 days of the last dose. We conclude that Celestone Chronodose does not provide prolonged release of betamethasone and offers no advantage over Celestone Injection.

Pharmacokinetics of betamethasone in healthy adults after intravenous administration.

The pharmacokinetics of betamethasone and its phosphate ester are described in 8 healthy adults after i.v. bolus injection of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultraviolet detection using sample handling methods which prevented hydrolysis of the ester in vitro. Betamethasone phosphate disappeared rapidly from plasma (mean half-life = 4.7 min) as betamethasone levels rose. Betamethasone plasma levels reached a peak 10-36 min after administration of the phosphate before declining in a biexponential manner. The terminal slow disposition phase had a mean half-life of 6.5 h. Only about 5% of the dose was recovered from urine as betamethasone, indicating extensive extrarenal clearance of betamethasone. Protein binding and blood/plasma concentration ratio were also determined. In comparison with its stereoisomer, dexamethasone, betamethasone is also cleared mainly by metabolism but has a lower plasma clearance, is less plasma bound, has a higher blood/plasma concentration ratio, and a higher volume of distribution. Endogenous cortisol levels were measured in the subjects who received betamethasone phosphate and in a matched control group of 4 subjects who did not. Betamethasone abolished the normal episodic secretion of cortisol and rapidly reduced its plasma concentration to a basal level. Cortisol plasma levels were not restored at 24 h but had returned to normal by 48 h after dosing.

Disposition of betamethasone in parturient women after intravenous administration.

The pharmacokinetics of betamethasone and its phosphate ester are described in nine women in late pregnancy who each received a bolus intravenous dose of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultra-violet detection using sample handling methods which prevent in vitro hydrolysis of the ester. The plasma clearance of betamethasone phosphate (mean = 980 ml/min) and its apparent distribution volume (mean = 5.61) were both higher than previously found for nonpregnant subjects, but its half-life (mean = 4.6 min) was unchanged. Plasma concentrations of betamethasone reached a peak 5-37 min after dosing with betamethasone phosphate, then declined biexponentially with a mean terminal half-life of 262 min. Plasma clearance in pregnant patients (mean = 287 ml/min) was higher than previously reported for nonpregnant subjects. Evidence from urinary excretion and plasma binding measurements and the previously reported transplacental plasma concentration gradient indicated that the increase in clearance was due to increased metabolism possibly by the placental/fetal unit. Plasma binding of beta-methasone was higher in maternal than fetal plasma; binding to alpha 1-acid glycoprotein was more important than binding to albumin as a determinant of this difference. In pregnant patients the decline of endogenous cortisol concentrations in maternal venous plasma was less marked and slower than in nonpregnant subjects. The data now available allows comparison of pharmacokinetic properties between betamethasone and its stereoisomer dexamethasone with respect to their use in preventing neonatal respiratory distress syndrome.

Relationship between the transplacental gradients of bupivacaine and alpha 1-acid glycoprotein.

1 The binding of bupivacaine (400 ng/ml) to isolated alpha 1-acid glycoprotein was studied at two protein concentrations. At 20 mg/100 ml the extent of bupivacaine binding was 31.0 +/- 1.8% (mean +/- s.d., n = 4), and at a protein concentration of 60 mg/100 ml binding of bupivacaine was 85.8 +/- 1.5% (n = 4). 2 Bupivacaine and alpha 1-acid glycoprotein concentrations were measured in plasma samples collected from a maternal peripheral vein and the umbilical vein at delivery (n = 23). The ratio of the foetal:maternal bupivacaine concentrations ranged from 0.17 to 0.52, while the foetal:maternal ration for alpha 1-acid glycoprotein concentrations ranged from 0.20 to 0.96. A positive relationship emerged between the two ratios (P less than 0.01). 3 The alpha 1-acid glycoprotein concentration gradient across the placenta, and interindividual variability in the gradient appear to contribute to the low and variable transplacental bupivacaine concentration ratio observed.

Leaching of 2-(2-hydroxyethylmercapto) benzothiazole into contents of disposable syringes.

A contaminant was found to leach into the contents of two brands of disposable syringes. It was identified as 2-(2-hydroxyethylmercapto) benzothiazole and is believed to be formed during manufacture of the syringes as a result of a reaction between 2-mercaptobenzothiazole, a rubber vulcanization accelerator, and ethylene oxide, used for sterilization. The contaminant was isolated form the rubber plunger-seal and identified using mass, NMR, and UV spectroscopic methods. The amount of contaminant appearing in the contents of syringes was measured; up to 140 micro g was found under clinically relevant conditions. This finding has important implications with respect to the use of these syringes for drug administration and for the collection of blood for drug analyses.

The placental transfer of betamethasone.

The plasma concentrations of betamethasone in a maternal peripheral vein (mv) and in the umbilical vein (uv) were measured at delivery in eleven patients after the administration of betamethasone phosphate equivalent to 8 mg betamethasone. Betamethasone concentrations were measured in plasma using a specific and sensitive HPLC assay. The time interval between the last dose and delivery ranged from 56 min to 800 min and over this time period the mean plasma concentration ratio Cuv/Cmv was 0.28 +/- 0.04 (SD) and exhibited no time dependence.

Simultaneous determination of betamethasone, betamethasone acetate and hydrocortisone in biological fluids using high-performance liquid chromatography.

A sensitive, specific, reproducible and rapid high-performance liquid chromatographic method for the simultaneous quantitation of betamethasone, betamethasone 21-acetate and hydrocortisone in biological fluids is described. Hydrocortisone acetate is used as an internal standard and the samples are extracted with dichloromethane before chromatographing on a reversed-phase system. Detection at two ultraviolet wavelengths (254 nm and 240 nm) was used to assess the specificity of the system, and the sensitivity was found to be greater than 10 ng for all steroids. The speed with which this assay can be performed makes it particularly useful for pharmacokinetic studies, and plasma concentration--time profiles resulting from the administration of betamethasone phosphate and betamethasone acetate are presented.

Disporition of synthetic glucocorticoids. II. Dexamethasone in parturient women.

The plasma level: time profile for dexamethasone after dexamethasone phosphate 8 mg by intravenous bolus (n = 6) or intramuscular injection (n = 6) to pregnant women near term who were to undergo cesarean section was determined by high-performance liquid chromatography. Although pregnancy did not affect the terminal half-life (mean, 142 min; n = 10), the estimate of total plasma clearance was greater in pregnant (559 ml/min) than in nonpregnant women (243 ml/min). The umbilical/maternal venous plasma level ratios of dexamethasone rose with time from last dose to delivery, toward a plateau value of about 0.45. Plasma binding was not different between blood from pregnant (66.6% bound, n = 11) and nonpregnant women (68.1% bound, n = 6) but was lower in umbilical vein blood (60.8% bound, n = 11). Blood/plasma level ratio was higher in maternal (0.92, n = 7) and umbilical vein blood (1.04, n = 7) than in blood from nonpregnant subjects (0.81, n = 12). We conclude that the fetus is a slowly equilibrating compartment for dexamethasone and that the transplacental dexamethasone concentration gradient as well as the increased total clearance in the mother near parturition are most likely attributable to metabolic clearance by the placenta.