Rye products have previously been shown to induce comparatively low post-prandial insulin responses; irrespectively of their glycaemic indices (GI). However, the mechanism behind this lowered insulin demand remains unknown. An improved insulin economy might contribute to the benefits seen in epidemiological studies with whole grain diets on metabolic risk factors and weight regulation. The objective of this study was to explore the mechanism for a reduced post-prandial insulin demand with rye products.12 healthy subjects were given flour based rye products made from endosperm, whole grain or bran, produced with different methods  as breakfasts in random order in a cross-over design. White wheat bread (WWB) was used as a reference. Blood glucose, serum insulin, plasma ghrelin and subjective satiety were measured during 180 minutes. To evaluate the course of post-meal glycaemia, a measure of the glycaemic profile (GP) was introduced defined as the duration for the incremental post-prandial blood glucose response divided with the blood glucose incremental peak (min/mM).The study shows that whole grain rye breads and endosperm rye products induced significantly (p < 0.05) lower insulinaemic indices (II's) than WWB. Rye bran bread (RBB) produced significantly higher II compared with all the other rye products. Furthermore, the acute insulin response showed better correlations with the GP than with the GI of the products. The endosperm rye bread and the whole grain rye bread with lactic acid induced a significantly higher GP than RBB, WWB, white wheat- and whole grain rye porridge, respectively. A low insulin incremental peak was associated with less severe late post-prandial hypoglycaemia , and hypoglycaemia was negatively correlated to subjective satiety at 180 min . A low insulin incremental peak was also associated with a milder recovery of plasma ghrelin in the late post-prandial phase .Our study shows that endosperm and wholegrain rye products induce low acute insulinaemic responses and improved glycaemic profiles. The results also suggest that the rye products possess beneficial appetite regulating properties. Further studies are needed to identify the unknown property or bioactive component(s) responsible for these beneficial metabolic features of rye. Whole grain products have been shown to protect against type 2 diabetes and CVD -7 and alBased on the above, whole grain foods characterized by a low GI/low insulineamia are of particular interest as type 2 diabetes and CVD preventing foods. Previous studies have demonstrated that whole grain rye products display low insulinaemic index (II), regardless of their GI -26. ThisThe aim of the present study was to investigate the potential improvement of insulin economy following rye products, with a particular focus on evaluating the influence of different fractions of rye. For this purpose, rye products were produced from different parts of the rye grain , and processed with different methods (baking vs. boiling). Since rye bread is commonly produced by use of sour-dough fermentation, the effect of lactic acid addition was also evaluated. The products were studied as to their effects on post-prandial glucose and insulin response in healthy subjects using white wheat bread as reference. In parallel, subjective satiety and total ghrelin responses were studied in the post-prandial phase. Additionally, the rate of in vitro starch hydrolysis was determined in order to evaluate the possibility of obstructed amylolysis.2, and without drug therapy participated in the study. All subjects had normal fasting blood glucose concentrations (4.6 ± 0.03 mM). The subjects were recruited in August 2005 and the study was performed from September to December 2005. All test subjects gave their informed consent and were aware of the possibility of withdrawing from the study at any time they desired. Approval of the study was obtained by the Ethics Committee in Lund, Sweden.Twelve healthy non smoking volunteers (9 men and 3 women) aged 25.3 ± 0.8 y with normal body mass indices: 23.1 ± 0.6 kg/mFour rye breads, two rye porridges, one white wheat (endosperm) porridge and white wheat (endosperm) bread  were included in the study. Whole grain rye flour, endosperm rye flour and rye bran from commercial blends were provided by Lantmännen R&D  and commercial white wheat flour was obtained from Kungsörnen AB . The rye bran was milled to pass through a 0.8 mm screen . Dry yeast was obtained from Jästbolaget AB  and lactic acid (88-92% extra pur) was obtained from Riedel-de Haën . Monoglycerides were obtained from Aromatic .The ingredients of the breads are shown in Table Four types of rye breads were made: Endosperm rye bread (ERB), whole grain rye bread (WGRB), whole grain rye bread with lactic acid (WGRB-lac) containing 18 mmol lactic acid/100 g flour and rye bran bread (RBB). All rye breads were made using a uniform method: The dough was mixed in a mixing bowl for 6 min and was proofed in room temperature for 30 min. The dough was divided into pieces of 1 kg each and placed in a bread making tin, followed by a second proofing for 60 min in room temperature. Baking was performed at 250°C for 40 min.The WWB was left to cool for 1 hour and the rye breads for 18 hours under a cloth. Thereafter, the crust was removed and the breads were sliced and wrapped in aluminium foil in portions sizes, put into plastic bags and stored in a freezer (-18°C) until use. The day before the experiment, the breads were taken from the freezer and were thawed at ambient temperature, still wrapped in aluminium foil and in the plastic bag.Three types of porridges were cooked: white wheat porridge (WWP), endosperm rye porridge (ERP) and whole grain rye porridge (WGRP). The ingredients of the porridges are shown in Table Prior to all analyses, except for the determination of starch hydrolysis, the samples were dried and milled to pass through a 0.5 mm screen .The available starch content of the products was determined according to Holm et al. . InsolubThe products were provided as breakfasts on 8 different occasions in random order with approximately 1 wk between each test. The subjects were instructed to eat a standardized meal in the evening (21.00-22.00) prior to the test, consisting of a few slices of white wheat bread. They were instructed to avoid eating and drinking anything but small amounts of water until the start of the test. In addition, they were told to avoid alcohol and excessive physical exercise the day before each test. The subjects arrived at the laboratory at 07.45 on the test day. A peripheral venous catheter  was inserted into an antecubital vein to be used for blood sampling and fasting blood samples were taken prior to the meal. All test products