Static in vitro digestion model adapted to the general older adult population: an INFOGEST international consensus.

Understanding the mechanisms of food digestion is of paramount importance to determine the effect foods have on human health. Significant knowledge on the fate of food during digestion has been generated in healthy adults due to the development of physiologically-relevant in vitro digestion models. However, it appears that the performance of the oro-gastrointestinal tract is affected by ageing and that a model simulating the digestive conditions found in a younger adult (<65 years) is not relevant for an older adult (>65 years). The objectives of the present paper were: (1) to conduct an exhaustive literature search to find data on the physiological parameters of the older adult oro-gastrointestinal tract, (2) to define the parameters of an in vitro digestion model adapted to the older adult. International experts have discussed all the parameters during a dedicated workshop organized within the INFOGEST network. Data on food bolus properties collected in the older adult were gathered, including food particle size found in older adult boluses. In the stomach and small intestine, data suggest that significant physiological changes are observed between younger and older adults. In the latter, the rate of gastric emptying is slowed down, the pH of the stomach content is higher, the amount of secretions and thus the hydrolytic activities of gastric and intestinal digestive enzymes are reduced and the concentration of bile salts lower. The consensus in vitro digestion model of the older adult proposed here will allow significant progress to be made in understanding the fate of food in this specific population, facilitating the development of foods adapted to their nutritional needs. Nevertheless, better foundational data when available and further refinement of the parameters will be needed to implement the proposed model in the future.

Determination of blood pressure percentiles in normal-weight children: some methodological issues.

Blood pressure in children has consistently been related to adult blood pressure, with implications for long-term prevention of cardiovascular disease. The epidemic of obesity in children has resulted in corresponding increases in childhood blood pressure. In this paper, the authors develop norms for childhood blood pressure among normal-weight children (body mass index <85th percentile based on Centers for Disease Control and Prevention guidelines) as a function of age, sex, and height, using data from 49,967 children included in the database of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (the Pediatric Task Force). The authors considered three types of models for pediatric blood pressure data, including polynomial regression, restricted cubic splines, and quantile regression, with the latter providing the best fit. The sex-specific norms presented here are a nonlinear function of both age and height and are generally slightly lower than previously developed norms based on Pediatric Task Force data including both normal-weight and overweight children.

Evaluation of white coat hypertension in children: importance of the definitions of normal ambulatory blood pressure and the severity of casual hypertension.

To better describe the phenomenon of white coat hypertension (WCH) in children, we reviewed our single-center experience using ambulatory blood pressure monitoring to determine: 1) how the choice of threshold limits for defining ambulatory hypertension affects the determination of WCH, and 2) whether the severity of casual hypertension predicts the occurrence of WCH. Using the same daytime ambulatory blood pressure (ABP) data from 71 children (age 11.9 3.4 years) with persistently elevated casual blood pressure (BP), the prevalence of WCH was compared using 95th percentile BP limits from the Task Force on High Blood Pressure in Children (TF) and from normative pediatric daytime ambulatory BP (ABP) data. To quantify casual hypertension severity, average clinic BP was divided by the patient-specific TF 95th percentile BP to generate a BP index (ie, BP index of 1.1=10% above 95th percentile). The WCH prevalence was lower by normative ABP criteria than by TF criteria (31% v 59%, P < .001), but did not vary significantly by age, gender, race, or body mass index. Logistic regression showed that higher systolic BP index (P < .001) or diastolic BP index (P < .01) was associated with a lower probability of WCH. Specifically, as systolic BP index increased from 1.0 to 1.2, the estimated probability of WCH decreased from 87% to 15%, respectively. These data suggest that the use of the lower TF limits, derived solely from resting BP measurements, may overestimate WCH prevalence in ambulatory children. In addition, these data confirm in children the finding in adults that WCH is highly prevalent when casual hypertension is borderline or mild, but uncommon when moderate or severe.

Ambulatory blood pressure measurements.

Ambulatory blood pressure monitoring (ABPM) has emerged as a valuable clinical and research tool in the assessment of pediatric hypertension. Large databases of 24-hour blood pressure monitorings in healthy children are under development for establishing normal reference values analogous to the Task Force data for casual blood pressure. In the clinical setting, pediatric studies using ABPM to evaluate elevated blood pressure have shown that the prevalence of white coat hypertension in children is similar to that reported in adults. Furthermore, 24-hour blood pressure parameters are correlated with hypertensive end-organ injury such as left ventricular hypertrophy. ABPM has allowed detailed assessment of circadian blood pressure patterns that show early subtle abnormalities in some high-risk groups and normal patterns in other groups previously thought to be at high risk. These studies will assist in the practice of evidence-based medicine regarding pediatric hypertension that will improve the long-term care that pediatricians provide to their patients.

