In situ DMSO hydration measurements of HTS compound libraries.

Compounds used in high throughput screening (HTS) are typically dissolved in DMSO. These solutions are stored automation-friendly racks of wells or tubes. DMSO is hygroscopic and quickly absorbs water from the atmosphere. When present in DMSO compound solutions, water can accelerate degradation and precipitation. Understanding DMSO hydration in an HTS compound library can improve storage and screening methods by managing the impact of water on compound stability. A non-destructive, acoustic method compatible with HTS has been developed to measure water content in DMSO solutions. Performance of this acoustic method was compared with an optical technique and found to be in good agreement. The accuracy and precision of acoustic measurements was shown to be under 3% over the tested range of DMSO solutions (0% to 35% water by volume) and insensitive to the presence of HTS compounds at typical storage concentrations. Time course studies of hydration for wells in 384-well and 1536-well microplates were performed. Well geometry, fluid volume, well position and atmospheric conditions were all factors in hydration rate. High rates of hydration were seen in lower-volume fills, higher-density multi-well plates and when there was a large differential between the humidity of the lab and the water content of the DMSO. For example, a 1536-well microplate filled with 2microL of 100% DMSO exposed for one hour to a laboratory environment with approximately 40% relative humidity will absorb over 6% water by volume. Understanding DMSO hydration rates as well as the ability to reverse library hydration are important steps towards managing stability and availability of compound libraries.

Fabrication and characterization of metal-molecule-metal junctions by conducting probe atomic force microscopy.

Metal-molecule-metal junctions were fabricated by contacting Au-supported alkyl or benzyl thiol self-assembled monolayers (SAMs) with an Au-coated atomic force microscope (AFM) tip. The tip-SAM microcontact is approximately 15 nm(2), meaning the junction contains approximately 75 molecules. Current-voltage (I-V) characteristics of these junctions were probed as a function of SAM thickness and load applied to the microcontact. The measurements showed: (1) the I-V traces were linear over +/-0.3 V, (2) the junction resistance increased exponentially with alkyl chain length, (3) the junction resistance decreased with increasing load and showed two distinct power law scaling regimes, (4) resistances were a factor of 10 lower for junctions based on benzyl thiol SAMs compared to hexyl thiol SAMs having the same thickness, and (5) the junctions sustained fields up to 2 x 10(7) V/cm before breakdown. I-V characteristics determined for bilayer junctions involving alkane thiol-coated tips in contact with alkane thiol SAMs on Au also showed linear I-Vs over +/-0.3 V and the same exponential dependence on thickness. The I-V behavior and the exponential dependence of resistance on alkyl chain length are consistent with coherent, nonresonant electron tunneling across the SAM. The calculated conductance decay constant (beta) is 1.2 per methylene unit ( approximately 1.1 A(-)(1)) for both monolayer and bilayer junctions, in keeping with previous scanning tunneling microscope and electrochemical measurements of electron transfer through SAMs. These measurements show that conducting probe-AFM is a reliable method for fundamental studies of electron transfer through small numbers of molecules. The ability to vary the load on the microcontact is a unique characteristic of these junctions and opens opportunities for exploring electron transfer as a function of molecular deformation.

Integrated billing and accounts receivable management system needed to maximize payments and cope with managed care.

The billing and accounts receivable management process in medical practices today has evolved into a multidisciplinary function. This function requires efficient, coordinated performance by physicians and all staff members, from the point of initial patient contact through aggressive follow-up on delinquent payments for services rendered. Offices with deficient or nonexistent billing and accounts receivable management systems typically experience collection ratios that are less than industry norms. They also experience poor cash flow and unnecessary overhead costs. To avoid costly inefficiencies and ensure that it maximizes payments from third-party payors and patients, a medical practice must have an integrated billing and accounts receivable management system that includes components outlined in this article.

Synthetic surfactant for rescue treatment of respiratory distress syndrome in premature infants weighing from 700 to 1350 grams: impact on hospital resource use and charges.

