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Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.

Resident evaluations remain controversial. Metric systems are employed to objectify evaluations. Our institution adopted the question "Relative to all other trainees that I have supervised over my career, I place this individual's performance in the following percentile" with the goal of objectifying the evaluations. We report the distribution and the correlation of this value to other evaluation parameters., Design: Retrospective single-institution review of general surgery resident evaluations (2008-2020). Demographic characteristics, level of training and internal evaluation variables were collected. Percentile distribution and association between subjective and objective measures were analyzed., Results: 3117 evaluations (116 residents) were reviewed. 96% had the percentile question answered. Faculty ranked 68% of residents at or above 80th percentile. Faculty subjective evaluation on residents' overall performance and technical skills correlate with resident objective assessment scores in PGY-1 and -2 but not in PGY-3 to PGY-5., Conclusion: Rank failed to produce a bell-shaped curve, remaining right-skewed; indicating grade inflation. The lack of association between variables indicates that both assessments remain useful for residency programs. Work is needed to benchmark evaluations, ensuring proper feedback about performance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Ltd.)

Background: Concurrent resection of the primary cancer and synchronous colorectal cancer liver metastases (CRCLM) was evaluated for differences in outcomes following stratification of both the liver and colorectal resection., Methods: Consecutive cases of synchronous resection of both the CRC primary and CRCLM were reviewed retrospectively at a single, high-volume institution over a 17-year period (2000-2017)., Results: 273 patients underwent simultaneous resection of CRCLM. The distribution of the primary lesion was similar between the colon (52.4%) and rectum (47.6%), while 46.9% of patients had bilobar liver disease. Major liver/major colorectal resection (n = 24) were significantly more likely to experience colorectal specific morbidity (OR 3.98, 95% CI 1.56-10.15, p = 0.004), liver specific morbidity (OR 7.4, 95% CI 2.22-24.71, p = 0.001), total morbidity (OR 2.91, 95% CI 1.18-7.18, p = 0.020) and 90-day mortality (OR 5.50, 95% CI 1.27-23.81, p = 0.023). Failure to receive adjuvant chemotherapy secondary to postoperative morbidity was associated with significantly worsened survival (HR for death 5.91, 95% CI 1.59-22.01, p = 0.008)., Conclusions: Postoperative morbidity precluding the administration of adjuvant chemotherapy is associated with an increase in mortality. Combining a major liver with major colorectal resection is associated with a significant increase in major morbidity and 90-day mortality, and should be avoided., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: How malignant insulinomas present relative to benign insulinomas is unknown., Methods: A single-institution retrospective study identified patients with insulinoma. Malignancy was defined by distant metastases, positive lymph node(s), T stage of 4, direct invasion into surrounding peripancreatic tissue, or presence of lymphovascular invasion. Wilcoxon Rank Sum tests and Kaplan-Meier analysis were used., Results: A total of 311 patients were identified: 51 malignant and 260 benign. Patients with malignant insulinoma presented with higher levels of insulin, proinsulin, and c-peptide. Malignant lesions were larger: 4.2 ± 3.2 vs 1.8 ± 0.8 cm in benign lesions, p < 0.01. Overall survival at 5 years was 66.8% vs 95.4% for malignant and benign insulinoma respectively, p < 0.01., Conclusions: Larger size of insulinoma and increased serum β-cell polypeptide concentrations were associated with malignancy. Malignant insulinoma has poorer survival. Further work-up to rule out malignancy may be indicated for larger pancreatic lesions and for patients with higher pre-operative insulin and pro-insulin., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Benign capsular nevi (BCN) are not infrequent in sentinel lymph nodes (SLN) of patients with melanoma. Their prognostic significance is unknown and the literature is limited. This study evaluated the clinical significance of incidentally found BCN in these patients., Methods: A multi-institutional retrospective review of patients undergoing SLN biopsy for cutaneous melanoma between 2000 and 2016. Patients were divided into the following groups: (a) negative SLN and no BCN, (b) negative SLN and presence of BCN, (c) positive SLN seen only on immunohistochemistry (IHC), and (d) positive SLN via hematoxylin and eosin (H&E). Outcomes measured were overall survival and any recurrence., Results: A total of 1253 patients were identified (group 1 = 978, group 2 = 56, group 3 = 32, and group 4 = 187). Fifty-seven percent were male and the mean age was 59.3 years. BCN was identified in 77 patients (6.2%), of which the majority was in the node-negative group (72%). Multivariable analysis showed that BCN was associated with lower recurrence rates, though not statistically significant (hazard ratio [HR] = 0.5; P = .06). IHC- and H&E-positive SLNs were associated with a higher risk of recurrence (HR = 2.4; P = .02 and 2.0, P < .0001, respectively)., Conclusion: Patients with BCN and negative SLN had lower recurrence rates than patients with negative SLN and no BCN. Our data suggest a possible protective effect against recurrence., (© 2020 Wiley Periodicals LLC.)

Background: Traditional duodenal switch (DS) typically leaves a short common channel and is infrequently performed in part due to increased risk of malnutrition. We compared nutritional deficiencies between DS with a moderate channel length and standard proximal Roux-en-Y gastric bypass (RYGB)., Methods: We conducted a retrospective review of 61 matched pairs who underwent DS or RYGB using our institutional database; patients were matched on sex, age, race, and BMI. DS was performed with a common channel length between 120 and 150 cm. Thirty-day complications, total body weight loss (TBWL) %, and nutritional labs up to 24 months were compared using paired t test and Wilcoxon rank sum tests., Results: Weight loss was similar at each time point (all p > 0.1). DS patients had lower vitamin D levels at 6 months, lower calcium levels at 6 and 12 months, and lower hemoglobin at 12 months and otherwise equivalent (all p < 0.05). Revision was rare (1 DS; 0 RYGB). There were no differences in short-term complications (p = 0.28)., Conclusion: DS with a moderate common channel length is safe with a low revision rate. Weight loss and nutritional outcomes appear to be comparable to RYGB, and it may be considered an effective RYGB alternative.

