Nephrotic syndrome (NS) represents a common disease in pediatric nephrology typified by a relapsing and remitting course and characterized by the presence of edema that can significantly affect the health-related quality of life in children and adolescents. The PROMIS pediatric measures were constructed to be publically available, efficient, precise, and valid across a variety of diseases to assess patient reports of symptoms and quality of life. This study was designed to evaluate the ability of children and adolescents with NS to complete the PROMIS assessment via computer and to initiate validity assessments of the short forms and full item banks in pediatric NS. Successful measurement of patient reported outcomes will contribute to our understanding of the impact of NS on children and adolescents.This cross-sectional study included 151 children and adolescents 8-17 years old with NS from 16 participating institutions in North America. The children completed the PROMIS pediatric depression, anxiety, social-peer relationships, pain interference, fatigue, mobility and upper extremity functioning measures using a web-based interface. Responses were compared between patients experiencing active NS (n = 53) defined by the presence of edema and patients with inactive NS (n = 96) defined by the absence of edema.All 151 children and adolescents were successfully able to complete the PROMIS assessment via computer. As hypothesized, the children and adolescents with active NS were significantly different on 4 self-reported measures . Depression, peer relationships, and upper extremity functioning were not different between children with active vs. inactive NS. Multivariate analysis showed that the PROMIS instruments remained sensitive to NS disease activity after adjusting for demographic characteristics.Children and adolescents with NS were able to successfully complete the PROMIS instrument using a web-based interface. The computer based pediatric PROMIS measurement effectively discriminated between children and adolescents with active and inactive NS. The domain scores found in this study are consistent with previous reports investigating the health-related quality of life in children and adolescents with NS. This study establishes known-group validity and feasibility for PROMIS pediatric measures in children and adolescents with NS. Children with nephrotic syndrome (NS) represent a unique patient population in pediatrics. The sigA number of disease characteristics inherent to NS including the presence of edema, repeated corticosteroid exposures, and the relapsing nature of NS pose particular challenges to patient HRQOL. Recent http://www.nihpromis.org). In the first phase of PROMIS, 9 item banks were developed for measurement of child self-reported outcomes: depression, anxiety, social-peer relationships, pain interference, fatigue, mobility, upper extremity, anger, and asthma impact[The Patient Reported Outcomes Measurement Information System (PROMIS) project was established as part of the National Institutes of Health Roadmap Initiative to create item banks for both adults and children, which are publically available, efficient, precise, and valid across a variety of diseases to assess PROs  and included 151 pediatric patients with NS from 16 participating member institutions. Each site obtained individual institutional Institutional Review Board approval. Parents and children gave informed consent and assent respectively, prior to performing the study.Personnel at each site (investigators and study coordinators) received web-based training in study procedures; the study operations manual was a reference tool for study conduct, quality control, and recruitment. Ongoing education of site personnel occurred during investigator and coordinator conference calls.Consistent with the target age for the PROMIS pediatric item banks, the PROMIS NS cohort study included children 8-17 years. The NS eligibility criteria included presence or history of proteinuria  and/or a kidney biopsy that confirmed a NS-inducing condition. Another eligibility criterion was the ability to speak and read English. Exclusion criteria included co-existing medical, psychiatric, or cognitive impairments that would prevent the patient from answering the computer administered questionnaire.Both the parent and child completed questionnaires. The parent completed the Family and Medical Information form, which included relationship to child, guardian education level, socioeconomic, and disease specific questions. Child and disease characteristics included: gender, age, race, ethnicity, disease etiology, dialysis, transplant, co-existing conditions, hospitalizations in the previous 6 months , surgery in the previous 12 months, number of medications, corticosteroid therapy, self-rated edema status, and the guardian’s perception of the child’s weight status . Clinical data such as diagnosis, kidney function represented by estimated glomerular filtration rate (eGFR), chronic kidney disease stage with a higher stage equivalent to poorer kidney function, and stehttp://www.nihpromis.org/measures/domainframework1. All of these PROMIS items use the context statement “In the past 7 days.” Responses included 5 options ranging from “never” to “almost always” in the majority of domains and from “with no trouble” to “not able to do” for the physical functioning measures. Each PROMIS pediatric domain generates a T-score with a mean of 50 and a standard deviation of 10. The mean of 50 reflects the calibration population and does not represent the general population or other specific group. Higher scores indicate more of the measured symptom, thus signifying worse symptoms of depression, anxiety, fatigue, and pain interference and better functioning for mobility, upper extremity, and peer relationships. These measures have been previously tested in a large group of children and adolescents, confirming their unidimensionality and the extent to which each item is associated with the measured variable (http://www.assessmentcenter.net)[The children completed the PROMIS pediatric depression, anxiety, social-peer relationships, pain interference, fatigue, mobility, and upper extremity functioning domains using a web-based interface. The definitions of the domains are located at ter.net),10-13. Pter.net),10,12,13In order to decrease the response burden, a sampling plan was devised and is summarized in Table Participants were randomly assigned to one of two study arms by the PROMIS Assessment Center after they were registered to take the survey. In total, participants completed 70 to 90 questions over 30 to 40 minutes using this strategy.When full bank data were collected, a short-form score was also calculated. The full item bank and short form domain scores for depression, anxiety, pain interference, fatigue, upper extremity functioning, and mobility were highly correlated, Pearson’s R ranging 0.95-1.0. Consequently, the short form results for all domains are presented here.Descriptive summary statistics were calculated as frequencies and percentages for demographic and clinical characteristics and as means and standard deviations for eGFR scores and number of medications. Mean scores as well as standard deviations were calculated for each of the 7 domains by full bank and short form. To assess the association of full bank and short-form scores, Pearson’s correlations were calculated where applicable. Known-group validity was assemvregress. The EM algorithm is known as a very powerful statistical approach to carrying out statistical analyses with missing data because in this algorithm the distribution of missing data, instead of imputed values, are utilized in the estimation and inference. With the exception of the mvregress simultaneous regression analysis, all other statistical analyses were conducted using SAS v9.2.Although missing clinical data were minimal, two patient reported outcome (PRO) domain scores (Pain Interference and Fatigue) have responses from 50% of patients by design of this study. Note that the other 5 PRO scores are available for the entire cohort. We applied the Expectation-Maximization (EM) algorithm to handlChild demographic, disease characteristics, and guardian demographic characteristics are presented in Table Four children (2.6%) had missing scores for at least one of the PROMIS domains. Four of 151 (2.6%) ended the survey early, so that measures at the beginning of administration were completed but responses were missing at the end of the administration. Thirty-three of 151 (22%) skipped one or more PROMIS questions within the administration. A missing value analysis examined patterns of missingness by the type of measure administered (full bank or short form), by domain, and by patient age. The domains were administered in random order and no pattern of missingness was observed.p =0.007), and the social-peer relationship scores were worse in children of Hispanic ethnicity compared to those not in the Hispanic ethnic group (p = 0.02).The mean scores for the PROMIS domains ranged from 43.9 (fatigue) to 52.5 (upper extremity functioning). There were no differences in the PROMIS measures by gender. However, the PROMIS fatigue domain scores were associated with race (p = 0.04). The remaining domains were not significantly different.As hypothesized, mean scores for several PROMIS domains differed between the NS active and NS inactive groups. Children and adolescents with active NS had significantly worse scores than participants with inactive NS on 4 of the 8 measures, including anxiety, pain interference, fatigue, and mobility (Effect Sizes 0.56-0.79). The two groups did not differ on upper extremity functioning, depression, and social-peer relationships in bivariate analysis Table . An analp = 0.001, p = 0.01, p < 0.001, and p < 0.001, respectively). There was no evidence for gender differences over the 7 PROMIS domains. Child age was found to be associated with upper extremity functioning scores, such that older children had better upper extremity functioning (p < 0.001). Hispanic ethnicity was predictive of worse social-peer relationship (p =0.003), upper extremity functioning (p = 0.05) and mobility (p = 0.03) scores. Children whose guardians had higher education reported lower (better) pain interference scores (p = 0.006). Black children reported higher pain interference scores compared with white children (p = 0.04). The pain interference scores of Asian children were not different. A sensitivity analysis was performed with the exclusion of children who had CKD stage V or renal transplants. There were 120 patients included in this analysis and the analysis demonstrated no change in the domains that were significant compared to the full model with only minimal changes in the magnitudes of the differences in domain scores (data not shown).Regression analysis of all 7 domain scores with covariates of interest, including NS disease activity, gender, age, ethnicity, guardian education, and race, was conducted. This method enables us to borrow information