Women & Children's Hospital of Buffalo

The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.

The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

A new method is described for rapid and economical screening of large numbers of hospital nursery infants for elevation in blood phenylalanine associated with phenylketonuria. Results are presented for 682 infants, 96% of whom were 4 days of age. None of the blood phenylalanine values were found to be as high as 4 mg/100 ml, and only 8% were above 2 mg/100 ml. These values appear to be in agreement with values obtained by other methods, and indicate that a very low rate of "false-positives" will be encountered during screening of the 10,000 or more infants that may be necessary to detect a case of phenylketonuria. It is recommended that any result of 6 mg/100 ml or above be considered positive, and require confirmation by phenylalanine determination of a second blood specimen.

This two-part meta-analysis combined data from eight prospective randomized trials designed to compare the nutritional efficacy of early enteral (TEN) and parenteral (TPN) nutrition in high-risk surgical patients. The combined data gave sufficient patient numbers (TEN, n = 118; TPN, n = 112) to adequately address whether route of substrate delivery affected septic complication incidence. Phase I (dropouts excluded) meta-analysis confirmed data homogeneity across study sites, that TEN and TPN groups were comparable, and that significantly fewer TEN patients experienced septic complications (TEN, 18%; TPN, 35%; p = 0.01). Phase II meta-analysis, an intent-to-treat analysis (dropouts included), confirmed that fewer TEN patients developed septic complications. Further breakdown by patient type showed that all trauma and blunt trauma subgroups had the most significant reduction in septic complications when fed enterally. In conclusion, this meta-analysis attests to the feasibility of early postoperative TEN in high-risk surgical patients and that these patients have reduced septic morbidity rates compared with those administered TPN.

The Belgrade (b) rat has an autosomal recessively inherited, microcytic, hypochromic anemia associated with abnormal reticulocyte iron uptake and gastrointestinal iron absorption. The b reticulocyte defect appears to be failure of iron transport out of endosomes within the transferrin cycle. Aspects of this phenotype are similar to those reported for the microcytic anemia (mk) mutation in the mouse. Recently, mk has been attributed to a missense mutation in the gene encoding the putative iron transporter protein Nramp2. To investigate the possibility that Nramp2 was also mutated in the b rat, we established linkage of the phenotype to the centromeric portion of rat chromosome 7. This region exhibits synteny to the chromosomal location of Nramp2 in the mouse. A polymorphism within the rat Nramp2 gene cosegregated with the b phenotype. A glycine-to-arginine missense mutation (G185R) was present in the b Nramp2 gene, but not in the normal allele. Strikingly, this amino acid alteration is the same as that seen in the mk mouse. Functional studies of the protein encoded by the b allele of rat Nramp2 demonstrated that the mutation disrupted iron transport. These results confirm the hypothesis that Nramp2 is the protein defective in the Belgrade rat and raise the possibility that the phenotype shared by mk and b animals is unique to the G185R mutation. Furthermore, the phenotypic characteristics of these animals indicate that Nramp2 is essential both for normal intestinal iron absorption and for transport of iron out of the transferrin cycle endosome.

BACKGROUND: Emergence delirium has been investigated in several clinical trials. However, no reliable and valid rating scale exists to measure this phenomenon in children. Therefore, the authors developed and evaluated the Pediatric Anesthesia Emergence Delirium (PAED) scale to measure emergence delirium in children. METHODS: A list of scale items that were statements describing the emergence behavior of children was compiled, and the items were evaluated for content validity and statistical significance. Items that satisfied these evaluations comprised the PAED scale. Each item was scored from 1 to 4 (with reverse scoring where applicable), and the scores were summed to obtain a total scale score. The degree of emergence delirium varied directly with the total score. Fifty children were enrolled to determine the reliability and validity of the PAED scale. Scale validity was evaluated using five hypotheses: The PAED scale scores correlated negatively with age and time to awakening and positively with clinical judgment scores and Post Hospital Behavior Questionnaire scores, and were greater after sevoflurane than after halothane. The sensitivity of the scale was also determined. RESULTS: Five of 27 items that satisfied the content validity and statistical analysis became the PAED scale: (1) The child makes eye contact with the caregiver, (2) the child's actions are purposeful, (3) the child is aware of his/her surroundings, (4) the child is restless, and (5) the child is inconsolable. The internal consistency of the PAED scale was 0.89, and the reliability was 0.84 (95% confidence interval, 0.76-0.90). Three hypotheses supported the validity of the scale: The scores correlated negatively with age (r = -0.31, P <0.04) and time to awakening (r = -0.5, P <0.001) and were greater after sevoflurane anesthesia than halothane (P <0.008). The sensitivity was 0.64. CONCLUSIONS: These results support the reliability and validity of the PAED scale.