Objective: Acute lower limb ischemia (ALLI) is a challenging vascular emergency with notable morbidity. Aspiration mechanical thrombectomy (AMT) devices are an alternative approach to remove thrombus in the peripheral arterial system and to restore limb perfusion, but data are limited. We evaluated the outcomes of AMT for the treatment of ALLI at our institution., Methods: We performed a single-center retrospective review of patients with ALLI treated with Indigo (Penumbra Inc, Alameda, Calif) AMT device from 2014 to 2017. The primary outcome was technical success (restoration of blood flow with <50% residual thrombus without need for catheter-directed thrombolysis [CDT] or open surgery) as main treatment or adjunctive treatment (after failure of another modality). Indications, anatomic segments treated, outcomes, and complications were reviewed., Results: There were 41 patients (68% male, 32% female; mean age, 67 years; range, 27-90 years) who underwent 43 procedures. The cause of ALLI was embolism (18), native vessel thrombosis (13), bypass thrombosis (7), intraluminal thrombus due to pseudoaneurysm (1), stent thrombosis (1), intraprocedural embolization (1), recurrent thrombosis of native vessel (1), and chronic thrombosis (1). AMT was the main treatment in 29 cases and adjunctive in 14. Technical success was 52% (15/29) as main treatment and 50% (7/14) as adjunctive treatment. Thrombolysis was avoided in 53% of patients (23/43). There were six thrombotic recurrences, one after successful isolated AMT. The other five required multiple modalities after AMT failure. There were no 30-day deaths. Five patients required amputations, but only one after successful AMT. Complications included intraoperative distal embolization (two), access site hematoma (one), pseudoaneurysm (one), acute kidney injury (one), and spontaneous calf hematoma (one). There were no blood transfusions required or severe bleeding complications., Conclusions: With an overall success rate of 51% in selected patients, the Indigo AMT device avoided the need for CDT or open surgery in about half of patients with ALLI. The device has a favorable safety profile, particularly in high-risk cases. Given its moderate effectiveness, the role of Indigo AMT in the management of ALLI will further be defined by the description of optimal technique, the determination of treatment indications, and a direct comparison with CDT., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The pharmacokinetic characteristics of cefepime were determined after first dose (n = 35) and again under steady-state conditions (n = 31) with a group of 37 infants and children. In eight subjects, a cefepime dose given by intramuscular injection was substituted for an intravenous dose, and disposition characteristics were studied again. Study subjects ranged in age from 2.1 months to 16.4 years, and all had normal renal function. Each patient received 50 mg of cefepime/kg of body weight intravenously every 8 h, up to a total maximum individual dose of 2 g. With the exception of one study patient who received a single cefepime dose for surgical prophylaxis, the patients received cefepime for 2 to 13 days. Elimination half-life (t1/2), steady-state volume of distribution, total body clearance, and renal clearance after first dose administration averaged 1.7 h, 0.35 liter/kg, and 3.1 and 1.9 ml/min/kg, respectively. Although cefepime t1/2 and mean residence time (MRT) were slightly longer for subjects <6 months of age than for older subjects, no differences in cefepime disposition characteristics between first dose and steady-state evaluations were observed. t1/2 (1.8 versus 1.9 h) and MRT (2.3 versus 3.2 h) were slightly prolonged after intramuscular administration, reflecting the influence of absorption from the intramuscular injection site on cefepime elimination. Bioavailability after intramuscular administration averaged 82% (range, 61 to 124%). Fifty-seven percent of the first dose and 88.9% of the last dose were recovered as unchanged drug in urine over the 8- and 24-h sampling periods, respectively. These pharmacokinetic data support a single cefepime dosing strategy for patients > or =2 months of age. The integration of the cefepime pharmacokinetic data generated in our study with the MICs for important pathogens responsible for infections in infants and children supports the administration of a dose of 50 mg of cefepime/kg every 12 h for patients > or =2 months of age to treat infections caused by pathogens for which cefepime MICs are < or =8 mg/liter.

Objective: Define the pharmacokinetics of bumetanide after single intravenous doses in volume-overloaded critically ill infants., Methods: A prospective, open-label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques., Results: Peak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% +/- 15% of the administered dose., Conclusions: Distribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume-overloaded infants aged 0 to 6 months.

Objectives: Account for the interindividual variability in the pharmacokinetics and pharmacodynamics of bumetanide after intravenous administration of single doses to critically ill infants., Methods: This prospective open-label study was carried out in the pediatric intensive care unit of a university-based children's hospital. Fifty-three volume-overloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and those with lung disease (22 infants). Each patient received a single intravenous bolus dose of bumetanide. Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variable to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide. Hierarchical multiple regression analyses were used to assess the effects of age, disease, and other drugs on the variability in the effects of bumetanide., Results: Total clearance, renal clearance, and nonrenal clearance of bumetanide all increased with age (p < 0.05), but the ratio of renal clearance to total clearance remained constant at about 0.4. Half-life and mean residence time decreased markedly in the first month of life (p < 0.05). Bumetanide excretion rate normalized for dose also increased with increasing age. Patients with lung disease exhibited a significantly greater clearance and shorter half-life (p < 0.05) than those with heart disease, whereas volume of distribution was similar in both groups. The primary determinant of bumetanide excretion rate was the administered dose (73%). Dose-response curves for urine flow rate and electrolyte excretion were similar between disease groups. The time course of the effect of bumetanide excretion rate on pharmacodynamics responses was similar between disease groups, as was the duration of the diuretic effect., Conclusions: The pharmacokinetics of bumetanide were influenced significantly by age and disease. Differences in pharmacokinetics between patients with lung and heart disease were primarily due to differences in total clearance. The administered dose of bumetanide and age were positive determinants of bumetanide excretion rate and pharmacodynamic responses. Pharmacodynamic responses as a function of bumetanide excretion rate were not significantly different between disease groups.

Objectives: Determine the diuretic effects of single intravenous doses of bumetanide in volume-overloaded critically ill infants., Methods: A prospective, open-label study was carried out in 56 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single intravenous dose of bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Determinations of urine volume, electrolytes, creatinine levels, and osmolality were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine aliquots collected at time 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Individual changes in urine flow rate and electrolyte excretion were plotted against corresponding bumetanide excretion rates, taken as the effective dose of the drug., Results: Peak bumetanide excretion rates increased linearly with increasing doses of drug. Time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. Urine flow rate and electrolyte excretion increased linearly up to a bumetanide excretion rate of approximately 7 micrograms/kg/hr and either plateaued (urine flow rate) or declined at a bumetanide excretion rate of > 10 micrograms/kg/hr. Diuretic efficiency of bumetanide was maximal at doses of 0.005 to 0.010 mg/kg but decreased at higher doses., Conclusions: Maximal diuretic responses occurred at a bumetanide excretion rate of about 7 micrograms/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a proportionately higher bumetanide excretion rate but no increased diuretic effect. Lower doses of bumetanide had the greatest diuretic efficiency, suggesting that continuous infusion of low doses of bumetanide or intermittent low-dose boluses may produce optimal diuretic responses in critically ill infants.