across the PROMIS domain scores. To address the challenge of the 50% administration scheme for 3 domain scores, the EM algorithm was used to derive estimates and p values. Results of the simultaneous regression are reported in Table Confirmatory analysis was conducted using data available as collected to evaluate if missing data impacted the results of the simultaneous regression. Simultaneous regression of the 5 PROMIS domain scores completed by all participants had similar results; anxiety and mobility were sensitive to disease activity. In individual regression models for the remaining 2 domains, results were also similar to the simultaneous regression, where disease status was predictive of domain scores for pain interference and fatigue. However, race and ethnicity were not found to be significant predictors of anxiety, upper extremity functioning, mobility, or pain interference.We report the largest study to date evaluating PRO in children with NS. This North American multi-center study sought to evaluate known-group validity of the PROMIS pediatric measures with a large group of children with NS as an exemplar chronic health condition. Children with NS were able to complete the PROMIS instrument using a web-based interface. This study demonstrated that the PROMIS domains were responsive to NS disease activity using the presence or absence of edema as an indicator of active disease. Children with active NS demonstrated worse functioning in the domains of anxiety, pain interference, fatigue, and mobility when compared to children with inactive disease. These differences were in the domains and expected direction for children affected by active NS.The PROMIS instruments have been created through a National Institutes of Health initiative to improve the assessment of PROs. PreviouThe long-term impacts of childhood kidney disease have been addressed in longitudinal studies involving children. In children initiating dialysis, psychological problems have been identified and often persist into adulthood,26. ReceEdema represents one of the most visibly evident symptoms of NS. Patients with NS are prone to edema as their disease process relapses or proves resistant to available therapies. In those with NS, edema is often the only overt sign of disease activity, but does not necessarily reflect disease progression. The impact of edema on patients includes altered physical appearance, mobility challenges, and pain. The PROMIS instrument yielded PRO data that are consistent with previous reports showing that children with NS are vulnerable in the areas of emotional well-being and mobility,3,5,7. PThe PROMIS measures performed as we had anticipated in their ability to distinguish differences in PROs in individuals with active NS. Furthermore, our observed relationships between patient demographics and PROs are consistent with previous published reports in children with kidney disease and other chronic diseases. We describe that gender does not influence the outcomes of PROs in children with NS. This is consistent with previous reports and the recent findings of Gerson et al in their descriptions of children with mild to moderate chronic kidney disease,27, indiA potential limitation of this study is that it utilized an internal comparative patient population rather than healthy controls. However, this design allowed us to demonstrate the strength of the PROMIS instrument in that it can detect clinically meaningful differences within a patient population with a range of disease severity. The PROMIS pediatric self-report instruments are limited to ages 8-17. A parent proxy-report instrument is currently being validated for ages 5 to 17. At the time of this study, only an English version of the PROMIS pediatric instruments was available. Consequently, this study included only children with English literacy. Lastly, this study was cross-sectional and does not document longitudinal changes. A longitudinal study validating the responsiveness of the PROMIS measures in patients with NS during episodes of relapse and remission is currently underway.Specific strengths of this study include the inclusion of patients from a wide variety of participating centers across North America. This represents one of the broadest patient samplings studying PROs in children with NS and supports the potential generalizability of these results.This study suggests possible strengths and limitations of the PROMIS instrument for children with NS. The instrument allows the assessment of factors that are important from the patient perspective but which may not receive due attention in the research or office setting. The availability of the instrument in a web-based format allows the collection of data in home and office settings for ease of administration. Auto scoring functions may facilitate the timely review and integration of the most concerning areas if implemented within the clinical care environment. This study suggests that domains of anxiety, pain, fatigue, and mobility but not depression change with disease status. This study also demonstrates the consistent results from long or short forms. As the PROMIS measures were developed to allow the selection of domains of relevance to a particular population, the number of domains and items selected for use in research or clinical settings can be tailored to minimize response burden. Limitations of the instrument most relevant to pediatric NS are the minimum age for self-report of 8 years and a lack of multiple language versions . Incident pediatric NS affects all ages but a disproportionate number affects children under the age of 5 years. The absence of self-report below age 8 years and absence of parent proxy report for children less than 5 years is a gap that requires attention if PROMIS is to gain widespread implementation across the affected population.Children and adolescents with NS were able to successfully complete the PROMIS measures using a computer-based interface in an outpatient setting. The PROMIS pediatric instruments were sensitive to differences in clinical status in the largest multi-center study to date of children with NS in North America to date. Specifically, we demonstrated that children with active NS had an increased burden in the domains of pain interference, anxiety, fatigue, and mobility relative to children in remission. The next step in the PROMIS validation process for children will be to evaluate self- and parent-proxy report PROMIS in a longitudinal study and to quantify the minimally important differences in change in PROMIS scores in patients with NS.PRO: Patient reported outcomes; PROMIS: Patient reported outcomes measurement information system; NS: Nephrotic syndrome; ESRD: End stage renal disease; HRQOL: Health-related quality of life; eGFR: estimated glomerular filtration rateThe authors declare that they have no competing interests. The authors have no financial relationships or conflicts of interest relevant to this article to disclose.DTS, LW, BWP, DSG, KLM, DAD, HEM, DT: Drafting the manuscript revising it critically for important intellectual content. DSG, SFM, EH, CB, MEF, JDM, LAG, JM, GK, DHC, JG, GMB, DG, DBK, CGP, RG, GH, JL, JDL,: Substantial contributions to the acquisition of data and execution of the study at the multiple sites including site principle investigators. DSG, KLM, JM, DT, YL, HEG, DAD: Substantial contributions to conception and design. Design and execution of the study, scoring of the PROMIS instruments, analysis of the PROMIS scores, and interpretation of data. Drafting the article or revising it critically for important intellectual content. All authors read and approved the final manuscript.


Over 290,000 patients are undergoing hemodialysis (HD) in Japan. With old age, the odds of undergoing HD treatment sharply increase, as does the prevalence of cognitive impairment. The aim of the present work was to assess cognitive impairment in HD patients and its relation to clinical characteristics.Using a cross-sectional design, we administered the Mini-Mental State Examination (MMSE) to 154 HD outpatients and 852 participants from the Iwaki Health Promotion Project 2010, representing the general population.The prevalence of cognitive impairment based on the MMSE was 18.8% in HD patients. HD patients showed a higher prevalence of cognitive impairment in older groups (50 years and older). In a logistic regression model with age, gender and amount of education as covariates, undergoing HD was a significant independent factor  associated with a lower MMSE score. Among HD patients, we found that level of education was associated with MMSE score.There is a high prevalence of cognitive impairment among HD patients that has adverse implications for hospitalization and shortens their life expectancy. HD treatment was an independent risk factor for cognitive impairment. Clinicians should carefully monitor and treat cognitive impairment in HD patients. Further studies are required to determine the reasons for cognitive impairment in HD patients. Advances in medical technology and improvements in public health have brought about a progressive increase in the population undergoing hemodialysis (HD). Over 290,000 patients receive HD in Japan, which has the world's highest rate of dialysis treatment  as of December 2009 . The preRecently, the relationship between HD and cognitive impairment has attracted attention -5, and iThe etiology of cognitive impairment among HD patients is thought to be multifactorial, and includes factors such as cerebrovascular lesion ,8, hypotThere have only been a few studies ,4,17 thaIn this study, we assessed the risk factors for cognitive impairment in HD patients and investigated the prevalence of cognitive impairment among HD patients compared with that of the general population in Japan. To the best of our knowledge, this is the largest study to date to assess the effect of HD on cognitive function and the first report comparing HD patients with the general population in Japan.This study was conducted between September 2009 and January 2010. A total of 154 patients  undergoing HD were recruited at Oyokyo Kidney Research Institute in Japan. Demographic data  were obtained from self-questionnaires and interviews. Clinical information  was obtained from medical charts. Blood sampling was performed no later than 2 weeks prior to cognitive assessment. Red blood cell count, albumin, sodium, potassium, uric acid, creatinine, blood urea nitrogen and amount of hemodialysis were also measured by standard analytical techniques. As a reference group, 852 healthy volunteers  who participated in the Iwaki Health Promotion Project 2008 were also included. The data collection for this study was approved by the Ethics Committee of the Hirosaki University School of Medicine and all subjects provided written informed consent before participating in this study.The MMSE  was giveP <0.05 was considered significant. The unpaired Student's t test was performed to analyze continuous variables, and a χ2 test or Fisher's exact test was performed