Experimental and clinical evaluation of a noninvasive reflectance pulse oximeter sensor.

The objective of this study was to evaluate a new reflectance pulse oximeter sensor. The prototype sensor consists of 8 light-emitting diode (LED) chips (4 at 665 nm and 4 at 820 nm) and a photodiode chip mounted on a single substrate. The 4 LED chips for each wavelength are spaced at 90-degree intervals around the substrate and at an equal radial distance from the photodiode chip. An optical barrier between the photodiode and LED chips prevents a direct coupling effect between them. Near-infrared LEDs (940 nm) in the sensor warm the tissue. The microthermocouple mounted on the sensor surface measures the temperature of the skin-sensor interface and maintains it at a present level by servoregulating the current in the 940-nm LEDs. An animal study and a clinical study were performed. In the animal study, 5 mongrel dogs (weight, 10-20 kg) were anesthetized, mechanically ventilated, and cannulated. In each animal, arterial oxygen saturation (SaO2) was measured continuously by a standard transmission oximeter probe placed on the dog's earlobe and a reflectance oximeter sensor placed on the dog's tongue. In the first phase of the experiment, signals from the reflectance sensor were recorded while the dog was immersed in ice water until its body temperature decreased to 30 degrees C. In the second phase, the animal's body temperature was normal, and the oxygen content of the ventilator was varied to alter the SaO2. In the clinical study, 18 critically ill patients were monitored perioperatively with the prototype reflectance sensor. The first phase of the study investigated the relationship between local skin temperature and the accuracy of oximeter readings with the reflectance sensor. Each measurement was taken at a high saturation level as a function of local skin temperature. The second phase of the study compared measurements of oxygen saturation by a reflectance oximeter (SpO2[r]) with those made by a co-oximeter (SaO2[IL]) and a standard transmission oximeter (SpO2[t]). Linear regression analysis was used to determine the degree of correlation between (1) the pulse amplitude and skin temperature; (2) SpO2(r) and SaO2(IL); and (3) SpO2(t) and SaO2(IL). Student's t test was used to determine the significance of each correlation. The mean and standard deviation of the differences were also computed. In the animal study, pulse amplitude levels increased concomitantly with skin temperature (at 665 nm, r = 0.9424; at 820 nm, r = 0.9834; p < 0.001) and SpO2(r) correlated well with SaO2(IL) (r = 0.982; SEE = 2.54%; p < 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)


Noninvasive cardiac output determined with a new method based on gas exchange measurements and carbon dioxide rebreathing: a study in animals/pigs.

A system has been designed to determine cardiac output noninvasively. The system's main component is a closed breathing circuit and it measures oxygen uptake (VO2), carbon dioxide elimination (VCO2), and end-tidal CO2 partial pressure (PET). As an integral part of the system, periods of CO2 rebreathing can be automatically implemented. The CO2 partial pressure of oxygenated mixed venous blood (Pv) is obtained from the measured exponential rise of the PET value during such a CO2 rebreathing maneuver. A new method is described for estimating the pulmonary blood flow, alveolar ventilation, cardiac output (CO), and mixed venous oxygen saturation (SVO2) from PV, PET, VO2, VCO2, tidal volume, and arterial oxygen saturation. The method was evaluated in 6 anesthetized and mechanically ventilated pigs. A wide range of cardiac output, shunt fractions, and dead space to tidal volume ratios were induced by combinations of bronchoalveolar lavage, hypervolemia, hypovolemia, and variable levels of positive end-expiratory pressure (PEEP). The bias between the CO obtained with the noninvasive technique (CO L/min) and the thermodilution CO (Qt L/min) was 0.13 L/min (SD = 0.78 L/min) and the correlation was N = 64; R = 0.92; CO = 0.95*Qt + 0.38. The bias obtained for double determinations with the noninvasive CO technique was 0.3 L/min (SD = 0.5 L/min). The bias between the noninvasive estimates of Svo2 and the directly measured values was 1.1% (SD = 9.3%). For double determination with the noninvasive technique the bias was -0.9% (SD = 4.7%). It is concluded that in mechanically ventilated pigs the proposed method produces good estimates of CO and SVO2 also in the presence of significant ventilation/perfusion mismatch.


Methods to produce calibration mixtures for anesthetic gas monitors and how to perform volumetric calculations on anesthetic gases.

A simple procedure for making calibration mixtures of oxygen and the anesthetic gases isoflurane, enflurane, and halothane is described. One to ten grams of the anesthetic substance is evaporated in a closed, 11,361-cc glass bottle filled with oxygen gas at atmospheric pressure. The carefully mixed gas is used to calibrate anesthetic gas monitors. By comparison of calculated and measured volumetric results it is shown that at atmospheric conditions the volumetric behavior of anesthetic gas mixtures can be described with reasonable accuracy using the ideal gas law. A procedure is described for calculating the deviation from ideal gas behavior in cases in which this is needed.


Evaluation of users' abilities to recognize musical alarm tones.

The problem of accurate identification of alarm sounds in the operating room, recovery room, and intensive care environment has persisted for many years. Monitors made by different companies may have different alarm sounds for the same monitored variable, and similar alarm sounds for different variables. In an effort to illustrate universal alarms sounds, a system of six musical alarm tones was designed with musical themes from popular songs used for oxygenation, ventilation, cardiovascular monitoring, temperature monitoring, artificial perfusion, and drug administration systems. These melodies were played for a group of anesthesiologists and others, who were initially asked to guess the organ system for each melody. The answers were then given to the participants, and after a short delay the melodies were played again in a different order. Seventy-nine response sheets were collected. The expected random score was 1.0 +/- 1.0 SEM correct. The observed score on the first hearing was 1.5 +/- 1.6 SEM, p = 0.01 compared with the random score. The observed score on the second testing was 4.3 +/- 2.2 SEM, p = 0.001 compared with the first hearing. Indeed, 42 of 79 (53%) respondents got all six answers correct on the second testing, versus three respondents for the first testing. The implications of these findings are discussed in the context of integrated alarm systems used in complex medical environments such as the operating room.


A widely unappreciated cause of failure of an automatic noninvasive blood pressure monitor.

Many anesthesiologists have come to depend on automatic noninvasive blood pressure monitoring to obtain blood pressure (BP) readings. A case is presented in which, during a critical phase of the anesthetic, an automatic noninvasive blood pressure (ANIBP) device not only failed to provide meaningful clinical data but, in fact, gave an error message that was misleading. At the time of the message, the patient was noted to be in ventricular trigeminy at a rate of 92 beats/min. It appears that the repetitive beat-to-beat fall in blood pressure due to the dysrhythmia "fooled" the automatic noninvasive blood pressure device's software algorithm into believing that there was an air leak in the system. Thus, in addition to pointing out an unappreciated and potentially troubling device-related critical event, the present case demonstrates the importance of good human factors design for medical devices used in the critical care setting. In particular, the issue is raised of how medical devices should deal with uncertain or potentially misleading data.


Anesthesia systems. Part 1: Operating principles of fundamental components.

This article is the first in a two-part series on the operation of principal components within Narkomed anesthesia systems. Part 1 illustrates the structure and function of various sections of the machine's internal piping, including components of the pneumatic circuit and the oxygen flush valve, and several safety features, such as the oxygen supply pressure alarm, oxygen failure protection device, and oxygen ratio monitor controller. The article progresses to other basic components of the anesthesia system. Topics include the function of the absorber unit and the flow of gas through it, the principle of operation of the positive end-expiratory pressure valve, the function and mechanics of the adjustable pressure limiter valve, and the open reservoir scavenger system. Part 1 is a valuable tool in understanding the function and pneumatics of the primary components of the anesthesia system.


Patient-related data management.

Patient-related data management (PDM) has become an increasingly important and time-consuming task in intensive care medicine. Currently, all data are usually collected in a poorly structured patient chart consisting of forms and pictures, with about 400 manual entries a day. To handle this amount of data, we have designed a three-level patient system: level 1, summarizing the whole patient; level 2, summarizing one organ system or one isolated problem; and level 3, variables describing morphology and function of organ systems. PDM must be adapted to different clinical situations. We observed three different scenarios: (1) Exploratory PDM, where the clinician learns about the patient and builds up an individual patient model in his or her mind. (2) Operational PDM, where in routine care clinicians are part of a feedback control system, in which they use the patient-related model. (3) Summary PDM, where a clinician summarizes all the information gathered during a period when he or she was responsible for the patient. Computing tools based on clinical thinking and adapted to different situations can ensure accurate, clear, and concise patient care communication among the members of the intensive care staff.


How can a standard software package for data management in anesthesia be achieved?

Collecting data for administrative, statistical, medical, and organizational purposes is becoming increasingly important in anesthesia. In 1986 the Swiss Society for Anesthesiology decided to create a program that would be compatible for different computers and would expedite data collection. The system developed was called Information System for Operations (ISOP), which was written in the database and programming system Massachusetts General Hospital Utility Multi Programming System (MUMPS). It was installed in eight hospitals and met the initial requirements, but the individual requirements of the hospitals were greatly underestimated. MUMPS has an impressive data storage capability and handling when used in a personal computer (PC) network. The user-interface, however, is inferior to other PC packages, partly because windowing and mouse support were not implemented when the ANSI standard was set. Improved statistical programs, a module for on-line data acquisition, and intensive care unit (ICU) use will be additional modules to the program.


Prognostic value of quality-of-life scores during chemotherapy for advanced breast cancer. Australian New Zealand Breast Cancer Trials Group.

We observed that quality-of-life (QL) scores, collected to evaluate treatment in a randomized trial in advanced breast cancer, predicted survival duration. This report explores the prognostic associations between QL and survival in more detail. In a randomized clinical trial comparing intermittent and continuous therapy policies for patients with advanced breast cancer, QL was measured by linear analog self-assessment (LASA) and the Quality-of-Life Index (QLI). Baseline scores and subsequent changes were included in statistical models of survival duration, with and without other prognostic factors. Physician assessment of QLI and patient LASA scores for physical well-being (PWB), mood, nausea and vomiting, appetite, and overall QL (but not pain) at the commencement of treatment were significant predictors of subsequent survival. Scores for PWB and QLI were independent of other prognostic factors. Changes in scores were also prognostically important. Both baseline and change in scores for PWB, mood, pain, and QLI after the first three treatment cycles, but before an arbitrary 180-day time point, were significantly predictive of survival beyond that time. Both QLI and PWB were prognostically independent of tumor response. Although QL improvement was correlated with tumor response, continuous therapy yielded significantly better QL scores, even in nonresponders. These findings support the validity of the simple QL measures used in the trial. They are compatible with the simple explanation that patients perceive disease progression before it is clinically evident, but also with a causal relationship between QL and survival duration.