To determine the impact of the use of synthetic surfactant on hospital resource use and charges, we analyzed the economic data from a multicenter, randomized, placebo-controlled clinical trial of synthetic surfactant in infants with neonatal respiratory distress syndrome and birth weights between 700 and 1350 gm. Two 5 ml/kg doses of a synthetic surfactant (Exosurf Neonatal) or air placebo were administered to 419 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio < 0.22. In addition to the clinical endpoints for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days of mechanical ventilation, days of oxygen supplementation, and hospital charges until the infant reached 1 year adjusted age. Growth and development of infants who received synthetic surfactant therapy in the study and survived to 1 year adjusted age were equivalent to those of the survivors in the air placebo group. For 1-year survivors, synthetic surfactant reduced the average length of stay at the different levels of care needed during the hospitalization such as neonatal intensive care unit days, days of mechanical ventilation, and days of oxygen supplementation. For nonsurvivors, synthetic surfactant increased the average length of stay, especially at more intense levels of care. Total hospital charges for the initial hospitalization and through 1 year adjusted age for a hypothetic cohort of 100 infants treated with synthetic surfactant were, on average, the same as those for a comparable cohort of infants in the air placebo group. These results indicate that rescue therapy with synthetic surfactant in infants with respiratory distress syndrome and birth weights from 700 to 1350 gm can result in significantly improved survival without significant increases in hospital charges.

Economic outcomes of colfosceril palmitate rescue therapy in infants weighing 1250g or more with respiratory distress syndrome: results from a randomised trial.

An analysis of the economic data from a multicentre, randomised, placebo-controlled clinical trial of colfosceril palmitate in infants with neonatal respiratory distress syndrome (NRDS) and birthweights of 1250g or more is presented. Two 5 ml/kg (67.5 mg/kg) doses of a synthetic surfactant (colfosceril palmitate) or air placebo were administered to 1237 infants who were receiving mechanical ventilation and had an arterial/alveolar oxygen tension ratio of less than 0.22. In addition to the clinical end-points for safety and efficacy, data were collected on length of hospital stay, days in the neonatal intensive care unit, days on mechanical ventilation, days on oxygen, and hospital charges until the child reached 1-year adjusted age. One-year adjusted age is attained when the time elapsed since birth is equal to 365 days plus the number of days of prematurity. Rescue treatment with synthetic surfactant therapy has been shown to reduce the incidence of complications of NRDS. Growth and development of infants who received colfosceril palmitate therapy in the study and survived to 1-year adjusted age were equivalent to those of the survivors in the air placebo group. For the cohort of treated infants, colfosceril palmitate reduced the average length of stay at 2 levels of care needed during both the initial hospitalisation (a reduction of 8 days overall and 5 days in intensive care) and all first year hospitalisations (a reduction of 9 days overall and 5 days in intensive care). Total hospital charges for the initial hospitalisation and through 1-year adjusted age for a hypothetical cohort of 100 infants treated with colfosceril palmitate were less than those for a comparable cohort in the air placebo group. The results would, therefore, suggest that rescue therapy with colfosceril palmitate in infants with NRDS and birthweights over 1250g can result in substantial reductions in hospital resource utilisation and charges in addition to the clinical benefits associated with its use.

A pilot study of SPINE test scores and measures of tongue deviancy in speakers with severe-to-profound hearing loss.

Two developments show promise in the assessment and remediation of defective speech production in persons with hearing loss. A perceptual speech-intelligibility test, the SPINE (for Speech Intelligibility Evaluation), is a simple, clinician-administered instrument which is valid, reliable, and clinically efficient. In addition, the development of acoustic measures of tongue deviancy, computed from formant frequencies, makes possible a direct lateral visualization of tongue placement in relation to standard vowel placement. In this study, SPINE test scores of 28 persons with severe-to-profound hearing loss were correlated with two measures of tongue deviancy during production of the vowels /i/, /a/, and /u/. For both measures of tongue deviancy, correlations with the SPINE were significant for the three vowels combined and for the isolated vowel /i/. These findings suggest that clinicians may ultimately have two different but complementary means of assessing speech production in persons with hearing loss.

Pulmonary hemorrhage in premature infants after treatment with synthetic surfactant: an autopsy evaluation. The American Exosurf Neonatal Study Group I, and the Canadian Exosurf Neonatal Study Group.

