Isolating the roles of different forcing agents in global stratospheric temperature changes using model integrations with incrementally added single forcings.

Satellite instruments show a cooling of global stratospheric temperatures over the whole data record (1979-2014). This cooling is not linear, and includes two descending steps in the early 1980s and mid-1990s. The 1979-1995 period is characterized by increasing concentrations of ozone depleting substances (ODS) and by the two major volcanic eruptions of El Chichón (1982) and Mount Pinatubo (1991). The 1995-present period is characterized by decreasing ODS concentrations and by the absence of major volcanic eruptions. Greenhouse gas (GHG) concentrations increase over the whole time period. In order to isolate the roles of different forcing agents in the global stratospheric temperature changes, we performed a set of AMIP-style simulations using the NASA Goddard Earth Observing System Chemistry-Climate Model (GEOSCCM). We find that in our model simulations the cooling of the stratosphere from 1979 to present is mostly driven by changes in GHG concentrations in the middle and upper stratosphere and by GHG and ODS changes in the lower stratosphere. While the cooling trend caused by increasing GHGs is roughly constant over the satellite era, changing ODS concentrations cause a significant stratospheric cooling only up to the mid-1990s, when they start to decrease because of the implementation of the Montreal Protocol. Sporadic volcanic events and the solar cycle have a distinct signature in the time series of stratospheric temperature anomalies but do not play a statistically significant role in the long-term trends from 1979 to 2014. Several factors combine to produce the step-like behavior in the stratospheric temperatures: in the lower stratosphere, the flattening starting in the mid 1990's is due to the decrease in ozone depleting substances; Mount Pinatubo and the solar cycle cause the abrupt steps through the aerosol-associated warming and the volcanically induced ozone depletion. In the middle and upper stratosphere, changes in solar irradiance are largely responsible for the step-like behavior of global temperatures anomalies, together with volcanically induced ozone depletion and water vapor increases in the post-Pinatubo years.

Revising the slant column density retrieval of nitrogen dioxide observed by the Ozone Monitoring Instrument.

Nitrogen dioxide retrievals from the Aura/Ozone Monitoring Instrument (OMI) have been used extensively over the past decade, particularly in the study of tropospheric air quality. Recent comparisons of OMI NO2 with independent data sets and models suggested that the OMI values of slant column density (SCD) and stratospheric vertical column density (VCD) in both the NASA OMNO2 and Royal Netherlands Meteorological Institute DOMINO products are too large, by around 10-40%. We describe a substantially revised spectral fitting algorithm, optimized for the OMI visible light spectrometer channel. The most important changes comprise a flexible adjustment of the instrumental wavelength shifts combined with iterative removal of the ring spectral features; the multistep removal of instrumental noise; iterative, sequential estimates of SCDs of the trace gases in the 402-465 nm range. These changes reduce OMI SCD(NO2) by 10-35%, bringing them much closer to SCDs retrieved from independent measurements and models. The revised SCDs, submitted to the stratosphere-troposphere separation algorithm, give tropospheric VCDs ∼10-15% smaller in polluted regions, and up to ∼30% smaller in unpolluted areas. Although the revised algorithm has been optimized specifically for the OMI NO2 retrieval, our approach could be more broadly applicable.

Double free-flap reconstruction of massive defects involving the lip, chin, and mandible.

Two patients with massive, composite defects of the total lower lip, chin, and anterior mandible underwent double free-flap reconstruction. A fibular osteoseptocutaneous flap was used to reconstruct the mandible and floor of the mouth and a radial forearm fasciocutaneous composite flap, including the palmaris longus tendon, was used for total lower lip and chin reconstruction. Postoperatively, both patients had acceptable cosmesis, were orally competent, and recovered adequate mandibular function. Double free-flap reconstruction is indicated only in those circumstances in which composite tissue requirements or massive tissue defects preclude reconstruction with a single free-tissue transfer.

Can we improve breast pathology reporting practices? A community-based breast pathology quality improvement program in New Hampshire.