Objective: To assess the pharmacokinetics and pharmacodynamics of propofol sedation of critically ill, mechanically ventilated infants and children., Design: A prospective clinical study., Setting: A pediatric intensive care unit (ICU) in a university hospital., Patients: Clinically stable, mechanically ventilated pediatric patients were enrolled into our study after residual sedative effects from previous sedative therapy dissipated and the need for continued sedation therapy was defined. Patients were generally enrolled just before extubation., Interventions: A stepwise propofol dose escalation scheme was used to determine the steady-state propofol dose necessary to achieve optimal sedation, as defined by the COMFORT scale, a validated scoring system which reliably and reproducibly quantifies a pediatric patient's level of distress. When in need of continued sedation, study patients received an initial propofol loading dose of 2.5 mg/kg and were immediately started on a continuous propofol infusion of 2.5 mg/kg/hr. The propofol infusion rate was adjusted and repeat loading doses were administered, if needed, using a coordinated dosing scheme to maintain optimal sedation for a 4-hr steady-state period. After 4 hrs of optimal sedation, the propofol infusion was discontinued and simultaneous blood sampling and COMFORT scores were obtained until the patient recovered. Additional blood samples were obtained up to 24 hrs after stopping the infusion and analyzed for propofol concentration by high-performance liquid chromatography., Measurements and Main Results: Twenty-nine patients were enrolled into this study. One patient was withdrawn from this study because of an acute decrease in blood pressure occurring with the first propofol loading dose; 28 patients completed the study. All patients were sedated immediately after the first 2.5-mg/kg propofol loading dose. Eight patients were adequately sedated with the starting propofol dose regimen, whereas five patients required downward dose adjustment and 11 patients required dosage increases to achieve optimal sedation. Four patients failed to achieve adequate sedation after five dose escalations and the drug was stopped. Recovery from sedation (COMFORT score of > or = 27) after stopping the propofol infusion was rapid, averaging 15.5 mins in 23 of 24 evaluable patients. In 13 patients who were extubated after stopping the propofol infusion, the time to extubation was also rapid, averaging 44.5 mins. Determination of the blood propofol concentration at the time of recovery from propofol sedation was possible in 15 patients. The blood propofol concentration was variable, ranging between 0.262 to 2.638 mg/L but < or = 1 mg/L in 13 of 15 patients. Similarly, tremendous variation was observed in propofol pharmacokinetics. Propofol disposition was best characterized by a three-compartment model with initial rapid distribution into a small central compartment, V1, and two larger compartments, V2 and V3, which are two-and 20-fold greater in volume, respectively, than V1. Redistribution from V2 and V3 into V1 was much slower than ingress, underscoring the importance of the propofol concentration in V1 as reflective of the drug's sedative effect. Propofol was well tolerated. Two patients experienced an acute decrease in blood pressure which resolved without treatment., Conclusions: We conclude that a descending propofol dosing strategy, which maintains the propofol concentration constant in the central compartment (V1) while drug accumulates in V2 and V3 to intercompartmental steady-state, is necessary for effective propofol sedation in the pediatric ICU. Our proposed dosing scheme to achieve and maintain the blood propofol concentration of 1 mg/L would appear effective for sedation of most clinically stable, mechanically ventilated pediatric patients.

This study investigated maternal psychological distress, perceptions of social supports, and parenting strains after the birth of a very low birthweight (VLBW) infant. Compared to mothers of term infants, mothers of VLBW infants had significantly higher incidence of psychological distress during the neonatal period, but did not differ from mothers of term infants in their feelings of role restriction, parenting competence, or social supports. Lower general social support predicted high distress levels, but only for mothers of VLBW infants. Mothers with a low sense of parenting competence, but support from spouse/partners reported lower maternal distress.

We report on the construction of neural networks for determining whether pediatric patients requiring transport to a tertiary care center should be moved by air or by ground. The networks were based on the functional-link net architecture. In two experiments, feedforward supervised-learning neural nets were trained with examples of an expert's decisions and then were used in a consulting mode to provide advice on cases not previously encountered. Training and validation were performed by a combination of the k-fold cross-validation and leaving-one-out sampling methods. Use of the functional-link net rather than the customary backpropagation net enabled us to carry out the training with fairly large amounts of data in realistically short time periods. In the first experiment, capillary refill, skin color, and stridor were consistently the input variables that were most strongly associated with the decision output. In both experiments, the networks were validated by comparing their performance retrospectively against the determination of an expert pediatric transport physician. The network was trained based on the expert's opinion about the correct mode of transport for each case with error rates of less than 10(-5).

The pharmacokinetic characteristics of ticarcillin and clavulanic acid were determined after the first dose (n = 22) and again under steady-state conditions (n = 16) in a group of infants and children. Study subjects ranged in age from 1 month to 9.3 years; all but 3 study patients were 6 months of age or older. Each patient received 50 mg of ticarcillin and 1.7 mg of clavulanic acid (30:1 ratio) per kg of body weight given intravenously every 4 hours. Elimination half-life, steady-state volume of distribution, and body clearance averaged 1.1 hours, 0.22 L/kg, and 2.7 mL/min/kg, respectively, for ticarcillin, and 0.9 hours, 0.4 L/kg, and 6.2 mL/min/kg, respectively, for clavulanic acid. A total of 71% of the ticarcillin and 50% of the clavulanic acid dose were excreted unchanged in the urine over the 4-hour sampling period. Corresponding renal clearances averaged 2.1 and 3.2 mL/min/kg for ticarcillin and clavulanic acid, respectively. No differences were observed between first dose and steady-state evaluations in the pharmacokinetic behavior of either agent. In contrast, the pharmacokinetic behavior of clavulanic acid was significantly different from that observed for ticarcillin. These pharmacokinetic data combined with known in vitro susceptibilities of important clinical pathogens support a dose of 80 mg of ticarcillin and 2.7 mg/kg clavulanic acid per kg body weight given as a fixed dose combination every 8 hours for the treatment of most systemic infections that occur outside the central nervous system.

We developed a research database for a five-year prospective investigation of the medical, social, and developmental correlates of chronic lung disease during the first three years of life. We used the Ingres database management system and the Statit statistical software package. The database includes records containing 1300 variables each, the results of 35 psychological tests, each repeated five times (providing longitudinal data on the child, the parents, and behavioral interactions), both raw and calculated variables, and both missing and deferred values. The four-layer menu-driven user interface incorporates automatic activation of complex functions to handle data verification, missing and deferred values, static and dynamic backup, determination of calculated values, display of database status, reports, bulk data extraction, and statistical analysis.