contributed with 40 g of available starch and were served with 250 ml of tap water. The test subjects were instructed to finish the test product and water within 12 min. The subjects feeling of hunger and satiety was rated on a bipolar subjective rating scale graded from -10, representing extreme hunger, to + 10, representing extreme satiety. The feeling of hunger/satiety was rated before the meal (0 min) and at 15, 30, 45, 70, 95, 120 and 180 min after commencing breakfast. The test subjects were not allowed any further water or any caffeinated drinks during the test.Both capillary and venous blood samples were taken at 0, 7.5, 15, 30, 45, 70, 95, 120 and 180 min after the start of the meal for analysis of blood glucose, serum insulin and plasma ghrelin. Blood glucose concentrations were determined in capillary whole blood using a B-glucose analyzer . Serum and plasma (EDTA) were left in room temperature for approximately 1 h before being centrifuged for 11 min . Serum were frozen at -20°C and plasma where frozen at -40°C until analysis. The serum insulin measurement was performed on an integrated immunoassay analyzer  by using an enzyme immunoassay kit . Plasma ghrelin  were determined with a commercially available radioimmunoassay kit .Data are expressed as means ± SEM. The incremental areas under the curve (iAUC) for blood glucose, serum insulin, subjective satiety and in vitro rate of starch hydrolysis as well as the negative area under the curve for glucose (neg AUC), were calculated using the trapezoid model. The glycaemic and insulinaemic indexes (GI and II) were calculated from the 120 min incremental post-prandial area for blood glucose and serum insulin by using WWB as a reference (GI and II = 100). In addition, the course of glycaemia was analyzed by calculation a glycaemic profile (GP); The time (min) during which the blood glucose was above fasting concentration was divided with the incremental peak value (mM) of blood glucose for each subject and test meal . In the cases where the blood glucose concentration remained above fasting for the entire 180 min, the duration value was set to 180 min. A GP index was calculated from the GP by using WWB as a reference (GP Index = 100). HI was calculated from the 180 min incremental area for starch hydrolysis in vitro by using WWB as a reference. Relative changes (%) from fasting concentration to the nadir and to the concentration at 180 min after commencing breakfast were calculated for plasma ghrelin.The data were analyzed with a general linear model (ANOVA) followed by Tukey's multiple comparison test . In the cases of unevenly distributed residuals (tested with Anderson-Darling and considered unevenly distributed when p < 0.05), Box Cox transformation were performed on the data prior to the ANOVA.Significant difference between the products at different time points where evaluated using a mixed model  with repeated measures and an autoregressive covariance structure. When significant interactions between treatment and time were found, Tukey's multiple comparison test were performed for each time point .Correlation analysis was conducted to evaluate the relation among dependent measures with the use of Spearman's partial coefficients controlling for subjects (two-tailed test), .Due to problems drawing capillary blood samples from one subject, the blood glucose statistics was analyzed with n = 11. One subject failed to ingest the WGRP meal according to instructions and data from this product for that subject was therefore excluded from the statistical analysis.The endosperm products ERB and ERP, as well as the whole grain products WGRB-lac and WGRP induced significantly lower incremental areas (iAUC 0-120 min) than WWB, with glycaemic indices (GI's) of 64, 70, 74 and 72, respectively Table . In the The glycaemic profile  was significantly higher for ERB and WGRB-lac compared with WWB, RBB, WWP and WGRP.Significant differences in blood glucose were observed at specific time points (time × treatment p < 0.0001). RBB and WWB induced significantly higher glucose response than the non-supplemented rye products at 30 min (data not shown).With the exception of RBB, all rye breads, and the ERP, induced significantly lower incremental insulin areas (iAUC 0-120 min) than WWB, resulting in insulinaemic Indices (II's) ranging from 61 to 73 Table . InsteadSignificant differences in serum insulin were observed at specific time points (time × treatment p < 0.0001). RBB induced significantly higher insulin response than all other rye products at 45 and 70 min (data not shown).Plasma ghrelin levels after all products decreased to a nadir, occurring at 64.9 ± 3.1 min in the post-prandial phase. Table . The ghrWGRP and ERP induced significantly higher subjective satiety (expressed as iAUC from 0 to 180 min) than WWB and WGRB, with the iAUC for WGRP being 123% larger than that of WGRB Table . RBB indAll porridges and the ERB were characterized by a lower hydrolysis index (HI) than WWB and WGRB. In addition, WGRP showed a lower HI than WGRB-lac, RBB and ERP Table .Correlations between II, insulin incremental peak, GI, GP, hypoglycaemia, ghrelin and subjective satiety are presented in Table In the present study, the endosperm products and whole grain rye breads induced significantly lower II's than WWB, which is in agreement with previous findings -26. In cTo explain the low post-prandial insulin response of the endosperm and whole grain rye products, the course of glycaemia was analyzed. The rye products tended to induce blood glucose curves that remained above fasting for a longer time, with a lower glucose peak and a less pronounced late hypoglycaemia. It could be hypothesized that the inconsistency between GI and II, reported for some rye products, is caused by this low but prolonged net increment in post-prandial blood glucose response, resulting in an improved insulin economy, but maintaining a high GI as calculated from the 120 min area. In order to quantify the profile of the blood glucose curve, the glycaemic profile (GP) was introduced, defined as the duration for incremental post-prandial blood glucose response divided with the blood glucose incremental peak. Thus, a high GP is indicative of a facilitated post-prandial glycaemic regulation, with a lower glucose peak and a less pronounced hypoglycaemia. As judged from their higher GP's, it could be argued that ERB and WGRB-lac are characterized by a more beneficial glucose regulation than RBB, WWB, WWP and WGRP, respectively.In the present study, the II showed a stronger correlation with GP than with the GI of the products. Furthermore, the insulin incremental peak was negatively correlated to the GP but showed no correlation with the GI. This indicates that