We implemented a regional quality assurance program in New Hampshire (NH) to evaluate breast pathology practices and attempt to improve the completeness of information provided in breast surgical pathology reports. We also assessed the degree to which NH pathologists agree with National Guidelines. The program's objective was to promote a consistent standard of care for patients whose breast pathology is interpreted in NH. Using a sequential survey technique, we were able to obtain consensus on breast tissue report content that was similar to National Guidelines. We also found that 52% of the reporting elements improved in the post-intervention period, although only one reached statistical significance. In conclusion, pathology interpretation is the "gold standard" for determining both screening effectiveness and subsequent treatment of breast cancer, yet variability in breast tissue reporting exists. It is critical that more research be done to improve breast pathology interpretation and reporting practices.

Neonatal exposure to technical methoxychlor alters pregnancy outcome in female mice.

This study was designed to determine the ability of female mice who were exposed neonatally to the pesticide methoxychlor (MXC) to mate, ovulate, and become pregnant upon reaching sexual maturity. One-day-old female mice (5 to 8/group) were exposed daily by intraperitoneal (ip) injection for 14 d to either sesame oil or 10 microg estradiol-17beta or 0.1, 0.5 or 1.0 mg MXC suspended in sesame oil. The MXC exposures corresponded to 14 to 71, 68 to 357, or 135 to 714 mg/kg body weight, respectively. Three months later, female mice were placed with proven breeder males and checked daily for vaginal plugs. Mated female mice were sacrificed 18 d after the appearance of a vaginal plug to evaluate pregnancy. Uteri were examined for the presence of living fetuses and/or resorption sites. Ovaries were removed and prepared for histologic evaluation and tabulation of corpora lutea. All mice from all three MXC-treated groups did in fact mate, in comparison with only one of those exposed neonatally to estradiol. Increasing the dose of MXC produced a decreased number of pregnant animals at 18 d following mating. The mean number of live fetuses/litter was reduced in the 0.5 and 1.0 mg MXC-treated groups. Corpora lutea were significantly reduced in ovaries from only the 1.0 mg MXC group and the estradiol group. No effects of treatment were seen at 0.1 mg MXC. It is concluded that neonatal exposure to MXC does not interfere with mating. Instead, significant alterations are seen in initiating and/or maintaining pregnancy. The deleterious effects on pregnancy may be due to the influence of neonatal MXC treatments on the hypothalamic-pituitary-ovarian axis as well as on possible alteration of the uterine environment.

The BirthPlace collaborative practice model: results from the San Diego Birth Center Study.