Comparison of the actigraph versus patients' diary information in defining circadian time periods for analyzing ambulatory blood pressure monitoring data.

BACKGROUND: Assessment of 24-h changes in blood pressure is one of the unique features that ambulatory blood pressure monitoring (ABPM) can provide. Most studies agree that sleep/wake periods should be based on patients' actual sleep and wake times. Actual wake and sleep time determinations are often based on patients' diary information. Several publications indicate that actigraphy is, at least, as accurate as activity diary in determining sleep/wake periods. OBJECTIVES: To compare subjects' compliance with actigraphy and diary keeping and to compare actigraphy and diary data in determination of sleep and wake times, mean blood pressures, classification of hypertension, and assessment of nocturnal dipping status. METHODS: We evaluated ABPM studies of 62 subjects. Blood pressure data were obtained using Spacelabs monitors for 24h. Sleep and wake times were determined by both the actigraph and patients' activity diary. RESULTS: In the 62 studies, 56 subjects had successful actigraphy (90%), 44 had activity diary completion (71%), and 38 subjects had both (61%). There was no statistically significant difference between the mean wake and sleep onset using the two methods, but up to 3 hours' difference in wake or sleep onset was noted in some studies. Although the two methods did not significantly affect the calculated systolic blood pressure (SBP) or diastolic blood pressure (DBP) loads in either awake or sleep periods, approximately 55% of the subjects' dipping status was changed when diary information on sleep time was used compared to actigraph. CONCLUSIONS: Our data indicate that in children and young adults, compliance with the actigraph was superior to diary completion and use of the actigraphy method rather than diary information changed the interpretation of some ABPM data. Our study suggested that actigraphy is superior to diary keeping in providing the information needed for appropriate interpretation of some ABPM data.

Reduced variability of neoral pharmacokinetic studies in pediatric renal transplantation.

In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra-individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved.

White coat hypertension in children with elevated casual blood pressure.

OBJECTIVE: We reviewed our experience using ambulatory blood pressure monitoring (ABPM) in children referred to a hypertension clinic to determine the frequency of pediatric white coat hypertension (WCH). STUDY DESIGN: WCH was defined by 3 different diagnostic criteria: (1) mean 24-hour blood pressure (BP) less than Task Force-defined 95th percentile, (2) mean 24-hour BP less than 95th percentile from pediatric normative ABPM data, and (3) mean 24-hour BP less than ABPM 95th percentile and BP load (percentage of BP readings during 24-hour period exceeding the 95th percentile) less than 25%. RESULTS: Clinic BP values were available in 67 otherwise healthy children who underwent ABPM; 51 had confirmed clinic hypertension by Task Force criteria. WCH frequency in these 51 patients with the stated criteria was 53%, 45%, and 22%, respectively. Elevated BP load was found in 52% (12/23) of patients with normal mean BP. CONCLUSION: These results suggest that many children referred for casual BP elevation have WCH even by strict diagnostic criteria. ABPM may help differentiate WCH from persistent hypertension, thereby avoiding unnecessary diagnostic evaluation and identifying children most likely to benefit from early intervention.

Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE).

OBJECTIVE: The development of this review article evolved from a National Kidney Foundation consensus conference on recent advances in the importance of evaluating and treating proteinuria. From this conference, a series of recommendations for the evaluation of adults with proteinuria was published. Because specific pediatric aspects of the problem were outside the scope of the original National Kidney Foundation publication, an ad hoc committee of 6 pediatric nephrologists who were active participants in the National Kidney Foundation conference was established to provide primary care physicians with a concise, up-to-date reference on this subject. METHODS: The recommendations that are given represent the consensus opinions of the authors. These are based on data from controlled studies in children when available, but many of the opinions are, by necessity, based on uncontrolled series in children or controlled trials performed in adults, because controlled trials in children have not been performed to evaluate many of the treatments described. RESULTS AND CONCLUSIONS: These recommendations are intended to provide primary care physicians with a useful reference when they are faced with a young child or teenager who presents with proteinuria, whether this is mild and asymptomatic or more severe, leading to nephrotic syndrome.

Use of anti-hypertensive medications and post-transplant renal allograft function in children.

