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Protein kinase D1 (PKD1), a ubiquitously expressed serine/threonine kinase, regulates diverse cellular processes such as oxidative stress, gene expression, cell survival, vesicle trafficking, Ag receptor signaling, and pattern recognition receptor signaling. We found previously that exposure to hypersensitivity pneumonitis (HP) inciting Ag Saccharopolyspora rectivirgula leads to the activation of PKD1 in a MyD88-dependent manner in various types of murine cells in vitro and in the mouse lung in vivo. However, it is currently unknown whether PKD1 plays a role in the S. rectivirgula–induced HP. In this study, we investigated contributions of PKD1 on the S. rectivirgula–induced HP using conditional PKD1-insufficient mice. Compared to control PKD1-sufficient mice, PKD1-insufficient mice showed substantially suppressed activation of MAPKs and NF-κB, expression of cytokines and chemokines, and neutrophilic alveolitis after single intranasal exposure to S. rectivirgula. The significantly reduced levels of alveolitis, MHC class II surface expression on neutrophils and macrophages, and IL-17A and CXCL9 expression in lung tissue were observed in the PKD1-insufficient mice repeatedly exposed to S. rectivirgula for 5 wk. PKD1-insuficient mice exposed to S. rectivirgula for 5 wk also showed reduced granuloma formation. Our results demonstrate that PKD1 plays an essential role in the initial proinflammatory responses and neutrophil influx in the lung after exposure to S. rectivirgula and substantially contribute to the development of HP caused by repeated exposure to S. rectivirgula. Our findings suggest that PKD1 can be an attractive new molecular target for therapy of S. rectivirgula–induced HP.

Asthma and influenza are leading causes of worldwide morbidity and mortality. Although these two conditions can co-exist in the same patient, the immune parameters that impact disease outcomes are not fully elucidated. The importance of macrophages to both conditions suggested a role for CD14, a co-receptor for endotoxin, as a regulatory mechanism for innate immune responses during asthma and influenza co-morbidity. Herein, we hypothesized that parameters of influenza morbidity will be reduced in the absence of CD14. Age and gender matched wild-type (WT) and CD14 knock-out (KO) mice were subjected to our validated model of Aspergillus-induced model of asthma and/or influenza. Characteristics of disease pathogenesis were investigated using standard methods in weight loss, flow cytometry, airway resistance, histology, quantitative real-time PCR, and viral titer quantification. The absence of CD14 did not have an impact on morbidity as these mice were equally susceptible to disease with similar airway resistance. Peribronchovascular inflammation and goblet cell content were equivalent between WT and KO mice in asthma alone and asthma and influenza co-morbidity. Co-morbid KO mice had less lymphocytes and eosinophils in the airways although their lung viral burden was equivalent to WT. Inflammatory gene signatures were altered in co-morbid mice in each genotype. CD14 expression on macrophages is necessary for airway inflammation but not for viral pathogenesis in allergic hosts.

Although the need for effective long-term follow-up for patients with celiac disease (CD) has been recognized by many expert groups, published practice guidelines have not provided a clear approach for the optimal management of these patients. In an attempt to provide a thoughtful and practical approach for managing these patients, a group of experts in pediatric CD performed a critical review of the available literature in 6 categories associated with CD to develop a set of best practices by using evidence-based data and expert opinion. The 6 categories included the following: bone health, hematologic issues, endocrine problems, liver disease, nutritional issues, and testing. Evidence was assessed by using standardized criteria for evaluating the quality of the data, grade of evidence, and strength of conclusions. Over 600 publications were reviewed, and 172 were chosen for inclusion. The thorough review of the results demonstrated that the quality of the data available was often insufficient to provide unequivocal best practices. However, using the available data and the clinical experience of the panel, a practical framework for the management of children with CD was created. These recommendations were developed by our expert panel and do not necessarily reflect the policy of the American Academy of Pediatrics. The potential usefulness of these best practices is underscored by the fact that consensus, measured by the outcome of anonymous voting, was reached by the panel for 24 of the 25 questions. We hope that these best practices may be useful to the pediatric gastroenterology and larger general pediatric communities.