Prognostic value of DNA flow cytometry in the locally recurrent, conservatively treated breast cancer patient.

This study attempted to determine the prognostic value of DNA flow cytometry in the treatment of patients with locally recurrent, conservatively treated breast cancer. Of 433 patients with clinical stage I and II breast cancer treated with conservative surgery and radiotherapy at Yale-New Haven Hospital before January 1985, 50 patients experienced an ipsilateral breast relapse as a first site of treatment failure. Using standard flow-cytometric techniques, DNA ploidy, DNA index, and S-phase fraction (SPF) were measured for 38 of the 50 (76%) paraffin-embedded specimens available for analysis. At a median postrecurrence follow-up of 5.8 years, the 5-year and disease-free survival rates following ipsilateral breast treatment failure were 48% and 54%, respectively. Sixty-three percent of the recurrent tumors were DNA diploid and 37% were aneuploid. Both DNA ploidy and SPF were statistically significant prognostic indicators for 5-year survival and disease-free survival after local recurrence. The 5-year survival rate of the DNA diploid population was 64%, compared with 15% in the aneuploid population (P < .02). Patients with low SPF (< 12%) experienced an 83% 5-year survival rate, compared with a 24% 5-year survival rate in patients with high SPF (> or = 12%) (P < .03). Ploidy and SPF were combined to define the categories of favorable (diploid, low SPF) and unfavorable (diploid, high SPF or any aneuploid subgroups). Patients in the favorable category experienced an 89% 5-year postrecurrence survival rate and a 100% disease-free survival rate, whereas patients in the unfavorable category had a 24% 5-year survival rate and a 32% disease-free survival rate (P < .01). The flow cytometry as a factor correlated with other clinical parameters previously shown to be of prognostic significance in this patient population. In a multivariate analysis, flow cytometry was a statistically significant and independent prognostic factor for disease-free survival following local recurrence. DNA ploidy and SPF as measured by currently available flow-cytometric techniques show promise as a tool in determining prognosis for the patient with locally recurrent breast cancer. Implications of these findings with respect to issues of adjuvant systemic therapy at the time of local recurrence are discussed.


Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial.

A randomized trial was performed in premenopausal postoperative women with ipsilateral axillary node-positive (N+) breast carcinoma and known estrogen receptor (ER) status to assess the efficacy of an Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-based induction regimen and 5 or more years of tamoxifen (Tam). Patients received 12 28-day cycles of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8, prednisone 40 mg/m2 orally days 1 to 14, and Tam 10 mg orally twice daily (CMFPT), or the same regimen plus halotestin 10 mg orally twice daily (CMFPTH) alternating monthly with 22-day cycles of vinblastine 4.5 mg/m2 IV day 1, Adriamycin 45 mg/m2 IV day 1, thiotepa 12 mg/m2 IV day 1, halotestin, and Tam (ALTER). Prednisone in the ALTER regimen was stopped after the second CMFPTH cycle. After 12 cycles, patients were again randomized to stop or continue Tam. After 5 years, patients on Tam were again randomized to continue or stop Tam; the results from this randomization are still coded. Among 533 analyzed induction cases, 263 received CMFPT and 270 ALTER. Among 396 analyzed maintenance cases, 201 continued Tam and 195 were observed. Pretreatment characteristics were balanced among treatments. The median follow-up times are 5.1 years for induction and 4.1 years for maintenance. The time to relapse (TTR) was superior for the ALTER regimen (P = .04) and for the maintenance Tam (P = .05). Overall survival comparisons between the regimens are not statistically different. A longer TTR was associated with decreasing nodal involvement, ER+ status, and increasing age. The favorable effects of decreasing nodal involvement and ER+ status carried over to survival; a progesterone receptor-positive (PgR+) status and decreasing tumor size were also associated with longer survival. Development of amenorrhea was associated with improved TTR and survival. Toxicity was similar for the two induction regimens and for the two maintenance regimens. Overall relapse patterns were similar among the induction regimens, but continuing Tam led to fewer locoregional relapses. The results suggest significant overall TTR therapeutic benefits of an Adriamycin-containing alternating induction regimen and of continuing maintenance Tam therapy for at least 5 years.


Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.

The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.


Improvement in outcome for children receiving allogeneic bone marrow transplantation in first remission of acute myeloid leukemia: a report from the Groupe d'Etude des Greffes de Moelle Osseuse.

We retrospectively analyzed the outcome of children with acute myeloid leukemia (AML) in first complete remission (CR) who received HLA-identical bone marrow transplantation (BMT) in 13 French transplant centers. Seventy-four children were treated from June 1979 through December 1990. The conditioning regimen included total-body irradiation (TBI) in 54 cases and busulfan in 20. Prophylaxis of graft-versus-host disease (GVHD) consisted of cyclosporine (CycloA) plus methotrexate (MTX) for 38 patients, MTX for 17, CycloA for 18, and T depletion without other prophylaxis for one. The mean value of the interval from diagnosis to transplantation was 167 days. Sixteen patients died of transplant-related complications, 12 relapsed, and 46 are alive in continuous remission with a median follow-up of 46 months. We examined results obtained over three successive periods: 1979 to 1982 (n = 14 children), 1983 to 1986 (n = 29), and 1987 to 1990 (n = 31). Probabilities of event-free survival (EFS) were 43%, 48%, and 82% for the three successive periods, respectively (P < .02). This improvement in EFS was linked to a decreased risk of transplant-related mortality: 36%, 36%, and 3%, respectively (P < .01). Other factors associated with a better EFS in the univariate analysis were a short time interval from diagnosis to transplant (< 120 days), the absence of significant (grade > or = 2) acute GVHD, and the absence of chronic GVHD. In the multivariate analysis, two factors had a favorable impact on long-term survival: the year of transplantation (years 1987 to 1990 v others) and the absence of acute GVHD. The outcome for children receiving allogeneic BMT in first CR of AML has improved in France during recent years.


Standard-dose and high-dose peptichemio and cisplatin in children with disseminated poor-risk neuroblastoma: two studies by the Italian Cooperative Group for Neuroblastoma.

The objective of the present study was to determine whether an increase in the intensity of therapy improves outcome for children with disseminated poor-risk neuroblastoma. From January 1982 through November 1989, 181 children 1 year or older with newly diagnosed disseminated neuroblastoma were entered onto two consecutive studies of the Italian Cooperative Group for Neuroblastoma (ICGNB): 75 (study NB82) were enrolled from 1982 to 1984 and were treated with standard-dose (SD) chemotherapy, and 106 (study NB85) were enrolled from 1985 to 1989 and received high-dose (HD) chemotherapy. In both treatment protocols, induction therapy included peptichemio and cisplatin (at SD or HD, respectively) and removal of the primary tumor. In study NB82, children who achieved complete or partial tumor regression received SD consolidation therapy, and in study NB85 they received three cycles of HD chemotherapy (3cCT) or one cycle of myeloablative therapy (MAT) followed by autologous bone marrow transplantation (ABMT). Compared with group NB82, the NB85 group had significantly fewer failures (no tumor response or disease progression) after administration of peptichemio (9% v 31%; P < .01), had more complete responses (CRs) and partial responses (PRs) both after treatment with cisplatin (60% v 43%; P = .01) and after surgery (76% v 57%; P < .01), and was more likely to have achieved complete excision of the primary tumor (70% v 46%; P < .01). Overall survival (OS) and progression-free survival (PFS) at 5 years were 11% and 9% in NB82, and 27% and 18% in NB85 (P < .01 for both); however, in NB85, relapses occurred even after 5 years of CR, so that PFS curves converge approximately 7 years after diagnosis. Median survival time was 14 months in NB82 and 24 months in NB85. Children in the NB85 group who after achievement of CR were consolidated with 3cCT had a 5-year PFS of 24% compared with 32% of those treated with MAT followed by ABMT (P = .5). Intensified therapy improves response rate and prolongs survival of children with disseminated neuroblastoma, although its impact on the eventual cure rate remains to be established.


Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia.

More than 95% of children with B-lineage acute lymphoblastic leukemia (ALL) achieve a clinical remission after the induction phase of chemotherapy (first 28 days) as evaluated by morphologic criteria. However, relapse occurs in approximately 30% of these children. The objective of this study was to determine whether the outcome of patients in clinical remission at the end of induction therapy could be predicted using a highly sensitive method to detect residual disease. All children diagnosed with B-lineage ALL at the Children's Hospital of Philadelphia during a 2-year period were eligible. The extent of residual leukemia was quantitated in remission marrow samples obtained at the end of induction therapy in 44 children using a phage clonogenic assay in association with complementarity-determining-region 3 (CDR3)-polymerase chain reaction (PCR). Residual disease was a significant predictor of outcome independent of WBC count, age, or sex. The estimated relapse-free survival (RFS) during therapy was 50.4% (+/- 12.6%) for patients with high residual disease (> or = 0.6% leukemia cells among total marrow B cells) versus 91.9% (+/- 5.5%) for those with lower levels (P < .002). There were no significant differences in off-treatment RFS between patients with high or low residual disease who completed therapy in continuous remission (P = .82). The overall estimated RFS was 32.3% (+/- 11.6%) for patients with high residual disease versus 62.6% (+/- 10.7%) for patients with lower levels of residual leukemia cells, with a median follow-up of 5.3 years for patients in continuous remission (P < .008). PCR detection of high residual disease at the end of induction therapy identifies patients at increased risk for relapse during therapy.


Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children's Cancer Study Group investigation.