to analyze categorical variables. Although we divided the subjects into age subgroups by decades, the age-specific prevalence of a lower MMSE score was analyzed across three larger groups  due to the small sample size of each smaller subgroup. To assess the relationship between undergoing HD and poor cognitive function, a logistic regression analysis was performed after adjusting for confounding factors . In addition, a logistic regression analysis was also applied to determine the factors associated with MMSE score among the HD patient group. The data were analyzed using the PASW Statistics software (version 18.0.0) for Windows .Data are presented as mean ± SD. A value of The prevalence of cognitive impairment based on the MMSE score was 18.8% among HD patients and 6.0% among control. Table Table P < 0.10).The results of a logistic regression model that included age, gender, amount of education, duration of hemodialysis, red blood cell count, albumin, sodium, potassium, uric acid, creatinine, blood urea nitrogen, dry weight, amount of hemodialysis, and comorbidities are shown in Table In Japan, the mean age of HD patients has changed considerably over time, from 48.3 years old in 1983 to 65.8 years old in 2009 ,21. CognIn this study, 18.8% of HD patients were classified as having cognitive impairment. Among those who were 50 years or older, the prevalence of cognitive impairment was higher among HD patients than among the controls. We also found that HD patients had higher risk for poor cognitive function even after adjusting for covariates. Among HD patients, level of education was associated with MMSE score. In addition, serum sodium level, dry weight and history of cerebrovascular disease tended to associate with MMSE score of HD patients.Table et al. [The logistic regression analysis of risk factors associated with lower MMSE scores is shown in Table et al.  showed aet al.  showed tPrevious studies have shown a relationship between cerebrovascular disease and cognitive impairment ,24. The P = 0.05) between hyponatremia and the MMSE score among HD patients. This relationship was also reported in a previous study by Maugeri et al. [We also found a relationship (i et al. . Hyponati et al. . These fThere are several limitations to our study. First, we administered only the MMSE for assessing the cognitive function. Although the MMSE is suitable for screening of some cognitive functions including orientation to place and time, short-term memory, episodic long-term memory, subtraction and attention, the MMSE score does not always reflect the cognitive function exactly; it is known to sometimes be influenced by the education level of the subject. Improved detection of cognitive impairment among HD patients is required in future studies. Second, this was a cross-sectional study; thus, associations between HD and cognitive impairment suggest, but do not provide evidence for a causal relation. It is necessary to conduct a longitudinal study to clarify the reason for impaired cognition in HD patients. Third, not all possible parameters were included in this study such as dietary habits, atherosclerosis, genetic factors and medications. Further investigation including important confounders is required.This report describes the largest study to date assessing the effect of HD on cognitive function and the first report comparing cognitive function between HD patients and the general population in Japan. We found that HD treatment was an independent risk factor for cognitive impairment. In addition, serum sodium level, dry weight and history of cerebrovascular disease tended to associate with MMSE score among HD patients. There is a high prevalence of cognitive impairment among HD patients that has adverse implications for hospitalization and reduced life expectancy. Therefore, cognitive impairment in HD patients should be monitored carefully and treated in an appropriate manner.The authors declare that they have no competing interests.GO conceived the study, designed the study, and wrote the initial draft of the manuscript. NS conducted the statistical analysis, and interpreted the data. SK had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. AK, HS and NYF contributed to study design and assisted in drafting the manuscript. IT and TU participated in the data collection. All authors have approved the manuscript.


Alpha-fetoprotein (AFP) is an oncofetal protein produced by hepatocellular carcinoma (HCC). AFP level can also be elevated in other neoplastic or non-neoplastic conditions. An elevated AFP level has high diagnostic significance for HCC; at a level of >200 ng/mL, the probability of HCC is >90%. The aim of the present paper is to report a patient who underwent curative resection of HCC, who had a persistently elevated AFP level postoperatively but did not develop recurrence during a 2-year follow-up period. A review of the literature is also presented.An 82-year-old male was referred following a computed tomography scan showing a 160 mm diameter mass in the left lobe of the liver. This huge mass was diagnosed as HCC, arising in the absence of cirrhosis or viral hepatitis. After tumor removal, the patient’s high AFP level persisted for 2 years.As steatosis was the only pathological change in the remnant liver, this may have caused the persistently elevated AFP level in this patient. Hepatocellular carcinoma (HCC) is commonly associated with hepatitis B or C virus infection, and is particularly frequent in patients with cirrhosis . HCC ariHCC causes 1 million deaths every year, making it the fifth most common malignancy worldwide, and the incidence is increasing -8. The cIf the tumor is resectable, surgery is considered to be the curative treatment choice ,13. PostThe aim of the present paper is to report a patient with a normal liver who underwent curative resection of HCC, followed by a persistently elevated AFP level during two years of follow-up without recurrence. A review of the literature is also presented.An 82-year-old male was referred to us after CT scanning showed a 160 mm diameter mass in the left lobe of the liver . He underwent open resection in April 2009. The tumor occupied all of liver segments 2 and 3, and was adherent to the stomach. The right lobe of the liver was normal in appearance. A left hepatic lobectomy was performed. Histological examination of the surgical specimen showed hepatocellular carcinoma with a solid trabecular pattern, and thick fibrotic septa which extended into the normal hepatic tissue at the resection margin  scans showed no evidence of tumor recurrence. Serum AFP levels were 15.7 ng/mL in November 2009 and 8.6 ng/mL in February 2010. A CT scan in March 2010 and PET scan in April 2010 did not show any evidence of recurrence. AFP levels were 17.2 ng/mL in May 2010; 18.4 ng/mL in September 2010; 15.4 ng/mL in December 2010; 16.2 ng/mL in March 2011; 3.69 ng/mL in June 2011; 3.58 ng/mL in September 2011; and 3.4 ng/ml in December 2011  ,3,23. ItThe frequency of postoperative recurrence is similar in patients with hepatitis B or C virus infection and those without, but patients without chronic hepatitis have better liver function and tend to get fewer nodules in the remnant liver, which enables easier resection of recurrences .Extensive resection with a wide tumor margin is technically easier in HCC arising in a non-cirrhotic liver than a cirrhotic liver, resulting in a lower probability of recurrence and a better prognosis -26.Elevated AFP level is not always associated with liver disease. Other conditions (neoplastic or non-neoplastic) can also cause a transient or persistent elevation in APF level, and should be considered in the differential diagnosis. Non-seminoma testis cancer can cause an elevated AFP level in association with elevated levels of other tumor markers such as beta-human chorionic gonadotropin and lactate dehydrogenase ,28. A puPregnancy may cause an elevated AFP level, especially when the pregnancy is complicated by an abnormality such as a spinal cord defect .Obesity and diabetes seem to be associated with HCC. These conditions are risk factors for cirrhosis, but their role in the non-cirrhotic liver is more controversial .Hepatic steatosis can also cause a high AFP level. Steatosis can be divided into two phases; during the first phase, lipids accumulate in the hepatocytes, and in the second phase, factors such as oxidative stress, proinflammatory cytokines, mitochondrial dysfunction, and lipid peroxidation damage the hepatocytes and cause inflammation and fibrosis. In 2009, a study by Babali et al.  found thIn our patient, steatosis was the only abnormality of the hepatic parenchyma detected on pathological examination, and was the only condition that could have caused the persistently elevated AFP level, as laboratory tests and imaging results eliminated all other possible causes.Non-alcoholic steatohepatitis (NASH) can induce HCC by unknown mechanisms, in which insulin resistance seems to play an important role. Insulin resistance causes inhibition of hepatic mitochondrial fatty acid oxidation and stimulation of microsomal peroxidases, resulting in increased intracellular concentrations of fatty acids, which may cause oxidative DNA damage .NASH can evolve into cirrhosis before giving rise to HCC, but the cirrhosis stage is not necessary, as there are many reported cases in the literature of HCC arising directly from NASH. NASH therefore has to be considered as a possible cause when HCC arises in a non-cirrhotic liver ,35. HCC Another rare condition that may cause an elevated AFP level in a patient with a normal liver is hereditary persistence of AFP (HPAFP), which is asymptomatic. Only 19 families with HPAFP have been described over the past 28 years, many of whom also had urological disorders . HPAFP can, therefore, also be considered in patients with an unexplained high AFP level ,38.In conclusion, we present a case in which hepatic steatosis is the only possible cause of the persistently elevated AFP level after curative resection of HCC.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.AFP, Alpha-fetoprotein; CT, Computed tomography; HCC, Hepatocellular carcinoma; NASH, Non-alcoholic steatohepatitis; PET, Positron emission tomography; HPAFP, Hereditary persistence of alpha-fetoprotein.All authors declare that they have no competing interests.IDC was the principle investigator who prepared, organized, and edited all aspects of the manuscript, and the surgeon who performed the operation. MM supported the work of the principle investigator in writing and editing the manuscript. AT supported the work of the principle investigator in writing and editing the manuscript. AA supported the work of the principle investigator in preparing the manuscript. AG was the pathologist who performed the pathological examination of the surgical specimen. GC supported the work of the principle investigator in preparing the manuscript. GB supported the work of the principle investigator in preparing the manuscript. All authors read and approved the final manuscript.


