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Introduction: Monitoring the atypical antipsychotic drug clozapine is crucial to ensure patient safety. This article showcases a high-throughput analytical method for measuring clozapine and its primary metabolite norclozapine (N-desmethylclozapine) in serum using paper spray mass spectrometry (PS-MS). Objectives: This study aimed to assess the viability of a PS-MS method for the rapid measurement of clozapine and norclozapine in human serum samples as an alternative to liquid chromatography mass spectrometry (LC-MS). Methods: Serum samples were processed by protein precipitation followed by deposition of the supernatant containing labelled internal standards onto paper spray substrates mounted in cartridges. Analytes were then analyzed using a triple quadrupole mass spectrometer equipped with a commercial paper spray ionization source. The results obtained from the patient samples were compared to those from a validated LC-MS assay. Results: PS-MS calibrations for clozapine and norclozapine were linear (R2 > 0.99) over five days. Between-run precision was below 8 %, and within-run precision did not exceed 10 %. When compared to a validated LC-MS method, the mean bias for 39 patient samples was -9% for clozapine and -1% for norclozapine, with no outliers. Mass spectrometry ion ratio comparisons indicated no interference for patient samples above the lower limit of quantification. There was less than 7 % change in the measured concentrations of both analytes over five days for samples dried on paper substrates. Notably, virtually no maintenance of the MS source was required during this study. Conclusion: This study illustrates the potential of PS-MS for serum drug monitoring in the clinical laboratory.

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The authors wanted to determine whether adding interferon-alpha (IFN-alpha) to chemotherapy regimens, in either induction or maintenance settings, provides additional survival benefits in follicular non-Hodgkin's lymphoma (NHL). A meta-analysis was performed based on published data from randomized controlled clinical trials involving nine separate study populations. Patients receiving IFN-alpha (in either induction or maintenance therapy) had significantly increased 5-year and progression-free survival rates at 3 and 5 years compared with concurrent controls. The advantages of IFN-alpha therapy were most marked in studies using anthracycline-containing induction chemotherapy; in these studies, patients who received IFN-alpha had approximately 20% increased progression-free survival rates compared with controls and a lesser survival advantage. The available literature did not allow a determination of the relative benefit of IFN-alpha in induction or maintenance treatments for NHL or a determination of the optimum duration of IFN-alpha treatment. Although questions remain about its optimal use. IFN-alpha appears to prolong survival time in patients with follicular NHL.

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PHAST (for Phonological and Strategy Training) is a research-based remedial reading program that attempts to capitalize upon current research on reading disabilities and their remediation. The focus of the program is on the primary obstacles to word identification learning and independent decoding that most disabled readers face and the steps necessary to help these children achieve independent reading skills. A framework of phonologically based remediation was used as a foundation upon which a set of flexible and effective word identification strategies were scaffolded in an integrated developmental sequence. The program uses a combination of direct instruction and dialogue-based metacognitive training, with the pedagogical emphasis shifting from an initial direct instruction, remedial focus to increasingly metacognitive-strategy-based methods. A continuum of intervention over 70 hours provides both (a) remediation of the basic phonological awareness and letter-sound-learning deficits of disabled readers and (b) specific training of five word identification strategies that offer different approaches to the decoding of unfamiliar words and exposure to different levels of subsyllabic segmentation. Explicit instruction in the application and monitoring of multiple word identification strategies and their application to text-reading activities continues throughout the PHAST Program. PHAST training provides the disabled reader with the opportunity to become a flexible reader who approaches new words in or out of context with multiple strategies and has the ability to evaluate the success of their application. The PHAST Program was developed following the controlled evaluation of its components in laboratory classroom settings and recent positive results from their sequential combination. PHAST represents a new integrated approach to programming in this area using instructional components that have already demonstrated their efficacy with children with severe reading disabilities.