the GP is a better predictor, than the GI, of the acute insulin response of rye products.We suggest that the GP is a useful tool for evaluation of post-prandial glycaemia to carbohydrate foods in general. Granfeldt et al.  noted thThe beneficial glycaemic profile and low post-prandial insulin response seen with endosperm rye bread does not rule out a dietary fibre-related mechanism. In contrast to WWB (1.8 g DF/100 g bread), the endosperm rye bread (ERB) are rich in soluble fibres (6.7 g DF/100 g bread of which 2.5 g was soluble and 4.2 g insoluble fibres). However, since the more fibre rich RBB appeared to be devoid of acute metabolic benefits, it could be suggested that some unknown property or component(s) present in the endosperm, but not the bran fraction of rye, affects the course of glycaemia and lowers the insulin demand. This is a new observation showing that the benefits of rye products on insulin demand cannot be mimicked by adding rye bran to a white wheat background. The results also show the importance of maintaining all parts of the whole grain, including the endosperm, in rye products. The improved insulin economy seen with endosperm and whole grain rye breads could possibly be due to an improvement in insulin sensitivity or by an increase in first phase insulin release, previously seen with rye breads ,35.Whole grain and endosperm rye porridges induced significantly higher early insulin and glucose responses (0-30 min) compared with the corresponding bread products. Also the insulin incremental peak was higher for the porridges; ERP inducing a 48% higher peak than ERB and WGRP a 42% higher insulin peak than WGRB. Thus, in the present study, the type of processing affects the glycaemic and hormonal responses to flour based rye products, in favour of bread making.In a study by Juntunen et al  it was sA connection between low II features of foods and increased post-meal satiety has been shown in several studies comparing equicarbohydrate food portions -39. In tEndosperm rye products and whole grain rye breads induced significantly lower II's than white wheat bread (WWB). In addition, these products induced low and prolonged glucose profiles i.e. high GP's, in the post-prandial phase. The rye bran bread, devoid of the endosperm part of the rye grain, induced GI, GP and II similar to that of a WWB. The finding that the presently introduced GP better predict the insulin response of rye products in the acute post-prandial phase, compared with the GI, is important. It is put forward that the GP could be exploited when evaluating post-prandial glycaemia of food products. The results also indicate that a higher acute insulin response was associated with more prominent late hypoglycaemia, feeling of hunger and an increase in plasma ghrelin, respectively. Thus, low II rye breakfast products may improve appetite regulation. The latter warrants further investigations which are currently under way.BMI: body mass index; CVD: cardiovascular diseases; ERB: endosperm rye bread; ERP: endosperm rye porridge; GI: glycaemic index; GP: Glycaemic profile; HI: hydrolysis index; iAUC: incremental area under the curve; II: insulinaemic index; neg AUC: negative area under the curve; RBB: rye bran bread; WGRB: whole grain rye bread; WGRB-lac; whole grain rye bread made with lactic acid; WGRP: whole grain porridge; WWB: white wheat bread; WWP: white wheat porridge.The authors declare that they have no competing interests.LAHR coordinated the study and was responsible for the study design, the collection and analysis of the data, statistical analysis and for writing the paper. EMÖ was involved in the study design, interpretation of data and in writing the paper. IMEB was the guarantor for the founding of the study and was involved in the study design, interpretation of data and writing of the paper. LOBS was involved in the analysis and statistical analysis of total ghrelin. UKA and CH was involved in the study design.


Bartonella henselae and B. vinsonii subspecies berkhoffii in the blood of 14 immunocompetent persons who had frequent animal contact and arthropod exposure.Using PCR in conjunction with pre-enrichment culture, we detected  Bartonella sp. from immunocompetent persons with serologic, pathologic, or molecular evidence of infection are often unsuccessful; several investigators have indicated that Bartonella isolation methods need to be improved  region and heme-binding protein (Pap31) gene have been described  procedure  of 40 extracted blood samples, 13 (33%) of 40 pre-enrichment cultures, and 5 isolates. For 7 persons, B. henselae DNA was amplified at multiple time points. Bartonella DNA was never amplified from any PCR control or uninoculated culture control.When reciprocal titers of antigens . B. hensisolates . For 5 pB. henselae ITS and Pap31 strains were sequenced, B. henselae Houston I (HI) (GenBank NC-005956) and B. henselae San Antonio 2 (SA2) (GenBank AF369529). Within the noncoding ITS region, B. henselae SA2 strains have a 30-bp insertion (ATT GCT TCT AAA AAG ATT GCT TCT AAA AAG) located 518 bases downstream from the 16S gene. Only B. vinsonii subsp. berkhoffii types I and II were detected  is generally considered self-limiting  has proven problematic for other specialized laboratories that routinely culture for Bartonella spp. . Cats are considered the primary reservoir host for Bartonella infection in immunocompetent persons.Despite reporting chronic or episodic illness, most participants continued to effectively maintain daily professional and personal activities. The symptoms described in the study patients are very similar to those described in a community and hospital-based surveillance study of CSD patients, in whom CSD-associated arthropathy was an uncommon chronic syndrome affecting mostly young and middle-age women (Serologic and PCR results from blood collected at multiple time points from 14 persons with frequent animal and arthropod contact