Objective: The search for quality, cost-effective health care programs in the United States is now a major focus in the era of health care reform. New programs need to be evaluated as alternatives are developed in the health care system. The BirthPlace program provides comprehensive perinatal services with certified nurse-midwives and obstetricians working together in an integrated collaborative practice serving a primarily low-income population. Low-risk women are delivered by nurse-midwives in a freestanding birth center (The BirthPlace), which is one component of a larger integrated health network. All others are delivered by team obstetricians at the affiliated tertiary hospital. Wellness, preventive measures, early intervention, and family involvement are emphasized. The San Diego Birth Center Study is a 4-year research project funded by the U.S. Federal Agency for Health Care Policy and Research (#R01-HS07161) to evaluate this program. The National Birth Center Study (NEJM, 1989; 321(26): 1801-11) described the advantages and safety of freestanding birth centers. However, a prospective cohort study with a concurrent comparison group of comparable risk had not been conducted on a collaborative practice-freestanding birth center model to address questions of safety, cost, and patient satisfaction.Methods: The specific aims of this study are to compare this collaborative practice model to the traditional model of perinatal health care (physician providers and hospital delivery). A prospective cohort study comparing these two health care models was conducted with a final expected sample size of approximately 2,000 birth center and 1,350 traditional care subjects. Women were recruited from both the birth center and traditional care programs (private physicians offices and hospital based clinics) at the beginning of prenatal care and followed through the end of the perinatal period. Prenatal, intrapartum, postpartum and infant morbidity and mortality are being compared along with cost-effectiveness and acceptance of the model by patients. Data collection occurred primarily through medical record abstraction with the addition of two patient questionnaires. Comparability of the cohorts was established by using a validated methodology to determine medical/perinatal risk and birth center eligibility, which included assessment by two CNMs and an independent blind review by a perinatologist. The cost analysis uses a resource-utilization approach and new methodologies such as activity-based-costing to compare costs from both the perspective of the payor and the health care provider. Patient satisfaction was measured using a self-administered patient questionnaire.Results: Current preliminary results from approximately 38% of the final expected study sample are available. Crude and adjusted analysis have been conducted. Overall, the preliminary results suggest similar morbidity and mortality in the two groups. Fetal deaths are 0.75% in the index and 0.64% in the comparison group, with early neonatal deaths at 0.26% and 0.23%, respectively. The traditional care group showed adjusted rate differences of 5.83% more major maternal intrapartum complications and 9% more NICU admissions. While the birth center group showed adjusted rate differences of 5.5% more low birth weight and 0.95% more preterm birth. For other outcomes, the birth center group showed an adjusted rate difference of 22.34% more exclusive breastfeeding at discharge. Also, there was less utilization of cesarean section and assisted delivery in the birth center group as compared to the traditional care group. The adjusted rate difference for normal spontaneous vaginal deliveries in nulliparas was 10.23% more in the birth center group, with similar results in multiparas with and without history of cesarean (28.88% and 7.84%, respectively). Preliminary results also show that the average total cost for pregnancy-related services paid by California Medicaid was $4,550 for the birth center and $5,535 for the traditional care group. Final results based on the full study sample (full data available February 1998) details of payor costs such as provider, facility, NICU, and ancillary along with costs from the health care system perspective and patient satisfaction results will be presented.Conclusion: Current results suggest similar morbidity and mortality between the birth center program and traditional care groups, with less resource utilization translating to lower costs in the collaborative practice model. Results suggest that collaborative practice using a freestanding birth center as an adjunct to an integrated perinatal health care system may provide a quality, lower-cost alternative for the provision of perinatal services.

The effects of methoxychlor on early sea urchin development.

Methoxychlor (MXC) is a widely used pesticide which has been found in water sources near agricultural sites. Embryos of aquatic organisms are likely to encounter MXC due to land runoff. The sea urchin embryo (Strongylocentrotus purpuratus) was used as a model system to document the effects of MXC on early development up to the pluteus stage. Fertilized eggs and embryos were exposed to several concentrations (0.1, 1.0, 10, and 100 ppm) of the pesticide in both chronic and acute exposure regimens. With chronic exposure, percentages of embryos completing normal first cleavage decreased with increased concentrations of MXC, and subsequent cleavages became even more irregular in that blastomeres divided asymmetrically and asynchronously. Ten parts per million MXC allowed development through the hatched blastula stage, whereas embryos in 100 ppm MXC did not hatch. In acute exposure trials, fertilized eggs were pulsed (i.e., exposed for brief durations) to MXC for 30, 60, or 90 min. The MXC was then washed out. Recovery of normal development was proportional to the amount and duration of MXC exposure. Development was delayed in embryos exposed to 100 ppm MXC for 30 or 60 min. The embryos exposed to 100 ppm MXC for 90 min were abnormal as early as the four-cell stage, and by 72 hr more than 90% had abnormal gut development, indicating disruption of gastrulation. These data show that MXC exposure resulted in retardation of cleavage and abnormal gastrulation, basic morphogenetic processes.

Decreased superovulation in adult mice following neonatal exposures to technical methoxychlor.

To examine the effects of technical methoxychlor (MXC) on superovulation, neonatal mice received intraperitoneal (i.p.) injections of either sesame oil, 10 micrograms of estradiol 17 beta, or 0.1, 0.5, or 1 mg of technical MXC. At 2 and 4 months, half of the mice received a superovulatory regimen of 10 IU pregnant mare's serum gonadotropin followed by 10 IU human chorionic gonadotropin. The mice were sacrificed 15 to 20 h later, the number of ovulated oocytes were counted, and the ovaries were removed for histology. In the lowest MXC dose, the ovaries appeared normal and at 2 months, ovulated the same number of oocytes as controls. Estradiol or the highest two MXC doses induced ovarian atrophy. Following gonadotropin injections, these ovaries also ovulated oocytes. However, the number of oocytes recovered from experimental mice exhibited a time- and dose-dependent decline, and by 4 months, their number was significantly reduced. Neonatal exposures to MXC reduces ovulatory rates and ovarian functions in adults.