Objective: The aim of the present paper was to analyze factors affecting distal and proximal health behavior within a biopsychosocial model for examining their interactions and associations with respect to health. Methods: Path analysis was based on the nationwide, cross-sectional German Health Interview and Examination Survey for Children and Adolescents (2003 to 2006). The data was collected from 4,529 participants with an average age of 9.45 years (SD = 4.01). Socio-demographic data, psychosocial factors and health behavior were assessed via questionnaire. Participants also underwent physical fitness tests and a medical examination. Results: Over the five levels of the model analyzed with socioeconomic status, immigration background, and rural-urban differences on the first level; physical activity of relatives and peers, intrinsic motivation, and quality of life on the second level; eating patterns, sedentary behavior, and physical activity on the third level; physical fitness and objective health on the fourth level; and health complaints and subjective health on the fifth level; direct, moderation, and mediation effects could be shown. Conclusions: Several distal and proximal factors are needed to take account of the multivariate complexity of health: e.g., immigration background affected health behaviors only indirectly and the effect of physical activity on objective health was mediated by physical fitness. The value of physical activity (PA) ,2, approTo increase the ability to predict and potentially prevent health risk behaviors, and consequently objective health, both distal and proximal determinants of those behaviors should be considered. Distal determinants tend to be more stable relative to proximal determinants and are further expected to influence health behavior mainly via these proximal determinants ,12. ConsThe biopsychosocial model considered here therefore simultaneously examines distal factors on the first level , rural-urban differences and immigration background; see With the assistance of the biopsychosocial model, the objectives of the current paper were to provide evidence for comprehensive approaches and therefore to analyze several causes—distal as well as proximal—for disparities in PA, SB, and eating patterns among German children and adolescents, and their relationships with objective health, subjective health and health complaints. This concept is a first attempt to examine a significant number of correlates, both those that are well-known . The following analyses were based on the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), which was conducted between May 2003 and May 2006. The KiGGS survey is a nationwide, cross-sectional study on the health status of children and adolescents between the ages of 0 to 17 years, which was conducted by the Robert Koch Institute of Berlin (RKI) . The KiGParticipation was voluntary. Participants were chosen nationwide with the use of a stratified, two-stage probability sampling procedure. First, a systematic sample of 167 primary sample units was drawn from an inventory of German communities stratified according to the BIK classification system, which measures the grade of urbanization, and the geographic distribution. The number of primary sample units per strata was determined using the Cox procedure for community sampling with a sampling probability proportional to population size . Second,n = 4,529) of those who agreed to participate, actually took part [A total of 28,899 children and adolescents were randomly selected and invited to participate in the KiGGS study, 1,512 (5.3%) were later classified as quality-neutral drop-outs. For the MoMo substudy, only 4586 families with children between the ages of 4 and 17 were randomly selected from the KiGGS study and invited to participate. A total of 98.6% (ook part . All meaParticipants were considered as children and adolescents with parents with migration background (coded as 1) if they had emigrated from another country and if at least one parent was not born in Germany, or if both parents had emigrated from another country and had not accepted the German nationality. All other participants were treated as non-immigrants (coded as 2). Information on citizenship, country of birth, year of entry, and age at entry was assessed using a questionnaire. (without graduation) to 7 (high-school diploma); professional qualification  ranging from 1  to 7 (university degree); occupation  ranging from 1 (common laborer) to 7 (leading position); and the net household income  ranging from 1  to 7 . The mean score ranged from 1 (low SES) to 7 (high SES); Cronbach’s alpha = 0.69. The parent with the higher status, or, in the event of a divorce, the status of the parent where the child was living, was chosen [The SES information was based on the mean score of parents’ information concerning their school education (What is your high-school graduation level? Please mention only the highest grade) ranging from 1 s chosen . Rural areas (coded as 1) were defined as rural  and provincial areas , whereas urban areas (coded as 2) were defined as medium-sized towns  and metropolitan areas  .I strongly disagree) to 5 . Finally, a mean parcel over these items has been built. According to the Theory of Reasoned Action, attitude, and, as a follow-up, intention towards PA are important determinants of PA levels. Attitude is a function of the belief that participation in PA will result in certain outcomes . Such ouTo assess QOL, the KINDL-R questionnaire was used. The psychometric properties of the KINDL-R revealed a high degree of reliability and the procedure revealed a satisfactory convergent validity for the present data . CronbacTo assess psychopathological problems, the strengths and difficulties questionnaire (SDQ) was used. The psychometric properties of this screening instrument have been shown to be satisfactory to good for the present data . Cronbacttr = 0.72 (PA in leisure time) to ttr = 0.93 (PA in sports clubs). Construct validity related evidence was gathered by looking at the correlation with a multisensory electronic monitor including a biaxial accelerometer measuring PA (SenseWear Pro 2) [rmin = 0.56, rmax = 0.66) in comparison with other PA questionnaires [PA was assessed using the MoMo PA questionnaire containing previously validated items involving the duration, intensity, and frequency of PA in leisure time, school, and sports clubs in the past year. It consists of 35 items and has been developed in orientation to existing questionnaires. The test-retest reliability in a previous 7-day longitudinal study ranged from r Pro 2) . Resultsonnaires .In accordance with international recommendations ,34 for aFor the derivation of eating patterns, information from a semi-quantitative food frequency questionnaire (FFQ) was used . The desnot at all) to 5 . Questions were assessed using the Health Behavior in School-aged Children Questionnaire of the World Health Organization [The average time of television viewing and playing computer games on weekdays and on weekends/holidays was assessed to describe SB. The 5-point scale ranged from 1  throughout with regard to significance and feasibility as based upon expert ratings. Furthermore, good test-retest reliability coefficients  were found. The retest was conducted four days after the first test [Participants were tested with eight tests of the “Motorik”-Module (MoMo) test battery  to assesrst test . All mea2)) was calculated as an index of body fat. Because BMI shows the excessive increase of fatty tissue and its distribution only insufficiently, skinfold thickness (SFT) was assessed for estimating body fat with the aid of a Holtain caliper using two measurement points on the right side: triceps (the back of the upper arm) and subscapula (beneath the edge of the shoulder blade). Blood pressure and heart rate were assessed twice on the right side with the elbow at heart level. Systolic, diastolic, and arterial medium pressures, as well as pulse rate, were determined with the use of an automatic hemodynamometer (Datascope Accutor Plus). The first automatic measurement was taken while the participant was sitting after a 5 min break and the second measurement was taken after an eye test. The size of the Datascope blood pressure cuff was chosen with regard to the requirement of covering at least two thirds of the upper arm above the brachial artery. Cholesterol is described by HDL-cholesterol and LDL-cholesterol, and both were measured once with the use of a homogeneous enzymatic test (serum sample) based on color as modified by Roche. All measures were z-transformed and a mean score was calculated. Body mass index (BMI), skinfold thickness, blood pressure, and cholesterol were assessed. Body height (stature) was measured while standing with a calibrated, portable Holtain stadiometer and an accuracy of up to 0.1 cm. Participants were measured for body weight (mass) in their underwear on a calibrated scale with an accuracy of up to 0.1 kg. BMI (body weight (kg)/height (mvery good) to 5 (very bad). The psychosomatic complaints parcel consists of headache, stomach ache, abdominal pain, backache, and chest pain. Three response options were given: “yes, repeatedly”, “yes, once”, and “no”. The pains with regard to the locomotor system parcel is described by arm pain and leg pain with the same rating options as for the psychosomatic complaints and the earache, eyestrain, and sore throat parcels. Subjective health, psychosomatic complaints, pains with regard to the locomotor system, as well as ear, eye, and throat complaints, which were combined to form one set of