In Nepal, more than 90% of the deliveries take place at home where birth weight is often not recorded. In developing countries, low birth weight  accounts for 60–80% of neonatal deaths. Early identification and referral of LBW babies for extra essential newborn care is vital in preventing neonatal deaths. Studies carried out in different populations have suggested that the use of newborn anthropometric surrogates of birth weight may be a simple and reliable method to identify LBW babies in a home setting. However, a reliable anthropometric surrogate to identify LBW babies and its cut-off point is not known for Nepalese newborns.A cross-sectional study was carried out in Western Regional Hospital, Pokhara between April and June, 2006. All consecutive full-term, singleton, live born babies were included. To ensure reliability and avoid inter-observer bias one of the investigators weighed all the newborns and carried out anthropometric measurements within 24 hours after birth. Circumferences of head, chest, mid-upper arm, thigh and calf were measured according to standard techniques. Non-parametric receiver operating characteristic (ROC) curve analyses were carried out using bootstrap to calculate 95% confidence intervals of areas under the curve (AUC). The cut-points with lowest total misclassification rate were chosen to identify LBW babies.Out of 400 newborns studied, 204 (51%) were males and 196 (49%) were females. The mean birth weight was 3029 ± 438 grams and 34 (8.5%) newborns were LBW. By ROC-AUC analyses, head circumference  and chest circumference  were identified as the optimal surrogate indicators of LBW babies. The optimal cut-points for head circumference and chest circumference to identify LBW newborns were ≥ 33.5 cm and ≥ 30.8 cm respectively.Head and chest circumferences were the best anthropometric surrogates of LBW among Nepalese newborns. Further studies are needed in the field to cross-validate our results. Of the approximately four million global neonatal deaths that occur annually, 98% occur in developing countries, where most newborns die at home while they are being cared by mothers, relatives, and traditional birth attendants . About 3Several researchers have attempted to identify suitable anthropometric surrogates which are simple and reliable to identify LBW babies. Recent hospital-based studies from India, Bangladesh and other developing countries have suggested different anthropometric surrogates to identify LBW babies and have also recommended various cut-off values for identification of LBW babies -19. AvaiNepal is a Himalayan kingdom located between China and India. In 2004, infant mortality rate was 64 per 1000 live births and neonatal mortality rate was 39 per 1000 live births . In rura1) to identify a suitable anthropometric surrogate to identify LBW babies and2) to determine its cut-off value to identify LBW babies.A cross-sectional study was carried out in Western Regional Hospital, Pokhara, Nepal, during the time period April-June, 2006. Western Regional hospital is a teaching hospital affiliated to Manipal College of Medical Sciences (MCOMS). The institutional research ethics committee of MCOMS approved this study. All the consecutive full-term, singleton, live born babies during the study period were included for the study. The newborns with congenital anomalies/dysmorphic features, multiple births and gestational age of less than 37 completed weeks (pre term babies) were excluded. To ensure reliability and avoid inter-observer bias, one of the investigators (Brishna Shakya) weighed all the newborns and carried out all anthropometric measurements within 24 hours after birth. The investigator obtained informed consent from the mothers to examine their newborn. Gestational age of the newborns was obtained from the medical case file. Circumferences of head, chest, mid-upper arm, thigh and calf were measured to the nearest 0.1 cm using a non-elastic, flexible, fiber glass measuring tape according standard techniques described by Jelliffe .All the newborns were weighed naked on a spring type of weighing scale to the nearest 50 grams. The weighing machine was checked daily by known standard weight before weighing. Mid-upper arm circumference (MUAC) was measured at the midpoint between the tip of acromion process and olecranon process of the left upper arm. Head circumference (HC) was measured between glabella anteriorly and along the most prominent point posteriorly. Chest circumference (CHC) was measured at the level of nipple at the end phase of expiration. Thigh circumference (TC) was measured at the lowest furrow of gluteal region. Calf circumference (CC) was measured at the most prominent point in a semi-flexed position of the leg.t-test. Pearson's product-moment correlation coefficient was used to assess the association between anthropometric measurements. Receiver operating characteristic (ROC) curves were used to evaluate the accuracy of different anthropometric measurements to predict LBW coded as dichotomous . The area under the ROC curve (AUC) was calculated using the non-parametric method of De Long. Internal cross-validation was performed by calculating 95% confidence intervals (95%CI) of ROC AUCs on 1000 bootstrapped samples of 400 subjects. Sensitivity, specificity and positive likelihood ratios were calculated at all cut-points for any anthropometric measurement. We choose as "optimum" the cut-point with the highest [(sensitivity + specificity)/2] ratio, i.e. the lowest total misclassification error rate. This criterion was chosen to allow comparison with previous studies available in the literature. A p-value < 0.05 was considered statistically significant. All statistical tests are two-tailed. Statistical analysis was performed using SPSS 10 and STATA 10.0.Continuous variables are reported as mean and standard deviation while categorical variables are given as the number or the percentage of subjects with the characteristic of interest. Between-gender comparisons of continuous variables were performed using student's unpaired During the study period, a total of 613 deliveries took place in the hospital. Two hundred and thirteen deliveries were excluded from the study for the following reasons: 1) age > 24 hours (n = 9), 2) preterm birth (n = 184), 3) multiple births (n = 12), 4) still births (n = 6) and, 5) congenital anomalies or dysmorphic features (n = 2). A total of 400 newborns  were therefore studied. Their median age was eight hours (inter-quartile range 4 to 12 hours) and their anthropometric measurements are given in Table Thirty four of the 400 (8.5%) newborns were LBW. The best discrimination of LBW, as detected by ROC-AUC, was obtained by head circumference  followed by chest circumference , calf circumference , thigh circumference  and arm circumference   of spring type of weighing scale used in our study was another limitation. Further studies on a community-based sample of newborns using a more precise weighing scale and by measuring all the suggested anthropometric surrogates may be necessary. Moreover, the suggested surrogates to identify LBW newborn should be validated in the field setting. This is because the surrogate measurements are intended to be used by health workers in the field setting. Community-based studies may have to overcome the time delay involved in taking measurements. It is well known that a newborn looses weight during the first 72 hours after birth ,32. We iThe results of our study suggest that chest circumference may be an optimum anthropometric surrogate to