Using qualitative and quantitative patient satisfaction data to improve the quality of cardiac care.

BACKGROUND: In early 1993 leaders within the Hitchcock Clinic and cardiac services section at Dartmouth-Hitchcock Medical Center (Lebanon, NH) formed the Cardiac Services Improvement Group (CSIG) as a pilot program for patient-centered quality improvement (QI) at the sectional level. CSIG PROGRAM: For open heart surgery (OHS) and percutaneous transluminal coronary angioplasty (PTCA), a flowchart was constructed of sequential patient experiences. Content analysis of focus group discussions resulted in six key patient-defined quality characteristics: comfort, caring, certainty, convenience, communication, and cost. Linking of patient comments to points on the patient experience flowchart made it possible to determine where particular quality characteristics were most relevant. A patient satisfaction survey with questions that were specific to a patient experience and to a quality characteristic was mailed to 100 consecutively discharged OHS and PTCA patients; 35 of the 50 patients in each group responded. EVALUATING SUCCESS: Analysis of the survey results led to the formation of two QI teams. One team began work on development of a critical pathway for discharge preparation and identified marker questions to track and monitor pathway success in subsequent surveys. Another team began the development of protocols for more effective pain management during and after the PTCA procedure. A repeat patient satisfaction survey that took place from November 1994 to March 1995 suggested a global improvement in patient satisfaction for all patient experiences and all key quality characteristics. CONCLUSION: The CSIG pilot program of patients-based quality measurement and management at the sectional level has been successful in fostering QI team formation and has been associated with a positive deflection in patient-based quality measures. Additional sections of the medical center have initiated similar projects, beginning with process definition and focus groups.

Microsurgical reconstruction of the head and neck: interdisciplinary collaboration between head and neck surgeons and plastic surgeons in 305 cases.

Three hundred five microsurgical free flaps have been performed for defects of the head and neck by a team of two head and neck surgeons and two plastic surgeons over a 9-year period, with a success rate of 91.2%. The most common flaps used were the jejunum (89), radial forearm (57), rectus abdominis (48), latissimus dorsi (40), scapular (32), fibula (15), and iliac crest (11). Thirty-three flaps required reexploration for anastomotic thrombosis or hematoma (10.8%), of which 18 flaps were salvaged (54.5%). Thirteen flap failures occurred in 113 patients who had received preoperative irradiation (11.5%), but this was not statistically significant. Seven flaps failed in 20 patients who required an interposition vein graft (35%) and this was statistically significant. Ninety patients (31.5%) developed a major complication other than anastomotic thrombosis or death. Despite postoperative intensive care nursing and monitoring, 18 patients died postoperatively in the hospital (6.3%). The average hospital stay was 21.1 days with a range from 5 to 95 days. During this 9-year time period, various free flaps have evolved as the preferred choice for free flap reconstruction of a specific defect of the head and neck. The latissimus dorsal muscle flap surfaced with a nonmeshed split-thickness skin graft is the optimal free flap for reconstruction of the scalp and skull, whereas a multiple-paddle latissimus dorsi musculocutaneous flap is the best flap for reconstruction of complex defects of the middle third of the face and maxilla. The radial forearm flap and free jejunal transfer have become the preferred choices for intraoral reconstruction and pharyngo-esophageal reconstruction, respectively. There still remains no universally accepted flap for mandibular reconstruction, but the fibular osteocutaneous flap and a reconstruction plate protected by a radial forearm flap have largely superseded the iliac crest and scapular osteocutaneous flaps. Radical resection of tumors of the head and neck with immediate reconstruction by microsurgical free tissue transfer followed by adjuvant radiation therapy provides the best possible chance for cure and functional and social rehabilitation of the patient.

Functional ACL bracing. A survey of current opinion and practice.