OBJECTIVE: To evaluate the multicenter application of intraoperative lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection (LM/SL/SCLND) for the management of early-stage melanoma. SUMMARY BACKGROUND DATA: The multidisciplinary technique of LM/SL/SCLND has been widely adopted, but not validated in a multicenter trial. The authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT) 5 years ago to evaluate the survival of patients with early-stage primary melanoma after wide excision alone versus wide excision plus LM/SL/SCLND. This study examined the accuracy of LM/SL/SCLND in the MSLT, using the experience of the organizing center (John Wayne Cancer Institute [JWCI]) as a standard for comparison. METHODS: Before entering patients into the randomization phase, each center in the MSLT was required to finish a 30-case learning phase with complete nuclear medicine, pathology, and surgical review. Selection of MSLT patients in the LM/SL/SCLND treatment arm was based on complete pathologic and surgical data. The comparison group of JWCI patients was selected using these criteria: primary cutaneous melanoma having a thickness > or =1 mm with a Clark level > or =III, or a thickness <1 mm with a Clark level > or =IV (MSLT criterion); LM/SL performed between June 1, 1985, and December 30, 1998; and patient not entered in the MSLT. The accuracy of LM/SL/SCLND was determined by comparing the rates of sentinel node (SN) identification and the incidence of SN metastases in the MSLT and JWCI groups. RESULTS: There were 551 patients in the MSLT group and 584 patients in the JWCI group. In both groups, LM performed with blue dye plus a radiocolloid was more successful (99.1 %) than LM performed with blue dye alone (95.2%) (p = 0.014). After a center had completed the 30-case learning phase, the success of SN identification in the MSLT group was independent of the center's case volume or experience in the MSLT. CONCLUSIONS: Lymphatic mapping and sentinel lymphadenectomy can be successfully learned and applied in a standardized fashion with high accuracy by centers worldwide. Successful SN identification rates of 97% can be achieved, and the incidence of nodal metastases approaches that of the organizing center. A multidisciplinary approach (surgery, nuclear medicine, and pathology) and a learning phase of > or =30 consecutive cases per center are sufficient for mastery of LM/SL in cutaneous melanoma. Lymphatic mapping performed using blue dye plus radiocolloid is superior to LM using blue dye alone.

BACKGROUND: Infants with cardiac disease or prematurity are at risk for severe illness caused by respiratory syncytial virus. Immune globulin with a high titer of antibodies against respiratory syncytial virus may offer infants and young children at risk protection from this serious, common respiratory illness. METHODS: We studied 249 infants and young children (mean age, eight months) who had bronchopulmonary dysplasia due to prematurity (n = 102), congenital heart disease (n = 87), or prematurity alone (n = 60). Respiratory syncytial virus immune globulin was given monthly to some of these children in either a high dose (750 mg per kilogram of body weight; n = 81) or low dose (150 mg per kilogram; n = 79); 89 controls received no immune globulin. Group assignments were random. Assessments of respiratory illness and management were conducted without knowledge of the children's group assignments. RESULTS: There were 64 episodes of respiratory syncytial virus infection: 19 in the high-dose group, 16 in the low-dose group, and 29 in the control group. In the high-dose group there were fewer lower respiratory tract infections (7, vs. 20 in the control group; P = 0.01), fewer hospitalizations (6, vs. 18 in the control group; P = 0.02), fewer hospital days (43, vs. 128 in the control group; P = 0.02), fewer days in the intensive care unit (P = 0.05), and less use of ribavirin (P = 0.05). In the low-dose group there was a significant reduction only in the number of days in the intensive care unit (P = 0.03). Adverse events during the 580 infusions were generally mild and included fluid overload (in five children), oxygen desaturation (eight), and fever (six). Six children died: three in the high-dose group, three in the low-dose group, and none in the control group (P = 0.15), but no death was attributed to the use of immune globulin or to illness caused by respiratory syncytial virus. CONCLUSIONS: Administration of high doses of respiratory syncytial virus immune globulin is a safe and effective means of preventing lower respiratory tract infection in infants and young children at high risk for this disease.

BACKGROUND: Bariatric surgery is increasingly considered for the treatment of adolescents with severe obesity, but few prospective adolescent-specific studies examining the efficacy and safety of weight-loss surgery are available to support clinical decision making. METHODS: We prospectively enrolled 242 adolescents undergoing weight-loss surgery at five U.S. centers. Patients undergoing Roux-en-Y gastric bypass (161 participants) or sleeve gastrectomy (67) were included in the analysis. Changes in body weight, coexisting conditions, cardiometabolic risk factors, and weight-related quality of life and postoperative complications were evaluated through 3 years after the procedure. RESULTS: The mean (±SD) baseline age of the participants was 17±1.6 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 53; 75% of the participants were female, and 72% were white. At 3 years after the procedure, the mean weight had decreased by 27% (95% confidence interval [CI], 25 to 29) in the total cohort, by 28% (95% CI, 25 to 30) among participants who underwent gastric bypass, and by 26% (95% CI, 22 to 30) among those who underwent sleeve gastrectomy. By 3 years after the procedure, remission of type 2 diabetes occurred in 95% (95% CI, 85 to 100) of participants who had had the condition at baseline, remission of abnormal kidney function occurred in 86% (95% CI, 72 to 100), remission of prediabetes in 76% (95% CI, 56 to 97), remission of elevated blood pressure in 74% (95% CI, 64 to 84), and remission of dyslipidemia in 66% (95% CI, 57 to 74). Weight-related quality of life also improved significantly. However, at 3 years after the bariatric procedure, hypoferritinemia was found in 57% (95% CI, 50 to 65) of the participants, and 13% (95% CI, 9 to 18) of the participants had undergone one or more additional intraabdominal procedures. CONCLUSIONS: In this multicenter, prospective study of bariatric surgery in adolescents, we found significant improvements in weight, cardiometabolic health, and weight-related quality of life at 3 years after the procedure. Risks associated with surgery included specific micronutrient deficiencies and the need for additional abdominal procedures. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; Teen-LABS ClinicalTrials.gov number, NCT00474318.).