The goal of this study was to evaluate the toxicity of iodine 131 metaiodobenzylguanidine (mIBG) in metastatic neuroblastoma. A multicenter phase I study of 131I mIBG has been undertaken by the United Kingdom Children's Cancer Study Group (UKCCSG) in children with advanced chemoresistant neuroblastoma. Activity prescription was based on a prescribed whole-body radiation dose, which was established for individual patients by performing an initial tracer investigation with 75 MBq of 131I mIBG. An activity was derived from this pharmacokinetic study that would deliver an initial whole-body-absorbed radiation dose of 1 Gy. Subsequent dose escalations were based on observed toxicity. Twenty-five patients, aged 1 to 10 years, were treated with prescribed whole-body dose levels of 1.0 Gy (n = 2), 2.0 Gy (n = 13), and 2.5 Gy (n = 10). This necessitated administration of 2.4 to 12.1 GBq of activity. Hematologic, hepatic, kidney, and adrenal toxicity were observed, with bone marrow suppression being the principal dose-limiting toxicity. Bone marrow toxicity increased with prescribed whole-body-absorbed radiation dose, with 80% of patients developing grade 3 or 4 thrombocytopenia at a prescribed whole-body radiation dose of 2.5 Gy. Objective evidence of tumor response was seen in soft tissue (primary or nodal disease), bone, and bone marrow, with an overall response rate of 33% (partial response, n = 8; static disease, n = 9; progressive disease, n = 7). This study has established an effective method of activity prescription that predicts subsequent toxicity, with the maximally tolerated dose being sufficient activity to deliver a whole-body-absorbed radiation dose of 2.5 Gy. The objective response rate is comparable to other single agents in chemoresistant neuroblastoma and suggests that 131I mIBG may be a useful method for targeting radiotherapy in metastatic neuroblastoma.


Plasma pharmacokinetics and pharmacodynamics of a new prodrug N-l-leucyldoxorubicin and its metabolites in a phase I clinical trial.

N-l-leucyldoxorubicin (Leu-Dox) was developed as a prodrug of doxorubicin (Dox) to circumvent the cardiotoxicity associated with repeated administration of Dox. Our purpose was to assess the pharmacokinetics of Leu-Dox, Dox, doxorubicinol (Dol) and four other metabolites for pharmacokinetically guided dose-escalation and to verify the prodrug character of Leu-Dox. Blood and urine of 14 patients were sampled during the phase I clinical trial and analyzed by high-performance liquid chromatography. Dose levels of Leu-Dox ranged from 18 mg/m2 to 225 mg/m2, the maximum-tolerated dose (MTD). Hematologic parameters were monitored regularly in each patient. Leu-Dox was rapidly distributed (half-life at alpha phase [t1/2 alpha] = 2.5 +/- 0.6 minutes) followed by a biphasic elimination (half-life at beta phase [t1/2 beta] = 17.4 +/- 7.3 minutes; half-life at gamma phase [t1/2 gamma] = 1.5 +/- 0.5 hours), as measured over the first 12 hours after administration. In three patients, in whom Leu-Dox was found in the plasma for up to 48 hours after injection, a final elimination half-life (t1/2,elim) of 16 hours was observed. The t1/2,elim of Leu-Dox was short (0.6 to 16.5 hours) compared with the t1/2,elim of Dox (38 +/- 11 hours). The mean residence time and apparent volume of distribution were 23 +/- 5 minutes and 19 +/- 6 L/m2, respectively. Only 1.5% to 5% of the dose was excreted in the urine over 48 hours, with Dox as major constituent. Dox was rapidly formed, reaching its maximum concentration within 10 minutes after the end of Leu-Dox infusion. Areas under the plasma concentration versus time curve (AUC infinity, mean +/- SD, n = 16) of Leu-Dox, Dox, and Dol were 115 +/- 27 mumol.min/L, 41 +/- 12 mumol.min/L, and 33 +/- 14 mumol.min/L after a dose of 60 mg/m2 Leu-Dox (= 86 mumol/m2). After the same molar dose of Dox (50 mg/m2 = 86 mumol/m2), the AUC infinity of Dox was 179 mumol.min/L, indicating that Leu-Dox was converted into Dox for 23% in the plasma compartment. The AUCs infinity of Leu-Dox, Dox, and Dol increased linearly with the dose. Negligible AUCs were observed for the other four metabolites. The AUCs infinity of Leu-Dox and Dox at the MTD (517 and 145 mumol.min/L, respectively) were lower than those in mice at the LD10 (1,930 and 798 mumol.min/L, respectively), which means that the MTD could not be predicted from the preclinical pharmacokinetics in mice. Hematologic toxicity, especially the WBC count, appeared to correlate much better with the AUC of Dox (r = .91) than with the AUC of Leu-Dox (r = .74), thus confirming the prodrug character of Leu-Dox. Dox is rapidly formed from Leu-Dox, and seems causative in the observed myelotoxicity. The MTD could not be predicted from the AUC at the LD10 in mice.


Phase II study of pentostatin and intermittent high-dose recombinant interferon alfa-2a in advanced mycosis fungoides/Sézary syndrome.

This phase II study was undertaken to assess the efficacy and toxicity of alternating administration of pentostatin (deoxycoformycin [DCF]) and interferon alfa-2a (IFN) in patients with advanced or refractory mycosis fungoides (MF) or the Sézary syndrome (SS). Forty-one patients underwent therapy with alternating cycles of DCF 4 mg/m2 intravenously (IV) days 1 through 3 and IFN 10 million U/m2 intramuscularly (IM) day 22, and 50 million U/m2 intramuscularly (IM) days 23 through 26. Twenty-nine patients had not responded to prior chemotherapy or total-skin electron-beam irradiation (TSEB), six had not responded to topical therapies, and six had no previous treatment. Two patients achieved a complete response (CR) and 15 achieved a partial response (PR), for an overall response rate of 41% (95% confidence interval, 26% to 58%). No responses were observed in the seven patients with visceral involvement. The median progression-free survival of patients who responded was 13.1 months. IFN-related constitutional symptoms were reported in 39% of patients; severe toxicities included cardiomyopathy in one patient, acute and chronic pulmonary dysfunction in four, and reversible mental status changes in two. Seven patients developed herpes zoster during therapy and six had staphylococcal bacteremia. These results suggest that the combination of DCF and IFN is an active regimen in MF patients without visceral involvement.


Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: a University of Southern California pilot program.

A clinical trial for patients with gastric cancer amenable to curative resection was undertaken to determine feasibility and response to preoperative systemic chemotherapy followed by postoperative intraperitoneal (IP) chemotherapy. Thirty-eight patients with resectable gastric tumor received two cycles of protracted intravenous (IV)-infusion fluorouracil (5FU), 200 mg/m2/d, for 3 weeks with weekly IV leucovorin 20 mg/m2 and IV cisplatin 100 mg/m2 days 1 and 29. Resection of the gastric tumor followed within 3 weeks of completion of systemic chemotherapy. Those who had all visible tumor removed with clear margins received two cycles of IP floxuridine 3,000 mg (total dose) per day for 3 days and IP cisplatin 200 mg/m2 with IV sodium thiosulfate on the fourth day of IP therapy. Thirty-seven of 38 patients (97%) received two cycles of systemic chemotherapy. Thirty-five of 38 patients (92%) underwent laparotomy for gastric tumor resection. Thirty-three patients (87%) had gastric resections performed; 29 (76%) had all visible tumor removed with microscopically negative margins. No operative mortality was encountered. Twenty-six patients (68%) received IP treatment. IV neoadjuvant treatment was well tolerated and resulted in 68% of the patients reporting improvement in abdominal pain, 45% objective remissions by computed tomography (CT), 38% objective remissions by gastroscopy and biopsy, and 8% had complete surgical pathologic response. Neutropenic sepsis during the IP treatment phase contributed to the only treatment-related death. Four of 29 completely resected patients (14%) have had tumor recurrence. The median follow-up time of patients remaining alive is now 19 months. The median survival for 38 patients entered onto this protocol has not been reached at 17+ months. This novel approach to the treatment of adenocarcinoma of the stomach is feasible. The neoadjuvant systemic therapy results in significant primary tumor regression. The determination of whether systemic or IP components of the program contribute to decreased recurrence or increased survival awaits a prospectively randomized clinical trial.


A prospective randomized trial comparing the infectious and noninfectious complications of an externalized catheter versus a subcutaneously implanted device in cancer patients.

To compare the frequency of infectious episodes or other problems occurring with an externalized catheter (Hickman) versus a subcutaneously implanted device (Port-a-Cath, Pharmacia, Piscataway, NJ) in cancer patients, we performed a prospective, randomized study in 100 cancer patients (age range, 5 to 74 years). Patients who were chemotherapy candidates and required an indwelling catheter were monitored prospectively and evaluated during the 180 days after the insertion of the catheter and again at time of study closure. The frequency of catheter use, reason for access, and any problems that might have been related to catheter use were noted. All data were collected prospectively and included the patient's age, sex, underlying malignancy, temperature, and leukocyte and absolute granulocyte counts at the time of catheter insertion and when complications occurred. The time to and reason for removal of the catheter, as well as any intercurrent infectious or mechanical problems, were also determined. Most of the infections that occurred were caused by gram-positive organisms, especially staphylococci or streptococci. A total of 22 complications (11 in each group) resulted in removal of the central line. Only one infection in the Hickman catheter group and four in the Port-a-Cath group led to removal of the central line. All other infectious episodes were successfully treated without removal of the catheters. The mean device life was 230 days for the Hickman catheter and 318 days for the Port-a-Cath (not significant). There were no differences between the two study groups regarding incidence of documented infections or mechanical or thrombotic complications.


Salvage therapy with ProMACE-MOPP followed by intensive chemoradiotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma who failed to respond to first-line CHOP.

We used alternative chemotherapy immediately followed in early-response patients by high-dose chemoradiotherapy and autologous bone marrow transplantation (ABMT) to treat patients with non-Hodgkin's lymphoma (NHL) who had failed to respond to first-line chemotherapy. Thirty-one patients with NHL of intermediate- or high-grade malignancy who had failed to respond to first-line cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy were treated. Seventeen patients had primary refractory disease and 14 had relapsed from first complete response (CR). The treatment consisted of prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, and procarbazine (ProMACE-MOPP) salvage chemotherapy, followed, in case of responsive disease (at least partial response [PR]), by high-dose cyclophosphamide and total-body irradiation (TBI) with ABMT. Twenty-eight of 31 (90%) patients achieved PR (23 patients) or CR (five patients) with ProMACE-MOPP, and three failed to respond. Seventeen of 28 (61%) patients who responded underwent the ABMT procedure, which resulted in CR in 14 patients (82%); three failed to respond. Eleven responsive patients were not transplanted because of residual bone marrow infiltration (five patients), patient refusal (four patients), and ProMACE-MOPP-related mortality (two patients). To date, nine patients are alive and in CR, seven with a median follow-up of 41 months (range, 17 to 84 months). Referring to the original CHOP treatment, five of 17 (29%) patients with primary refractory disease remain free of disease at a median of 36 months after ABMT, and four of 14 (29%) patients in first relapse remain free of disease at a median of 33 months after ABMT. One patient died of AMBT-related toxicity. ProMACE-MOPP salvage chemotherapy produces a high early-response rate in patients who fail to respond to first-line CHOP, and more than half of the responding patients can be scheduled to receive ABMT, resulting in disease-free survival (DFS) at 3 years in 50% of the transplanted patients and in 25% of the original number of patients intended to receive this treatment.