identify LBW Nepalese newborns. Further studies are required to validate our results in the field setting and define an optimal cut-off value. A color coded, measuring tape may be suggested for use by health workers or family members to identify LBW newborns in home setting.The authors declare that they have no competing interests.CTS contributed to the design and protocol of the study, assisted in the data collection, was the primary researcher and drafted the manuscript for publication. NC contributed to the design and protocol of the study, assisted in the data collection, was the primary researcher and drafted the manuscript for publication. RP helped in conception of the study, designed data entry and analysis. DS provided assistance during the data collection, analyses and interpretation, criticized the earlier drafts of the manuscript for its intellectual content. BS carried out all the anthropometric measurements and assisted in manuscript preparation. All authors read and approved the final manuscript for submission for Publication.The pre-publication history for this paper can be accessed here:


Bartonella spp. infection is not rare and must be considered with great care in patients with suspected infective endocarditis, particularly if regular blood cultures remain sterile. Management of these infections requires knowledge of the identification and treatment of these bacteria.Bartonella quintana endocarditis was performed by molecular methods retrospectively after the death of the patient.A 50-year-old Senegalese man was admitted to our Department of Cardiac Surgery with a culture-negative endocarditis. Despite valvular surgery and adequate antibiotic treatment, recurrence of the endocarditis was observed on the prosthetic mitral valve. Heart failure required circulatory support. Weaning off the circulatory support could not be attempted owing to the absence of heart recovery. Bacteriological diagnosis of Bartonella quintana endocarditis. The clinical picture suggested possible Bartonella quintana associated myocarditis, a feature that should be considered in new cases.This case report underlines the severity and difficulty of the diagnosis of  Bartonella quintana is a Gram-negative bacterium first identified as the cause of louse-borne epidemic trench fever in Europe during World War One. Additional manifestations of B. quintana infection including endocarditis, bacillary angiomatosis, chronic bacteremia and pericarditis have been reported . We . We B. qreported .Bartonella henselae myocarditis affecting humans has been reported [B. quintana was suspected in a case report [B. quintana myocardial infection could be proved, it would argue in favor of an aggressive treatment of B. quintana induced cardiac failure associating inotropic support and circulatory support until heart recovery.The cardiac failure and troponin level that we observed were consistent with major myocardial dysfunction. This dysfunction was probably not a complication of the cardiopulmonary bypass usually observed no more than several hours after the surgery. Furthermore, vasopressor requirement was very low in the first postoperative hours. The patient's hemodynamic profile did not suggest septic shock. Thus, we assumed that this dysfunction was due to a direct infection of the myocardium as can be seen in fulminant myocarditis. reported  and a die report . HoweverBartonella spp. are fastidious growing bacteria. Blood or resected valve cultures remain negative for at least 10 days. In the case of blood culture-negative endocarditis, the first screening must include at least Bartonella spp. and C. burnetii serologies. Usually microimmunofluorescence serology has a high predictive value for the diagnosis of Bartonella spp. endocarditis if a cut-off value of 1:800 for Bartonella spp. Immunoglobulin G titer is used [Bartonella species diagnosis when coupled with cross-adsorption [Bartonella spp. endocarditis. Cross-adsorption was not realized because this technique required a large amount of antigens and the species identification was already established by two different PCR assays performed on the cardiac valve sample. In the case of negative serologies, broad-range PCR followed by sequencing performed on cardiac valve samples could help in the etiological diagnosis as this molecular technique allows the detection of numerous bacterial agents. In the case of positive broad-range PCR, species specific PCR should be applied to confirm the diagnosis. The usefulness of molecular techniques in blood is still debated. But their development would be helpful in guiding initial therapy in patients who do not undergo emergency valvular surgery [As we observed, bacteriological diagnosis is difficult and often retrospective. Indeed sorption . In our  surgery .B. quintana endocarditis treatment is non-specific. As in our patient, the delay in diagnosis may provoke serious valve destruction requiring its replacement. More than 90% of patients with B. quintana endocarditis require cardiac surgery [Bartonella spp. are susceptible in vitro to a wide range of agents including penicillins, cephalosporins, aminoglycosides, chloramphenicol, tetracyclines, macrolides, rifampicin, fluoroquinolones and cotrimoxazole. However, aminoglycosides are currently the only known antibiotic class bactericide for Bartonella spp. [Bartonella spp. than amoxicillin [Bartonella spp. endocarditis had been suspected, doxycycline could have been added [B. quintana endocarditis remains about 12% [ surgery . Bartonella spp. . Patientlla spp. . That islla spp. . In thisxicillin . If Barten added . Given tBartonella spp. infection is not rare and must be considered with great care in the case of patients with suspected infective endocarditis, particularly if regular blood cultures remain sterile despite absence of antibiotic treatment. African origin should be considered by itself as a risk factor for Bartonella infection. Owing to the high death rate and the difficult diagnosis, culture-negative endocarditis should include aminoglycoside therapy, the only antibiotic treatment bactericide for Bartonella spp., for at least 14 days.Bartonella quintana should be included among the myocarditis infectious agents.The cardiac failure we observed may evoke fulminant myocarditis. Myocardial biopsy could be decisive to determine whether Written informed consent was obtained from the patient's next-of-kin 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.AM and FB wrote the manuscript while FF performed the bacteriological identification. AR and FC performed the surgical valves replacements and have revised the manuscript for surgical content. MB and CG corrected the manuscript. All authors read and approved the final manuscript.


Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1–9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefrontal cortex dysfunction in children with HFA. These tSustained attention is the endogenous ability to mindfully and consciously process stimuli, whose non-arousing qualities would otherwise lead to habituation and distraction . The abiThere is evidence of anatomical and physiological dysfunction in the fronto-parietal and fronto-striatal networks in ADHD. Researchers have found bilateral reductions in prefrontal volume , reducedThere is also anatomical and physiological evidence of fronto-striatal  and fronEquivocal evidence exists for sustained attention deficits in both ADHD and autism, although a greater amount of research has been directed at elucidating sustained attention deficits in ADHD, when compared with autism e.g. . Some reWithholding to a rare target, as opposed to responding to a rare target in CPT tasks, shifts the automatic response set to the non-targets. Successful withholding of the primed response places greater demand on the sustained attention system in order to interrupt the ongoing action  and slow variability using a Fast Fourier Transform (FFT) , based og action . In addig action .The SART activates the same right fronto-parietal attentional network  that appThe central aim of this study was to assess the ability of children with ADHD, with autism and normal healthy children on these tasks, in order to examine if these groups differed on aspects of sustained attention, response inhibition and response time variability (fast and slow). Based on the previous experimental literature, we hypothesised that the ADHD group would make more errors of commission and omission and show greater fast and slow variability in RT than the control group, on both versions of the SART. Based on anatomical and physiological evidence, we hypothesised that the HFA group, on both versions of the SART, would make more errors of commission and omission and show greater fast and slow variability in RT than the control group and in a similar manner as the ADHD group, but that there may be some evidence of compensatory mechanisms in the measures.22.1Twenty three children with ADHD , 21 children with HFA  and 18 control children  participated in the study see . There wExclusion criteria for participation in the study included known neurological conditions or pervasive developmental disorders (apart from the presently studied disorders for each group), serious head injuries and below average intelligence (below 70 on the WISC-III) . ControlThe participants with ADHD and HFA were recruited as part of ongoing genetic studies . These pDiagnosis for the participants with ADHD was confirmed by psychiatrists using the parent form of the Child and Adolescent Psychiatric Assessment (CAPA) . Twenty-Diagnosis for the participants with HFA was confirmed by psychiatrists using the Autism Diagnostic Interview–Revised (ADI-R)  and AutiThe control children were recruited from Dublin schools. Parents of control children completed the CPRS-R:S  at the t2.2All participants performed the Fixed and Random versions of the Sustained Attention to Response Task, presented on a laptop computer  please . In the 2.3For both the Fixed and Random SARTs, errors of commission (responses made on the no-go digit 3) and omission  were calculated both for the entire trial (“full-run”) and for the first and second halves of the trial . The Mean and standard deviation (S.D.) of the RTs on the go-trials were calculated for the full-run and half-by-half analyses. The sequence of 225 RTs was also analysed using a fast Fourier transform (FFT), following the methodology of Data preparation for FFTs: To calculate the FFTs, the RTs for the digit 3 and RTs of less than 100 ms were linearly interpolated from the immediately preceding and following RTs. For the fast-frequency area under the spectra (FFAUS), individual RT data were detrended, subtracting out any linear components, which were analysed separately.Derivation of FFT spectra: The RT data were analysed according to Welch's averaged, modified periodogram method. The RT data were analysed both over the full-run  and in the half-by-half analysis. The full time-series was first divided into 7 segments of 75 data points, with an overlap of 50. Each segment was Hamming-windowed and zero-padded to length 450.RT variance may be measured by calculating the area under the spectrum (AUS) over a broad band of interest. The AUS represents a measure of the ‘power’ or overall variance in the signal. The peak power at a particular point in the spectra measures consistency and distinctness of a particular RT pattern. Healthy adult control participants often show a slowing in RT on digit 1 relative to digits 9 and 2 in preparation for the upcoming no-go response on the Fixed SART . If thisIn a separate test, the linear component in isolation was analysed by fitting regression lines to the RTs of each participant using a first order polynomial fit (linear). The slope of the regression line was then calculated.Statistics: All dependent variables were calculated per participant and averaged per group for the Fixed and Random SARTs. The number of errors of commission and omission, mean RT and S.D. of RT were analysed in a Group (ADHD versus HFA versus Control) by Half  by SART (Fixed versus Random) three-way mixed factorial ANOVA design. The FFAUS was analysed in a Group by Half two-way mixed factorial ANOVA design for the Fixed and Random SARTs separately, to ensure the largest number of participants in each analysis. This was due to the exclusion criteria of the FFAUS (see above). The SFAUS and slope of regression line were analysed in a Group by SART two-way mixed factorial ANOVA. The alpha level was set at 0.05 and Bonferroni adjustments were used throughout the analysis.3p < 0.001) and control groups  (p < 0.001), . The HFA and control groups also differed significantly (p < 0.001). The HFA group  scored significantly more highly on the ASDI than the ADHD  (p < 0.001) and control groups  (p < 0.001), . The ADHD and control groups also differed significantly (p < 0.01). The higher than normal ratings of the ADHD and HFA groups on the ASDI and Conners’ ADHD Index, respectively, suggest that these groups may share some common symptoms. The significantly greater scores of the two groups on their respective symptom-rating scales nevertheless suggest that the two groups are distinct.The ADHD group  scored significantly more highly on the Conners’ ADHD Index than the HFA   = 5.39, p < 0.007] (see p < 0.002) or HFA groups  (p < 0.011). There was no significant difference between the HFA and control groups. On the Random SART, the HFA group  made as many commission errors as the ADHD group . The control group  made significantly less errors than either the ADHD (p < 0.01) or HFA (p < 0.01) groups. The increase in commission errors in the Random SART by the HFA group was driving this interaction. All groups made significantly more errors on the Random SART compared with the Fixed SART. A significant Half main effect was further explained by a significant Half by SART interaction, . More