CONTEXT: Tissue-type plasminogen activator (tPA) is the only therapy for acute ischemic stroke approved by the Food and Drug Administration. OBJECTIVE: To assess the safety profile and to document clinical outcomes and adverse events in patients treated with intravenous tPA for acute stroke in clinical practice. DESIGN AND SETTING: Prospective, multicenter study of consecutive patients enrolled between February 1997 and December 1998 at 57 medical centers in the United States (24 academic and 33 community). INTERVENTION: Intravenous tPA (recombinant alteplase). PATIENTS: Three hundred eighty-nine patients with a mean age of 69 years (range, 28-100 years); 55% were men. MAIN OUTCOME MEASURES: Time intervals between stroke symptom onset, hospital arrival, and treatment with tPA; pretreatment computed tomographic scan results, intracerebral hemorrhage, and major systemic bleeding. The modified Rankin Scale score was used to assess clinical outcomes at 30 days. RESULTS: Median time from stroke onset to treatment was 2 hours 44 minutes, and the median baseline National Institutes of Health Stroke Scale score was 13. The 30-day mortality rate was 13%. At 30 days after treatment, 35% of patients had very favorable outcomes (modified Rankin score, 0-1) and 43% were functionally independent (modified Rankin score, 0-2). Thirteen patients (3.3%) experienced symptomatic intracerebral hemorrhage, including 7 who died. Twenty-eight patients (8.2%) had asymptomatic intracerebral hemorrhage within 3 days of treatment with tPA. Protocol violations were reported for 127 patients (32.6%), and included treatment with tPA more than 3 hours after symptom onset in 13.4%, treatment with anticoagulants within 24 hours of tPA administration in 9.3%, and tPA administration despite systolic blood pressure exceeding 185 mm Hg in 6.7%. A multivariate analysis found predictors of favorable outcome to be a less severe baseline National Institutes of Health Stroke Scale score, absence of specific abnormalities (effacement or hypodensity of >33% of the middle cerebral artery territory or a hyperdense middle cerebral artery) on the baseline computed tomographic scan, an age of 85 years or younger, and a lower mean arterial pressure at baseline. CONCLUSIONS: This study, conducted at multiple institutions throughout the United States, suggests that favorable clinical outcomes and low rates of symptomatic intracerebral hemorrhage can be achieved using tPA for stroke treatment.

IMPORTANCE: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. OBJECTIVES: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN: Epidemiological and retrospective observational study. SETTING: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE: Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

Cognitive impairment is common in multiple sclerosis (MS), yet patients seen in MS clinics and neurologic practices are not routinely assessed neuropsychologically. In part, poor utilization of NP services may be attributed to a lack of consensus among neuropsychologists regarding the optimal approach for evaluating MS patients. An expert panel composed of neuropsychologists and psychologists from the United States, Canada, United Kingdom, and Australia was convened by the Consortium of MS Centers (CMSC) in April, 2001. Our objectives were to: (a) propose a minimal neuropsychological (NP) examination for clinical monitoring of MS patients and research, and (b) identify strategies for improving NP assessment of MS patients in the future. The panel reviewed pertinent literature on MS-related cognitive dysfunction, considered psychometric factors relevant to NP assessment, defined the purpose and optimal characteristics of a minimal NP examination in MS, and rated the psychometric and practical properties of 36 candidate NP measures based on available literature. A 90-minute NP battery, the Minimal Assessment of Cognitive Function in MS (MACFIMS), emerged from this discussion. The MACFIMS is composed of seven neuropsychological tests, covering five cognitive domains commonly impaired in MS (processing speed/working memory, learning and memory, executive function, visual-spatial processing, and word retrieval). It is supplemented by a measure of estimated premorbid cognitive ability. Recommendations for assessing other factors that may potentially confound interpretation of NP data (e.g., visual/sensory/motor impairment, fatigue, and depression) are offered, as well as strategies for improving NP assessment of MS patients in the future.

IMPORTANCE: The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce. OBJECTIVE: To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged <5 years), older children (aged 5-9 years), and adolescents (aged 10-19 years) between 1990 and 2013 in 188 countries from the Global Burden of Disease (GBD) 2013 study. EVIDENCE REVIEW: Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14,244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35,620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates. FINDINGS: Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905.059 deaths; 95% UI, 810,304-998,125), diarrheal diseases among older children (38,325 deaths; 95% UI, 30,365-47,678), and road injuries among adolescents (115,186 deaths; 95% UI, 105,185-124,870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world's deaths from neonatal encephalopathy. Half of the world's diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. CONCLUSIONS AND RELEVANCE: Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed.