Clinical evaluation of MGI 209, an anesthetic, film-forming agent for relief from painful oral ulcers associated with chemotherapy.

This open-label, multicenter trial evaluated the efficacy of a mucoadherent, anesthetic medication (MGI 209) for relief from painful oral ulcers associated with cytotoxic chemotherapy. Twenty-eight eligible cancer patients who had up to five discrete oral ulcers (total area < or = 5 cm2) completed this study. Mean age was 53.5 years (range, 21 to 81). Subjective assessments of oral discomfort before and after an orange juice pain challenge (OJPC), which was measured using a visual analog scale (VAS), and visual estimates of the amount of MGI 209 that remained on treated ulcers were collected at (1) baseline (before MGI 209 treatment); and (2) 30, 60, 120, and 180 minutes posttreatment. Most subjects had low VAS scores (4 or less), which was indicative of oral discomfort, at baseline before and after the OJPC. At 30, 60, 120, and 180 minutes after MGI 209 treatment, most subjects had high VAS scores before and after an OJPC compared with baseline scores, which was indicative of a substantial increase in oral comfort; these differences were statistically significant (P < .0001). Mean percent of MGI 209 estimated to remain on ulcers at the previously mentioned times was 93.7%, 90.3%, 79.6%, and 71.3% of the total amount applied, respectively. Benzocaine hydrochloride in combination with the protective, mucoadherent film-coating relieved discomfort for at least 3 hours even with exposure to an irritating beverage. MGI 209 treatment should allow patients with chemotherapy-induced oral ulcers to drink and eat with significantly diminished pain or no pain.


Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting.

This study compares the efficacy and safety of two single-dose regimens with the approved three-dose regimen of ondansetron in the prevention of cisplatin-induced emesis. This multicenter study was a stratified, randomized, double-blind, and parallel group design. Chemotherapy-naive inpatients were randomized to receive intravenous (IV) ondansetron (Zofran; Glaxo Inc, Research Triangle Park, NC) 0.15 mg/kg times three doses, every 4 hours or a single 8-mg or 32-mg dose followed by two saline doses that began 30 minutes before cisplatin administration. Cisplatin (high-dose > or = 100 mg/m2 or medium-dose 50 to 70 mg/m2) was given as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. A total of 699 patients (359 high-dose, 340 medium-dose) were enrolled. Of these, 618 were assessable for efficacy (15 ineligible, 66 protocol deviations). The 32-mg dose was superior to the 8-mg single dose with regard to total number of emetic episodes (high-dose, P = .015; medium-dose, P < .001), complete response (no emetic episodes: high-dose, 48% v 35%; P = .048; medium-dose, 73% v 50%; P = .001) and failure rate (> 5 emetic episodes, withdrawn or rescued: high-dose, 20% v 34%; P = .018; medium-dose, 9% v 23%; P = .005). The 32-mg single dose was also superior to the 0.15 mg/kg times three dose regimen with regard to total number of emetic episodes (medium-dose, P = .033) and failure rate (high-dose, 20% v 36%; P = .009; medium-dose, 9% v 22%; P = .011). Ondansetron was well tolerated. The most common adverse event was headache. An approximate 10-fold increase in the incidence of clinically significant transaminase elevations was observed in the high-dose versus medium-dose cisplatin strata (aspartate aminotransferase [AST], 6.5% v 0.7%; serum alanine aminotransferase [ALT], 5.0% v 0.3%). A 32-mg single dose of ondansetron is more effective than a single 8-mg dose and is at least as effective as the standard regimen of 0.15 mg/kg times three doses in the prevention of cisplatin-induced acute emesis.


Cancer Pain Assessment and Treatment Curriculum Guidelines. The Ad Hoc Committee on Cancer Pain of the American Society of Clinical Oncology.

More than 70% of patients with cancer develop significant pain at some time during the course of their illness. Despite the general consensus that most cancer pain can be treated effectively, many patients receive inadequate treatment of their pain. One significant contributing factor is the failure of health care professionals to receive formal training in this important aspect of oncology. The Cancer Pain Assessment and Treatment Curriculum Guidelines reflect the American Society of Clinical Oncology's commitment to providing optimal pain relief to patients with cancer. These guidelines represent an effort to promote formal instruction on the assessment and treatment of cancer pain in training programs and continuing education courses. The curriculum is broad in scope and applicable to patients of all ages. The guidelines emphasize the need for (1) routine pain assessment, (2) proficiency in prescribing opioids, nonopioid analgesics, and adjuvant medications, and (3) an understanding of the potential benefits of antineoplastic, anesthetic, neurosurgical, and behavioral approaches, which often require a coordinated multidisciplinary approach. This curriculum should prove a valuable guide to those who wish further education on the optimal treatment of cancer pain.


Protein kinase C is activated and diacylglycerol is elevated in epidermal cells from Sencar mice fed high fat diets.

Studies reported here determined the effect of dietary fat level on membrane phospholipid composition, phosphoinositide labeling, 1,2-sn-diacylglycerol and protein kinase C activity in epidermal cells from female Sencar mice. Animals were fed either high fat (24.6 g/100 g diet) or control (5 g/100 g diet) diets at constant energy intake for 6 to 7 wk or 15 to 22 wk, and epidermal cells were isolated. The level of phosphatidylinositol was significantly lower in the animals fed the control diet than in the animals fed the high fat diet (0.6 vs. 1.2 nmol/10(6) cells). The fatty acid composition of the phospholipids showed significantly lower arachidonic acid level in phosphatidylinositol when the animals were fed the high fat diet. Protein kinase C activity in the solubilized particulate and soluble fraction of the cells was 131 +/- 18% and 62 +/- 14% greater, respectively, in animals fed the high fat diet compared with animals fed control diet. The level of 1,2-sn-diacylglycerol was significantly higher in animals fed the high fat diet (mean nmol/mg lipid +/- SEM: control, 4.5 +/- 0.5; high fat, 7.0 +/- 0.5). Incorporation of [3H]inositol into inositol lipid was not altered by diet. Because protein kinase C and 1,2-sn-diacylglycerol have been implicated in tumor promotion, the increase in protein kinase C activity and the elevation of 1,2-sn-diacylglycerol in cells from animals fed the high fat diet may be important in the high cancer rate observed with these diets.


Sweet lupin protein quality in young men.

The protein quality of Lupinus albus cv Multolupa was evaluated in young adult males using the nitrogen balance technique at graded levels of N intake, and compared with egg protein. Lupin protein was consumed at levels of 0.4, 0.6 and 0.8 g/(kg.d) and egg protein at 0.3, 0.45 and 0.6 g/(kg.d). Each period started with 1 d of consuming a protein-free diet; the next 6 d were used as adaptation and the last 4 d for balance. The levels of protein intake were randomly assigned by a modified Latin square. Energy intake was individually adjusted. Mean apparent N digestibility values of lupin protein were 78.8, 76.1 and 70.2% for the levels of 0.8, 0.6 and 0.4 g protein(kg.d), respectively, and 83.8, 78.3 and 67.1% for egg protein consumed at levels of 0.6, 0.45 and 0.3 g protein/(kg.d), respectively. The N balance results obtained when subjects consumed lupin were 16.4, 0.2 and -15.1 mg N/(kg.d) for protein intakes of 0.8, 0.6 and 0.4 g/(kg.d), respectively. Those obtained for egg consumption were 12.6, -3.6 and -17.1 mg N/(kg.d) for protein intakes of 0.6, 0.45 and 0.3 g/(kg.d), respectively. The linear regressions of intake and absorbed N to retained N for lupin were: N retained = -43.41 + 0.50 N intake and N retained = -36.30 + 0.53 N absorbed. The corresponding regressions for egg were: N retained = -45.0 + 0.65 N intake and N retained = -30.65 + 0.58 N absorbed. The net protein utilization of lupin was 77% that of egg protein.


Alkaline phosphatase activity and pyridoxal phosphate concentrations in the milk of various species.

Because pyridoxal phosphate does not normally cross membranes, it was intriguing that the concentration of pyridoxal phosphate is much higher in goat milk than in human milk. We also noted that, although the total vitamin B-6 concentration of bovine milk was similar to that of caprine milk, the bovine milk had lower pyridoxal phosphate. Preliminary data from five Alpine goats, five Brown Swiss cows, five Holstein cows and three humans suggested that there was an inverse relationship between pyridoxal phosphate concentration and phosphatase activity in the goats and cows but not in the humans. This was confirmed with additional data from Nubian goats, Jersey and Guernsey cows, and crossbred sows. Combining the animal data yielded the following relationship between pyridoxal phosphate (PLP, mumol/L) and alkaline phosphatase (P'ase) activity (mmol/(min.L): PLP = 2.03e(-2.26 P'ase) + 0.03. The human milk samples were low in both pyridoxal phosphate and alkaline phosphatase. We conclude that in goats, cows and pigs a significant fraction of the vitamin B-6 appearing in the milk is secreted as pyridoxal phosphate, probably bound to protein, and varying amounts may then be hydrolyzed back to pyridoxal depending on the alkaline phosphatase activity. Human mammary tissue apparently secretes very little pyridoxal phosphate.


Comparative metabolism and requirement of vitamin K in chicks and rats.

The metabolic basis for the high vitamin K requirement of chicks compared with rats was investigated. When chicks and rats were fed the same diet, containing 500 micrograms phylloquinone/kg, the total amounts of phylloquinone and its epoxide metabolite found in the liver and plasma were similar in both species. However, phylloquinone 2,3-epoxide was present in high concentrations in chick liver and serum but not in rat liver and serum. This metabolite of the vitamin is normally reduced by a hepatic vitamin K epoxide reductase. The activity of this enzyme in chicks was approximately 10% of that in rats, and the inability of chicks to effectively recycle the epoxide of vitamin K seems to be the major factor in its high requirement. Other species differences in vitamin K metabolism were observed. Much higher concentrations of bacterial menaquinones were present in rat feces compared with chick feces, but neither species had appreciable hepatic concentrations of menaquinones. Chicks, but not rats, were found to have a liver concentration of menaquinone-4 that exceeded that of phylloquinone. This vitamer was present even when its recognized precursor, menadione, was not present in the diet, and the data indicate that chicks convert phylloquinone to menaquinone-4 under the conditions of these experiments. The mechanism of this conversion was not established.