commission errors were made in the second half of the Fixed  and the Random SARTs  compared with the first half of the Fixed  and Random SARTs . More commission errors were made in the Random SART compared with the Fixed SART during both the first and second halves of the task.A significant Group and a significant SART version main effect were further explained by a significant Group by SART interaction, [007] see . On the 3.2p < 0.0001) made significantly more omission errors than the HFA group  (p < 0.001) and the control group  across both the Fixed and Random SARTs   = 4.56, p < 0.037]. The number of omission errors did not vary between the Fixed and Random SARTs.The ADHD group   = 3.516, p < 0.036]  = 8.352, p < 0.005].A significant Half main effect was further explained by a significant Half by Group interaction, . The HFA and control groups did not differ significantly. The positive slope of the regression indicated a slowing in RT over the course of the task for the ADHD group. There was no significant effect of the SART version.The linear regression of RT of the ADHD  was significantly greater than that of the HFA group , but did not vary significantly from the control group , . The variability in RT of the ADHD group  significantly increased over the course of both the Fixed and Random SARTs. The control  and the HFA groups  maintained a consistent S.D. of RT across both the Fixed and Random SARTs. The ADHD group was significantly more variable in RT than the control (p < 0.001) and HFA (p < 0.001) groups, for both the first and the second halves of the task. There was no significant difference in S.D. of RT between the control and HFA groups. The S.D. of RT did not vary between the Fixed and Random SARTs.A significant Half main effect was further explained by a significant Half by Group interaction, . The HFA and control groups did not differ significantly. There was no significant effect of SART version on the SFAUS.The average FFT spectrum for each group is shown in 3.7p < 0.004) and the HFA group  (p < 0.009),   = 3.932, p < 0.026] (please see p < 0.028) or the HFA group  (p < 0.034). The control and HFA groups did not differ significantly. Both the ADHD (p < 0.001) and control (p < 0.022) groups significantly increased the fast moment-to-moment variability in RT from the first to the second halves of the Random SART, whereas the HFA group did not change.A significant Group and a Half main effect were further explained by a significant Group by Half interaction, [4The lack of consensus in the literature as to whether children with ADHD or autism have sustained attention and/or response inhibition deficits may reflect differences in task characteristics. By manipulating the predictability of stimulus presentations in the current study, dissociation in error and RT performance was noted between children with ADHD, HFA and controls. The children with ADHD demonstrated clear deficits in response inhibition and sustained attention, as measured by the number of commission and omission errors, the S.D. in RT and the fast, moment-to-moment variability in RT. In addition, they demonstrated waning performance over the course of the task, suggestive of deficits in arousal levels. The children with HFA, in contrast, performed normally on every measure of the SARTs except for the large number of commission errors made on the Random SART. This suggests that children with HFA have intact sustained attention but deficient response inhibition. Since sustained attention is known to be sub-served by fronto-parietal networks of the right-hemisphere , as has The children with ADHD made a greater number of commission errors compared with the children with HFA and control children on the Fixed SART, suggesting sustained attention deficits. In contrast, the HFA group performed comparably with controls, possibly by making use of the externally cued, regular and predictable pattern of the Fixed SART. It is suggested that the children with HFA made special use of the regularly recurring sequence of digits leading up to the no-go “3”, in a systematic way, possibly by utilising compensatory cognitive mechanisms. With the unpredictable stimulus presentation of the Random SART, the children with HFA made as many commission errors as the ADHD group. Indeed, the similarity in the number of commission errors made by the two groups was striking. The nature of response inhibition deficits in participants with HFA appears to be task-dependent. The children with HFA may be demonstrating a response inhibition deficit when external cues are unavailable for use, as the Random SART has a greater response inhibition component, when compared with the Fixed SART . ResponsThe sustained attention deficit of the children with ADHD was clearly shown by the high number of omission errors, made both during the Fixed and Random SARTs. In contrast, the children with HFA and the control children made a similar, lower number of omission errors. All children showed an increase in omission errors as the task progressed, suggesting that a progressive decline in performance is normal at this age.The ADHD group showed a particular diminution in RT performance over the course of both the Fixed and Random SARTs, which was not shown by either the HFA or the control groups. The children with ADHD slowed in RT over the two halves of the tasks, as demonstrated by the mean RT and the linear regression analyses. The slow frequency variability in RT was significantly higher for the ADHD group. In comparison, the children with HFA and the control group maintained a steady performance across the tasks. The ADHD group may be affected by declining arousal. The SART runs for 5.5 min, which is a considerably shorter period compared with traditional vigilance tasks in which subjects must sustain attention for 15 , 30 Mac or even The ADHD group performed the Fixed and Random SARTs with greater fast-frequency (moment-to-moment) variability in RT and S.D. of RT than the children with HFA and the control children. The children with HFA and the control children performed the two SARTs with a similar amount of variability. Interestingly, the children with ADHD and control children showed greater fast-frequency variability in the second half of the Random SART compared with the first half, suggesting a time-on-task effect during this more difficult task. The HFA group, in both the Fixed and Random SARTs, appeared to have the capacity to maintain consistent fast-frequency variability in RT over the course of the task. Fast-frequency variation in RT likely reflects lapses in top-down attentional control that occur over relatively short time frames, up to the period of one SART cycle (13 s). There are suggestions that the areas of the fronto-parietal circuit are refreshed over time-spans of between 10 and 40 s . The ADHThe ability to sustain attention to a routine task is an important aspect of executive control. There may be at least two different processes involved in the behavioural manifestation of deficient sustained attention: a gradual deterioration in attention to a task and a fast phasic variation in top-down attentional control. An incremental