In an across study analysis of five multicenter, placebo-controlled trials of the synthetic surfactant, Exosurf Neonatal in infants weighing at least 700 gm, the incidence of clinical pulmonary hemorrhage was 1.9% in treated infants and 1.0% in control infants. To investigate whether a similar increase was also present histologically at postmortem examination, a blinded retrospective review of all autopsy reports from infants dying during these five trials was conducted. Pulmonary hemorrhage was present in 55% of 159 infants undergoing autopsy; the incidence was not different in infants treated with surfactant or air placebo. Birth weight was inversely related to the incidence of pulmonary hemorrhage in both groups. Pulmonary pathologic findings significantly associated with pulmonary hemorrhage included pulmonary interstitial emphysema and necrotizing laryngotracheitis in both groups. In the surfactant group, patent ductus arteriosus, intraventricular hemorrhage, and pneumothorax were significantly more frequent among those who developed pulmonary hemorrhage. In contrast to clinical diagnosis, pathologic diagnosis of pulmonary hemorrhage at autopsy was not more common in infants treated with Exosurf Neonatal.

Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-N1. Papilloma Study Group.

BACKGROUND: We earlier reported that patients with recurrent respiratory papillomatosis responded to six months of treatment with lymphoblastoid interferon alfa-n1. Because another study of patients treated for one year with leukocyte interferon alfa-n3 found that the growth rate of papillomas was slowed in the first six months but returned to base line during months 7 through 12 despite persistent interferon treatment, we now report the long-term results in our original study patients who were followed for a median of four years after the original one-year crossover study. METHODS: After the patients in our study had completed the first study year, their physicians could continue or recommence treatment with lymphoblastoid interferon alfa-n1 in a dose of either 2 MU per square meter of body-surface area per day or 4 MU per square meter every other day. The extent of disease was measured by endoscopy when clinically indicated. RESULTS: Data on late-follow-up were obtained for 60 of the 66 patients. There were 22 complete remissions and 25 partial remissions; 13 patients had no response. The median duration of the complete remissions was 550 days, and 15 patients continued to be in complete remission. The median duration of partial remissions was 400 days and seven patients were still in partial remission. Thirteen of 28 patients responded to a second course of interferon after an interruption in treatment of at least one month. The rate of response in the 11 of 53 patients who had neutralizing antibody to interferon was the same as in the patients without the antibody. CONCLUSIONS: Patients with severe recurrent respiratory papillomatosis may have a sustained or repeated response to treatment with lymphoblastoid interferon alfa-n1. We recommend that patients with recurrent respiratory papillomatosis who require surgery every two to three months be given a six-month trial of interferon alfa-n1.

Reduced mortality in small premature infants treated at birth with a single dose of synthetic surfactant.

A randomized controlled trial of Exosurf Neonatal, a synthetic exogenous surfactant, was performed. Exosurf was given to premature infants weighing 700-1350 g, by instillation down the endotracheal tube during mechanical ventilation, within 1 h of birth. Control infants were treated with air. Dose administration was performed in secrecy by clinicians who maintained the blind for 2 years. A total of 109 infants received air and 109 received Exosurf; 19 infants with congenital pneumonia or major malformations were excluded from the primary efficacy analysis. By the age of 28 days there were 14 deaths in the air group and 4 deaths in the Exosurf group, a 69% reduction with Exosurf (P = 0.020). Survival without bronchopulmonary dysplasia at the age of 28 days was significantly improved by 15% (P = 0.050). By the age of 1 year post-term there were 19 deaths in the air group and 10 deaths in the Exosurf group, a 42% reduction with Exosurf (P = 0.104). There were no significant changes in the incidence of bronchopulmonary dysplasia, pulmonary air leaks, intraventricular haemorrhage, patent ductus arteriosus, necrotizing enterocolitis or infection. The reduction in mortality indicates important results in high risk premature infants treated soon after birth with a single dose of Exosurf.

Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: a multicenter controlled trial. American Exosurf Pediatric Study Group 1.