complaints, are assessed. Subjective health is described by one item asking participants to rate their subjective health on a 5-point scale from 1 , as recommended by Hu and Bentler [For analyses, all measurements of children and adolescents were partialed out and thus controlled for gender and age. Path analyses and bivariate correlations were conducted with AMOS 20.0 using a maximum likelihood algorithm (FIML). Because of missing data, the assumption of multivariate normality could not be tested. In addition to the  Bentler , and, ad Bentler . Accordi Bentler , cut off Bentler . Even wh Bentler . In caseχ2(62) = 1,028.38, p < 0.001, RMSEA = 0.059, 90% confidence interval: 0.056–0.062, CFI = 0.80. The CFI is often smaller when analysis is based on questionnaire data [ire data . FurtherTable 1Bivariate correlations, loadings, and explained variance.Lower SES was observed in urban areas and for children and adolescents with parents with migration background. Further, children and adolescents with parents with migration background were more frequently seen to be living in urban environments see . Higher A more active environment was associated with a higher intrinsic motivation, less SB and more PA. More intrinsic motivation was associated with more PA, higher QOL, and fewer psychopathological problems. A higher QOL was associated with fewer psychopathological problems, more PA, but not with SB and eating patterns. The direct paths of psychopathological problems to SB, PA, and eating patterns were not significant. Better eating patterns were associated with less PA, less PF, and poorer objective health. PA showed neither a significant correlation to SB nor to objective health. However, more PA was associated with better PF. Less SB was associated with higher levels of PF and better objective health.Better PF was associated with better objective health, better subjective health, and fewer psychosomatic complaints. The direct relationships of PF to pains with regard to the locomotor system, and earache, eyestrain, and sore throat, were not significant. Better objective health correlated with better subjective health but not with pains with regard to the locomotor system or psychosomatic complaints. Subjective health was correlated with all three sets of complaints. Whereas fewer psychosomatic complaints and lower pains with regard to the locomotor system were associated with poorer subjective health, lower earache, eyestrain, and sore throat was associated with better subjective health. There is evidence that unhealthy behaviors are one of the major causes of chronic diseases and increased health care costs. Therefore, there is also a consensus that promoting good/positive health behavior would promote health and decrease health care costs . The aimAs expected, a higher SES was strongly  associated with a more active environment ,45. A hiIn general there has been a lack of research on rural-urban differences and (factors affecting) health behavior . Most oFilling research gaps, no difference was observed for immigration background and intrinsic motivation for being physically active . HoweverExpectedly, the PA of relatives and peers was positively associated with the intrinsic motivation of being physically active and even to a higher extent with PA itself . FillingAgain filling a research gap, we found that the intrinsic motivation to be physically active was strongly associated with QOL  and psycAs expected, QOL and psychopathological problems were strongly inversely related ,16. ReseUnexpectedly, we found no association between psychopathological problems and SB ,100. AgaEven though the effects were small, we found totally unexpectedly that unhealthier eating patterns were observed for more active children and adolescents  and thosUnexpectedly but plausibly, we found that the effect of PA on objective health  was mediAs expected , PF not Information about the interplay of different subjective health ratings was lacking; thus, the current findings should be a basis for future research. However, we did not expect the findings of fewer psychosomatic complaints and lower pains with regard to the locomotor system with poorer subjective health. Maybe children and adolescents refer to parameters other than psychosomatic complaints (strong effect) and pains with regard to the locomotor system  when rating their globally perceived subjective health. Thus, results suggest that a more differentiated measurement of subjective health is necessary. Proximal intrapersonal factors such as self-efficacy, which has been shown to be closely related to PA, or interpersonal factors such as social support and social interaction as important predictors for morbidity and mortality  were notWith regard to study and design, it should be noted that neither items to assess intrinsic motivation nor SB have been validated yet. Also, more items  should be used to assess SB in its entirety in future analyses. Additionally, future analyses might differentiate between different cultures when considering immigration background since different cultures of children and adolescents with parents with migration background might have different implications for factors affecting health behaviors. In summary, we analyzed several distal and proximal determinants of health behaviors and their associations to (subjective) health simultaneously in this paper in an attempt to shed light on this complex interplay of factors. With the use of a 5-level model, support for comprehensive approaches and detailed information on (subjective) health-affecting, biopsychosocial factors in children and adolescents was shown. Results led to the assumption of a number of suppression, moderation, and mediation effects within the biopsychosocial model. These findings also emphasize the importance of comprehensive compared to bivariate analyses in health research: In addition to the results we had expected, these unexpected findings  may provide directions for future research. Moreover, some initial research  was included on the biopsychosocial model, and again, directions for future research can be derived from these findings. Replication of unexpected and initial findings would be significant for future preventive measures .


There is a growing prevalence of gout in the US and worldwide. Gout is a recognized risk factor for cardiovascular disease (CVD). It is unclear whether other risk factors for CVD are also associated with increased risk of gout. Anemia is one such CVD risk factor. No studies have evaluated the relationship between anemia and gout. We tested whether anemia was associated with incident gout independent of comorbid conditions in Atherosclerosis Risk in the Communities.This population-based cohort recruited 15,792 individuals in 1987 to 1989 from four US communities and contained nine years of follow-up. Anemia was defined as hemoglobin <13.5 g/dL for men and <12 g/dL for women. Using a Cox Proportional Hazards model, we estimated the hazard ratio (HR) and confidence intervals (CI) of incident gout by baseline anemia, adjusted for confounders  and clinical factors .Among the 10,791 participants, 10% had anemia at baseline. There were 271 cases of incident gout. Patients with anemia had a two-fold increased risk of developing gout over nine years . Anemia was associated with incident gout independent of known gout risk factors, confounders and clinical risk factors . This association persisted after additionally adjusting for serum urate level .We identified anemia as a novel risk factor for gout. Anemia was associated with an approximately two-fold increased risk of gout-independent kidney function and serum urate. These findings suggest that anemia is a risk factor for gout on par with other chronic conditions such as obesity and diabetes. The biological mechanism linking anemia to gout remains unclear. The prevalence of gout is increasing in the United States; in 2005, the estimated prevalence was 3 million cases, which has increased from 2.1 million in 1995 -6. AdditIt is unclear whether other risk factors for cardiovascular disease (CVD) are also associated with increased risk of gout. Anemia is one such risk factor, and is associated with CVD , chronicWe hypothesized that anemia is associated with an increased risk of developing gout. Further, we postulated that the relationship exists above and beyond the effect of serum urate levels and kidney function. We sought to evaluate the independent association of anemia and gout, after controlling for possible confounders over nine years of follow-up in a longitudinal population-based cohort of middle-aged adults.The Atherosclerosis Risk in the Communities study (ARIC) is a prospective population-based cohort study of 15,792 individuals recruited from four US communities . The Institutional Review Board of the participating institutions approved the ARIC study protocol and study participants provided written informed consent. Participants aged 45 to 64 years were recruited to the cohort in 1987 to 1989. This cohort was established to study the natural history of atherosclerosis, and the study consisted of one baseline visit (visit 1) between 1987 and 1989 and three follow-up visits  administered three years apart. Details of the study design have been previously published .This analysis was limited to participants who were Caucasian or African American; few participants reported other races (n = 48). We excluded participants who did not report their gout status at visit 4  and those with prevalent gout at cohort entry, defined as the self-report of gout onset prior to the baseline visit (n = 419). Participants