The work of the National Center for Complementary and Alternative Medicine (NCCAM) has repeatedly been criticised. Much of this criticism relates to the past funding of studies of acupuncture. The aim of this article is to provide an independent, critical evaluation of the data produced by NCCAM-funded RCTs of acupuncture. Relevant studies were identified using PubMed. Studies were included if they were NCCAM-funded RCTs of acupuncture. Excluded were secondary reports of primary studies, RCTs not testing the effectiveness of acupuncture and National Institutes of Health-funded studies not mentioning NCCAM support. One author extracted the data according to predefined criteria and assessed the risk of bias. The other authors verified these tasks. Thirteen RCTs were included, with sample sizes ranging from seven to 570. Most studies reported pain as the primary outcome. Six RCTs suggested acupuncture was effective. Seven RCTs had a low risk of bias. Numerous methodological shortcomings were identified. Many NCCAM-funded RCTs of acupuncture have important limitations. These findings might improve future studies of acupuncture and could be considered in the ongoing debate regarding NCCAM-funding.

Despite gains in controlling mortality relating to diarrhoeal disease, the burden of disease remains unacceptably high. To refocus health research to target disease-burden reduction as the goal of research in child health, the Child Health and Nutrition Research Initiative developed a systematic strategy to rank health research options. This priority-setting exercise included listing of 46 competitive research options in diarrhoeal disease and their critical and quantitative appraisal by 10 experts based on five criteria for research that reflect the ability of the research to be translated into interventions and achieved disease-burden reduction. These criteria included the answerability of the research questions; the efficacy and effectiveness of the intervention resulting from the research; the maximal potential for disease-burden reduction of the interventions derived from the research; the affordability, deliverability, and sustainability of the intervention supported by the research; and the overall effect of the research-derived intervention on equity. Experts scored each research option independently to delineate the best investments for diarrhoeal disease control in the developing world to reduce the burden of disease by 2015. Priority scores obtained for health policy and systems research obtained eight of the top 10 rankings in overall scores, indicating that current investments in health research are significantly different from those estimated to be the most effective in reducing the global burden of diarrhoeal disease by 2015.

ResearchDetermine the age of acquisition of H. pylori infection in diverse populations and the mode of transmission.InterventionValidate noninvasive methods for determining H. pylori colonisation in childhood.EducationTrain physicians to identify early indicators of long-term morbidity (i.e., gastri

The transjugular intrahepatic portosystemic shunt procedure is an accepted treatment for adults with complications of portal hypertension. We performed a retrospective review of all pediatric TIPS placements performed at the University of California, San Francisco between 1990 and 1996. Twelve procedures were attempted in nine children, with a mean age (+/- SD) of 9.4 +/- 3.9 years (range, 5 to 15 years) and a mean weight of 31 +/- 18 kg (range, 16 to 70 kg). The indications for TIPS placement were portal hypertension complicated by chronic variceal hemorrhage not controlled with sclerotherapy (n = 7) and hypersplenism with thrombocytopenia (n = 2). TIPS placement was successfully completed initially in seven of nine (78%) patients. Unfavorable vascular anatomy was the cause of failure in two cases. The seven patients who underwent successful TIPS placement were followed up for an average of 136 days (range, 1 to 800 days); two still have patent shunts, three underwent liver transplantation, one had a splenorenal shunt after stenosis, and one died of underlying liver disease. Variceal bleeding was controlled in four of five patients who successfully underwent TIPS placement. Shunt occlusion occurred in four patients; patency was restored by transjugular shunt revision in three, and a splenorenal shunt was performed in one.

We prospectively studied clinical outcome and nutrition absorption in male children (6-36 months of age) with persistent diarrhea (PD) and severe protein-energy malnutrition (mean z score for age, -4.2 +/- 0.8). Fifty-one children were randomly allocated to receive a combination of khitchri, a rice-lentil mixture, yogurt, and half-strength buffalo milk (group A; n = 26) or full-strength soy formula (group B; n = 25) for 14 days. The initial caloric intake (p < 0.02) and mean weight gain (p < 0.02) were greater in the group B patients. The mean stool volume and frequency were comparable between the two groups. Seven children in group A were considered clinical failures by criteria of weight loss and PD, compared to three in group B. The coefficients of absorption (COA) for protein were similar between the two groups, but group B patients had higher values of COA for energy and fat (p < 0.05) in the second week of nutritional rehabilitation. The majority (63%) of the children improved on the khichri-yogurt-milk diet but the nutritional outcome was not as good as with the soy formula. These data indicate that a traditional diet can be successfully used in the dietary management of PD and severe malnutrition but that a more optimal composition, yielding a higher success rate, should be sought.