Neural networks offer a powerful new approach to information processing through their ability to generalize from a specific training data set. The success of this approach has raised interesting new possibilities of incorporating statistical methodology in order to enhance their predictive ability. This paper reports on two complementary methods of prediction. one using neural networks and the other using traditional statistical methods. The two methods are compared on the basis of their prediction applied to standardized developmental infant outcome measures using preselected infant and maternal variables measured at birth. Three neural network algorithms were employed. In our study, no one network outperformed the other two consistently. The neural networks provided significantly better results than the regression model in terms of variation and prediction of extreme outcomes. Finally we demonstrated that selection of relevant input variables through statistical means can produce a reduced network structure with no loss in predictive ability.

The pharmacokinetics of piperacillin and tazobactam were assessed after single-dose administration to 47 infants and children. Study subjects ranging in age from 2 months to 12 years were randomized to receive one of two different doses of a piperacillin-tazobactam combination (8:1): a low dose (n = 23) of 50 and 6.25 mg of piperacillin and tazobactam per kg of body weight, respectively, or a high dose (n = 24) of 100 and 12.5 mg, respectively. The pharmacokinetic behavior of tazobactam was very similar to that observed for piperacillin, supporting the use of these two agents in a fixed-dose combination. No differences in the pharmacokinetics of piperacillin or tazobactam were observed between the two doses administered. The elimination parameters half-life and total body clearance decreased and increased, respectively, with increasing age, whereas volume parameters (volume of distribution and steady-state volume of distribution) remained relatively constant for both compounds. The primary metabolite of tazobactam, metabolite M1, was measurable in the plasma of 18 of the 47 study subjects; 17 of these 18 subjects received the high doses. More than 70% of the administered piperacillin and tazobactam doses were excreted unchanged in the urine over a 6-h collection period. These data combined with the known in vitro susceptibilities of a broad range of pediatric bacterial pathogens indicate that a dose of 100 mg of piperacillin and 12.5 of mg tazobactam per kg of body weight administered as a fixed-dose combination every 6 to 8 h would be appropriate to initiate clinical efficacy studies in infants and children for the treatment of systemic infections arising outside of the central nervous system.

This study sought to determine whether very low birth weight (VLBW) infants (< 1500 gm) with fetal cocaine exposure differed from non-cocaine-exposed VLBW infants in incidence of neonatal medical complications and in later developmental outcome. Forty-one cocaine-exposed, VLBW infants, followed in a longitudinal study, were compared with 41 non-cocaine-exposed, VLBW infants of comparable race, social class, age, and incidence of bronchopulmonary dysplasia. Cocaine-exposed infants were identified on the basis of combined findings of maternal and/or infant urine immunoassay and on the basis of maternal self-report. At birth, groups did not differ on medical risk factors except that cocaine-exposed infants had a higher incidence of mild (grades I to II) intraventricular hemorrhage. Cocaine-using women were also more likely to use other drugs, especially alcohol, marijuana, and tobacco. At follow-up, at mean corrected ages of 16.5 +/- 8 months for 30 cocaine-exposed infants and 18.5 +/- 7 months for 37 non-cocaine-exposed infants, standardized assessments of cognitive (Mental Development Index) and motor (Psychomotor Development Index) development were administered. Cocaine-exposed infants had lower mean cognitive (83 +/- 27 vs 91 +/- 19), and motor (85 +/- 25 vs 96 +/- 18) scores; the incidence of developmental delay was significantly higher even after control for the effects of intraventricular hemorrhage and chronologic age. Cocaine-exposed VLBW infants were also more likely to be living with relatives or in foster homes. We conclude that these VLBW, cocaine-exposed infants were at increased risk of intraventricular hemorrhage, were more likely to be placed outside maternal care, and had higher incidences of cognitive and motor delays at follow-up.

Objective: To derive a target range of optimal sedation for the COMFORT Scale and to prospectively test that target range against intensivist assessment of adequacy of sedation., Design: Serial prospective agreement cohort studies., Setting: Twelve-bed pediatric intensive care unit in an urban academic teaching hospital., Patients: Eighty-five mechanically ventilated children (aged 0 to 102 months)., Interventions: Three serial prospective studies comparing simultaneous, independent ratings conducted by trained observers using an objective scale and intensive care physicians using global assessment. The initial study was designed to derive the target range. The second study was conducted to verify that target range in a second population. The third study was added to evaluate relative variability in methods used in the second study., Measurements and Main Results: Adequacy of sedation using visual analog scale and descriptive ratings or the COMFORT Scale (a previously validated behaviorally anchored scale to rate eight behavioral or physiologic dimensions of distress). The first study comprised 100 observations. Groups of patients described by the intensivist as inadequately sedated, optimally sedated, and excessively sedated had different mean COMFORT scores (30.5 +/- 0.7 vs. 22.9 +/- 5.8 vs. 14.3 +/- 0.7, respectively, p < .05). The target range of optimal sedation was defined as COMFORT scores of 17 to 26. The second study verified the target range prospectively in a second group of 96 observations. The COMFORT score was strongly associated with the sedation adequacy rating by the intensivist (p < .001; r2 = .662). COMFORT scores accurately predicted the patient assignment to adequacy of sedation categories by the intensivist in 66.1% of observations. Discrepancy between physicians occurred in 38.5% of 16 paired physician ratings in the second study. In the third study, 120 observations comparing paired COMFORT scores to paired physician ratings of the same subjects demonstrated significantly less variability in COMFORT assessment of adequacy of sedation. COMFORT scores were similarly unbiased (1.1% vs. 0.22%) but more precise (8.0% vs. 16.7%) than intensivist ratings (p < .025)., Conclusion: Adequacy of sedation is measured more consistently by observers using the COMFORT Scale than by intensivist global assessment.

The present investigation addresses two primary hypotheses: (a) that a subset of children with developmental language disorders exhibits significantly more disfluencies than other children with language disorders and (b) that differences between the disfluent and nondisfluent groups observed in fluency may be related to differences in language deficits. Spontaneous language samples from 60 preschool children with developmental language disorders were analyzed for frequency and type of disfluencies. Comparisons of the frequency of disfluencies across subjects revealed that a subset of 10 subjects exhibited significantly more disfluencies than the other subjects with language disorders. Demographic, intelligence, and language variables were compared across the two groups to determine whether such factors could account for the differences in fluency. The subjects with greater percentages of disfluencies were found to be significantly older and demonstrated significantly higher scores on two standard measures of vocabulary. These findings were interpreted in light of two models of disfluencies: the neuropsycholinguistic (Perkins, Kent, & Curlee, 1991) and Demands and Capacities (Adams, 1990; Starkweather, 1987). This suggests that some children with language disorders are at risk for fluency breakdown because of dysynchronies in the development of lexical and syntactic aspects of language or as a result of mismathces between speaking demands and capacities.