with missing baseline information on the main covariates of interest were not included , Body Mass Index (BMI), alcohol intake and hypertension). Participants who were older, had diabetes, lower education and higher serum urate were more likely not to be included in this analysis. However, baseline hypertension, BMI, eGFR, use of an antihypertensive medication (including diuretic use) or sex were associated with being included in this analysis. Therefore, it is unlikely that our results are not generalizable to the ARIC cohort.a priori and the sole focus of this analysis.There were 10,791 participants included in this study of the association of anemia and gout. This study hypothesis was developed At baseline, each participant had their blood drawn and the procedures have been described elsewhere . Hemogloever told you that you had gout?" Participants who answered, "Yes," to the gout query then reported the age at gout diagnosis. The outcome of interest was incident gout based on self-reported onset of gout at an age greater than their age at ARIC visit 1. Our previous research suggests that self-report of a physician diagnosis of gout is a reliable (three-year reliability kappa = 0.73) and a sensitive (sensitivity = 84%) measure of gout [At ARIC visit 4, participants were asked, "Has a doctor  of gout .2), coronary heart disease (CHD) , hypertension  or diuretic use in the two weeks prior to the baseline visit. Self-report of a history of heart failure or coronary heart failure (CHF) at visit 4 was also considered. Serum creatinine was estimated using a modified kinetic Jaffé reaction. Glomerular filtration rate (eGFR) was estimated using the CKD-Epi equation [2.Other covariates of interest at baseline (1989) included self-reported age (in years), sex , race (white or African American), education  and alcohol intake (grams/week). Additionally, we included clinical factors that were thought to be related to anemia or gout, including diabetes , measured BMI , as well as the prevalence of the covariates, were calculated and compared by baseline anemia status using a Using a Cox Proportional Hazards model, the hazard ratio (HR) and 95% confidence interval (CI) of incident gout by baseline anemia was estimated with age as the time scale. The unadjusted survival functions were plotted using Kaplan-Meier plots. Models were adjusted for confounders of the association of anemia and gout, including sex and race, as well as baseline measures of BMI, categorical eGFR and alcohol intake. In a separate model, we additionally adjusted for baseline diabetes, hypertension, CHD, history of CHF and diuretic use. All of these measures were considered confounders of the gout and anemia relationship, based on exploratory data analysis and previous research ,25. We h2 or < 60 ml/min/1.73m2). The stratified models were adjusted for the previously listed confounders. Using a Wald test, we assessed whether these factors were effect measure modifiers  of the association of anemia and incident gout.We tested whether the association of anemia and incident gout differed by sex, race and eGFR , use of non-steroidal anti-inflammatory drugs (NSAIDs), mean corpuscular volume and for women menopausal status and history of surgical menopause.As a sensitivity analysis, we restricted the population to those with an eGFR> 30 ml/min/1.73mAll analyses were performed in SAS, version 9.1 . The cumulative incidence plots were constructed in Stata, version 11 .A total of 10,791 ARIC participants met the study criteria. The study population was 43% male, 21% African American and the mean age at cohort entry was 54 years (SD = 5.70). The mean hemoglobin level was 13.9 g/dL (SD = 1.37); for men 14.9 g/dL (SD = 1.05) and for women 13.1 g/dL (SD = 1.05)  and the mean age at gout diagnosis was 59 (SD = 6.4). At baseline, 64% of the women with gout were post-menopausal. The mean serum urate level at baseline was 8.0 mg/dL (SD = 2.0) for those who developed gout during follow-up.2 were more likely to have anemia .Table P-value <0.001), Table Incident gout occurred more frequently in participants with anemia at baseline compared with those without anemia  or kidney function . However, there was limited support for an interaction by sex . Among female participants, the HR of incident gout by baseline anemia status was 2.38  compared to a HR of 1.43  for male participants.There was no evidence of effect measure modification by race . Adding visit 2 eGFR to the model as a time-varying confounder did not change the results (results not shown). Although we did not have a direct measure of socioeconomic status, the results did not differ when education and baseline smoking status were added to the multivariate model . Adjusting for baseline NSAIDs use did not alter the association between anemia and gout . Additionally, in the models restricted to women, the results did not change when we additionally adjusted for menopause . When we adjusted for baseline history of surgical menopause, as a proxy for fibroids [In an analysis restricted to those who had an eGFR greater than 30 ml/min/1.73 mfibroids , the assThis study is, to our knowledge, the first to identify anemia as a risk factor for gout over nine years of follow-up in a large population-based study of middle-aged adults. Even after adjustment for kidney function, comorbid conditions, and education and baseline smoking status, anemia remained an independent predictor of incident gout. Unlike traditional risk factors, anemia was associated with gout, even after adjustment for urate levels, suggesting an independent pathway. No differences in the association between anemia and gout were observed by race, or baseline kidney function. However, there is slight evidence of a difference in the association between anemia and gout between men and women, with a stronger association observed for women.Although, at this time there is no clear biological link between anemia and gout, there are potential explanations for this observed association. Anemia is an independent risk factor for the development of adverse cardiovascular outcomes, both short-term ,28 and lAdditionally, anemia increases cardiovascular mortality in specific disease states, such as CKD, both in dialysis patients  and inteOxidative stress is increased in anemia , perhapsSerum urate levels are thought to be positively correlated with iron levels -42. PrevBoth gout and anemia are associated with CKD ,45 and aAnemia could also be a marker of chronic conditions and not an independent risk factor for gout. Previous studies have identified anemia as predictor of mortality and morbidity ,13-15,33Additionally, different female-specific health factors may be driving the association of anemia and incident gout. Anemia was much more common in women and traditional gout risk factors, such as BMI, alcohol intake and diuretic use, are stronger predictors of gout in men compared to women . Our resFinally, anemia may be a cause of gout. Although it is unclear whether the observed association of anemia and gout is causal, anemia is thought to be more than just a bystander on the biological pathway between anemia and chronic conditions . We did To our knowledge, this is the first study to identify anemia as a risk factor for incident gout. This is one of the largest biracial studies of gout, which included both men and women with gout. Anemia was established prior to the onset of gout, thus supporting temporality. Additionally, we were able to control for kidney function at baseline and other important risk factors for both gout and anemia. For example, we adjusted for race, hypertension and kidney function, which are known common risk factors for gout and anemia ,46,49. FAs with any epidemiology study there are limitations to our study. The main limitation of our study was that gout was self-reported by participants at visit 4 and incidence of gout was based on reported age at onset. However, our previous work has suggested that self-reported gout and age of onset is both sensitive and reliable . ParticiOur population-based, longitudinal study is the first to identify anemia as a novel risk factor for gout in middle-aged men and women of both races. Future studies should not only confirm the risk of gout associated with anemia but also further elucidate the biological pathways of anemia and gout by measuring epoetin and the use of iron supplements. In particular, the role of anemia on the onset of gout in women should be explored in greater detail, especially with a prospective ascertainment of fibroids.ARIC: Atherosclerosis Risk in the Communities study; BMI: body mass index; CHD; coronary heart disease; CHF: coronary heart failure; CKD: chronic kidney disease; CVD: cardiovascular disease; eGFR: glomerular filtration rate; SD: standard deviation; WHO: World Health OrganizationThe authors declare that they have no competing interests.MMD made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, and was involved in drafting the manuscript and revising it critically for important intellectual content. JM made substantial contributions to conception and design, interpretation of data, and was involved in revising the manuscript critically for important intellectual content. JC made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, and was involved in drafting the manuscript or revising it critically for important intellectual content. AB made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, and was involved in drafting the manuscript and revising it critically for important intellectual content. All authors gave final approval of the version to be published.