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We conducted a systematic review of all published randomized, controlled trials to assess the risk of cancer or death in patients receiving verapamil for hypertension, angina pectoris, or cardiac arrhythmias. Meta-analysis comparing the risk of new cancers, cancer deaths, and all deaths was performed. Thirty-nine trials comprising 11,201 patients were eligible. Study durations ranged from 8 days-6 years (mean 29.5 wks). Nine trials (6507 patients) were 24 weeks in duration or longer. For cancer and cancer death, OR was 1.20 (95% CI = 0.60-2.42) for verapamil versus active controls and 0.73 (95% CI = 0.39-1.39) for verapamil versus placebo. For all deaths, OR was 1.13 (95% CI = 0.70-1.82) for verapamil versus active controls and 0.85 (95% CI = 0.71-1.00) for verapamil versus placebo. Sensitivity analysis for the 9 trials 24 weeks' duration or longer gave similar results. There is no statistically significant increased risk of cancer or deaths with verapamil compared with active controls or placebo.

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We are particularly grateful to Dr. Annemarie Sullivan Palincsar for her helpful advice and generosity in sharing materials, procedures, and sample dialogues for use in the version of Reciprocal Teaching used in the present study. This research was supported by an operating grant to the first author from the Ontario Mental Health Foundation. We gratefully acknowledge the contributions of Janet Hinchley and Karen Steinbach in assisting with data collection and Nancy Benson, Carolyn Kroeber, and Karen Steinbach in assisting with data analysis. We thank Sheila Wroblewski and Rosemary Slyne for their contributions in program development and lesson planning. We are grateful to the Principals and staff of Winona and Jesse Ketchem Schools and the Toronto Board of Education for providing satellite locations and support for our programs. The enthusiasm and efforts of the 46 students enrolled in the present programs, and the cooperation and interest of their parents and teachers, are particularly acknowledged.

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OBJECTIVES: The purpose of the study was to determine the clinical and economic impact of alternative contraceptive methods. METHODS: Direct medical costs (method use, side effects, and unintended pregnancies) associated with 15 contraceptive methods were modeled from the perspectives of a private payer and a publicly funded program. Cost data were drawn from a national claims database and MediCal. The main outcome measures included 1-year and 5-year costs and number of pregnancies avoided compared with use of no contraceptive method. RESULTS: All 15 contraceptives were more effective and less costly than no method. Over 5 years, the copper-T IUD, vasectomy, the contraceptive implant, and the injectable contraceptive were the most cost-effective, saving $14,122, $13,899, $13,813, and $13,373, respectively, and preventing approximately the same number of pregnancies (4.2) per person. Because of their high failure rates, barrier methods, spermicides, withdrawal, and periodic abstinence were costly but still saved from $8933 to $12,239 over 5 years. Oral contraceptives fell between these groups, costing $1784 over 5 years, saving $12,879, and preventing 4.1 pregnancies. CONCLUSIONS: Contraceptives save health care resources by preventing unintended pregnancies. Up-front acquisition costs are inaccurate predictors of the total economic costs of competing contraceptive methods.

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The "lanes" concept of training was integrated into a medical site support mission of the 804th Medical Brigade, U.S. Army Reserve, during Annual Training, 1993 at Fort Drum, New York. This training, termed Hospital Integrated Lanes Training (HILT), included STX, FTX, patient play, and full use of Deployable Medical Systems equipment. The medical care of over 33,000 personnel participating in tactical annual training exercises was not interrupted during any concurrent phase of lanes training. Brigade operations planners developed an array of medical exercises that involved both moulaged and paper patient play. These exercises began prior to hospital set-up and continued for 24 hours a day throughout the tactical exercise. Injuries likely to be encountered during combat operations were inserted into the play singly and under a mass-casualty scenario. The standard of care for all injuries was determined with the Army Medical Department Center and School guidance. Prior coordination of brigade medical assets with external air and ground ambulance organizations broadened the scope of the training and facilitated effective use of command and control, communications, and equipment over a wide geographic area. Medical records were collected and evaluated at the conclusion of all exercises. After-action reviews were conducted by all medical units to assist in the planning of future HILT exercises. The HILT concept is a valuable tool for the complex training requirements of field medical units organized under medical Force 2000. The concept of integrated lanes training allows for the development and continuous improvement of individual and sectional skills for medical personnel and should be applied within all echelons of care.