2001 CONSENSUS COMMITTEE MEMBERS Laura K. Bachrach, M.D. Robert J. Beall, Ph.D. Preston W. Campbell, III, M.D. Susan C. Casey, B.S., R.D. Mitchell B. Cohen, M.D. Mary Corey, Ph.D. W. Hobart Davies, Ph.D. Judy A. Fulton, R.D. Richard J. Grand, M.D. John E. Grunow, M.D. Dana S. Hardin, M.D. Lesles Hendeles, Pharm.D. James E. Heubi, M.D. Van S. Hubbard, M.D. Hui-Chuan Kai, Ph.D. Sheila Innis, Ph.D. Elisabeth Luder, Ph.D., R.D. Karen MacGuiness, R.D. Richard K. Mathis, M.D. Annie McKenna, M.S., R.D., C.N.S. Antoinette Moran, M.D. Laurie Moyer-Mileur, Ph.D., R.D. Kimberly O. O'Brien, Ph.D. Hebe Quinton, M.S. Lynne M. Quittell, M.D. Ross W. Shepherd, M.D., FRACP Ronald J. Sokol, M.D. Lori J. Stark, Ph.D. John N. Udall, Jr., M.D., Ph.D. Babette Zemel, Ph.D. INTRODUCTION Patients with cystic fibrosis should have normal growth. Growth requires appropriate energy and nutrient intake, but gastrointestinal and pulmonary function and genetic potential are also important. Poor clinical outcomes are associated with undernutrition in patients with CF (1–6). The Cystic Fibrosis Foundation recognizes that attention to nutrition is an integral part of CF care. In March 2001 a Consensus Committee, co-sponsored by the Cystic Fibrosis Foundation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, met to review the literature and update a Consensus Conference Statement published in 1992 addressing these issues (7). The CF care team should monitor growth, provide anticipatory counseling, and plan intervention strategies when patients are at risk for undernutrition or are diagnosed with nutritional failure. A registered dietitian must be a part of the team to provide the discipline-specific expertise needed for optimal nutritional management and may, along with other team members such as the physician, nurse, social worker or a psychologist, provide expertise concerning developmental and behavioral aspects of eating. Prevention and early intervention are most successful in combating nutritional failure. This document outlines the current recommendations of the Consensus Committee on how best to monitor growth and nutrition, strategies to prevent undernutrition, and interventions for patients with nutritional failure. It is based on the limited evidence available in the literature and also represents expert opinion. As with all such documents, these recommendations are likely to change as new data becomes available. MONITORING GROWTH, BODY COMPOSITION, PUBERTAL AND BONE STATUS Early detection of suboptimal growth allows for appropriate intervention and timely rehabilitation. Present Cystic Fibrosis Foundation (CFF) guidelines suggest that patients be seen on a routine basis, every 3 months (8). Growth and nutritional status should be monitored at these intervals (Table 1).TABLE 1: Nutritional assessment in routine CF center careThere are three specific times when special attention should be focused on growth and nutritional status within the scope of usual clinical care. These are: (1) the first 12 months after the diagnosis of CF for each patient; (2) birth to 12 months of age for infants diagnosed prenatally or at birth, until a normal pattern of growth (head circumference, weight, and length) is clearly established; and (3) the peripubertal growth period (girls about 9 to 16, and boys about 12 to 18 years of age). By establishing a pattern of normal growth and development after the diagnosis of CF, patients enter mid-childhood and pubertal growth well nourished, and are more likely to continue this pattern of normal growth. Surveillance of Growth and Body Composition Accurate, sequential measurement, plotting and interpretation of head circumference, weight, length, and height are essential to the care of children with CF. Standard anthropometric measurement techniques are well described in the literature (9–11). Mid-arm circumference and triceps skinfold thickness measurements provide clinical information about lean body mass (muscle and organ) development and subcutaneous fat (energy) stores, respectively. Each center should select and maintain anthropometric instruments, establish a detailed measurement protocol, and train those responsible for obtaining anthropometric measurements. Each clinic should also have standard protocols for cleaning the instruments between patient assessments to protect against the spread of infectious agents. Clinical Evaluation of Measures of Growth and Body Composition Evaluation of Growth Measurements Weight and length (measured supine) or height (measured standing), as well as head circumference in infants, should be monitored and analyzed as growth parameters. In 2000, new NCHS/CDC growth charts were distributed for plotting weight, head circumference, length, and height (CDC web site, http://www.cdc.gov/growthcharts to download charts). The percentiles for all growth measures are expanded, compared to the 1977 charts, with two new percentile curves (97th and 3rd) for more precise evaluation at the extremes of the growth distribution. In addition, charts are provided for body mass index (BMI =(weight in kg)/(height in meters)2) with percentiles for boys and girls, age 2 to 20 years. Reference values are available for tracking head circumference in children beyond 36 months of age (12). The 2000 edition growth charts should be used for all CF clinical care, and have been used in calculation of the CFF Patient Registry data beginning with the 1999 annual report. For optimal care, it is suggested that patients less than 24 months of age have all previously collected growth data (weight, length, head circumference) completely transferred to a 2000 edition growth chart. For patients older than 24 months, it is suggested that previously collected growth data be transferred to the 2000 growth charts for each six-month interval. Based upon clinical judgment of the pattern of growth and related clinical events (i.e., prolonged illness, use of a feeding tube, lung transplantation), more extensive growth data should be transferred to the 2000 edition growth chart. One strong indicator of global nutritional sufficiency is if patients are growing in height to their full genetic potential (13). The genetic potential for height of each patient can be estimated by a variety of methods (14–16). This should be determined for each patient and the target height range (genetic potential related to biologic parental height) should be noted on the growth chart. Catch-up linear growth may take up to four years in children with CF diagnosed in infancy (17). A steady increase in percentile height towards the target height range indicates adequate nutritional status. Evaluation of Weight for Height Proportion Assessment of the weight for height proportion for an individual patient is of clinical importance. The 1992 CFF Consensus Report (7) contained some inconsistencies in how to use the recommended weight-for-height index. In practice, some CF Centers adopted the Moore modification (18) while others used the original McLaren and Read method (19). To standardize the approach to assessing relative proportion of weight for height, the committee now recommends that the term `percent ideal body weight' (abbreviated as `%IBW') and the modification of Moore et al. be used. This recommendation will be followed in subsequent discussions (Fig. 1). Users of software that calculates %IBW must know what method the program employs, since not all programs use the Moore method. Although somewhat cumbersome to calculate, %IBW remains a very sensitive index of body weight allowing for gender, age, and height. Weight-for-height percentile from NCHS/CDC growth charts is less valuable because the age of the child is ignored.FIG. 1.: Calculation of percent ideal body weight (% IBW).BMI is an estimate of adiposity, which should remain relatively constant throughout adulthood. However, BMI is not constant across the pediatric age range; therefore, BMI percentiles available on the 2000 CDC growth charts, rather than