To determine whether a single prophylactic dose of synthetic surfactant would reduce mortality and morbidity rates, we performed a randomized, controlled trial of Exosurf Neonatal at 19 hospitals in the United States. The Exosurf preparation (5 ml/kg) was instilled into the endotracheal tube of premature infants weighing 700 to 1100 gm during mechanical ventilation, as soon as practical after birth. Control infants were treated with air (5 ml/kg). Dose administration was performed in secrecy by clinicians who did not reveal for 2 years what they had instilled. A total of 222 infants received air and 224 received the synthetic surfactant; 36 infants with congenital pneumonia or malformations were excluded from the primary efficacy analysis. By the age of 28 days, there were 44 deaths in the air group and 27 deaths in the surfactant group (p = 0.022). By the age of 1 year after term there were 61 deaths in the air group and 35 deaths in the surfactant group (p = 0.002). Although there was no reduction in the incidence of respiratory distress syndrome, a significant reduction in the number of deaths attributed to respiratory distress syndrome, a significant reduction in the incidence of pulmonary air leaks, and significantly lower requirements for oxygen and mean airway pressure indicated that lung disease was less severe in the Exosurf-treated infants. There were no significant differences in the incidence of complications such as bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, and infection. The results indicate that a single prophylactic dose of Exosurf, in high-risk premature infants treated soon after birth, reduces the number of deaths from respiratory distress syndrome and the overall mortality rate.

Improved outcome at 28 days of age for very low birth weight infants treated with a single dose of a synthetic surfactant.

Two identical double-blind, controlled, randomized trials were initiated to determine whether the administration of a single 5 ml/kg dose of a synthetic surfactant (Exosurf Neonatal), soon after the delivery of infants with birth weights 700 to 1350 gm, would improve rates of survival without bronchopulmonary dysplasia. Both trials were terminated before enrolling their planned sample sizes because of the availability of Exosurf under the provisions of a Treatment Investigational New Drug program. We report the combined results of these trials. Study infants were stratified according to birth weight and gender before random assignment to a treatment regimen. One hundred ninety-two infants received Exosurf and 193 received an air placebo. The study groups were similar when a variety of demographic features describing the mothers, their pregnancies, the circumstances of the births, and the infants were compared. Exosurf-treated infants required significantly less oxygen and respiratory support during the first 3 days of life in comparison with the air-treated infants. Fewer infants in the Exosurf group had pulmonary interstitial emphysema (26 vs 13; p = 0.028). In the Exosurf group, there was a significant reduction in the combined outcome, neonatal death or survival with bronchopulmonary dysplasia (57 vs 39; p = 0.042), and there was a significant increase in rates of survival without this disease (128 vs 137; p = 0.042). There were no differences between treatment groups in the incidences of a variety of complications of prematurity, including apnea, patent ductus arteriosus, intraventricular hemorrhage, and necrotizing enterocolitis. We conclude that improvements in respiratory physiology after a single prophylactic dose of Exosurf result in an increased likelihood of neonatal survival without bronchopulmonary dysplasia.

Tracheoesophageal speech: with and without tracheostoma valve.

The tracheostoma valve, developed by Blom and Singer combines the advantages of pulmonary air for phonation with hands-free speech. Patients have anecdotally reported "more normal speech" with the use of the valve. This study was designed to objectively determine if speech acoustic and temporal measures existed between tracheoesophageal puncture using the valve, and those without the valve prosthesis, during speech production among the same subjects. The speech samples of nine male laryngectomees were recorded with and without the valve. Six speech acoustic and temporal measures were calculated and compared under both speaking conditions. No statistically significant differences were found between the two speaking conditions for the six tasks measured. However, other advantages and disadvantages were observed and reported under the valve condition.

Interferon alpha-n1 (Wellferon) for refractory genital warts: efficacy and tolerance of low dose systemic therapy.