Recurrent episodes of hypoxemia may affect the growth, cardiac function, neurologic outcome, and survival of infants with bronchopulmonary dysplasia (BPD). As oral feeding might stress these infants by compromising pulmonary function even after hospital discharge, we measured oxygen saturation (SaO2) via pulse oximetry before, during the initial 10 minutes of, and immediately after oral feeding in 11 patients with BPD, 12 very low birth weight infants, and 23 healthy full-term infants. All infants with BPD had been previously discharged from the hospital after weaning from supplemental oxygen. Studies were done at a mean postconceptional age of 43 weeks while the infants were fed at home by one of their parents. Levels of SaO2 for the three groups were comparable before and during feeds. After feeding, the infants with BPD had significantly lower mean levels of SaO2 (84 +/- 8% [SD] vs 93 +/- 4% and 93 +/- 3%, respectively; P less than .01). They also spent more time after feeding with an SaO2 less than 90% (64 +/- 34% of time vs 27 +/- 33% for the very low birth weight and 22 +/- 20% for the term group; P less than .01) and greater time with an SaO2 less than 80% (37 +/- 28% vs 4 +/- 10% and 4 +/- 8%, respectively; P less than .01). Desaturation in infants with BPD was related to larger volume and faster oral intake during feeding. Thus, the data indicate that desaturation after feeding remains a recurrent problem for survivors of BPD after discharge.(ABSTRACT TRUNCATED AT 250 WORDS)

Children and adolescents with unilateral left- or right-hemisphere lesions were administered a standardized test of mathematics ability and a battery of experimental tests that examined the components of numerical and arithmetic processing. All lesioned groups showed at least marginally lower scores on the standardized test than the controls. More importantly, lesion-related deficits in performance were observed, especially for younger left-lesioned subjects (ages 7-12), on the verbal counting, digit matching, speeded addition, and written subtraction tasks; deficits among younger right-lesioned subjects were similar in nature, yet less pronounced than in the left-hemisphere group. Older left-lesioned subjects showed differences from their controls only on complex verbal counting and speeded addition. Correlations among the various measures indicated two further points. First, earlier onset of left-hemisphere lesion is associated with more serious disruption of mathematical processing. Second, these disruptions are not well assessed by a typical standardized test of mathematical performance, but are clearly in evidence with more precise, focused tasks.

The single-dose pharmacokinetics of ceftizoxime sodium were studied in 52 neonates and infants between 0.1 and 189 days of age. Subjects received ceftizoxime 25 or 50 mg/kg iv over 15-30 minutes. The drug was administered q8-12h for five days to permit tolerance evaluation on repetitive dosing. No differences were observed in ceftizoxime pharmacokinetic parameter estimates relative to dose. However, marked differences were observed in ceftizoxime pharmacokinetic characteristics relative to infant age; ceftizoxime half-life and mean residence time decreased, whereas body clearance increased with infant age. Ceftizoxime volume of distribution remained relatively constant over infant age. No adverse effects associated with ceftizoxime administration were observed. These data suggest that ceftizoxime 50 mg/kg q12h be used for infants less than or equal to 2 weeks of age (less than or equal to 40 weeks postconceptional age) and that 50 mg/kg q8h be administered for older infants.

The first-dose and multidose pharmacokinetics of imipenem and cilastatin were evaluated in 41 premature infants during their first week of life. Premature infants (gestational age, less than or equal to 37 weeks) were assigned to receive 10-, 15-, 20-, or 25-mg/kg doses of imipenem-cilastatin (1:1) as a single- or multiple-dose regimen. A total of 39 infants received a single dose, whereas 18 infants received multiple doses. No differences were observed in pharmacokinetic parameter estimates for either agent relative to the dose administered or infant body weight; thus, the data were pooled. Elimination half-life, steady-state volume of distribution, and body clearance averaged 2.5 h, 0.5 liter/kg, and 2.5 ml/min per kg, respectively, for imipenem and 9.1 h, 0.4 liter/kg, and 0.5 ml/min per kg, respectively, for cilastatin. Similar values for these parameter estimates were observed after multidose administration, although substantial accumulation of cilastatin in serum was observed. A total of 21% of the imipenem and 43% of the cilastatin were excreted unchanged in the urine over a 12-h collection period. Corresponding renal clearances averaged 0.4 and 0.2 ml/min per kg for imipenem and cilastatin, respectively. Substantial differences were observed in the route by which imipenem was cleared from the body compared with data from adult volunteers. These data suggest that infants should receive an imipenem dose of 20 mg/kg administered every 12 h for the treatment of bacterial infections outside the central nervous system.

The efficacy and pharmacokinetics of piperacillin monotherapy were studied in 46 patients with cystic fibrosis. Two patients were dropped from the study within 24 hr of enrollment because of drug-associated nausea and vomiting. Initially fourteen older patients (greater than 12 years) receiving piperacillin 450 mg/kg/day underwent a preliminary evaluation. Based on the results, 30 younger patients (less than or equal to 12 years) randomized in a double-blind fashion received either 600 or 900 mg/kg/day of piperacillin in six divided doses. Pharmacokinetic parameter estimates for t1/2 Vdss, and Cl were similar for first dose and steady-state evaluations. In 27 patients, approximately 43% of the administered dose was recovered in the urine after 4 hr. Piperacillin CiR averaged 49% of the total Cl. No difference in overall clinical efficacy could be identified between 600 and 900 mg/kg/day of piperacillin using two different objective scoring systems. Although a reduction in sputum Pseudomonas colony counts was greater following the 900 mg/kg/day regimen, this appeared to be independent of clinical effect. In 14 patients (32%), a distinct adverse serum-sicknesslike reaction was observed. The incidence of this reaction appeared to increase as the dose of piperacillin increased. All signs and symptoms of this reaction resolved within 36 hr of discontinuing piperacillin administration but recurred immediately on rechallenge in four patients. All patients with the adverse reaction were subsequently treated with beta-lactam antibodies without ill effect. Overall, clinical improvement appeared to be independent of the piperacillin dose. Our data support the use of total daily piperacillin dosages not exceeding 600 mg/kg.

The first-dose and steady-state pharmacokinetics of trimethoprim and sulfamethoxazole were determined in 14 patients with cystic fibrosis. When pharmacokinetic data from the first dose were compared with those at steady state, both TMP and SMZ showed expected accumulations in serum concentrations and decreases in total body clearance. The area under the SMZ serum concentration-time curve was significantly greater at steady state, suggesting drug accumulation during long-term therapy. When pharmacokinetic characteristics for TMP and SMZ obtained in patients with cystic fibrosis were compared with those reported for normal adults, the patients were found to have shorter elimination half-lives and greater plasma clearances. In addition, the apparent volume of distribution for TMP was smaller for patients with cystic fibrosis than for normal adults, consistent with their reduced mass of adipose tissue. Our data support the need for increased dosing or decreased dosing intervals when administering TMP-SMZ to patients with cystic fibrosis.