Neither dietary fructose, dextrose nor starch modifies in vitro glycerol release by adipocytes from streptozotocin-diabetic rats.

Because we found previously that fructose feeding could alter lipolytic responses to isoproterenol and insulin in normal rats, we studied the effects of the same diet in neonatal, streptozotocin-diabetic rats. Twenty-seven 5-wk-old diabetic Sprague-Dawley rats were fed a diet containing 57% carbohydrate as either fructose, dextrose or starch for 6 wk. At the end of the nutritional period, plasma glucose and insulin concentrations in fed rats were similar in the three diabetic groups. Plasma triacylglycerol concentrations were higher in the fructose-fed group than in the other two groups (P < 0.05). Neither the maximal adipocyte lipolytic response (fructose = 1147 +/- 165%, starch = 1823 +/- 329% and dextrose = 1287 +/- 239% of basal values) nor the sensitivity to isoproterenol (ED50) was changed by the dietary carbohydrate exchange. The maximal antilipolytic action of insulin (starch = 68 +/- 10%, dextrose = 41 +/- 13%, fructose = 95 +/- 29% of stimulated lipolysis values) was comparable in the three diet groups. Thus, 6 wk of fructose feeding in diabetic rats increased plasma triacylglycerol concentrations, but had no detectable effect on plasma glucose or insulin concentrations, isoproterenol-induced lipolysis or the antilipolytic action of insulin.


An extract of Gymnema sylvestre leaves and purified gymnemic acid inhibits glucose-stimulated gastric inhibitory peptide secretion in rats.

Gastric inhibitory peptide release into the portal vein in response to duodenal infusion of D-glucose was studied in the presence of a leaf extract of Gymnema sylvestre, purified gymnemic acid and inhibitors of some putative glucose sensors and carriers in the intestinal lumen. Intraduodenal infusion of D-glucose significantly increased the portal immunoreactive gastric inhibitory peptide concentration in a dose-dependent manner. The increase in the portal immunoreactive gastric inhibitory peptide induced by glucose was significantly depressed by concomitantly infused leaf extract of Gymnema sylvestre, purified gymnemic acid and phlorizin but not by cytochalasin B. Mannoheptulose, which inhibits glycolysis, and procaine and lidocaine, which inhibit the vagal glucoreceptor in the lumen, did not affect portal immunoreactive gastric inhibitory peptide concentrations. These results suggest that a glucose receptor, which interacts with the leaf extract of Gymnema sylvestre, purified gymnemic acid and phlorizin, exists for the release of immunoreactive gastric inhibitory peptide and that the glucose receptor for gastric inhibitory peptide release is not likely to be identical with a glucose transporter or a vagal glucoreceptor in the lumen.


Placental composition does not respond to changes in maternal dietary carbohydrate intake in rats.

In this study we investigated whether placental glycogen reserves and protein and DNA content could be manipulated by altering the level of glucose in the maternal diet. Pregnant rat dams were fed isocaloric diets containing graded levels of glucose (0, 12, 24 and 60%), and placentas were analyzed for glycogen, protein and DNA content on gestational days 18.5 to 21.5. Regardless of the level of glucose in the maternal diet, there was a significant increase in placental size with advancing age, which was characterized by protein accretion but not by an increase in cell number of glycogen content. Restriction of glucose in the diets of pregnant dams failed to produce statistically significant reductions in placental protein, DNA and glycogen and did not retard placental growth, even though intrauterine growth retardation was observed. Fetal weight, plasma glucose, and liver and heart glycogen were positively correlated with placental weight and inversely correlated with placental glycogen and DNA concentrations; by contrast, no significant correlations were calculated between maternal and placental variables. Our study indicates that the placenta is not affected by a specific dietary glucose restriction and that changes in placental weight or glycogen content do not account for the growth retardation observed in fetuses of dams fed glucose-restricted diets.


Prevention of immunologic stress contributes to the growth-permitting ability of dietary antibiotics in chicks.

The growth-permitting ability of antibiotics fed to broiler chicks was studied as it relates to the state of activation of the immune system. In Experiment 1, chicks were fed two levels of antibiotics (0 or 100 mg streptomycin + 100 mg penicillin/kg diet) and were raised either in an environment with poor sanitation to create a chronic immune stress or in a clean environment. Chicks raised in the unsanitary environment and not fed antibiotics had significantly lower (P < 0.05) rates of weight gain and efficiencies of feed utilization, and higher levels of plasma interleukin-1, compared with chicks raised in the clean environment or chicks raised in the unsanitary environment and fed antibiotics. Adding antibiotics to the diet of birds in the clean environment did not affect any variable. In Experiment 2, chicks were raised in a conventional environment and fed two levels of an antibiotic (0 or 100 mg tetracycline/kg diet). After a 15-d feeding period, half of the chicks were injected with Salmonella typhimurium lipopolysaccharide to create an acute immunologic stress. Feeding antibiotic resulted in improved weight gain, feed consumption and efficiency of feed utilization. Lipopolysaccharide-injected birds developed heavier livers, spleens and intestines relative to body weights and higher rectal temperatures and hepatic metallothionein concentrations, presumably due to an immunologic stress. Omitting antibiotic from the diet resulted in similar changes. These results indicate that feeding antibiotics may permit growth by preventing immunologic stress and associated metabolic changes brought about by monokines including interleukin-1.


Dietary guar gum halts further renal enlargement in rats with established diabetes.

Guar gum, a dietary fiber known to improve glucose tolerance, was fed to rats with established diabetes to determine its effect on renal enlargement and microalbuminuria. Diabetic rats were fed a modified AIN-76A (basal) diet for 4 wk, at which time half the rats continued to receive the same basal diet (DB-BA group) and half were switched to a 5% guar gum diet (DB-GG group). Nondiabetic rats fed the basal diet served as controls (NRL group). After 8 additional weeks the animals were killed. Glycated hemoglobin, a measure of long-term blood glucose control, was 14.4% in the DB-BA group and 12.4% in the DB-GG group, a statistically significant difference (P < 0.05). Kidney weight of the DB-BA group (3.51 g) was significantly greater than that of the DB-GG group (2.76 g) (P < 0.05). Eight weeks after induction of diabetes, 24-h urinary albumin excretion was highest in the DB-BA group and lowest in the NRL group; excretion in the DB-GG group (4 wk of guar feeding) was intermediate. However, by 12 wk no differences in albumin excretion among the groups were apparent. These results suggest that guar gum may be useful for slowing the progression of diabetic nephropathy and that guar gum deserves further study in this regard.


Phenylalanine flooding dose procedure is effective in measuring intestinal and liver protein synthesis in sheep.

We conducted two experiments to evaluate the flooding dose method for measuring intestinal and liver protein synthesis in sheep. Experiment 1 showed that large doses of phenylalanine did not cause marked metabolic disturbances. Experiment 2 examined the effectiveness of flooding with phenylalanine and the time dependency of the protein synthesis calculation. Rams were injected with 1.2 MBq L-[ring 2,6-3H]phenylalanine/kg body wt and slaughtered 20, 40 or 60 min later. Plasma specific radioactivity reached a plateau within 2.5 min and did not change significantly (P > 0.05) throughout the experiment. Tissue intracellular free pool specific radioactivity also remained constant from 20 to 60 min postinfusion. Flooding conditions were achieved in the intracellular free pool of intestinal tissues (specific radioactivity 70-96% of plasma specific radioactivity), although liver flooding was less successful (57-67%). Protein synthesis rates measured after 20 min were significantly (P < 0.05) higher in the liver, jejunum and ileum than those measured at 60 min. Protein synthesis rates also tended to decline with time in the duodenum and colon (P > 0.05). There were no significant differences (P > 0.05) between protein synthesis rates calculated using the intracellular specific radioactivity vs. plasma specific radioactivity in the duodenum, ileum or colon. Therefore, this method represents an improvement over continuous infusion methods for measurements of protein synthesis in visceral tissues.


Erythrocyte metallothionein response to dietary zinc in humans.

The response of erythrocyte metallothionein to dietary zinc in human subjects was evaluated in a controlled metabolic protocol including standard indices of zinc status. Fifteen male subjects, age 27 +/- 3.6 y, participated in a 90-d, four-phase study consisting of acclimation (7 d; 15 mg Zn/d), treatment (6 wk; either 3.2, 7.2 or 15.2 mg Zn/d), depletion (12 d; 0.55 mg Zn/d) and supplementation (30 d; self-selected diet plus 50 mg Zn/d) phases. During the treatment phase erythrocyte metallothionein decreased in the group fed 3.2 mg Zn/d. Erythrocyte metallothionein decreased during the depletion phase (46 +/- 10%) to below the normal concentration in all groups and increased in the supplementation phase. Plasma zinc concentration decreased in the group fed 3.2 mg Zn/d during the treatment phase relative to the acclimation phase. Erythrocyte zinc decreased in all groups during the depletion phase relative to the treatment phase, and then increased during the supplementation phase. These data suggest that erythrocyte metallothionein can be used as a measure of status in severe zinc depletion and that comparing the change in erythrocyte metallothionein over a 6-wk period can differentiate between low and adequate levels of dietary zinc intake.


5-Methyltetrahydrofolate is reabsorbed and metabolized in isolated perfused rat kidney.

The renal regulation of folate excretion is an important component in maintaining the body burden of folate. The tubular processes for folate disposition have been examined by a variety of methods to elucidate the mechanism by which renal folate excretion is regulated. Accordingly, the isolated perfused rat kidney technique was evaluated by investigating the clearance and metabolic patterns of 5-methyltetrahydrofolate (5-CH3-H4PteGlu). Kidneys from male Sprague-Dawley rats were perfused in vitro with [3H]5-CH3-H4PteGlu (1-2000 nmol/L). Linear regression analysis of 5-CH3-H4PteGlu excretion vs. filtered load revealed a tubular transport maximum of 7.5 pmol x min-1.g-1. A dual component system for tubular transport of 5-CH3-H4PteGlu was found: a high capacity, nonsaturable system and a low capacity, saturable system represented by the transport maximum. Furthermore, HPLC analysis of urine demonstrated renal uptake and metabolism of the labeled tracer. Tetrahydrofolate was identified as one metabolic product that indicated secretion of this compound. Additional metabolites were identified from kidney samples. Results suggest that 5-CH3-H4PteGlu undergoes net reabsorption by a dual component transport system; some of the reabsorbed 5-CH3-H4PteGlu is metabolized to other products that may be secreted in the urine.