Familial glucocorticoid deficiency, or hereditary unresponsiveness to adrenocorticotropic hormone, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. It may present in infancy or early childhood with hyperpigmentation, failure to thrive, recurrent infections, hypoglycemic attacks and convulsions that may result in coma or death. Here, we report the case of an 18-month-old Egyptian boy with familial glucocorticoid deficiency.-month-old Egyptian boy was referred to our institution for evaluation of generalized hyperpigmentation of the body associated with recurrent convulsions; one of his siblings, who had died at the age of nine months, also had generalized hyperpigmentation of the body. The initial clinical examination revealed generalized symmetrical deep hyperpigmentation of the body as well as hypotonia, normal blood pressure and normal male genitalia. He had low blood glucose and cortisol levels, normal aldosterone and high adrenocorticotropic hormone levels. Based on the above mentioned data, a provisional diagnosis of familial glucocorticoid deficiency was made, which was confirmed by a molecular genetics study. Oral hydrocortisone treatment at a dose of 10 mg/m2/day was started. The child was followed up after two months of treatment; the hyperpigmentation has lessened in comparison with his initial presentation and his blood sugar and cortisol levels were normalized.An 18Familial glucocorticoid deficiency is a rare, treatable disease that can be easily missed due to nonspecific presentations. The consequences of delayed diagnosis and treatment are associated with high rates of morbidity and mortality. FGD is  in 1959 . Patholo in 1959 .FGD may be caused by mutations in the gene of the ACTH receptor , classified as FGD type 1, or by mutations in the melanocortin-2 receptor accessory protein (MRAP), classified as FGD type 2. Mutations of the ACTH receptor (type 1) account for 25% of FGD cases, while FGD type 2 accounts for approximately 15% to 20% of FGD cases . These mAn 18-month-old Egyptian boy was referred to our pediatric endocrinology clinic for evaluation of generalized hyperpigmentation of the skin associated with weakness, vomiting and recurrent convulsions. He was born to consanguineous parents after an uneventful pregnancy with a birth weight of 3450 g. He was the fourth child of the family; one of his siblings, who had died of an unknown cause at the age of nine months, had generalized hyperpigmentation of the body, recurrent convulsions and mental retardation. His other siblings were reported to be healthy.th percentile while his length and head circumference were in the 50th percentile. His blood pressure was 90/60 mmHg. Unlike his fair-skinned parents, he had generalized symmetric deep hyperpigmentation of the body, especially of his elbows, knees, hands, feet and buccal mucosa  and ACTH, 708 pg/mL . An ACTH stimulation test did not cause a rise in his cortisol level. His 17-OH progesterone level was 0.01 ng/mL ; androstenedione, 0.01 ng/mL , dehydroepiandrosterone, 3 ng/mL ; plasma rennin activity, 57 ng/mL/hour ; aldosterone, 801 pg/mL .2/day was started.His bone age, evaluated by an X-ray of his left hand and wrist according to the Greulich-Pyle atlas, was equivalent to two years. Adrenal ultrasonography revealed that both his adrenal glands were small; his left was 6 × 8 mm and right 7 × 8 mm in diameter. Computerized tomography of his brain was normal. A molecular genetics study revealed normal ACTH receptor gene sequences, excluding FGD type 1, and a homozygous deletion (c. 111+1delG) in intron 3 of the MRAP gene was detected. Based on these findings, a diagnosis of FGD type 2 was made. Oral hydrocortisone treatment at a dose of 10 mg/mOur patient was seen two months after starting treatment. His general condition was greatly improved and he was able to walk alone. The hyperpigmentation was less in comparison with his initial presentation Figures  and 4, hUnawareness of FGD can lead to delay in diagnosis, not only in the affected patient but also among other members of the family. The disorder can be fatal if proper treatment is not provided. FGD should be distinguished from other causes of adrenal insufficiency, which include congenital adrenal hyperplasia, adrenal hypoplasia, adrenoleukodystrophy, Allgrove syndrome, adrenal hemorrhage, trauma and infections, by taking a thorough history, clinical examination and appropriate investigations .A review of the literature revealed that the age of onset of symptoms in patients with FGD ranges from birth to nine years old. All the symptoms and signs seen in FGD are the result of either hypocortisolemia or elevated ACTH levels, of which our patient had both. Hypocortisolemia may cause weakness, fatigue, weight loss, anorexia progressing to nausea, vomiting, diarrhea, constipation, flank or abdominal pain, hypoglycemia and hypothermia. High ACTH causes increased melanin production, resulting in generalized hyperpigmentation and advanced bone age ,8. Bone et al. [Our patient was diagnosed with FGD at the age of 18 months; he had two attacks of convulsive episodes prior to the presentation that could be attributed to unrecognized hypoglycemia. Modan-Moses et al.  reportedMRAP, located at 21q22.1, is an essential cofactor for MC2R expression in certain cell types and seems to have a role in the processing, trafficking or function of MC2R [et al. [Our patient was diagnosed with FGD type 2 by a molecular genetics study, through detection of mutations in the MRAP gene OMIM 607398).  of MC2R . MRAP ha of MC2R . Akin et07398.  o2/day in three divided doses is usually sufficient. The suppression of plasma ACTH levels in FGD can be very difficult and should not be used as the goal of treatment. Educating parents and patients on the need to increase hydrocortisone dosages during illness and emergency management with intramuscular hydrocortisone is vital [The treatment of FGD is by replacement with hydrocortisone. An oral dose of 10 to 12 mg/mis vital . In addiFGD is a rare, treatable disease that can be easily missed due to its nonspecific presentation. The consequences of delayed diagnosis and treatment are associated with high rates of morbidity and mortality. Clinical awareness of this condition is of considerable prognostic and therapeutic significance.ACTH: adrenocorticotropic hormone; FGD: familial glucocorticoid deficiency; MC2R: melanocortin-2 receptor; MRAP: melanocortin-2 receptor accessory protein.Written informed consent was obtained from the patient's parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.KA and HS diagnosed, investigated, followed up and managed the patient drafted the manuscript. Both authors read and approved the final manuscript.


Poor oral health in early childhood can have long-term consequences, and parents often are unaware of the importance of preventive measures for infants and toddlers. Children in rural, low-income families suffer disproportionately from the effects of poor oral health. Participants were 91 parents of infants and toddlers enrolled in Early Head Start (EHS) living in rural Hawai'i, USA. In this quasi-experimental design, EHS home visitors were assigned to use either a didactic or family-centered video with parents they served. Home visitors reviewed short segments of the assigned videos with parents over an eight-week period. Both groups showed significant prepost gains on knowledge and attitudes/behaviors relating to early oral health as well as self-reported changes in family oral health routines at a six-week followup. Controlling for pretest levels, parents in the family-centered video group showed larger changes in attitudes/behaviors at posttest and a higher number of positive changes in family oral health routines at followup. Results suggest that family-centered educational videos are a promising method for providing anticipatory guidance to parents regarding early childhood oral health. Furthermore, establishing partnerships between dental care, early childhood education, and maternal health systems offers a model that broadens potential reach with minimal cost. Report on Oral Health in America in 2000 celebrating progress in improving overall oral health nationwide; the report also identified a “silent epidemic” of poor oral health that disproportionately affects vulnerable populations [The U.S. Surgeon General released the ulations , 2. Low-ulations , 3–9. Poor oral health in early childhood can compromise the functional capacity of children to eat, sleep, and learn to speak properly . MoreoveGiven these realities, preventing poor oral health in early childhood has become a major emphasis of national and state entities concerned with child health and wellbeing , 12. BecThis leads to the question of how to most effectively provide parent education and anticipatory guidance. Research on parent education demonstrates that video interventions are more effective than printed pamphlets effecting positive changes in short-term attitudes and reported behaviors and in long-term retention . Adult eBaby's First Smiles: Pass It On video provides an alternative to didactic approaches by integrating peer-to-peer strategies with family-centered approaches . Mecal Home –34. The cal Home , 34–36. cal Home , 36.Early Head Start (EHS) provides programs to low-income families with young children totaling approximately 150,000 pregnant women and children age birth to three nationwide , 38. ForThe Pacific island state of Hawai'i has some of the worst child oral health outcomes in the United States partly due to a lack of fluoridation in community water, lack of a state-sponsored dental sealant program, legal limitations preventing dental hygienists from administering fluoride varnish without the direct oversight of a dentist, and shortage of dental providers who accept Medicaid patients , 40. HawBaby's Oral Health: Pregnancy Through Childhood (BOH) produced by the School of Dentistry, University of Toronto [Baby's First Smiles: Pass It On (BFS) produced by Webfish Pacific, LLC [This evaluation compared family responses to two different approaches to oral health video interventions implemented by Early Head Start Home Visitors for low-income families with young children living in rural Hawai'i: (1) a state-of-the-art didactic video,  Toronto , 42; andfic, LLC . This reThis research project compared two video interventions related to oral health education for parents and caregivers of young children. Participants were 104 parents of children enrolled in one of two EHS programs serving rural areas of the islands of O'ahu and Hawai'i  has the largest landmass while O'ahu has the largest population). The recruitment pool included all families who had been active in EHS for at least four months and were not expecting to move out of their program's service area during the study period. Ninety-one parents (87%) completed the intervention and posttest interviews. Seventy-six parents with posttest data (86%) also participated in a followup interview. Roughly two-thirds of participants lived on O'ahu (68%) and one-third lived on Hawai'i. Among those participants that completed both pre- and posttest interviews, 53% saw the BFS video and 47% saw the BOH video. Almost all participants (96%) were mothers; the sample also included two grandmothers and two fathers. Forty-five percent of families were of Native Hawaiian/Pacific Islander heritage, 27% were of mixed ethnicity, 14% were Asian American, 6% were Caucasian, and less than 4% each were Latino, Native American, or African American. Slightly more participants were married (46%) than single (45%) and 8% were separated or divorced. Twenty-four percent of households spoke a foreign language at home. The modal level of education was a high school diploma or GED (38%) while 15% had less than a high school education, 33% had some college experience, and 13% had a college degree.Participants had an average of 2.45 children overall, and 1.30 children in the age range served by EHS. Most families (74%) had one child enrolled in EHS, 23% had two children in EHS, and 3% had three enrolled children. Fifty-two percent of the EHS children were boys and 48% were girls. In terms of age distribution, 11% were younger than six months, 16% were 6–12 months, 43% were 13–24 months, and 29% were 25–36 months.Initial discussions were held with all three EHS programs in the state of Hawai'i; one program was not able to participate during the intended time period of the study. Eligible staff participants were home visitors with six or more months experience in their position and who had a caseload of six or more families living in rural communities. Nineteen home visitors (100% of those eligible) agreed to participate. A quasi-experimental design was used where home visitors from both EHS programs  were randomly assigned to use either the BOH or BFS videos.  