BMI, should be used to evaluate the pediatric patient. Guidelines for classifying underweight by BMI have been reported in the general population for adults but have not been validated in children with CF (20,21). Although the cut-off values for BMI percentiles that relate to health status are not yet well established, low BMI has been shown to be associated with increased mortality (22). Since children are growing in weight and stature, the Consensus Committee recommends that BMI percentile should be used for clinical evaluation. Just as with percentile height and weight charts, an individual BMI percentile value reflects genetic as well as health factors. Plotted sequential values indicate problems when the pattern varies from a consistent percentile. For now, it is suggested that both %IBW and BMI percentile be calculated and used for clinical care decisions. BMI percentiles are not available for children under age 2 years, so weight-for-length percentile should be used. Evaluation of %IBW, BMI percentiles, and weight-for-length percentiles permits the identification of patients at risk for nutritional failure (Table 2). However, not all patients in the `at risk' category will have nutritional insufficiency. Use of percentiles, by definition, only describes the distribution of growth in a population. Expertise will need to be used to determine who requires closer evaluation and follow-up to prevent nutritional failure. Patients who meet the definition of nutritional failure, as outlined in Table 2, should be evaluated and treated (see below).TABLE 2: Definition of nutritional failure in patients with CF and those at riskEvaluation of Body Composition Measurements The two body composition measurements, mid-arm circumference and triceps skinfold thickness, are translated to age- and gender-specific percentiles using reference data from Frisancho (23). Two additional values are calculated from the mid-arm circumference and triceps measurements, and provide more accurate assessments of muscle and fat stores. These are the mid-arm muscle area (mm2) and mid-arm fat area (mm2) with age and gender reference data also provided by Frisancho (23). Clinical Evaluation of Pubertal Development Pubertal development is often delayed in patients with CF. This delay is usually related to growth failure and poor nutritional status, rather than to a rare primary endocrine disorder. Progressing through pubertal development is an important component of physical growth as well as psychosocial health of the child and family. In addition, studies now show that the period of pubertal growth is also very important to achieving peak bone mass and adult bone health (24). A standardized method of self-assessment (child or child/parent) (25) or physical examination (trained physician or registered nurse) (26) should be completed at least annually, in girls beginning at age 9 years and boys at age 10. Delayed puberty should be considered a marker of nutritional failure (Table 2). CLINICAL EVALUATION OF BONE HEALTH Bone health is of increasing interest for patients with CF, as several studies have demonstrated bone fragility in children and adults with CF (27,28). Peak bone mass is one of the major determinants of life-long bone health and is attained by early adulthood (29–31). CF with pancreatic insufficiency poses many potential risk factors for poor bone health: failure to thrive, delayed or truncated pubertal development, malabsorption of calcium, magnesium, and vitamins D and K, hepatobiliary disease, and reduced weight-bearing physical activity. Chronic use of corticosteroid medications for lung disease is also a risk factor for poor bone health, and may decrease calcium absorption and suppress linear growth (32). Bone health can be evaluated by history (e.g., atraumatic bone fracture), physical examination (poor growth, back pain), and by radiologic and laboratory assessment. Plain radiography films (chest, long bones) that demonstrate osteopenia are usually indicative of significant loss of bone mass or lack of normal accretion of bone mass. Conventional x-ray is not nearly as sensitive or quantitative as dual energy x-ray absorptiometry (DEXA) using an age- and gender-adjusted standard deviation score (z-score) for the lumbar spine (L1–4 or L2–4). Further adjustments for small bone size and/or delayed skeletal maturation may be required to avoid over-diagnosis of low bone mass, although currently there are no standard methods for these adjustments. Comparison of scans from children or adolescents with adult reference data (T-score) is not appropriate. Children 8 years old and older who have one of the following risk criteria for poor bone health should have an assessment of bone mass by lumbar spine DEXA: candidate for organ transplantation, post-organ transplantation, end-stage lung disease, bone fracture associated with low-impact activity (i.e., fracture with a fall from standing height), chronic use of corticosteroid medication, delayed pubertal development, and nutritional failure. In addition to the DEXA, children at risk for poor bone health should have annual serum calcium, phosphorous, intact parathyroid hormone measured in addition to routine annual 25-hydroxyvitamin D level. Also, the dietary intake of calcium and vitamin D should be determined by diet history. Abnormal blood values or suboptimal dietary intake should be corrected by treatment. Current treatment of osteopenia or osteoporosis in children with CF is usually limited to general health measures, including optimizing growth by supplying adequate calories, general nutrition by ensuring sufficient vitamin D and K intake to normalize blood levels, encouraging calcium intake that meets the recommendations for age (33), and by fostering weight-bearing physical activity as tolerated. Antiresorptive drug therapy remains experimental, but may be used in lung transplant patients and may ultimately prove appropriate for patients with a history of low-impact bone fractures. Referral to a physician specializing in treating bone health in children may be considered. NUTRITION MANAGEMENT IN THE WELL CHILD Issues Related to Pancreatic Insufficiency Identifying Pancreatic Insufficiency Eighty-five to 90% of patients with CF have pancreatic insufficiency (PI) (34). The majority of pancreatic function must be lost before symptoms of PI are apparent (35). PI leads to malabsorption of dietary fat, protein, and other nutrients. Pancreatic functional status is a strong predictor of long-term outcome (36) and has a direct influence on nutritional status; therefore, knowing the pancreatic phenotype is useful not only in nutritional management but as a prognosticator. Specific CFTR mutations are associated with pancreatic sufficiency in a dominant fashion (see Table 3). Possessing an allele from this group offers protection even in combination with an allele normally associated with PI (37).TABLE 3: Pancreatic function and mutationsWhen the diagnosis of CF has been established, PI is often inferred by clinical signs and symptoms such as: frequent, malodorous, greasy stools, the presence of meconium ileus, or distal intestinal obstruction syndrome. Tests to document PI include: (1) duodenal intubation with stimulation; (2) 72-hour fecal fat balance study; (3) immunoreactive trypsinogen after 8 years of age; and (4) other markers as they become more widely available, such as fecal elastase-1 and fecal chymotrypsin determinations (38). Indirect tests to infer PI include low serum fat-soluble vitamins and/or low serum beta-carotene (after the introduction of fruits and vegetables). It is important to assess the pancreatic function of patients as soon as the diagnosis of CF is made. Steatorrhea may be the result of other conditions. When PI is present, enzyme, and vitamin therapy (Table 4) as well as proactive nutritional management should be started.TABLE 4: Recommendations for vitamin supplementation In addition to a standard, age appropriate dose of non-fat-soluble