Intestinal amino acid and monosaccharide transport in suckling pigs fed milk replacers with different sources of carbohydrate.

Omnivorous mammals are able to adaptively modulate rates of intestinal nutrient transport to match changes in diet. Because adaptive responses during suckling, when dietary composition is relatively constant, have not been adequately determined, we measured in vitro sugar and amino acid uptake [nmol/(mg tissue.min)] in suckling pigs fed milk replacers with either lactose (LAC) or a 60:40 mixture of maltodextrin and sucrose (MDS). The MDS-fed pigs initially grew slower, but had intestinal dimensions similar to those of LAC-fed siblings when normalized to body weight. Carrier-mediated uptake for three monosaccharides (glucose, galactose, fructose) did not differ between LAC- and MDS-fed pigs at 5, 10, 15 and 20 d of age. Interdiet differences in rates of leucine and proline uptake, despite identical types and concentration of protein in both milk replacers, are indicative of non-specific responses to diet during suckling. Uptake capacities (grams of monosaccharide absorbed per 24 h) never exceeded estimates of monosaccharide intake by more than fourfold and were less than aldohexose intake during early suckling. Our results indicate 1) age-related changes in rates of nutrient uptake are genetically programmed and little influenced by diet; 2) any responses to diet are nonspecific and likely involve a shift in the timing of the genetic program; and 3) at birth and throughout suckling, pigs are capable of absorbing limited quantities of alternative nutrients.


Sesame seed lignans and gamma-tocopherol act synergistically to produce vitamin E activity in rats.

Vitamin E activity of sesame seed, which contains only gamma-tocopherol, a compound that has vitamin E activity equal to only 6-16% that of alpha-tocopherol, was examined in two experiments. In the first experiment, groups of rats were fed four diets: vitamin E-free control diet, alpha-tocopherol-containing diet, gamma-tocopherol-containing diet and sesame seed-containing diet. Changes in red blood cell hemolysis, plasma pyruvate kinase activity, and peroxides in plasma and liver, as indices of vitamin E activity, were examined. The sesame seed diet has high vitamin E activity, whereas this activity was low in the gamma-tocopherol diet. In plasma and liver, alpha-tocopherol was found in high concentration only in the alpha-tocopherol-fed group, and gamma-tocopherol was found in high concentration only in the sesame seed-fed group, with negligible amounts of gamma-tocopherol in liver of the gamma-tocopherol-fed group. In the second experiment, two diets containing sesame lignan (sesaminol or sesamin) and gamma-tocopherol were tested. Results in both of the sesame lignan-fed groups were comparable to those observed in the sesame seed-fed group in Experiment 1. These experiments indicate that gamma-tocopherol in sesame seed exerts vitamin E activity equal to that of alpha-tocopherol through a synergistic interaction with sesame seed lignans.


Soluble wheat pentosans exhibit different anti-nutritive activities in intact and cecectomized broiler chickens.

The role of the ceca in the anti-nutritive effect of wheat pentosans was studied in intact and cectomized broiler chickens. Addition of wheat pentosans (equivalent to 30 g pure arabinoxylans/kg diet) depressed the digestibilities of starch, protein and fatty acids in both types of birds. Cecectomized birds were less efficient (P < 0.01) in dry matter and energy utilization, but starch digestion was not influenced by cecectomy. Inclusion of isolated wheat pentosans decreased the fecal protein digestibility by 18% in intact birds and by 7% in cecectomized chickens, with the bird type x pentosan interaction being significant (P < 0.05). The ileal pentosan digestibility was not affected either by addition of isolated pentosans or by cecectomy; however, the fecal pentosan digestibility was significantly (P < 0.001) influenced. Thus, in intact birds the fecal pentosan digestibility coefficient was 0.216 in birds fed the control diet and 0.646 in those fed the diet with wheat pentosans; in cecectomized chickens the corresponding values were 0.193 and 0.399, indicating a significant influence of the hindgut microflora on pentosan digestion. The ileal and fecal digestibilities of fatty acids were also determined. There was no interaction between bird type and pentosan addition in the ileal digestibilities of fatty acids. Depressions in the fecal digestibilities of fatty acids 14:0 and 18:0 were significantly (P < 0.05) greater in intact birds. Our results indicate that anti-nutritive effects of wheat pentosans in poultry are partially due to an increased activity of hindgut microflora.


Reduction of phytic acid in soybean products improves zinc bioavailability in rats.

The inhibitory effect of phytic acid in soybean products on zinc bioavailability was evaluated in two experiments in rats. In Experiment 1, soybean flours containing different natural phytic acid levels produced by sand culture techniques that limited phosphorus during growth of the soybean plants were formulated into diets. The rats fed a higher phytic acid level diet had lower food intake, depressed weight gain, and lower tibia zinc gain (P < 0.05). A negative, linear relationship between tibia zinc gain and dietary phytic acid level was found. In Experiment 2, two commercially produced soybean isolates containing either normal phytic acid level or a reduced level were formulated into diets. Slope ratio analysis revealed that relative zinc bioavailability from phytic acid-containing soybean isolate-based diets was significantly reduced (P < 0.05) compared with control diets. Reduced phytic acid soybean isolate-containing diets resulted in a significant increase of zinc bioavailability compared with normal phytic acid diets (P < 0.01). These results coupled with other reports indicate that phytic acid is the primary inhibitory factor in soybean products that results in reduced zinc bioavailability and that phytate reduction in soybean protein increases zinc bioavailability.


Estimation of the dietary riboflavin required to maximize tissue riboflavin concentration in juvenile shrimp (Penaeus monodon).

The riboflavin requirements of marine shrimp (Penaeus monodon) were evaluated in a 15-wk feeding trial. Juvenile shrimp (initial mean weight, 0.13 +/- 0.05 g) were fed purified diets containing seven levels (0, 8, 12, 16, 20, 40 and 80 mg/kg diet) of supplemental riboflavin. There were no significant differences in weight gains, feed efficiency ratios and survival of shrimp over the dietary riboflavin range. The riboflavin concentrations in shrimp bodies increased with the increasing vitamin supplementation. Hemolymph (blood) glutathione reductase activity coefficient was not a sensitive and specific indicator of riboflavin status of the shrimp. The dietary riboflavin level required for P. monodon was found to be 22.3 mg/kg diet, based on the broken-line model analysis of body riboflavin concentrations. Shrimp fed unsupplemented diet (riboflavin concentration of 0.48 mg/kg diet) for 15 wk showed signs of deficiency: light coloration, irritability, protuberant cuticle at intersomites and short-head dwarfism.


Absorption and metabolism of pyridoxamine in mice. II. Transformation of pyridoxamine to pyridoxal in intestinal tissues.

The absorption of pyridoxamine from the intestine of the mouse was studied in whole animals. [3H]Pyridoxamine was orally administered and the distribution of isotope between the six recognized forms of vitamin B6 was determined in portal blood after the administration. When small doses (1.4 or 14 nmol) were administered, labeled pyridoxamine could hardly be found in the portal blood, although labeled pyridoxal and pyridoxal phosphate were found in the same blood. However, when a large amount (46 or 140 nmol) was given, a significant amount of labeled pyridoxamine was found with labeled pyridoxal and pyridoxal phosphate in the portal blood. These results suggest that a physiological dose of pyridoxamine is rapidly transformed to pyridoxal in the intestinal tissues and then released in the form of pyridoxal into the portal blood.


Vitamin C activity of 2-O-alpha-D-glucopyranosyl-L-ascorbic acid in guinea pigs.

The vitamin C activity of 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), which is one of chemically stable derivatives of L-ascorbic acid (AsA), in guinea pigs was investigated. Male guinea pigs were divided into 9 groups and fed AsA-deficient diet for 24 days with the following supplement: AA-2G- or AsA-supplemented groups were orally supplemented with 0.96, 1.92, 9.6 and 192 AA-2G mg/animal/day or equimolar amounts of AsA (0.5, 1, 5 and 100 mg/animal/day, respectively); AsA-deficient group received neither of them. The body weight gain, serum alkaline phosphatase activity, and the concentration of AsA and AA-2G in the liver, adrenals and urine of the guinea pigs were measured at the end of the experimental period. The AA-2G-supplemented guinea pigs showed similar body weight gain to the animals supplemented with equimolar amount of AsA. Serum alkaline phosphatase activity in both AA-2G- and AsA-supplemented groups was significantly higher than that of AsA-deficient group. But there was no significant difference between the groups supplemented with AA-2G and the equimolar amount of AsA. AA-2G-supplemented guinea pigs showed no apparent symptoms of scurvy. In AA-2G-supplemented groups, AA-2G was not detected in the liver, adrenals and urine, but AsA was found and the AsA concentration increased with increasing AA-2G dosage. The AsA concentration in the tissues of each AA-2G-supplemented groups was higher than that of AsA-deficient group, which was similar to that of the groups supplemented with equimolar amount of AsA. These results showed that AA-2G has the same vitamin C activity as AsA on a molar basis for the orally supplemented guinea pigs.


Comparative effect of casein and soybean protein isolate on body fat accumulation in adult rats.

The effect of dietary protein on the body fat accumulation was studied in rats. Adult rats weighing about 300 g were fed 21% protein (casein or soybean protein isolate) and 5% oil diets by pair-feeding for 65 days in Experiment 1. In Experiment 2, only protein and oil contents were changed, 25 and 10%, respectively. Final body weights of the two dietary groups were similar in both experiments, especially in Experiment 2. Total body fat was slightly lower in the soybean protein diet group than in the casein diet group in Experiment 2, only when it was expressed as the percentage against body weight. However, intra-abdominal fat was significantly lower in the soybean protein diet groups than in the casein diet groups in both experiments. Serum lipid levels were greatly lower in the soybean protein diet group than in the casein diet group in Experiment 2 (the data were not available in Experiment 1). The results suggest that dietary soybean protein has the effect to lower the intra-abdominal fat accumulation as compared with casein.


Effects of dexamethasone on experimental atherosclerosis in cholesterol-fed rabbits.