Serum retinol and hemoglobin levels were determined in 532 children aged 6-60 months living in urban slums of Karachi, Pakistan. Overall 67% (358 of 532) of children had hemoglobin levels of less than 11 g/dl, the World Health Organization definition of anemia for this age group. Estimations for red blood cell indices (hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and red blood cell count) were done on a sample of 391 children to classify anemia morphologically. A similar percentage (69.8% [273 of 391 children]) of anemia was found in this group. The anemia was predominantly microcytic and hypochromic. Normocytic normochromic anemia was present in only 16.5%. Serum retinol levels were significantly correlated with hemoglobin (P < 0.002), hematocrit (P < 0.01), and red blood cell (P < 0.001) levels. However, anemia was found to be a poor predictor (positive predictive value [PPV] = 2.5%) for the presence of vitamin A deficiency (retinol < 10 micrograms/dl). The PPV increased to 54% if 20 micrograms/dl, which is an indicator of marginal vitamin A status, was used as the cutoff point. The sensitivity of the hemoglobin test was found to be 75% in correctly identifying vitamin A deficiency when retinol levels of 10 micrograms/dl and 20 micrograms/dl were both used as the cutoff points for deficiency. The specificity for the hemoglobin test varied from 33% to 40% when levels of 10 micrograms/dl and 20 micrograms/dl were used as the cutoff points for vitamin A deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine how closely US pediatricians follow the 1985 American Academy of Pediatrics Committee on Nutrition's recommendations on oral therapy for acute diarrhea, a questionnaire was administered to four groups: New England private practitioners, pediatricians from 27 states attending a postgraduate course, representatives of departments of pediatrics at US schools of medicine, and housestaff at Boston Children's and Massachusetts General hospitals. The responses from departments of pediatrics and housestaff were not significantly different from those of community practitioners in most categories. The reported rate of use of glucose-electrolyte solutions recommended by the American Academy of Pediatrics was not different from the use of nonphysiologic, high-osmolar, low-salt solutions such as sodas and juices. The usage rate for glucose-electrolyte solutions meeting the American Academy of Pediatrics-recommended carbohydrate-to-sodium ratio of less than 2:1 was less than 30%. Other findings included the general lack of agreement on the use of a single type of therapy and the common use of oral therapy only for mild or no dehydration. Although the American Academy of Pediatrics recommends that feeding be reintroduced in the first 24 hours of a diarrheal episode, the majority of respondents withhold feeding until the second day or later. These findings indicate that educational programs on oral therapy during acute diarrhea are needed in the United States.

The objective of this project is to characterize the programming speed and the programming voltage requirements of floating gate EEPROM cells made in a generic CMOS process (e.g. a MOSIS tiny chip - AMI C5N 0.5 micron technology). The charge trapping and injection is based on carrier injection using cold tunneling (Fowler-Nordheim effect). The variable constraints are the sizes of the injector capacitors and control gate capacitors. All necessary positive voltages will be generated using a charge pump requiring a single power supply.

Rice based oral rehydration therapy (ORT) solutions have been shown to be superior to glucose oral rehydration salts (World Health Organisation (WHO) ORS) in reducing stool volume and duration of diarrhoea in children and adults. Rice based ORT has been used only sparingly in young infants, however, because of theoretical concerns about digestibility. A randomised controlled trial of rice based ORT (50 g rice and electrolytes identical to WHO ORS) and WHO ORS was carried out in 52 male infants less than 6 months old with moderately severe acute diarrhoea to evaluate efficacy and digestibility. Nineteen (70%) of 27 children who received rice based ORT and 18 (72%) of 25 children who received WHO ORS were treated successfully. The mean (SD) diarrhoeal stool output for the first 24 hours of treatment was significantly lower in the infants receiving the rice based ORT than in those receiving WHO ORS (101.0 (60.5) v 137.1 (74.6) g/kg). The stool output was also significantly less in the rice based ORT group in the second 24 hours. Infants in the rice based ORT group drank significantly less rehydration solution than infants in the WHO ORS group (mean (SD) 165.4 (77.4) v 217.9 (86.1) during the first 24 hours of treatment. There was no difference in the duration of diarrhoea between the groups. The volume of breast and formula feeding was similar in the two groups. No difference was seen in the frequency of finding reducing substances or acid pH in the stools of either group of children. The results suggest that rice based ORT is as effective as WHO ORS in infants with moderately severe diarrhoea and that rice based ORT is as well tolerated as WHO ORS in infants.