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To develop quantitative analysis of regional left ventricular wall motion in the absence of a gold standard, an objective statistical measure to compare models of wall motion is described. This measure can be derived from wall motion analysis of subgroups of patients with different patterns of wall motion. A priori knowledge of the exact localization of wall motion abnormalities is not needed. Two-dimensional echocardiograms were analyzed from 79 patients with myocardial infarction. The following 4 models were compared: Model I was based on the descent of the base toward the stable apex during systole. Models II and III measured area reduction with fixed- and floating-reference systems, respectively. Model IV was the centerline model. Classification by the electrocardiogram of the myocardial infarction as anterior (n = 37), posterior (n = 17) and inferior (n = 25) provided the a priori probability for classification of myocardial infarction. The a posteriori probability for classification of myocardial infarction was derived from the detection of wall motion abnormalities by echocardiographic analysis. The mean difference between a posteriori and a priori probability is a measure for the diagnostic value of the model, and was measured for 200 regions/patient. Use of the described measure revealed model I to be the most informative model and model III the least informative. Thus, the described statistical measure contributes to the development of regional wall motion analysis.

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The value of pulsed-wave transmitral Doppler for the diagnosis of moderate acute rejection was examined in a total of 347 Doppler recordings obtained in 32 consecutive cardiac allograft recipients. Serial Doppler examinations (median, 11 per patient; range, 1 to 23) were performed simultaneously with endomyocardial biopsies from the first week after heart transplantation to a follow-up of 186 days (median; range, 10 to 395 days after transplantation). Pulsed-wave transmitral Doppler did not allow noninvasive diagnosis of moderate acute rejection in individual patients. Peak filling rate normalized for mitral stroke volume, early diastolic velocity, and mean diastolic velocity were significantly increased, whereas diastolic filling period was decreased during moderate acute rejection compared to other biopsy classes. The wide overlap of measurements in individual recipients with or without rejection may be due, however, to a variety of hemodynamic factors after transplantation affecting diastolic function, which are superimposed on the restrictive left ventricular filling pattern caused by persistent mild acute rejection and left ventricular hypertrophy. These hemodynamic factors include pulmonary hypertension, perioperative ischemia, reperfusion injury, and changes in both blood pressure and loading conditions caused by hypertension and its treatment. Differences between studies with regard to the detection of moderate acute rejection by transmitral Doppler may be caused by chance, because most studies were relatively small. Differences in methods, patient selection, duration of follow-up, prevalence of hypertension and left ventricular hypertrophy, and differences in antihypertensive drug regimens may also play a role. Furthermore differences in the incidence of mild acute rejection, its treatment, and the type of maintenance immunosuppressive regimen used may have influenced the outcome of these studies considerably.

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OBJECTIVE: Assessment of changes in left ventricular diastolic function and wall thickness after heart transplantation to verify whether these changes predicted acute rejection assessed by endomyocardial biopsy. DESIGN: Follow up according to a predefined protocol of consecutive patients from the first week after transplantation. SETTING: Heart transplantation unit of the Thoraxcentre, University Hospital Rotterdam Dijkzigt, The Netherlands. PATIENTS: All 32 patients undergoing orthotopic heart transplantation from 1 January 1989 to 31 March 1990 were examined. Two were excluded from the analysis. Patients were treated with cyclosporin and low dose steroids. MAIN OUTCOME MEASURES: Data obtained by digitised M mode echocardiography were compared with the results of endomyocardial biopsy (Billingham classification). Mean values for left ventricular wall thickness, internal dimension, and their standardised rates of change and fractional shortening were determined from 4-6 consecutive expiratory beats. Mean values and individual trends during follow up were also investigated for each ultrasound variable. The results of these average values were compared with values in a group of 10 healthy volunteers. RESULTS: Median follow-up was 177 days (range 10-399). Two hundred and sixty three consecutive M mode studies were examined in relation to concurrent biopsy results. No significant differences were observed between the ultrasound variables at the time of moderate acute rejection (Billingham class 2, n = 37) and other biopsy classes (n = 226). Nor did changes in individual patients predict (moderate) acute rejection episodes. Twenty six of the 30 patients had an abnormal (slow) left ventricular relaxation pattern throughout follow up. CONCLUSIONS: Digitised left ventricular M mode echocardiography did not predict the presence of acute rejection. In most patients there was a persistent slow left ventricular relaxation pattern.