Since most studies designed to prove the efficacy of functional anterior cruciate ligament (ACL) bracing have been equivocal, we felt it would be helpful to know the practices of orthopedic sports medicine physicians. Physicians were questioned about their brace prescription practices via a mailed survey. The response rate was 56% (114/205). Most physicians use functional braces for ACL patients, prefer custom braces, and brace patients for 9 months after reconstruction. Thirty-six percent reported having recently made changes in their brace prescription practices, including using bracing less often. There was no effort made in this study to determine the best bracing practice. Researchers must continue studying brace efficacy in an effort to provide some rationale for bracing regimens.

OB-GYN Consultants and Sharp the BirthPlace: an exemplar of nurse-midwife and obstetrician interdependence and integration.

The "co-management" model of perinatal care as practiced at OB-GYN Consultants and Sharp The BirthPlace maximizes the practice strengths of both nurse-midwives and obstetricians. The nurse-midwife is the primary provider for 95% of the clients; high-risk women are referred to the physician as appropriate. The model provides extensive health education and an option of a freestanding birth center for low-risk women. In the face of rapid health care changes, which emphasize cost effectiveness, this model has appealing features for managed care systems.

Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis. A double-blind, placebo-controlled trial with open-label extension.

OBJECTIVE: This pilot phase II, double-blind, placebo-controlled trial of 1 month duration, with a 2-3-month open-label extension, evaluated the safety, tolerability, biologic effects, and efficacy of interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis (RA). METHODS: Forty-five RA patients were enrolled in the trial, and were randomized, after a 3-4-week disease-modifying antirheumatic drug washout, to receive a daily intravenous dose of either DAB486IL-2 or placebo (saline) for 5 days. A blinded, third-party observer evaluated arthritis activity. Clinical response was defined as > or = 25% improvement in swollen and tender joints and > or = 25% improvement in at least 2 of 6 additional parameters. The double-blind phase was 4 weeks; placebo patients could cross over to receive open-label treatment for a maximum of 3 monthly DAB486IL-2 cycles. RESULTS: In the double-blind phase, 4 of 22 patients (18%) in the treated group and none in the placebo group (P = 0.05) met the criteria for clinical response. During the open-label treatment phase, 11 of 36 patients (31%) and 11 of 33 patients (33%) had a clinical response after completing 2 and 3 courses of DAB486IL-2, respectively. Adverse events included transient fever/chills (45%), nausea/vomiting (50%), elevated (< or = 3 x normal) transaminases (55%), and increased joint pain (45%). Twelve patients (8 placebo, 4 DAB486IL-2) did not complete 3 treatment cycles. No apparent differences were noted in CD4+ CD25+ cells of responders versus nonresponders, or of DAB486IL-2-treated versus placebo-treated patients. CONCLUSION: Clinical responses were noted in patients treated with DAB486IL-2 (18%) compared with placebo (0%) in the double-blind phase. In the open-label phase, 33% of patients completing 3 monthly DAB486IL-2 cycles had improvement in arthritis activity. Further studies of IL-2 diphtheria fusion proteins are warranted to elucidate factors that may predict clinical response and define mechanism(s) of action.

Report cards or instrument panels: who needs what?

BACKGROUND: The report card movement in health care is a positive response to legitimate customer needs and requirements for comparative information on quality and costs. At the same time, providers have a legitimate concern about potential problems with gathering and using valid data in a prudent manner. Report cards have problems that often detract from their potentially constructive uses. In response to this concern, the authors propose that instrument panels--a newer concept in health care--compared to the static, judgmental image of report cards project an action-oriented, decision-making image. EXAMPLES: Descriptions are given of three types of instrument panels based on work in progress in the Dartmouth-Hitchcock health care system, a regional, integrated delivery system that serves the population of New Hampshire and parts of Vermont and Massachusetts: a 450-physician group practice (The Hitchcock Clinic), which provides more than one million visits per year in more than 25 locations; a tertiary health care facility (Mary Hitchcock Memorial Hospital) with more than 300,000 patient days; and prepaid health plan (Matthew Thornton Health Plan) with approximately 120,000 members. SUMMARY: It would be wise and efficient for providers to design instrument panel data collection systems that can feed directly into report cards, leading to the triple benefit of enhancing accuracy, reducing total costs, and increasing overall utility to both providers and their customers.