We assessed the vitamin A status of 532 children with an age range of 6-60 months who were living in slum areas of Karachi, Pakistan, using three methodologies: clinical eye examination, dietary vitamin A intake, and serum retinol level. No definite clinical signs of xerophthalmia were observed in any of these children. The mean +/- SD vitamin A intake estimated from a food frequency questionnaire for the group with inadequate (low and deficient) serum retinol levels (20 micrograms/dl) was 362 +/- 332 retinol equivalents (RE) compared with 431 +/- 332) RE in the group with adequate serum levels (P0.005). Deficient serum retinol levels (10 micrograms/dl) were present in 12 children (2%); two of these had a healed corneal scar. Low serum retinol levels (10-19 micrograms/dl) were present in 46%, while 51% children had adequate levels (or = 20 micrograms/dl). The mean +/- SD serum retinol level for the inadequate (20 micrograms/dl) and adequate groups were 15.3 +/- 2.8 and 26.6 +/- 6.7 micrograms/dl, respectively. These results suggest that a significant number of children in these communities have low vitamin A levels and thus may constitute an at risk group. These results also suggest that the dietary intake method may be a simple and inexpensive screening tool for assessment of vitamin A status in communities.

An educational program on oral rehydration therapy (ORT) for diarrhea was instituted in our residents' continuity clinics to evaluate the impact that residents teaching parents would have on the knowledge and practices of both groups. Sixty-one residents and 287 parents answered the initial written questionnaire before the teaching program began, and 48 residents and 147 parents completed a second questionnaire at the end of the program. Nineteen residents in two clinics were told to participate frequently in teaching the parents, while 29 residents in three other clinics were given no such instructions. The parents were divided into three groups: 58 received teaching and an instructional handout on the management of diarrhea; 73 received only the instructional handout; and 16 received neither intervention. The 19 "teaching" residents had a significantly improved overall score compared with the "nonteaching" residents (p

Although the causes of persistent diarrhea are largely unknown, dietary protein sensitivity has been identified as one possible mechanism. Since nutritional therapy appears to be an essential component of treatment for persistent diarrhea, a clearer understanding of the importance of dietary protein allergy is needed to provide optimal dietary recommendations. This paper reviews the current concepts of the pathophysiology, clinical features and criteria for diagnosis of dietary protein sensitivity. Evaluation of the results of several clinical studies indicates that dietary protein sensitivity does occur especially in young infants fed cows' milk but that it is an uncommon event, especially in older infants and children.

In a prospective study we randomized 102 male children (age 6-36 months) with persistent diarrhea to receive a traditional rice-lentil (Khitchri) diet and yogurt (K-Y) or a soy formula (alone for seven days and then in combination with K-Y for seven days). Of 73 children satisfying the study criteria, 66 were successfully treated and there were 7 treatment failures. There was poor concordance between parental accounts of severity of diarrhea or vomiting and that observed after admission. Significant risk factors associated with treatment failure included younger age (p0.005) and vomiting at presentation (p0.02). The greatest number of risk factors associated with delayed recovery (10 days) were identified during an initial evaluation period (the first 8 h after admission). These included greater severity of watery diarrhoea (p0.01) and increased ORS intake (p0.02). Our data suggest that an initial evaluation period, including objective observations, may identify children with persistent diarrhea who are at greatest need of hospitalization.

The Department of Child and Adolescent Health and Development (CAH) of the World Health Organization (WHO) and the Child Health and Nutrition Research Initiative (CHNRI) applied the CHNRI priority- setting methodology to address research priority issues on childhood diarrhoea to improve the rate of progress in reducing global diarrhoea mortality by 2015, as set out in the UN’ s Millennium Development Goal #4. CAH/WHO invited 24 technical experts to systematically list and then score 154 research questions on diarrhoeal diseases according to likelihood of their (i) answerability, (ii) potential contribution to effectiveness, (iii) deliverability, affordability and sustainability, (iv) maximum potential for death burden reduction and (v) predicted effect on equity. The top 10% of research investment priorities were dominated by health systems and policy research questions and epidemiological questions. They were mainly targeted at better understanding the barriers towards implementation, the effectiveness and optimization of use of available interventions and programmes such as oral rehydration solution, zinc supplementation, exclusive breastfeeding and integrated management of childhood illness.