multivitamins, the following should be given:Some patients whose tests initially indicate that they are pancreatic sufficient (PS) become PI. PS patients should be reevaluated annually for the conversion to PI, especially if genetic testing reveals two mutations that are generally associated with PI. This evaluation can consist of monitoring growth, nutrition, and stool pattern; one or more of the tests listed above for assessing pancreatic function may be needed for more objective evidence. Recommendation for Pancreatic Enzyme Replacement Therapy Pancreatic enzyme replacement therapy is initiated once PI has been identified. Enzymes are given with all foods and milk products including predigested formulas and breast milk. Medium chain triglycerides (MCT) require less lipase activity than long-chain fats for efficient absorption, although lipase is still needed (39). Microsphere or microtablet preparations are preferable to powders because the acid-resistant enteric coating prevents acid-inactivation of the enzymes, and are not associated with mouth and/or perianal excoriation. Decreased pancreatic bicarbonate secretion combined with gastric acid may cause the duodenum and proximal jejunum to remain acidic, preventing dissolution of the protective coating until the capsules have bypassed a significant amount of intestinal absorptive surface. This can be treated by the administration of a histamine-2 receptor blocker or a proton pump inhibitor (40,41). Enzymes work best when taken before each meal and snack. For prolonged meal events, such as at a buffet or party, the enzymes may be more effective if distributed throughout the meal. Parents and adolescent should learn to adjust enzyme dosage according to the anticipated amount of fat in the meal or snack based on guidance from their CF team. Schools and should be of the need for enzymes with all and enzymes are not to enzymes it is recommended that only enzymes be and that the be or an The of enzyme therapy can be by following growth and stool the best objective available is a 72-hour fecal fat with calculation of a of fat formulas or patients formulas must have stool analyzed for fat using the method to avoid A variety of methods are to determine the of enzyme but are not yet available for clinical use This is an important Tests such as fecal elastase-1 and stool chymotrypsin are measures of pancreatic function but not establish the of enzyme A more of pancreatic enzyme replacement therapy can be in the of the Consensus Conference on Enzyme Therapy and To avoid it is recommended that enzyme should be less than lipase meal or less than lipase fat to Nutritional of is recommended for most infants as the primary of nutrition for the first of formulas can also be used. to from or is no more in patients with CF than in the general population. a than the standard 20 may be needed and can be by breast by or by the addition of fat and/or or feeding should continue for the first 12 months of milk can be used in the foods should be at to months developmental age according to the recommendations of the American of should be with or breast not or of and should be within the first in addition to the vitamin supplementation recommended for children with CF (Table and need to be given if the dietary intake is may in the breast or with CF. with especially the is (see For infants who are but not achieving their of growth, additional can be to with the addition of (e.g., Ross and/or fats such as or As infants are to it is important that the that children with CF should a diet that is to in fat and Parents and should be that this is to the usual nutritional for children CF. to this age, dietary intake and of physical activity from to to foods may with growth at this The should milk for the child with CF and fat milk for other members two years of Parents should avoid their children with CF low fat or low the of children establish and dietary is a social as well as a nutritional for patients with CF should about feeding to and to prevent before they become should be This is a period for of growth in children with CF in to limited for and enzyme and of disease may be responsible for this decrease in growth interventions should be considered in this age group if are identified. children must have a of and aspects of enzyme This is associated with nutrient to growth, pubertal development, and of physical activity. CF adolescent development and the general population. are more in this also increasing nutritional are at risk for nutritional failure This is an age when such as or disease, may nutrition Growth failure and pubertal may and at a of social and psychosocial Nutritional will be more effective if the patient as well as the may be more to to and body as a for nutrition than weight and disease status. Recommendations for and Specific dietary intake is an essential component of nutritional care of the patient with CF especially in the presence of pancreatic insufficiency. Patients with CF often require a fat intake to of than that recommended for the general population intake should be evaluated based on the pattern of weight and of fat stores. is no method to estimate the of an individual with CF. The clinical outcome is a steady of weight in growing and malabsorption can to the loss of vitamins that are with Patients with CF who are treated with pancreatic enzymes continue to fat-soluble also are for absorption of fat and fat-soluble patients with CF have malabsorption of as well as pancreatic Patients with CF who have disease or of the acid are at even risk for fat-soluble vitamin is evidence that patients with CF become of Recommendations for and replacement of these are given in and monitoring of nutritional is a of vitamin A and may also function as an It is a beta-carotene in patients with CF or A of studies have low serum of beta-carotene in patients with CF with can be corrected One a of on for patients that it may a Further evidence for a clinical is A A is important for and Pancreatic lipase is required to before In studies between and of CF patients have been to be vitamin A In one of adult CF patients were to have in The combination of these studies that A in CF is A is a so measured may low should not be at the of to the for D D to increase calcium D on because of the of osteoporosis and bone patients with CF to percent of patients with CF have been demonstrated to be in vitamin D children and adults and those in are more likely to have vitamin D levels, because of limited to is an to as well as and has been reported to be low in patients with CF, even in those pancreatic enzymes and multivitamins, and have been reported to percent of CF patients continue to have low serum vitamin supplementation K K in the of factors and with as well as in Since measurement of serum vitamin K is not has been used as a Although it is not widely available, by K or is a more sensitive of vitamin K Insufficiency of vitamin K leads to the of under vitamin factors. will of a while of suggested that vitamin K while using the more sensitive it to be very even if enzymes and are given are a of vitamin K. of the enteric by use can vitamin K In a of adults with CF who were vitamin K at of four times a not sufficient to This that recommendations for vitamin K replacement therapy may be and essential acid is in patients with CF, and can be seen in PS patients as well as in those who are PI However, clinical signs and symptoms are although should be considered in infants with failure to The in patients with are fats that can be to and acid acid is to acid and acid is to acid of to may be a factor in the increased seen in in patients with CF. has been that acid is a primary in CF (i.e., is not to fat supplementation is in patients with CF is the of no recommendations can be at the such as and and are in are a of energy and can be breast milk and should be for and dietary calcium recommendations for the general population have been has also been an increased of