Prospective, multicenter study of managing lower extremity venous ulcers.

Seventy patients with 90 venous ulcers were randomly assigned to hydrocolloid or conventional dressing and compression therapy at four study centers. The ulcers had been present for a mean of 47.8 in the control and 46.2 weeks in the treatment group and 42% of all patients had recurrent ulcers. Ulcers treated with hydrocolloid dressings reduced 71% and control treated wounds reduced 43% in area after 7.2 weeks of treatment. Thirty-four percent of all ulcers healed. Mean time to healing was 7 weeks for the hydrocolloid dressing group and 8 weeks for the control group. Most ulcers were less painful at final evaluation, but reduction in pain was more pronounced in hydrocolloid-dressed ulcers (p = 0.03). At baseline as well as during follow-up, significant differences between study centers were observed. Ulcers in patients in the United Kingdom were larger and less likely to heal (p = 0.001). Size of the ulcer at baseline was associated with treatment response and time to healing (p = 0.002). Percent reduction in ulcer area after 2 weeks was also correlated with treatment outcome (p = 0.004) and time to healing (p = 0.002). When all treatment outcome predictors were analyzed together, only percent reduction in area after 2 weeks remained statistically significant (p = 0.002), with percent reduction during the first 2 weeks of treatment > 30% predicting healing.

Making the alternative the mainstream. Maintaining a family-centered focus in a large freestanding birth center for low-income women.

The BirthPlace program in San Diego, California, is an example of a successfully "mainstreamed" alternative maternity care program. It was developed to address an access to prenatal care problem in the county, and it has successfully integrated four systems of care: 1) a private practice of nurse-midwives and obstetricians, 2) the public community clinic system, 3) the tertiary university hospital, and 4) a freestanding birth center. It provides a model of care that, if replicated, could be an answer for ensuring universal access to maternity care in the United States. The BirthPlace program primarily serves a public-funded, Hispanic population, with certified nurse-midwives as the primary providers. The program's greatest challenge has been to maintain a personalized, family-centered focus, which has been the hallmark of freestanding birth centers to date, in the face of large numbers of clients and low reimbursement for care. The program has addressed the challenge of increasing access and cost-effectiveness while ensuring family-centered care through decentralized clinic management, informed consent, culturally sensitive care, and appropriate use of technology. However, in the face of an ever-changing health care system, balancing these issues will remain a constant challenge as we reshape our maternity care services.

Local full-thickness skin-graft coverage for the radial forearm flap donor site.

Closure of the radial forearm flap donor site has been achieved by triangulating the defect and using a full-thickness skin graft from the adjacent volar forearm. Coverage of the flexor carpi radialis tendon has been more robust, and the aesthetic results have been superior to split-thickness skin-graft coverage of the forearm flap donor site.

Response of adult murine uterine epithelium to 50% methoxychlor.

This study was designed to assess the response of uterine epithelia of adult mice to a 4-week exposure of 50% methoxychlor (MXC) to ascertain whether significant changes were induced by 50% MXC that might compromise future implantation. Sexually mature virgin female mice were exposed to 0.1, 0.5, 1.0, 2.5, or 5.0 mg MXC via oral gavage for 5 consecutive days for 4 weeks. Controls received either sesame oil or 25 micrograms estradiol-17 beta (E-17 beta) also by gavage. At sacrifice, segments from each uterine horn were prepared for morphometric studies or for transmission electron microscopy. Results revealed a dose-dependent increase in the heights of uterine epithelial cells. Epithelial cell heights of the two groups treated with the highest doses of the pesticide were similar to that of the E-17 beta-treated group. Electron microscopy revealed increased vacuolization and swelling of mitochondria in cells of the 2.5 and 5.0 mg treated groups when compared to either of the control groups. In addition, there were effects on the number and size of microvilli in the uterine epithelial cells. The present study clearly demonstrates that a 4-week exposure of adult female mice to 50% MXC elicits significant estrogenic and toxic effects on the uterine epithelium.

Implantable venous Doppler microvascular monitoring: laboratory investigation and clinical results.