Feeding practices may have an important impact on diarrheal diseases in developing countries. This study evaluated feeding practices in three groups of male children aged 6-36 mo: 100 with persistent diarrhea (PD), 79 with acute diarrhea (AD), and 86 in a comparison group (CG). The children came from comparably poor socioeconomic settings in Karachi, Pakistan, except that the literacy rates were higher in mothers of the CG (P = 0.0001). Although greater than 95% of all infants were breast-fed, delayed initiation of breast-feeding was more common in the diarrhea groups. Children with diarrhea were also more likely to receive supplemental milk (PD = 92%, AD = 87%) than were children in the CG (69%, P less than 0.05). Feedings were not withheld during diarrhea but changes were made in the nature of foods given. These results indicate that several feeding practices may be important risk factors for diarrhea in Pakistan.

Since few data are available on epidemiologic features of Barrett's esophagus in young persons, we reviewed the case records of patients undergoing esophageal biopsies at Children's Hospital, Boston, from 1982 through 1986. There were 1423 esophageal biopsies obtained from 1173 patients, and histological evidence of esophagitis was present in 397 cases; Barrett's epithelium was diagnosed in 10 patients (0.9% of total and 2.5% of esophagitis cases). Specialized columnar epithelium was present in seven of these 10 patients. The mean age of those with Barrett's epithelium was 19.0 +/- 7.9 years (range 3.7-27 years) compared to 8.7 +/- 6.7 years (range 4 days to 31 years) for all patients biopsied (P less than 0.0001); 80% (8/10) of the Barrett's cases were male compared to 54% of all cases. The relative importance of the possible risk factors was assessed by comparing the 10 patients with Barrett's with the 541 patients that had esophageal biopsies in calendar years 1984-1985. Mental retardation, a risk factor not previously described for young persons with Barrett's esophagitis, was present in 70% (7/10) of the Barrett's patients but in only 15% of all patients biopsied (P less than 0.0002). The frequency of mental retardation was also higher, but not significantly so (P greater than 0.07), in patients with biopsies that were positive for esophagitis (19%) than in those with normal biopsies (14%). No significant differences were found between the Barrett's group and all patients biopsied in regards to racial origin, prior stricture, or fundoplication.

IN an editorial in the Journal in 1982,1 Charles Carpenter wrote: We physicians all presumably accept the "primum non nocere" principle. On the basis of... studies... this principle would dictate that oral rehydration be accepted not only as an equal, but perhaps as the superior, means of treating acute diarrheal illnesses in the sophisticated and sanitized medical centers of the Western world as well as in rural Bangladesh. Despite such editorials based on the large volume of research data available and despite the endorsements of such organizations as the American Academy of Pediatrics, the World Health Organization (WHO), and the . . .

The discovery in the mid-1960s of the coupled transport of sodium and glucose across the intestinal mucosa led directly to the development of oral rehydration therapy, which has become the critical...

Background. H pylori infections are implicated as the cause of nearly all primary (no other known cause) gastritis (PG), especially primary chronicactive gastritis (PCAG). Recent data in adults and children suggest that the association of H pylori and primary gastric and duodenal ulcers may be less than previously reported. To determine whether the association of H pylori and PCAG in children is also lower than initially thought, we reviewed the biopsies of all children undergoing upper GI endoscopy (EGD) at UCSF. Methods. Gastric biopsies obtained from children at UCSF from 1/1/98-8/1/99 were reviewed in a blinded fashion by one GI pathologist. At least 3 specimens from the antrum, fundus, and/or cardia were obtained from each child and were stained with hematoxylin and eosin. Histologic evidence of inflammation was evaluated using the modified Sydney criteria. Specimens demonstrating PCAG but no H. pylori were stained with Giemsa. Patients were excluded from the analysis if they had a known cause for PG. Results. Biopsies from 153 patients (56% male) were evaluated. The mean age was 8.7 (±5.5, std dev) years for all patients, 11.6 (±4.9) years for patients with PCAG and 12.7 (±4.1) years for those with H pylori . The Table shows the rates of PG, PCAG, and H. pylori: All children with H pylori had PCAG but nearly half of the children with PCAG (10/22) had no evidence of H pylori. Significantly more older children (10-20 yrs) had PCAG (p H pylori is a common cause of PCAG but nearly half of the cases of PCAG are idiopathic. These data indicate that the association of H pylori and PCAG is lower than suggested by published reports.

As Dr O'Banion points out, most of the oral therapy solutions available in the United States are classified as maintenance solutions by the American Academy of Pediatrics (AAP). However, as mentioned in the paper, these solutions have proven to be very effective treatment for children with dehydration in this country. Solutions conforming to the AAP recommendations as rehydration solutions are not as widely available in this country. The WHO/UNICEF oral rehydration salts formulation, which is supplied as inexpensive packets throughout the world, is not found easily in the US.