The effect of several naturally occurring dietary flavonoids including quercetin, naringin, hesperetin, and catechin on the infectivity and replication of herpes simplex virus type 1 (HSV-1), polio-virus type 1, parainfluenza virus type 3 (Pf-3), and respiratory syncytial virus (RSV) was studied in vitro in cell culture monolayers employing the technique of viral plaque reduction. Quercetin caused a concentration-dependent reduction in the infectivity of each virus. In addition, it reduced intracellular replication of each virus when monolayers were infected and subsequently cultured in medium containing quercetin. Preincubation of tissue culture cell monolayers with quercetin did not affect the ability of the viruses to infect or replicate in the tissue culture monolayers. Hesperetin had no effect on infectivity but it reduced intracellular replication of each of the viruses. Catechin inhibited the infectivity but not the replication of RSV and HSV-1 and had negligible effects on the other viruses. Naringin had no effect on either the infectivity or the replication of any of the viruses studied. Thus, naturally occurring flavonoids possess a variable spectrum of antiviral activity against certain RNA (RSV, Pf-3, polio) and DNA (HSV-1) viruses acting to inhibit infectivity and/or replication.

Influenza virus is a globally important respiratory pathogen which causes a high degree of morbidity and mortality annually. The virus is continuously undergoing antigenic change and thus bypasses the host's acquired immunity to influenza. Despite the improvement in antiviral therapy during the last decade, vaccination is still the most effective method of prophylaxis. Vaccination induces a good degree of protection (60-90% efficacy) and is well tolerated by the recipient. For those at risk of complications from influenza, annual vaccination is recommended due to the antigenic changes in circulating strains. However, there is still room for improvement in vaccine efficacy, long-lasting effect, ease of administration and compliance rates. The mucosal tissues of the respiratory tract are the main portal entry of influenza, and the mucosal immune system provides the first line of defence against infection. Secretory immunoglobulin A (SIgA) and IgM are the major neutralizing antibodies directed against mucosal pathogens. These antibodies work to prevent pathogen entry and can function intracellularly to inhibit replication of virus. This review describes influenza virus infection, epidemiology, clinical presentation and immune system response, particularly as it pertains to mucosal immunity and vaccine use. Specifically, this review provides an update of the current status on influenza vaccination and concentrates on the two main types of influenza vaccines currently in use, namely the cold-adapted vaccine (CAV) given intranasally/orally, and the inactivated vaccine (IV) delivered subcutanously or intramuscularly. The commercially available trivalent IV (TIV) elicits good serum antibody responses but induces poorly mucosal IgA antibody and cell-mediated immunity. In contrast, the CAV may elicit a long-lasting, broader immune (humoral and cellular) response, which more closely resembles natural immunity. The immune response induced by these two vaccines will be compared in this review.