The purpose of this study was to compare the sensitivity of a 20-mHz ultrasonic Doppler device to detect microvascular thrombosis placed on the vein with that placed on the artery. A feasibility study in animals preceded a comparative clinical study in patients. Six rabbits were used to develop a bilateral hind limb perfusion model. The femoral artery and vein were isolated, and Doppler probes were affixed to each. Clamping of the artery and vein separately was followed by simultaneous measurements in both vascular probes using audio signals and strip-chart recordings. A total of 48 measurements were obtained. Probes placed on the artery immediately detected an arterial occlusion but continued to record pulsation for 220 +/- 40 minutes following venous occlusion. Mean arterial waveform amplitudes diminished by 50 percent of initial values 1 hour following venous occlusion but showed little change thereafter when followed for 6 hours. By contrast, probes placed on the vein detected venous occlusion immediately and arterial occlusion at 6 +/- 2.4 minutes (p < 0.001). Over a 4-year period, 133 patients had free-tissue transfers monitored by implantable 20-mHz ultrasonic Doppler devices: 30 arterial and 103 venous. The arterial monitors detected vascular thromboses in 4 of 6 patients, with 3 flaps salvaged. Venous Doppler monitors detected 16 of 16 thromboses, with 12 flaps salvaged. Six patients had probe/machine malfunctions during their postoperative course and were monitored by clinical means thereafter without thrombosis. There were two late extrusions of the probe cuffs implanted in subcutaneous locations. No adverse effects on the flap vessels were noted in the study. The 20-mHz ultrasonic Doppler device is an effective monitor of blood flow in microvascular anastomoses. When it is placed on the vein, a greater degree of sensitivity is demonstrated, particularly to venous obstruction, compared with probes monitoring arterial flow. The device has been reliable in a variety of institutions and nursing units without need for intensive care monitoring and has resulted in an increased salvage rate for flaps experiencing vascular thrombosis.

DAB486IL-2 fusion toxin in refractory rheumatoid arthritis.

OBJECTIVE: To evaluate the safety and antiarthritic effects of DAB486IL-2. This agent is a fusion toxin and the product of a synthetic gene, engineered by replacing the codons for the receptor-binding domain of diphtheria toxin (DT) with the codons for human interleukin-2 (IL-2). DAB486IL-2 targets cells expressing the 2-chain, high-affinity form of the IL-2 receptor (IL-2R), and achieves selective diphtheria toxin-mediated cytotoxicity of activated T cells by inhibition of protein synthesis. METHODS: Nineteen patients with rheumatoid arthritis (RA) that had been refractory to methotrexate participated in an open-label, phase I/II trial evaluating 3 dose levels of intravenous DAB486IL-2 given for 5 or 7 consecutive days. Thirteen patients received additional courses, at higher doses if the original response had been inadequate or at an equivalent dose if the original course produced a response, for a total of 38 courses. Arthritis response was assessed at 28 days, with biweekly followup of patients with substantial response (> or = 50% improved) or meaningful response (> or = 25% improved). Laboratory monitoring included measurement of CD4+ cells and circulating shed IL-2R. RESULTS: Nine of 19 patients treated with high- or medium-dose DAB486IL-2 had a substantial or meaningful response after 1 or 2 treatment courses. No significant responses occurred with the low-dose regimen. Clinical benefit was rapid, with full effect noted by 14 days following completion of infusions. Antibodies to DT developed in all patients, or levels of preexisting antibodies were boosted. Adverse effects included transient elevation of transaminase levels (55% of the patients), fever (40%), nausea or anorexia (30%), hypersensitivity (6%), and thrombocytopenia (5%). Repeat courses were associated with less transaminase elevation and were clinically effective despite induction of anti-DT antibodies. CONCLUSION: The results of this open trial provide preliminary evidence for a potential therapeutic effect of DAB486IL-2 in RA, with an acceptable safety profile. Reversible transaminase elevations limit escalation of the dosage beyond 0.1 mg/kg/day. A controlled study of DAB486IL-2 is required to determine the efficacy of this high-affinity IL-2R-targeted fusion toxin in the treatment of RA.