We studied the effects of a synthetic adrenocortical steroid, dexamethasone, on the development of experimental atherosclerosis in cholesterol-fed rabbits. Daily intramuscular injection of dexamethasone (0.125 mg/day) remarkably inhibited the aortic atherosclerosis induced by feeding a 1% cholesterol-rich diet for 8 weeks, although it aggravated diet-induced hyperlipidemia. Histologically, less foam cell accumulation was observed in the atherosclerotic lesions of the dexamethasone-treated rabbits as compared with the control animals. When rabbits were fed a normal chow diet for 10 weeks after receiving the 1% cholesterol-rich diet for 8 weeks, no regression of atherosclerotic lesions was observed with the daily injection of dexamethasone (0.125 mg/day); however, the drug again tended to inhibit further progression of atherosclerosis. The anti-atherogenic mechanism of dexamethasone may involve an inhibition of recruitment of blood monocytes and the insudation of atherogenic lipoproteins, mainly beta-very low density lipoprotein (beta-VLDL) in the present experiments, into the aortic intima, or it may involve a change in the size and structure of the lipoproteins, resulting in their decreased passage through the aortic endothelium into the intima.


Diurnal variation and increase of disaccharidase activity in diabetic rats.

The small intestinal disaccharidase activity and its daily variation in the diabetic rat have not been well described. Therefore, the small intestinal disaccharidase (maltase, lactase and sucrase) activity and its daily profile were studied in streptozotocin-induced diabetic rats under physiological conditions. In diabetic rats, a similar pattern of diurnal variation of disaccharidase activity to control rats was observed, while the relationships between daily change of disaccharidase activity and that of food consumption suggested that there was a different mechanism of diurnal variation in diabetic rats. On the other hand, a significant increase of mean 24-h lactase and sucrase activities was noted in diabetic rats, while that of maltase was not significant. Using the in vitro incubation method, a significant correlation between glucose concentration and lactase or sucrase activity but not maltase activity was observed. However, insulin showed no effect on disaccharidase activity. Thus we clarified the presence of a diurnal variation of disaccharidase activity and an increase in its activity in diabetic rats. This change was suggested to be derived from high plasma glucose level.


Effect of maltitol intake on intestinal calcium absorption in the rat.

To examine whether sugar alcohol affects intestinal calcium absorption, 5-week-old male Wistar rats were fed a basal diet (66% starch) or the diets containing either 10% maltitol, 10% sorbitol or 10% lactose. At 2 and 6 weeks after the start of feeding, the animals were subjected to 5-day-period calcium balance study. Feeding maltitol diets as well as sorbitol diet led to a significantly elevated intestinal calcium absorption and calcium retention. Lactose diet did not produce an increased intestinal calcium absorption in the condition used in the present study. To explore whether maltitol can exert its effect in a short period of time, the rats were starved for 16h and were fed by a polyethylene tube the diet containing 0.44% calcium together with either 10% maltitol or 10% glucose. The total calcium remaining in the gastrointestinal tract at 6h after feeding was significantly decreased in the rats given maltitol diet as compared to the rats given glucose diet. When 10 microCi of 45CaCl2 was given orally with the diets containing maltitol or glucose, the amount of 45Ca remaining in the gastrointestinal tract at 6h after its administration was smaller in the rats fed maltitol diet than in the rats fed glucose diet. These results suggest that both di- and monosaccharide alcohols might affect intestinal epithelium, resulting in an enhanced intestinal calcium absorption.


Qualitative and quantitative estimation of soluble indigestible polysaccharides as substrate for hindgut fermentation by mini-scale batch culture.

Pectin, guar gum, transgalactosylated oligosaccharide and glucose were estimated as substrate for hindgut fermentation by measuring the volume of gas released from a 1 ml scale batch culture using rat cecal contents. The amount of short-chain fatty acids (SCFA) in cultures of glucose and pectin was also measured. The amount of SCFA (Y mumol/culture) or volume of gas released (Y ml/culture) was expressed as an exponential function of incubation time (t) (Y = A+B x (1-e-kt); A, B and k are constants). The amount of potential production of gas and SCFA (B) for glucose was higher than that for pectin and the rate constant of gas and SCFA (k) for pectin was higher than that for glucose. The volume of gas released (ml/culture) correlated positively and linearly with the amount of total SCFA (acetic, propionic and n-butyric acids, mumol/culture). A single regression stood for both glucose and pectin. The gas release followed saturation kinetics. The half maximal concentration and maximal velocity for gas release from pectin were higher than those from other substrates (glucose, guar gum and transgalactosylated oligosaccharide).


Driving and Alzheimer's disease.

To examine the driving status of Alzheimer's disease (AD) patients presenting to a geriatric clinic, and to investigate the ability of brief cognitive assessment measures to identify those who are no longer able to continue driving safely. Based on caregivers' reports of driving status, AD patients were divided into three groups: those who were still driving with no difficulty, those still driving but having difficulty, and those who had stopped driving due to their cognitive problems. Scores on commonly used cognitive tests were compared across groups. Age, gender, and duration of dementia were also investigated. The University of Washington Medical Center (UWMC) outpatient Geriatric and Family Services Clinic. One hundred consecutive patients who met DSM-III-R criteria for primary degenerative dementia and were either currently driving or had stopped driving due to cognitive deficits. Twenty-two subjects were reportedly still driving with no difficulty, 23 were still driving with difficulty, and 55 were no longer driving. Both mental status screening and functional assessments were significantly different between drivers and nondrivers, as were scores on a visual-spatial task. In addition, gender and age distinguished the groups: younger drivers and men drivers were less likely to stop driving despite significant cognitive impairment. Given the large number of AD patients who continue to drive and who experience problems with driving, this investigation highlights the need for assessment of driving safety as part of a clinical dementia evaluation. In addition, the results suggest a combination of cognitive and functional measures that may be helpful in identifying patients who are at greatest risk for unsafe driving.


Demographic differences in health status of homeless adults.

To determine how the physical health of homeless adults varies by the demographic characteristics of age, gender, ethnicity, lifetime length of homelessness, and work status. A community-based sample of 529 homeless adults. In multivariate analyses, the authors studied the independent contributions of five demographic groups to variations in 12 physical health measures (based on self-reports from face-to-face interviews, screening physical examinations, and venous blood samples). Older persons were more likely to have a functional disability (p < 0.001), chronic disease (p < 0.001), and greater risk of dying (p < 0.001), but less likely to abuse substances (p < 0.001). Men were more likely than women to be substance users (p < 0.001) and to have a greater risk of dying (p < 0.001). Whites and blacks were less likely than respondents in other ethnic groups to have an abnormal blood test (p < 0.001). Persons homeless longer were more likely to be substance users (p < 0.001) and to have experienced trauma (p < 0.001). Working for pay was not related to any of our health measures. Age and gender contributed most to the understanding of differences in health status among homeless adults. Since the homeless have a wide variety of physical, mental, social, and substance-abuse problems, primary care providers are in the best position to provide the broad-based care needed by such persons.


Patient characteristics related to intensity of weight reduction care in a university medical clinic.

To identify patient characteristics related to intensity of weight reduction care provided in a primary care practice. Cross-sectional study linking data from a patient survey and data from medical records. Internal medicine housestaff clinic in an urban university hospital. 321 outpatients who represented a systematic sample of all outpatients who had visited the clinic over one year. The patient population was largely black (86%) and female (65%). Most patients (54%) were overweight [body-mass index (BMI) > 85th percentile for the United States by gender]. Intensity of care was defined by a composite scale: points were awarded for actions documented in the medical chart or recalled by the patient. Factors independently associated with a higher intensity of care among the 161 overweight patients were: BMI [odds ratio (OR) = 1.13 per kg/m2; 95% confidence interval (95% CI) = 1.04, 122; p = 0.002], the patient's self-perception of being overweight (OR = 5.37; 95% CI = 1.99, 14.46; p = 0.001), and age of 64 years or younger (OR = 2.48; 95% CI = 1.12, 5.48; p = 0.02). Race, gender, and presence of hypertension or hypercholesterolemia were not associated with greater intensity of care. Patients with hypertension and hypercholesterolemia may be receiving suboptimal weight reduction care. Heightened awareness of being overweight may enhance the provision of weight reduction care. Prospective studies are required to confirm these findings.


Detection of injury-prone behaviors among internal medicine patients.

1) To describe the prevalence of eight injury-prone behaviors (IPBs) and the associations of these behaviors with ten standard chronic disease and sociodemographic risk factors (CDSRFs) among internal medicine patients and 2) to identify a subset of patients with multiple IPBs who might be at particularly high risk of injury. Cross-sectional survey. The University of Colorado Health Sciences Center general internal medicine clinic. Four hundred ninety-two consecutive continuity care patients were eligible. The response rate was 94.3% (464/492). A validated, self-administered questionnaire. Thirty-four percent of patients did not wear safety belts regularly and 32% had no smoke detector in their homes. Nearly 26% of patients had firearms at home and 6% had a loaded and unlocked gun at home. Fourteen percent of patients had seriously thought about suicide and 6% had attempted suicide. In the prior month, 10% had ridden with a drunk driver, and 4% had driven after drinking too much. Of patients aged 65 years or older, 50% had had recent falls. After adjustment for other CDSRFs, problem drinking was the CDSRF most frequently associated with IPBs. Among men, problem drinking was significantly associated with drinking and driving (OR = 35.3), safety belt non-use (OR = 4.3), and previous thoughts of or attempts at suicide (OR = 6.2). Among women, problem drinking was significantly associated with drinking and driving (OR = 8.7). Among men, being unmarried was the demographic risk factor associated with the most IPBs. Of all IPBs, safety belt non-use was most frequently associated with CDSRFs (ORs ranged from 2.8 to 4.4). Men with three or more IPBs were more likely to be problem drinkers (OR = 9.6), smokers (OR = 15.8), obese (OR = 6.3), and unmarried (OR = 67.1). 1) Injury-prone behaviors are common among patients attending a university-based internal medicine clinic; 2) men and women have substantially different patterns of risk factor associations; 3) CDSRFs, such as problem drinking smoking, and being unmarried, are associated with many IPBs; 4) safety belt non-use is the IPB associated with the most CDSRFs; and 5) CDSRFs appear to cluster in men with multiple IPBs, suggesting that screening for high-risk individuals may be feasible in clinical practice.


The unit of analysis error in studies about physicians' patient care behavior.