The purine analogue O6-methylguanine is an effective biochemical modulator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase. Inactivation of the alkyltransferase by O6-methylguanine sensitizes tumor cells to nitrosoureas in vitro. The pharmacokinetics of O6-methylguanine were evaluated in female Sprague-Dawley rats following administration of a single 40 mg/kg i.v. bolus dose. Two-compartment pharmacokinetic analysis revealed a terminal elimination half-life of 2.3 +/- 0.68 h, a total body clearance of 6.0 +/- 0.53 ml/min/kg, and a volume of distribution at steady state of 948 +/- 186 ml/kg. To inactivate the alkyltransferase, 80 mg/kg O6-methylguanine was given at 0 and 2 h. Alkyltransferase decreased in bone marrow, kidney, lung, spleen, and intestine by 20-90%. Regeneration of alkyltransferase activity was observed 22-70 h after the first bolus dose of O6-methylguanine. A continuous infusion protocol, which achieved a steady state serum concentration of 10.3 +/- 1.5 micrograms O6-methylguanine/ml at 15 h, resulted in a similar degree of inactivation of tissue alkyltransferase to that observed following bolus drug infusion. O6-Methylguanine tissue concentrations, including that determined in brain, were 1.7- to 4-fold higher than that in serum, indicating that O6-methylguanine is concentrated in most if not all tissues. These studies establish pharmacokinetic parameters of O6-methylguanine in rats and suggest that effective biochemical modulation of alkyltransferase can be achieved in vivo. Further studies are indicated to assess the extent to which biochemical modulation of alkyltransferase reduces tumor nitrosourea resistance in vivo.

The single-dose pharmacokinetics of oral ciprofloxacin 750 mg were evaluated in six subjects with cystic fibrosis (CF subjects) and six age, sex and approximate weight-matched control subjects (controls). In addition, the effect of concurrently administered oral pancreatic enzyme replacement on the pharmacokinetics of ciprofloxacin was studied in 12 CF subjects. Ciprofloxacin t1/2, VSSF, CLF, and CLR in the matched CF subjects averaged 4.5 hours, 2.8 L/kg, 2.73 mL/min/kg and 5.7 mL/min/kg, respectively. Forty-two percent of the ciprofloxacin dose was excreted in the urine (0-48 hours) as the parent compound. No statistically significant differences in these ciprofloxacin pharmacokinetic parameter estimates were observed between CF and control subjects. In three CF subjects and two controls, the urinary excretion of ciprofloxacin and four of its metabolities were similar. In contrast, CF subjects demonstrated a prolonged tmax (2.3 versus 1.3 hours P less than .05) though ciprofloxacin Cmax was similar (4.7 versus 3.8 mg/L, NS). The concurrent administration of oral pancreatic enzyme replacement had no effect on the pharmacokinetics of ciprofloxacin. Apparent ciprofloxacin pharmacokinetic parameters in sputum were similar to those observed in serum. Sputum ciprofloxacin concentrations lagged behind serum concentrations but, on average, exceeded serum concentrations for 20 hours of the 24-hour sampling period. These sputum ciprofloxacin concentrations exceeded the reported MIC90 for Pseudomonas aeruginosa for approximately 15 hours. These data suggest an oral ciprofloxacin dose of 750 mg administered q8h to promote accumulation and maintenance of sputum drug concentrations well above pathogen MICs for the majority of a dosing interval in patients with CF.

Cephalosporins modified at the C-3 and C-7 positions of the cephem-nucleus have high antimicrobial activity and are safe. With evolution through first, second, and third generations, they have gained increasing gram-negative activity, but often at the expense of potency against gram-positive organisms. All third-generation cephalosporins have some intrinsic anti-Pseudomonas activity, indicating their potential benefit in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Rational therapy in this clinical setting requires recognition of the pharmacodynamic and pharmacokinetic idiosyncrasies intrinsic to this patient population. When these priorities are recognized, only two of the available agents, cefsulodin and ceftazidime, appear to be of any therapeutic value. Both agents have been evaluated extensively in the treatment of acute pulmonary exacerbation in cystic fibrosis, and both have been found to be safe and effective.

We determined lymphocyte aryl hydrocarbon hydroxylase (AHH) inducibility for members of 13 families with one or more children with acute lymphoblastic leukemia (ALL) and 12 control families. Pedigree analysis suggested that aromatic hydrocarbon responsiveness (i.e. inducibility) is a codominant trait. Heterozygotes were found to be moderately responsive with IR values intermediate between homozygous minimally responsive and homozygous highly responsive individuals. Homozygous recessive and heterozygous genotypes accounted for 54% and 36% of ALL children respectively. The risk of ALL among minimally aromatic hydrocarbon responsive children was twice that of highly responsive children.

An investigation was undertaken to determine if susceptibility and/or immune response to Mycobacterium tuberculosis was associated with histocompatible leukocyte antigen (HLA) phenotype frequencies of class I or II antigens. Comparisons of the HLA phenotypes of 51 Mexican-American patients with tuberculosis and 54 healthy subjects who differed in their skin-test reactivity to purified protein derivative (PPD) revealed that HLA-DR3 was significantly decreased in patients with tuberculosis, compared with healthy persons who were tuberculin skin-test positive. Although no association was observed between HLA phenotype and skin test reactivity to PPD in tuberculous patients, we did observe an increase in the HLA-A9-B40 phenotype in patients who manifested a strong in vitro proliferative response to PPD, whereas the HLA-B14-DR1 phenotype was increased in patients who exhibited a low proliferative response to this antigen.

This paper develops a micro probabilistic model to describe the family extension process. The parameters are: the probability that a newborn is a boy (P), the number of desired boys (B), the number of desired girls (G), and the maximum possible number of children (N). This maximum is a stopping rule rather than a biological maximum. The variables are the ultimate number of boys and girls. According to this model, each couple determines B, G, and N, at the beginning of the reproductive period and continues to reproduce until at least B and at least G are achieved, or until the total number of children reaches N. The probability distribution of the ultimate number of boys and girls in the population is derived for this model. Simulation techniques are used to generate offspring. The results showed that the population size increases with the absolute differences, [B-G] for fixed N. They also suggested that son or daughter preference may be an important factor in fertility determinants, which may have important implications in population policies.