The present investigation examined the validity of the revised Hopkins Verbal Learning Test (HVLT-R). In a principal components analysis with varimax rotation, measures of new learning and delayed recall loaded on a single factor distinguishable from measures related to general cognitive function and visual memory. The HVLT-R also correlated most strongly with other tests of verbal memory and relatively weakly with a test of general intelligence. Group comparisons showed that normal controls performed better than age- and education-matched patients with probable Alzheimer's disease (AD) or vascular dementia (VaD). Discriminant function analyses and Bayesian statistics revealed high classification accuracies for dementia patients versus controls. When scores on the HVLT-R and other neuropsychological tests were subjected to discriminant function analyses, performance on the HVLT-R delayed recognition task was found to be the most useful in discriminating patients with AD from those with VaD. We conclude that the HVLT-R is a valid test of verbal learning and memory that is best suited for use with elderly patients suspected of dementia.

BACKGROUND: Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM- 1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. METHODS AND RESULTS: Constitutive expression of TNF-alpha and not IL-1beta was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-alpha in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-alpha in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-alpha. CONCLUSIONS: Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-alpha. We suggest that mast cell-derived TNF-alpha may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury.

Conclusions(1) The technic described measures all of the creatinine and only creatinine in blood and urine. (2) There is a gradual rise in the serum concentration and in the rate of urinary excretion of creatinine from one month of age to puberty, when adult levels are reached.

BACKGROUND: The intratracheal administration of a perfluorocarbon liquid during continuous positive-pressure ventilation (partial liquid ventilation) improves lung function in animals with surfactant deficiency. Whether partial liquid ventilation is effective in the treatment of infants with severe respiratory distress syndrome is not known. METHODS: We studied the efficacy of partial liquid ventilation with perflubron in 13 premature infants with severe respiratory distress syndrome in whom conventional treatment, including surfactant therapy, had failed. Partial liquid ventilation was initiated by instilling perflubron during conventional mechanical ventilation to a volume approximating the functional residual capacity. Infants were considered to have completed the study if they received partial liquid ventilation for at least 24 hours. RESULTS: Ten infants received partial liquid ventilation for 24 to 76 hours. In the other three infants, partial liquid ventilation was discontinued within four hours in favor of high-frequency ventilation, which was not permitted by the protocol, and the data from these infants were excluded from the analysis. Within one hour after the instillation of perflubron, the arterial oxygen tension increased by 138 percent and the dynamic compliance increased by 61 percent; the mean (+/- SD) oxygenation index was reduced from 49 +/- 60 to 17 +/- 16. Chest radiographs showed symmetric filling, with patchy clearing during the return from partial liquid to gas ventilation. There were no adverse events clearly attributable to partial liquid ventilation. Infants were weaned from partial liquid to gas ventilation without complications. Eight infants survived to 36 weeks' corrected gestational age. CONCLUSIONS: Partial liquid ventilation leads to clinical improvement and survival in some infants with severe respiratory distress syndrome who are not predicted to survive.