To estimate the frequency with which patients are incorrectly used as the unit of analysis among statistical calculations in published studies of physicians' patient care behavior. Retrospective review of studies published during 1980-1990. ARTICLES: 54 articles retrieved by a computerized search using medical subject headings for physicians and study characteristics. Article selection criteria included the requirement that the physician should have been the correct unit of analysis. Presence of the error was determined by consensus using published criteria. The error was present in 38 articles (70%). The number of study physicians was reported in 35 articles (65%). The error was found in 57% of articles that reported the number of study physicians and in 95% of those that did not. The error rate was not lower among articles published more recently nor among those published in journals with higher rates of article citations in the medical literature. The unit of analysis error occurs frequently and can generate artificially low p values. Failure to report the number of study physicians can be a clue that this type of error has been made.


Long-term success with the national health objective for influenza vaccination: an institution-wide model.

To assess the long-term effectiveness of an influenza vaccination program. 725-bed university-affiliated VA teaching hospital providing care to over 35,000 outpatients. 500 randomly selected outpatients were surveyed following each immunization season using a validated, self-administered, postcard questionnaire. The institution-wide program, designed to function automatically and to be independent of physician initiative, emphasizes organizational and patient-oriented educational strategies: 1) a hospital policy allowing nurses to vaccinate without a physician's order; 2) a walk-in flu shot clinic; 3) reminders on clinic progress notes; and 4) an educational mailing to all outpatients. The program was initiated in 1987 and has been maintained for each subsequent immunization season. The response rate was over 75% for each of the four years in which there were two mailings. The response rate for 1988-1989, in which there were three mailings, was over 85%. Approximately 70% of the respondents were at high risk for influenza and its complications. Vaccination rates for these high-risk outpatients have been sustained at over 58% for each immunization season. The program is well received by the hospital staff and now functions on autopilot each year. This highly successful institution-wide influenza vaccination program can be sustained long-term. Elements of this program may help others take advantage of opportunities for influenza prevention.


Health behavior changes in the United States, the United Kingdom, and France.

To determine changes in health behaviors in the United States, the United Kingdom, and France over the previous two years. Cross-sectional survey of nationally representative samples. Surveys conducted between June and November 1988 on persons aged 16 to 50 years in the United States (n = 1,940), the United Kingdom (n = 1,833), and France (n = 2,294) regarding health behaviors, attitudes toward health, and changes in health practices during the previous two years. Using Bonferroni's adjustment for multiple comparisons, residents of the United States had significantly (p < 0.05) higher Quetelet indices and reported higher egg and red meat consumption, but had lower alcohol consumption, than did residents of either the United Kingdom or France. Americans were also significantly more likely to report attitudes accepting personal responsibility for their health and much more often endorsed the role of health behaviors (e.g., exercise) for decreasing the risk of cardiovascular disease. Changes in health behavior over two years were consistently more likely in the United States for weight loss, decreased alcohol consumption, decreased red meat and egg consumption, and increased exercise. Americans were also much more likely to have changed at least three health behaviors in the previous two years (United States 41.5%, United Kingdom 25.5%, France 13.8%, p < 0.002). A multivariate linear model confirmed the high likelihood of health behavior changes in the United States compared with the United Kingdom or France. The findings confirm that changes in health behaviors are continuing to occur in the United States, but remain comparatively modest in the United Kingdom and France. These international variations in health behaviors parallel differential declines in mortality rates in ischemic heart disease.


What's preventing more prevention? Barriers to development at academic medical centers.

To determine the views of leaders in academic medicine concerning the need for programs in preventive medicine (PM) and the prevailing barriers to program development. Structured interviews. Medical schools of the United States. 90% of deans and chairpersons of departments of medicine and preventive medicine. None. 91% considered academic PM underdeveloped and 100% considered their own programs average or worse. Identified barriers to development included funding constraints, academic partiality to biomedicine, inadequate quality of preventive medicine research and faculty, public preferences for technologic care, and organization of academic medical centers (AMCs). While 80% perceived a shortage of able PM faculty and 60% considered PM research quality to be inadequate, only 12% of PM units gave research training high priority. While 95% of respondents held that AMCs should develop community programs and 75% identified social problems as a cause of chronic diseases, 65% agreed that community programs are not considered scholarly. Only 23% of PM units gave community service high priority. A policy contradiction exists: academic leadership agreed on the problems and needed changes in PM, yet the problems were often attributed to nonacademic sources, particularly finding and public preferences, and current academic practices commonly fail to address recognized developmental barriers within academic institutions. A chain of barriers is apparent. Breaking the chain may require a change in our understanding of the role of prevention.


Sex differences in signs and symptoms from masticatory and other muscles in 19-year-old individuals.

Pain and tenderness of masticatory muscles are often related to muscle tenderness elsewhere in the body. It has been shown that women are more prone to musculoskeletal disorders than men. We sought to determine whether sex differences of muscular symptoms were established by the age of 19. The subjects comprised 51 boys and girls who received a questionnaire regarding the function of their masticatory system, frequency of headache, and neck, shoulder and low back pain. Their masticatory system was examined, and neck and shoulders were palpated. For all variables in the questionnaire girls reported symptoms more often than the boys. Of the subjects 50% had tender chewing muscles upon palpation. Again the girls had the most. There was good correlation between reports of pain in one area as compared to others. The number of clinically tender neck and shoulder muscles correlated with the number of tender masticatory muscles. It was concluded that girls presented more muscular symptoms than boys.


Complete mandibular denture stability when posterior teeth are placed over a basal tissue incline.

Six patients with previous denture experience were provided with new dentures. Metal indicators were placed on either side of the mandibular denture and a cobalt-chromium alloy marker was inserted in the left bucco-posterior area of the mandible in each case. In the new dentures posterior teeth were positioned up to the retro-molar pad, over the basal tissue slope of the posterior mandibular alveolar ridge. After habituation had taken place, a cineradiographic recording was made of chewing. Prior to the second recording the mandibular teeth were removed to a point where the remaining teeth were not over inclined residual alveolar ridges. Denture movement was observed by measuring the distances between the markers on an analytical projector. The results show a significant difference between the cranial values of the two chewing experiences. Values for all denture movements were less after removal of the teeth over an incline. These results support the clinical observation that teeth placed over a basal tissue incline have a destabilizing effect during complete mandibular denture function.


Internal medicine training in ambulatory gynecology.

To assess internists' perceptions of their training in the management of common problems in ambulatory gynecology and to compare these perceptions with their clinical practice experiences. We surveyed 325 internists in the Portland, Oregon, metropolitan area about their residency training and practice experiences in the diagnosis and management of 25 clinical problems in ambulatory gynecology and five nongynecologic problems. Responses were received from 159 internists (48.5%). Overall, the internists reported relatively little residency training in the management of many common gynecologic disorders. Women internists managed gynecologic problems more than did their male counterparts, independent of the number of women patients in their practices. Internal medicine residency programs need to expand training in ambulatory gynecology to better prepare graduates for clinical practice.


Discrimination of clenches at varied jaw positions using autoregressive model coefficients of myoelectrical activities of anterior temporal and masseter muscles.

During 10% maximum clenching at intercuspal, protruded, retruded contact and lateral positions, the surface electromyograms (EMG) of bilateral anterior temporal and masseter muscles of 20 normal subjects with intact natural dentitions were recorded. The autoregressive (AR) model of the sampled EMG was then built and the obtained coefficients of the AR model were accepted as featured parameters of the EMG. Finally Bayes' stepwise discriminant analysis was used for establishing discriminant functions of estimating low level clenches at varied jaw positions. It was found that total conformation rates of internal and external sample substitution (15 and 5 subjects) were 82.67% and 78% respectively; the discriminant effect between intercuspal and retruded contact position was not up to predicted standard. The results indicate that AR model coefficients may describe the characteristics of surface EMG of masticatory muscles and easily be used in multiple statistical analysis, from which the classification and diagnosis may be taken.


Microleakage of indirect inlays placed on different kinds of glass ionomer cement linings.

The objective of this study is to compare the marginal seal of Class II cavities restored with indirect inlays constructed on glass ionomer cement linings having different curing properties. Also the effect of acid-etching of these liners on microleakage was investigated. Mesio-occlusal and disto-occlusal cavities in 80 extracted human molars having the cervical floor below the cementoenamel junction were prepared (n:160). Half of the preparations were restored with Ceramco II porcelain and the rest with SR-Isosit resin inlay material. Liners as light curing Ionoseal light+chemically curing LCL 8 and Zionomer and chemically curing Ketac-Bond glass ionomer cements (GICs) were used. On mesial preparations GICs were acid-etched but were not on distal preparations. All inlays were cemented with Ultrabond composite material. After thermocycling the teeth were placed in a basic fuchsin dye solution for 24 h, then each tooth was sectioned. By using a stereomicroscope the extent of marginal leakage was scored and statistically evaluated. Microleakage was observed beneath all GIC linings and was more extensive between light curing GIC/dentine interface. By acid-etching of GICs the microleakage between GIC/dentine interface was increased significantly. Whether acid-etching was applied or not a significantly increased microleakage was recorded between chemically curing GIC/composite interfaces. Although the marginal microleakage was witnessed in both inlays, it appeared that porcelain inlays provided a better marginal seal, in comparison to SR-Isosit inlays.


Physics and the sounds produced by the temporomandibular joints. Part I.

In clinical dentistry, the sounds (clicking) and noises (grating) produced by the temporomandibular joints (TMJ) usually signify dysfunction or disease of the mandibular locomotor system. In an attempt to provide guidance to the general practitioner, this article discusses some pertinent parameters defining the physics of airborne and solid-borne vibrations.


Maximum jaw opening capacity in adolescents in relation to general joint mobility.

Mandibular jaw opening was related with general joint mobility in a non-patient adolescent group. The angular rotation of the mandible at maximum jaw opening was slightly larger in females than in males and significantly larger in hypermobile individuals. No significant relationship between linear measuring of maximal mandibular opening capacity and peripheral joint mobility was found either at active (AROM) or at passive range of mandibular opening (PROM). PROM was strongly correlated to the mandibular length. Clinical signs in the great jaw closer muscles could not be associated to decreased AROM. The mean value of the difference between PROM-AROM (DPA) was 1.2 mm. Frequent clenching and/or grinding was correlated to increased DPA only in hypermobile adolescents (r = 0.49***). Those with DPA exceeding 5mm had all reciprocal clicking.