Post-transplant hypertension is a common occurrence in children. The relative effect of this hypertension on renal allograft function is uncertain. Examining the accumulated data for pediatric renal transplant recipients at our institution from monthly visits for up to three years, we determined whether the use of anti-hypertensive medications (anti-HTN medications) was associated with allograft dysfunction. Monthly clinical data included height, weight, serum creatinine, cyclosporin A (CsA) trough levels, number of acute rejection episodes, and number of anti-HTN medications. Estimated glomerular filtration rate (eGFR) was calculated monthly for each patient using the Schwartz formula. Time post-transplant was grouped into 6-month intervals. One thousand three hundred and sixty-three monthly data sets from 6 months (n = 76 patients) to 3 yr post-transplant (n = 47 patients) were analyzed. Overall mean eGFR was 75 mL/min/1.73 m2 at 6 months and 54 mL/min/1.73 m2 at 3 yr. A lower eGFR was found at all post-transplant time intervals for patients receiving anti-HTN medications compared with those who were not (p < 0.01). This lower eGFR was found at some but not all times post-transplant when patients were grouped by donor type or history of acute rejection episodes and analyzed separately. Mean CsA trough levels were higher at all post-transplant time intervals in patients receiving anti-HTN medications (p < 0.05). While a causal relationship between post-transplant hypertension and graft dysfunction cannot be established from this study, we conclude that the need for anti-HTN medications is associated with worse allograft function.

Abnormal 24-hour blood pressure patterns in children after renal transplantation.

Hypertension after renal transplantation occurs commonly and is associated with decreased allograft survival. Hypertension is usually diagnosed by casual blood pressure (BP) measurements in the outpatient clinic that may not reflect the overall 24-hour BP pattern. To better describe the pattern of BP in children after renal transplantation, 24-hour ambulatory BP monitoring (APBM) was performed in 42 patients with stable renal function. BP was measured every 20 minutes during the daytime and every 30 minutes at night. Mean patient age was 12.8 +/- 5.2 years, and mean time after transplantation was 34 +/- 36 months. Seventy-six percent of the patients were administered antihypertensive medications. Twenty-four-hour mean systolic BP (SBP) was 127 +/- 11 mm Hg, and diastolic BP (DBP) was 80 +/- 11 mm Hg. Mean 24-hour BP load values (percentage of BP readings > 95th percentile based on Task Force criteria) were 59% for SBP and 50% for DBP, which were significantly elevated compared with healthy children (P < 0.001). An attenuated decline in sleep BP (nondipping) was found in 78% of the patients for SBP and 50% for DBP. Sleep BP exceeded awake BP in 24% of the patients for SBP and 17% for DBP. Boys had a greater SBP load (66% versus 45%; P = 0.03) and DBP load (57% versus 38%; P = 0.04) than girls. These results confirm in children the high prevalence of hypertension by ABPM criteria after renal transplantation and show attenuation of normal sleep BP decreases. These BP disturbances may shorten renal allograft survival and predispose children to long-term hypertensive end-organ damage.

Serial estimation of glomerular filtration rate in children after renal transplant.

Evaluation of serial monthly estimated glomerular filtration rate (eGFR) may be useful for studying pediatric renal allograft outcome. To determine the validity of this approach, we reviewed our single-center experience in pediatric renal transplant recipients to determine the effect of risk factors for renal allograft failure on eGFR. Clinical parameters recorded monthly through 5 years post transplant allowed serial assessment of eGFR. Monthly clinical data included height, weight, serum creatinine, cumulative number of acute rejection episodes, cyclosporine dose, and cyclosporine trough levels. From these data, eGFR was calculated monthly for each patient using the Schwartz formula. Time post transplant was grouped in 6-month intervals and plotted against mean eGFR to compare eGFR in patients grouped by demographic and clinical factors; 1,786 monthly data sets from 6 months post transplant (n=76 patients) to 5 years post transplant (n=25 patients) were analyzed. Overall mean eGFR from 6 months to 1 year was 75 ml/min per 1.73 m(2) and from 4. 5 to 5 years 46 ml/min per 1.73 m(2). eGFR was lower at all time intervals for recipients of cadaver versus living-related donor grafts, and patients with >/=1 versus 0 acute rejections (P<0.01). After 1 year, eGFR was lower in black patients compared with white or Hispanic patients (P<0.01). Cyclosporine dose greater than 5 mg/kg per day was associated with better early and worse late graft function. These results are similar to those reported in multi-center studies using the outcome variable of graft failure and suggest that serial eGFR may be valid as an outcome variable to study chronic renal allograft dysfunction in children.

A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients.

The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 x C0 + 1.77 x C2 + 4. 1 x C4 (mean prediction error +/- SD = 0.3 +/- 6.4%, 95% confidence interval=-1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period.

Comparison of arbitrary definitions of circadian time periods with those determined by wrist actigraphy in analysis of ABPM data.