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Registration of respiration allows analysis at the end-expiratory phase and may thus favor the use of the fixed-reference system versus the floating-reference system in echocardiographic quantitative wall motion analysis. Analysis is performed on two-dimensional echocardiograms of 44 normal subjects, 38 patients with anterior myocardial infarction, and 17 patients with posterior myocardial infarction. Two different models for wall motion analysis are applied, each using the fixed-reference system and the floating-reference system, respectively. In patients with anterior myocardial infarction, the fixed-reference system indicates severe wall motion abnormalities at the anterior, septal, and apical walls, whereas the floating-reference system indicates less severe wall motion abnormalities almost equally at every wall. In patients with posterior myocardial infarction, the fixed-reference system indicates severe wall motion abnormalities at the posterior wall, whereas the floating-reference system indicates less severe wall motion abnormalities almost equally at every wall. These findings indicate that the fixed-reference system is superior to the floating-reference system in quantification of wall motion of end-expiratory two-dimensional echocardiograms.

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We recorded two-dimensional echocardiograms simultaneously with the respiration measurements of 20 normal subjects and 20 patients with anterior myocardial infarction. The apical long-axis and four-chamber views were quantitatively analyzed. Measurement variability of global ejection fraction and regional ejection fraction of 100 regions was calculated during inspiration and at end-expiration for two observers. To minimize variability, the endocardial contour was redefined and traced with an improved computer-assisted tracing system. Variability (absolute mean difference) between two beats at end-expiration was significantly less than during inspiration (p less than 0.05): for ejection fraction the variability at end-expiration was 3.4% and the variability during inspiration was 6.4% (mean, 54%; SD, 7%); for regional ejection fraction the variability at end-expiration was 11.8% and the variability during inspiration was 21.5% (mean, 56%; SD, 15%). Intraobserver and interobserver variability values of one beat at end-expiration for ejection fraction were 3.1% and 3.8%, respectively, and 9.5% and 12.8%, respectively, for regional ejection fraction. Variability in patients with myocardial infarction was comparable. This method of recording respiration and analyzing left ventricular function at end-expiration, with a new contour definition and tracing system, provides a measurement variability that is considerably less than that reported in previous echocardiographic studies and that is comparable to angiographic methods.

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We investigated the value of several Doppler echocardiographic measurements for the diagnosis of acute allograft rejection after orthotopic heart transplantation. In all, 144 transmitral flow velocity curves and 159 internal jugular venous flow velocity curves were recorded by continuous wave Doppler echocardiography, and the results were compared with the histologic findings. The recordings were evaluated with a computer-aided analysis system. The Doppler measurements did not show any significant correlation with the biopsy results. Only one recording obtained during a moderate acute rejection episode supported the hypothesis about the relation between jugular venous flow and cardiac rejection. We conclude that these Doppler echocardiographic measurements are not suitable to detect acute allograft rejection noninvasively.

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To establish an appropriate echocardiographic model for wall motion analysis we first determined the precise dynamic geometry of the left ventricle during systole, as visualized by two-dimensional echocardiography. With the epicardial apex and the aortic-ventricular and mitral-ventricular junctions as anatomic landmarks, we quantitatively analyzed apical long-axis views in 61 normal subjects, 41 patients with anterior myocardial infarction, and nine patients with posterior myocardial infarction. Thoracic impedance registration allowed exclusion of extracardiac motion from the measurements. In normal subjects the epicardial apex moved outwardly only 0.6 +/- 0.3 mm (mean +/- standard error). Examination of 15 hearts fixed in formalin revealed apical myocardial thickness of 1.5 +/- 0.2 mm. These data suggest that the observed inward motion of the endocardial apex (4.1 +/- 0.7 mm) resulted from obliteration of the apical cavity as a result of inward motion of the adjacent walls. Translation of the base was considerable in normal subjects (14.1 +/- 0.4 mm) and decreased in myocardial infarction (9.1 +/- 0.5 mm, p less than 0.0001). Unequal shortening of the adjacent walls in anterior and posterior myocardial infarction caused basal rotation in the opposite direction (-9.1 +/- 0.8 degrees and 9.7 +/- 1.4 degrees, respectively, p less than 0.0001 versus that of normal subjects, -3.4 +/- 0.7 degrees). Long-axis rotation was not clinically significant (less than 1 degree). We conclude that during ventricular contraction the apex serves as a stable point, whereas the base translates toward the apex because of shortening of the adjacent walls. We then propose a model for analyzing regional wall motion from two-dimensional echocardiograms on the basis of these observations.