The single-dose pharmacokinetics of aztreonam was evaluated in 10 clinically stable subjects with cystic fibrosis. Each child received 30 mg aztreonam/kg intravenously over 2 to 3 minutes. Multiple timed blood samples were obtained over 8 hours for determination of aztreonam elimination kinetics; all urine excreted for 24 hours was collected in timed aliquots for the determination of aztreonam and its microbiologically inactive metabolite, SQ 26,992. Aztreonam pharmacokinetic parameters were determined by model-independent methods. Mean t1/2, steady-state volume distribution, and body clearance were 1.3 hr, 0.25 L/kg, and 127.2 ml/min/1.73m2, respectively. In 9 of the 10 subjects, two-compartment pharmacokinetic analysis was possible and compared favorably with model-independent parameter estimates. Twenty-four-hour urinary recovery of aztreonam was 76.3% of the administered dose; 2.6% was recovered as the metabolite SQ 26,992. The renal clearance of aztreonam averaged 92.5 ml/min/1.73m2. When these data are combined with in vitro susceptibility data for aztreonam against Pseudomonas aeruginosa isolated from the sputum of patients with cystic fibrosis, a dose of 200 mg aztreonam/kg/day divided six hourly would be predicted to maintain serum concentrations above the minimum inhibitory concentration (MIC) for these organisms for the majority of the dosing interval.

We examined the inheritance of susceptibility to RA in families with multiple cases of RA, and studied existence of any linkage between the putative RA disease susceptibility locus and the HLA-DR locus. A pedigree analysis programme, PAP, was used for both analyses. Our investigation suggests that familial RA is the effect, in part, of an inherited autosomal dominant susceptibility gene with incomplete penetrance rather than that of a recessive gene. Linkage analysis indicates a tight linkage between the putative RA disease susceptibility locus and the HLA-DR locus under an autosomal dominant mode of inheritance.

The accurate determination of area under the biologic fluid concentration-time curve (AUC) and area under the first moment curve (AUMC) are important in the calculation of a compound's pharmacokinetic parameter estimates. Although numerous mathematical methods exist for the calculation of both AUC and AUMC under varying conditions, some permit direct computation of areas, whereas others only approximate the true areas. In this study, we describe an alternative mathematical method which allows the direct calculation of either the AUC or AUMC after any dose of drug administered by any route. Simulated data with known areas were used to assess the accuracy of the proposed method and compared to area calculations obtained from widely used published methods. Experiments were also performed under conditions of varying elimination half-lives and reduced numbers of concentration-time values. Under any experimental condition, the newly proposed method was the most accurate in determining both the AUC and AUMC. Percent deviations from exact area values were less than or equal to 0.11% with the proposed method, whereas as much as 30% deviation was observed using other methods of calculation. These findings support the accuracy of the proposed method in calculating the AUC or AUMC and its utility in data analysis.

The in vitro activity of ceftazidime against Pseudomonas aeruginosa and P. cepacia isolates from patients with cystic fibrosis was compared with that of other antipseudomonal drugs. Ceftazidime was as potent as imipenem against P. aeruginosa and the only drug effective against P. cepacia. An evaluation of the elimination kinetics of ceftazidime in 20 cystic fibrosis patients revealed an elimination half-life of 1.76 hours, an apparent distribution volume of 0.27 liters/kg, and a serum clearance rate of 133.9 ml/minute/1.73m2. Urinary recovery of ceftazidime was 87 percent within the first 24 hours after administration of the drug, with 65 percent recovered in the first two-hour fraction. Probenecid administration had no effect on the elimination kinetics of ceftazidime. Forty-three patients who had either shown no response to conventional therapy or had sputum Pseudomonas isolates that were susceptible only to ceftazidime received 75 courses of therapy. In 67 percent of these patients, the clinical response, when evaluated using an objective clinical efficacy scoring system, was considered favorable. Clinical failures were not associated with the development of drug resistance. Thus, ceftazidime can be recommended for the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

We have studied HLA-A, B, C, and DR antigens in 75 unrelated white families, each with multiple cases of adult-onset definite or classical rheumatoid arthritis (RA) (by ARA criteria). There was no difference in age of onset or serological features of RA between males and females. HLA-DR4 phenotype frequency among female (68%) and male (71%) patients also did not differ significantly. The observed frequencies of HLA-DR4 genotypes (homozygous, heterozygous, and those lacking it) differed significantly (p less than 0.005) between affected and unaffected individuals. However, the observed genotype distribution did not differ from what is expected given the Hardy-Weinburg equilibrium. There is a direct correlation between the number of DR4 allele(s) carried (two, one, or zero) and the percent affected (p less than 0.026 for females and p less than 0.052 for males). These findings highlight the importance of discerning the additional genetic determinants, including those that are gender-associated, which influence susceptibility to RA.

Hemostatic changes and hyperestrogenemia have been reported in men during myocardial ischemia and acute myocardial infarction. Because marked augmentation of Hageman factor (factor XII) titer is induced by estrogen intake in humans, we studied the factors participating in the surface-mediated reactions of clotting in patients with documented acute myocardial infarction. We report lower coagulant titers of Hageman factor, prekallikrein, high molecular weight kininogen, and plasma thromboplastin antecedent (factor XI) in the plasma samples of patients with acute myocardial infarction than in control samples. Further, the plasma estradiol titers of patients with acute myocardial infarction were not significantly different from those of controls. In contrast, the prolactin concentration of patients with acute myocardial infarction was elevated. These data suggest that other nonhormonal factors such as excessive consumption may influence the observed reduction in the titers of surface-mediated clotting factors in acute myocardial infarction.

Twenty children ranging in age from 1 week to 19 years with documented or suspected bacterial infections arising outside the central nervous system were studied. Pharmacokinetic analysis was possible in 15 children; 8 after the first dose, 6 during steady-state conditions, and 4 on both occasions. Data were obtained utilizing noncompartmental pharmacokinetic methods. Peak piperacillin serum concentrations ranged from 51 to 232 mg/l and correlated directly (r = 0.75) with the dose administered. In children with normal renal function, there was an age-dependent decrease in elimination half-life and apparent steady-state volume of distribution, whereas plasma clearance increased logarithmically. All but 1 child responded favorably to piperacillin therapy, and 1 child with a urinary tract infection relapsed 10 days after discontinuation of the therapy. Although improved clinically, piperacillin monotherapy failed to eradicate pathogens in 2 children. No adverse clinical or biochemical effects were observed in any child.

A pilot community-based screening program for gestational diabetes has been in operation in Cleveland, Ohio, since April 1, 1977. A socioeconomic and racially heterogeneous group of pregnant women are being routinely tested at approximately 24-28 wk of gestation by a capillary whole blood glucose determination, 2-h after a 75-g oral challenge. The results of the first 2225 screenings are analyzed in terms of the variables of maternal race, age, and stage of gestation. The overall incidence of positive screenings (greater than or equal to 120 mg/dl) is shown to be 11.5%, with significantly more positive tests among the whites than the nonwhites. Follow-up oral glucose tolerance testing results in an overall detection rate for abnormal carbohydrate metabolism of 3.1%. The data suggest that a 2-h screening procedure is more efficient than a 1-h procedure in that fewer confirmatory glucose tolerance tests need to be performed in order to yield this rate of detection. It may soon be feasible to introduce such a program on a wider community basis in concert with regionalized perinatal care.