Determining blood pressure (BP) values at different daily time periods is a well recognised measure to assess the risk of end-organ damage. However, the use of various definitions of these periods, eg, day vs night, sleep vs wake or arbitrary definitions, makes clinical decisions based on available data difficult. In the present study, we compared BP loads in actual sleep-wake periods to default day-night definition provided by the ambulatory BP monitoring (ABPM) software (day 06.00 to 22.00; night 22.00 to 06.00) as well as to an arbitrary definition of sleep-wake periods in children published in Soergel et al (J Pediatr 1997; 130: 178-184)1 (awake 08.00 to 20.00 and sleep 00.00 to 06.00. We used an actigraphy, an accelerometer, to define the actual sleep-wake periods in 46 patients with essential hypertension who are on various treatment regimens. BP data was obtained by using Spacelabs 90207 monitors for a full 24 h. There were significant differences between actual sleep-wake and default definition for BP load. No similar finding was noted when arbitrary definition was used. The proportion of hypertensives was not significantly different when default and arbitrary definitions were used. Classification of dippers and non-dippers is greatly affected by the definition of sleep interval using the default method. Although some of the misclassifications were not statistically significant, their clinical importance must be considered. Determination of sleep and wake periods for analysis of ABPM data should be based on careful determination of actual periods. Using other definitions may not provide complete information or accommodate for individual variation.

Population studies of ambulatory blood pressure monitoring in Brazilian children.

BACKGROUND: The determination of hypertension in a given population depends on the knowledge of population norms for blood pressure. This is true for both casual blood pressure (CBP) measurements and the newest and most promising technology of ambulatory blood pressure monitoring (ABPM). OBJECTIVE: To design an ambitious multinational co-operative study to determine normal blood pressure data in Brazilian children. METHODS: The study was designed to determine normative data for CBP, using the Task Force technical recommendations for age-, sex- and height-percentile-specific blood pressure values. The proposed procedure is as follows. ABPM will be studied in a random subgroup of individuals, to develop similar normative data. These data will be correlated to CBP measurements and to echocardiographic findings as a measure of end-organ damage. All patients who are diagnosed by CBP measurement to be hypertensive will also be studied by ABPM, and studies of target-organ damage will be performed. Family and medical histories will be evaluated by questionnaire and first-degree relatives will be evaluated for CBP measurement. Hypertensive patients will form a cohort for long-term follow-up. These data will be the foundation for studies of hypertension in Brazilian children.

Technical aspects of blood pressure measurement in pediatric patients.

BACKGROUND: Prolonged hypertension in adults has been associated with end-organ damage, in addition to increased morbidity and mortality. Accurate measurement of blood pressure in pediatric and adult patients is imperative for the appropriate diagnosis of hypertension, so that measures may be instituted to prevent these adverse sequelae. Although intermittent office measurement of blood pressure is practiced in most parts of the world, the technique is fraught with problems. Errors during the actual measurement and difficulties in interpretation of the data are well-studied challenges associated with intermittent blood pressure measurements that have been well studied. Ambulatory blood pressure monitoring offers several advantages over intermittent measurement: blood pressure measurements are available over a prolonged period of time (including the sleep period), measurements are not as dependent on observer biases as are intermittent measurements, and in adults the data appear to correlate well to measures of end-organ damage. In children, the ambulatory blood pressure monitor is well tolerated and accurate. This new technology may offer pediatric specialists the opportunity to identify more accurately the child with increased blood pressure, so that preventive measures can be instituted to reduce the well-known morbidity and mortality associated with hypertension. OBJECTIVE: To review the technical aspects of blood pressure measurement in children, with special attention to the emerging field of ambulatory blood pressure monitoring and its potential use in children.

Stress-induced alterations of blood pressure and 24 h ambulatory blood pressure in adolescents.

OBJECTIVE: To examine the extent to which ambulatory blood pressure was predicted by blood pressure levels exhibited during talking segments of a laboratory protocol and by resting blood pressures in male and female adolescents from three ethnic groups: African, European and Hispanic Americans. DESIGN: This was a laboratory-field study incorporating an experimental study of reactivity of blood pressure during a laboratory protocol and an observational study of 24h ambulatory blood pressure (ABP) monitoring. METHODS: Resting blood pressure, reactivity of blood pressure, 24h ABP, and activity, height, and maturation of a multi-ethnic sample of 373 male and female adolescents aged 11-16 years were measured. A mixed-effects model for repeated measures was the statistical approach, with systolic and diastolic blood pressures as separate, dependent variables. RESULTS: Percentiles of ABP by sex, ethnic group, and height are presented. High and mixed blood pressure reactors in the laboratory had higher levels of 24h ABP and higher levels of blood pressure load during the daytime. African Americans had higher ABP than did European and Hispanic Americans. CONCLUSIONS: Blood pressure measured during laboratory tasks that require talking might be useful as a screening device to identify adolescents with high blood pressures. Further study will be necessary in order to quantify the sensitivity of the laboratory protocol as an indicator of high blood pressure compared with casual measurement of blood pressures. If laboratory patterns of blood pressure could be used to predict which individuals have high levels of blood pressure during the course of daily activities, the laboratory protocol would be a useful screening tool, identifying high-risk individuals.