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The clinical course of a child who developed an adenocarcinoma of the stomach at 11 years of age is described. At 6 years of age, the child was evaluated for abdominal pain, weight loss, and vomiting. She was found to have hemorrhagic, atrophic gastritis, achlorhydria, and panhypogammaglobulinemia. The gastritis improved with corticosteroid therapy, but relapsed each time that the steroid dosage was tapered. The clinical course was marked by severe growth failure, recurrent infections, and intermittent abdominal pain. Radiographic studies done when the patient was 11 years of age demonstrated a large fungating mass on the lesser curvature of the stomach. Endoscopy and biopsies done 1 year previously had not revealed any sign of malignancy. A radical gastrectomy was performed. Microscopic studies revealed multifocal adenocarcinoma of the stomach with no evidence of invasion of the submucosa or local lymph nodes. The patient died of Candida septicemia and pneumonia 6 months after the gastrectomy. There was no evidence of recurrence of the tumor on autopsy. The relationship between common variable immunodeficiency and gastrointestinal disease is described.

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Four cases of plastic bowing of the ribs are presented. In three patients with Werdnig-Hoffman disease, plastic curvatures were associated with chronic pneumonia and atelectasis. We postulate that intrapulmonary retractive forces can deform ribs thinned by muscular atrophy. In turn, thoracic collapse can perpetuate lobar and segmental atelectasis. In one case of osteogenesis imperfecta without pneumonia, we believe normal muscle forces bent ribs weakened by deficiency of normal cortical architecture.

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Seven infants with wheezing and cyanotic spells were diagnosed as having tracheobronchomalacia by bronchoscopy or fluoroscopy. These studies demonstrated narrowing of the central airways by 75% or more on exhalation. Five patients were premature infants who had been ventilated for hyaline membrane disease. The mean time from onset of symptoms to diagnosis was six months. Determination of the optimal positive end-expiratory pressure (PEEP) during fluoroscopy facilitated subsequent management. Six of the seven patients required PEEP of 8 to 18 cm H2O for at least three months, and five of the seven still require mechanical ventilation. All patients improved, with decreased cyanotic spells and a reduced requirement for ventilatory support. Tracheostomy without PEEP did not appear to be helpful. Tracheobronchomalacia may be more frequent than usually appreciated; the treatment of choice appears to be long-term PEEP.

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A retrospective study of 90 cases of ileocolic intussusception seen over a 5-year period was undertaken to identify features of failed hydrostatic reductions. A new, reliable sign of nonreducible intussusception was found: the dissection sign. Of the 90 cases, 23 demonstrated barium dissecting between the intussusceptum and intussuscipiens ; of those, nine had necrotic bowel found at surgery. All of the 23 cases with dissection failed hydrostatic reduction. Of the 23 patients, 22 were below age 2 years. None of those reduced by barium enema had dissection. The dissection sign on barium enema for ileocolic intussusception is an indication to discontinue hydrostatic reduction and to institute surgical treatment, especially in patients under age 2 years.

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A system for the on-line production of anaesthetic records with a microcomputer is described. The requirements of the system are a keyboard, a video display unit and a colour plotter. The system requires no programming expertise from anaesthetists and nurses. The records have improved information display, patient care and reduced time spent in administration effort. Disadvantages are the relatively high cost and requirement of preprocessing of haemodynamic and respiratory parameters.

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