Home visitors received a three-hour training session. Content included background information on risk factors for poor early oral health, viewing the assigned video, practice showing video topics on portable DVD players, and instructions for following the research protocol. Home visitors were asked to use the assigned video with all consented families they served. For the purpose of intervention design, each video was divided into eight segments lasting four to seven minutes in duration. The segments were to be shown on an overlapping schedule: segment 1 on week one, segments 1 and 2 on week two, segments 2 and 3 on week three, and so forth. Home visitors were asked to complete the series within eight to ten weeks. During the video intervention period, home visitors continued to implement the ongoing EHS protocol. How and when to incorporate the video during each home visit was left to the home visitor's discretion. To minimize differences in presentation, home visitors were asked to simply play the video and to provide only brief answers to any questions from family members. Home visitors were asked to refrain from showing the nonassigned video or from designing and implementing any supplementary curriculum. When each family had completed the video series, the home visitor was asked to give the participant a copy of the assigned video and encourage the family to share the video with other parents in their social circle. At the time EHS home visitors were trained, all families were served via a home visiting model. However, both EHS programs had preexisting plans to offer a group-based option to enrolled families. Overall 11 families (12%) decided to move to the group format. To maintain equivalence across home and group formats, staff were asked to show the videos one-on-one to families who opted for group services; this was done either before or after regularly scheduled program activities.Home visitors were provided with DVD players, assigned DVD videos, and recruitment and record-keeping materials. Home visitors kept a viewing log for each participating family. Logs were submitted to the research team on a monthly basis; the team was also available for consultation via email at any time. Pre- and posttest structured interviews were conducted in person with each participant by a research team member who was blind to the participants' condition. Research team members obtained informed consents from family participants on first contact at the time of the pretest. Posttest interviews were conducted within two weeks of completing the video series. A telephone followup interview was conducted six to eight weeks later. Compensation of $25 per interview was provided to participants; home visitors received a gift of an educational video on early childhood development, and the EHS programs received a combination of cash and material donations worth about $1,000.Interview items developed for this study were partly adapted from pediatric and dental research and reviewed by the project's dental advisors , 44, 45.knowledge items were presented in a multiple-choice format. Items were written to address the content areas of dental development and professional care , family routines in oral hygiene , and nutrition related to oral health . The total number of items answered correctly was used to measure overall knowledge. Internal consistency was adequate; coefficient alpha was 0.73 at pretest and 0.78 at posttest. See sample items in The 21 oral health attitudes/behavior items were answered using a Likert scale format (1 = strongly disagree to 5 = strongly agree). Again, content was designed to address dental development, family routines in hygiene, and nutrition. However, the focus was on attitudes and concrete behaviors. Items were reverse coded when needed so that a high score indicated responses supportive of good oral health. Items were summed to form an overall score. Coefficient alphas were 0.82 and 0.88 at pre- and posttest, respectively. See items in The 25 oral health strongly disagree to 5 = strongly agree). Coefficient alpha was 0.94.The six satisfaction items were answered on a five-point Likert scale (1 = t-tests were used to test for the main effects of change over time. Knowledge scores increased significantly from pretest (mean = 15.19 or 72% correct) to posttest (mean = 16.98 or 81% correct), t(91) = 1.79, P < 0.0005, Cohen's d = 0.52. Significant gains were also found for the attitude/behavior scale, , t(90) = 3.31, P < 0.0005, and d = 0.31. The relative effect sizes  suggest that changes in knowledge were greater than changes in attitudes/behavior.Descriptive statistics for pretest, posttest, and followup data are shown in F = 0.01, P < 0.91, and d = 0.02. The BFS group had higher scores for oral health attitudes/behaviors at posttest, F = 3.96, P < 0.05; this effect was modest in magnitude, d = 0.27.Group comparisons were conducted to test the hypothesis that the family-focused BFS video would be more appealing to parents and more effective. To adjust for each parent's level of pretest knowledge and attitudes, data were analyzed using a one-way analysis of covariance, with video as the between subjects factor and pretest score as a covariate.  There were no significant group differences on knowledge or attitudes/behavior at pretest, although there was a trend in the direction of BFS parents having higher pretest knowledge scores. Controlling for pretest knowledge, there were no posttest differences in knowledge scores, F = 7.50, P < 0.007, and d = 0.57. BFS families also reported a higher number of changes in family oral health routines, nutritional practices, and dentists visits , F = 5.82, P < 0.02, and d = 0.55. A two-group analysis of variance was used to test for group differences at posttest on consumer satisfaction and for group differences at followup on changes in oral health behavior. The BFS group had higher satisfaction scores , A content analysis was conducted on parents' open-ended responses. When asked to list the types of changes their family had made since watching the videos, the most common changes mentioned were (a) increased frequency, duration, or attention to brushing children's teeth, (b) decreasing intake of sugary foods, snacks, and drinks, (c) increasing consumption of fruits and vegetables, (d) increasing the frequency of flossing children's teeth, and (e) increases in actual visits or the intention of taking the child to the dentist. Some changes that were mentioned only by the BFS group included parents or siblings serving as role models of oral hygiene, increasing water consumption, increases in the parents seeing the dentist, attention to fluoride, and changes in bottle feeding. These group differences are consistent with the content of each video series, that is, the BFS series suggests that children should watch their parents brush and floss and mentions repeatedly the importance of fluoride. The early childhood period is one of relatively untapped potential for setting positive lifelong oral health practices and preventing later oral health problems. However, access to parents for the purposes of anticipatory guidance is often limited, particularly parents of infants and toddlers. Parents of very young children may be unaware of the need for early oral hygiene and dental examination schedules. If a family lacks dental insurance, there may be few opportunities for a child to receive dental screening unless such services are provided in their childcare, preschool, or elementary school settings.Parent education via short, realistic videos is a low-cost and potentially engaging avenue for disseminating information. Visual media also have the advantage of being effective regardless of levels of literacy among the target population. Results of this study suggest that educational videos can be effective, at least in the short term. Parents of children age birth to three showed small but statistically significant increases in knowledge, attitudes, and self-reported family oral health practices after seeing segments of the BOH or BFS video series over an eight-week period.Two questions regarding the delivery of media-based anticipatory guidance are (a) does the presentation style of the video itself make a difference, and (b) how can more families be exposed to video-based education? In terms of presentation style, the results of this study indicate that a family-centered approach (BFS) is more effective than the more traditional didactic approach (BOH). A didactic approach focuses on facts and suggested practices, with narration provided by professional voice-over and/or by interviews with authority figures. While visuals may still be realistic and engaging, the tone tends to be more formal and the audience is positioned as the recipient of the experts' advice. A family-centered approach is still research based, but the tone is more informal, and peers act as messengers who share their personal experiences and strategies for implementing what the experts suggest should be done. In this experimental study, we found that didactic (BOH) and family-focused (BFS) styles resulted in similar gains in factual knowledge. However, the family-focused video (BFS) resulted in higher consumer satisfactions and greater parental attitudinal and self-reported behavioral change. This suggests that the family-focused style is more effective.Delivery strategies for anticipatory guidance are a second key consideration. While short videos such as the ones used in this study are inexpensive and feasible for use in pediatric dental practices and medical clinics (where parents can watch video segments in the waiting area), the model followed in this study was to capitalize on the use of an existing system of early childhood service providers. In this study, we asked Early Head Start (EHS) home visitors and group leaders to disseminate the video to the families they serve. This model has the potential to reach many more children, especially those who are not already receiving early pediatric dental care. In the U.S., over 150,000 low-income children enroll in EHS on an annual basis . Over 6.In addition to the number of children served, relying on early childhood educators and maternal and child health care providers as a conduit of information has other potential benefits. These personnel  often have close and long-term personal relationships with the children and families they serve. There is a level of trust and knowledge of child development that allows for open discussion, individualized advice, and followup. There is also the element of time, where teachers and home visitors are not working within a schedule of short appointments and long waiting times. In early childhood settings, attending the program is already part of the family's regular routine, and there is also the expectation that staff work actively to support parents' positive influence on the child's overall development and wellbeing. This study has several limitations. First, the BFS and BOH videos differed on characteristics such as overall length and some aspects of informational content as well as presentation style. For this reason, differences cannot be attributed solely to the didactic versus family-focused presentation style. The sample size was modest and was taken from a small geographic area. Most importantly, outcomes were all based on parent report, and no objective measures of changes in family behavior or children's oral health were collected. Finally, the followup period was relatively short. However, the results provide an informative first step in developing new materials and dissemination models for educating parents about early oral health.Family-focused educational videos are a promising method for providing anticipatory guidance to parents of infants, toddlers, and preschoolers regarding early childhood oral health. Furthermore, supporting partnerships among dental care and early childhood education and maternal health systems represents a model that offers wide potential reach with minimal cost.