This multi-center trial compared two doses of parenterally administered interferon alpha-n1 (Wellferon) in men and women with recurrent/resistant genital warts. Patients received either 1 or 3 MU/m2 daily for 14 days, then 3 times weekly for 4 weeks; non-responders could receive an additional four weeks of treatment. A total of 107 patients were enrolled, and 102 were evaluable after six weeks of study. The principal dose comparison was in 57 women assigned alternately to the two doses. Median lesion measurements were reduced significantly from baseline at weeks 2, 4 and 6 in both groups. Statistical analysis showed no difference in response to 1 versus 3 MU/m2. The overall complete response (CR) plus partial response (PR) rate at week 6 was 69% for the two doses. Two additional groups of 21 women and 24 men were treated at the higher dose with CR plus PR rates of 75 and 50%, respectively. Week 10 disease evaluations for all groups showed 19 of 77 patients to be completely cleared. Of these 19, only one had recurrent disease at the end of the 6-month study period. Analysis of the incidence of symptomatic side effects showed a significantly higher frequency among women treated with 3 MU/m2 than among women treated with 1 MU/m2. Five dose reductions and two withdrawals for toxicity occurred, all in the high dose group. This study demonstrates that parenterally administered Wellferon produces clearance of resistant genital warts in many patients, and that rates of clearance do not appear to vary between groups receiving moderate or low dose therapy.

Comparative study of permethrin 1% creme rinse and lindane shampoo for the treatment of head lice.

The efficacy and safety of permethrin 1% creme rinse and lindane shampoo were compared for the treatment of head lice (Pediculus humanus var. capitis). A total of 1040 patients in the Nezahualcoyotl community of Mexico City representing 296 family groups were enrolled and randomized to treatment, with one patient in each family designated as the index patient. Among index patients 98% treated with permethrin and 76% treated with lindane were louse-free 2 weeks after treatment (P less than 0.001). Comparable results were found with nonindex patients as well. Mild dermal reactions, such as pruritus or erythema, occurred in 1.2% of permethrin-treated patients and 2.6% of lindane-treated patients. There were no reports of central nervous system adverse effects or conjunctivitis.

Arsenic: homicidal intoxication.

Arsenic-induced deaths have been known to occur from accidental poisoning, as a result of medical therapy, and from intentional poisonings in homicide and suicide. Twenty-eight arsenic deaths in North Carolina from 1972 to 1982 included 14 homicides and seven suicides. In addition, 56 hospitalized victims of arsenic poisoning were identified at Duke Medical Center from 1970 to 1980. We present four case histories of arsenic poisoning in North Carolina and discuss the clinical manifestations.

A noninvasive acoustic method using frequency perturbations and computer-generated vocal-tract shapes.

This study investigated improved processing of acoustic data with two adult Down's syndrome subjects. Sustained vowel samples were processed through a fast-Fourier-transform spectrum analyzer, and digital waveform data were used to obtain period-by-period measurements of the fundamental frequencies. Unusual frequency perturbation (jitter), later identified as diplophonia, was found for one of the Down's subjects. In addition, the first three formant frequencies of the vowels were determined and, utilizing an algorithm described by Ladefoged and his colleagues, computer-generated vocal-tract shapes were plotted. Differences in vocal-tract shapes, especially for the back vowels, were observed between the Down's female and the normal shape. Correlations between vocal-tract shapes of the Down's subjects and those for a normal man or woman were computed. A partial three-way factor analysis was carried out to determine those load factors or coefficients for each subject that were due to individual differences. These procedures, offering synthesized techniques portraying the interpharyngeal/oral functioning of the speech structures, may eventually have direct noninvasive diagnostic and therapeutic benefit for voice/resonance-disordered clients.

Complications associated with immunotherapy of equine phycomycosis.

Five horses with pythiosis of the limbs were treated unsuccessfully by surgery or topical application of amphotericin B, or both. Follow-up immunotherapy resulted in 1 horse responding favorably. Three horses were cured of the fungal infection but developed osteitis or deep-seated laminitis, which necessitated their destruction. The remaining horse, which had severe anemia, died before the course of vaccination was completed.

Hearing loss of Down syndrome adults.

Audiological hearing-test data were obtained for 51 Down syndrome adults. Depending upon hearing-loss criteria, from 51 to 74 percent of the subjects had some degree of hearing impairment. Correlation coefficients between these hearing-acuity measurements and receptive hearing vocabulary scores suggest a moderate relationship. These data indicate that Down syndrome adults are prone to a wide variety of hearing difficulties that may reflect a variety of ear pathologies. These data and other studies have shown that both Down syndrome adults and children need frequent hearing screening and, when indicated, otological and/or audiological management. When otological treatment will be of long duration, aural rehabilitation, including prescription amplification, may be indicated as an adjunctive therapeutic procedure.