Hyperestrogenemia has been implicated in the pathophysiology of myocardial infarction. Because marked augmentation of the titer of Hageman factor is brought about by the administration of estrogens in humans and by prolactin or estrogen infusion in hypophysectomized rats, we measured the plasma concentrations of estradiol, prolactin, and clotting factors participating in surface-mediated reactions of coagulation in survivors of myocardial infarction. We observed higher titers of Hageman factor, prolactin, and high molecular weight kininogen but no significant change in estradiol or prekallikrein in survivors of myocardial infarction compared with controls. The titer of Hageman factor tended to be directly associated with the prolactin titer. We also report an increase in factor VII activity and spontaneous shortening of prothrombin time in the cold-stored plasma of survivors of myocardial infarction. In such individuals as well as in the control group, the titer of Hageman factor appeared to be responsible for half of the observed increase in factor VII activity and two thirds of the observed shortening of prothrombin time. These data indicate that although the titer of Hageman factor strongly influences the cold activation of factor VII, other factors may affect these phenomena.

Ciprofloxacin has potent in vitro activity against Pseudomonas aeruginosa and Pseudomonas cepacia strains isolated from cystic fibrosis patients. Our previous single-dose pharmacokinetic and pharmacodynamic studies identified important differences between cystic fibrosis patients and age- and sex-matched controls. Based on these data, 30 acutely ill cystic fibrosis patients (aged 18 to 44 years) received 750 mg of ciprofloxacin orally every eight hours for 21 days. Multiple timed serum, urine, and sputum samples for pharmacokinetic analysis were obtained on Days 3, 12, 14, and 21 of the study. Estimates of steady-state pharmacokinetic parameters averaged (+/- SD): t1/2 beta, 3.8 (1) hours; Vd/F, 4.4 (2) liters/kg; Cl/F, 772.9 (301) ml/minute/1.73 m2; Fe, 46 percent; peak, 5.4 (2) mg/liter; and trough, 1.8 (0.8) mg/liter. Serum ciprofloxacin concentrations and pharmacokinetic estimates remained unchanged throughout the study. Sputum ciprofloxacin concentrations exceeded those observed in serum. Sputum cultures revealed 43 P. aeruginosa (MIC90 = 2 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml) strains. Sputum ciprofloxacin concentrations exceeded the MIC90 for P. aeruginosa approximately fivefold, yet only eight isolates were fully suppressed. Posttreatment sputum cultures revealed 35 P. aeruginosa (MIC90 = 16 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml). All patients showed clinical improvement based upon the results of pulmonary function tests and an acute clinical efficacy score (median pre 49/post 60). No patients experienced drug-related toxicity. Ciprofloxacin monotherapy is effective for the acute treatment of cystic fibrosis patients. The development of pathogen resistance during oral therapy may limit its utility in ambulatory patients.

Conventional relational database management systems fail to address three features of statistical data management in a biomedical/clinical database, namely, that (1) statistical and medical data (SMD) require a great deal of space and need to be stored in a reduced form with minimal duplication; indeed, SMD have many derived/calculated and summary statistics that make the number of attributes in a relation (i.e., a set of records) grow rapidly and dynamically; (2) most SMD have hierarchical structures that are difficult to manage using the relational data model since SMD are stored in separate relations for duplication and space considerations; and (3) the management of SMD is made easier if it is possible to reorganize relations or group data, a capability lacking in conventional relational database management systems. In this paper, we (1) introduce five extended relational operators, (lattice) NEST, (lattice) UNNEST, MERGE, SPREAD, and GEN, to reorganize relations; (2) integrate the extended operators with conventional relational algebra and introduce the concept of the lattice relational model; and (3) give applications of the extended relational operators and the lattice relational model in solving the problems of statistical data manipulation in medical databases.

The pharmacokinetics and pharmacodynamics of ranitidine were evaluated during three methods of administration in 12 children ranging in age from 3.5 to 16 years with documented gastric or duodenal ulcer disease. First, a continuous intravenous infusion of ranitidine was administered to determine the serum concentration necessary to suppress gastric acid secretion by at least 90%. From these data a therapeutic dose of ranitidine was calculated and administered on separate days via the intravenous bolus and oral routes. Half-life, volume of distribution, and clearance values for ranitidine were the same after intravenous bolus and oral doses (1.8 vs 2.0 hours, 2.3 vs 2.5 L/kg, and 794.7 vs 788.0 ml/min/1.73 m2, respectively). The bioavailability of ranitidine given orally averaged 48%. Serum ranitidine concentrations necessary to inhibit gastric acid secretion by at least 90% ranged between 40 and 60 ng/ml for all children studied. No adverse clinical or biochemical effects were observed in any child during the 6 weeks of orally administered treatment. Endoscopic reevaluation after 6 weeks indicated complete healing of initial ulcers.

The effect of exocrine pancreatic function on the pharmacokinetics of the choramphenicol oral capsule (CAP-base), chloramphenicol palmitate oral liquid (CAP-P), and chloramphenicol succinate intravenous (CAP-S) formulations was evaluated in 10 patients, aged 16-30 yr, with cystic fibrosis. Pancreatic insufficiency was assessed in each patient by measuring the absorption of p-amino-benzoic acid after oral administration of N-benzoyl-L-tyrosyl-p-aminobenzoic acid which requires chymotrypsin to cleave p-aminobenzoic from the parent molecule. In a controlled cross-over design, the overall biodisposition of each formulation was assessed in each patient with or without concurrent administration of oral pancreatic enzymes. The relative amounts of active chloramphenicol available in systemic circulation was CAP-base greater than CAP-S greater than CAP-P. Pancreatic enzyme replacement had little effect on the biodisposition parameters for the CAP-base and CAP-S formulation, but significantly increased the peak concentration and bioavailability of the CAP-P formulation. Although pancreatic enzyme replacement improved the absorption characteristics of the CAP-P formulation, absorption remained prolonged and unreliable. Serum concentration-time profiles for either CAP-base or CAP-S consistently exceeded the MIC of important nonpseudomonal pathogens. This finding was not observed after CAP-P administration independent of pancreatic enzyme replacement. The results of this study support the continued clinical use of either CAP-base or CAP-S, but the cautious use of CAP-P formulations in CF patients with concurrent pancreatic insufficiency.