worsening in attention to a task, as reflected by slow-frequency variability in RT (SFAUS), may be linked to a deficit in brain arousal levels, related to the functioning of sub-cortical structures , the anterior cingulate and neurotransmitter dysfunction  . These sThe clear distinction in performance between the children with ADHD and HFA on the Fixed and Random SARTs suggests that sustained attention may not be a deficit shared by the two disorders. Response inhibition may be a shared feature of the two disorders, especially in tasks when external cues that provide some structure are unavailable for children with HFA. These clear findings highlight the potential usefulness of CPT-like tasks in the assessment and conceptualisation of children with psychiatric disorders. The response inhibition, sustained attention and arousal deficits of children with ADHD should be addressed when designing cognitive behavioural therapies. The usefulness of external cues in providing a structure for cognition in children with HFA has been highlighted in this comparison of performance on the Fixed and Random SARTs.This study is limited by the retrospective use of the CPRS-R:S and the ASDI for a sub-group of the children and this must be taken into account when drawing conclusions from the data. It is important to note that 12 (57%) children with HFA scored at least 65 on the Conners’ ADHD Index. Whilst the HFA and ADHD groups differed significantly in their mean ADHD Index scores, some of the children with HFA displayed clinically-relevant ADHD-like behaviours, highlighting the potential comorbidity of these two disorders and the heterogeneity of the HFA group.In summary, four key findings resulted from the present study. First, the ADHD group showed pervasive deficits in sustained attention in both the Fixed and Random SARTs, particularly when the requirements for endogenous control of attention were high. The clear dissociation in performance of the ADHD group, compared with the HFA and control groups, highlights the potential utility of the SART measures as specific endophenotypes for ADHD. Second, the ADHD group demonstrated a time-on-task effect over the course of the Fixed and Random SARTs, as reflected in the increased slow-frequency variability, mean RT and linear regression of RT, possibly reflecting a decrease in arousal levels. That we found deficits for slow-frequency variability in the ADHD group but not in the HFA group also suggests that variability is not a simple consequence of cerebral disruption see also . Slow-fr


Concurrent comorbidity was assessed to characterize the clinical profile of this cohort.Subjects 6 to 18 years were diagnosed with the Schedule for Affective Disorders & Schizophrenia for School aged Children (K-SADS-P IVR).The most prevalent diagnoses co-occurring with ADHD were Oppositional Defiant Disorder (ODD) (40.6%), Minor Depression/Dysthymia (MDDD) (21.6%), and Generalized Anxiety Disorder (GAD) (15.2%). In Inattentive ADHD (n = 106), 20.8% had MDDD, 20.8% ODD, and 18.6% GAD; in Hyperactive ADHD (n = 31) 41.9% had ODD, 22.2% GAD, and 19.4% MDDD. In Combined ADHD, (n = 203), 50.7% had ODD, 22.7% MDDD and 12.4% GAD. MDDD and GAD were equally prevalent in the ADHD subtypes but, ODD was significantly more common among Combined and Hyperactive ADHD compared to Inattentive ADHD. The data suggested a subsample of Irritable prepubertal children exhibiting a diagnostic triad of ODD, Combined ADHD, and MDDD may account for the over diagnosing of Bipolar Disorder.rd of ADHD children have impairing comorbid diagnoses; Hyperactive ADHD represents less than 10% of an ADHD sample; ODD is primarily associated with Hyperactive and Combined ADHD; and, MDDD may be a significant morbidity for ADHD youths from clinical samples.Almost 2/3 The primary goal of this report is to characterize the concurrent comorbidy patterns identified in a clinical sample of ADHD subjects recruited for this genetic study. If more homogenous comorbid ADHD subtypes are identified, there is the potential for their validation through their genetic characteristics. In any assessment of psychopathology using standardized diagnostic interview schedules, comorbidity is the rule however it is infrequently considered in genetic studies. Concurrent comorbidity means the disorders are present at the same time of assessment as opposed to lifetime comorbidity which implies at any time over one's life. Comorbidity also can be classified into two broad patterns, homotypic or heterotypic . These crd of the MTA sample had concurrent comorbid disorders identified with a parental DISC interview.Reports of comorbidity in ADHD include both community and clinic samples. These are not compatible patient pools because of the biased referral patterns and the increased rates of disorder in any clinical group. Furthermore, only with a general population sample can a true base rate of a disorder be calculated and comorbid excessive identified . ReporteAngold et al's  extensivComorbidity rates are dependent on the assessment methodology. In assessing ADHD children Biederman's group ,8 has reThis report describes participants from an ongoing ADHD genetic study aiming to recruiting 500 parents/child triads with one or more ADHD probands. The sample currently consists of 342 children and adolescents from 302 families . All subjects were North-American of European descent. Other groups were excluded because haplotype frequencies can vary substantially across major world populations  loweringFamilies were recruited from general pediatric clinics as well as behavioral health clinics in the Philadelphia area. Phone screenings were conducted to verify initial inclusion criteria of age range between 6 and 18, presence of ADHD symptoms, Caucasian of European descent, availability and willingness to participate in a genetic study from both biological parents. Phone screenings also identified exclusionary criteria that included prematurity (< 36 weeks), mental retardation, major medical (excluding asthma) neurological disorders  and neuropsychiatric disorders such as pervasive developmental disorder, psychoses, bipolar disorder, major depressive disorder with symptoms starting prior to ADHD or where ADHD symptoms occurred primarily during depressed episodes. All anxiety disorders were included. Children with documented IQ scores < 75 were excluded as were children with histories suggestive of mental retardation or inability to comprehend or complete the K-SADS.Subjects who passed the phone screen proceeded with the K-SADS evaluation. Twelve subjects were excluded from the study after completing the diagnostic interview: Three subjects did not have impairing ADHD symptoms, 2 subjects met ADHD criteria primarily during a Major Depression and 2 subjects during a Generalized Anxiety Disorder, 1 subject with ADHD and Adjustment Disorder thought to significantly contribute to ADHD symptoms, 1 subject with ADHD and mild psychotic symptoms, 1 subject each with Cyclothymia, Bipolar Disorder and absence seizures. Siblings meeting inclusion and exclusion criteria were also invited to participate in the study, but their participation was not required.A child psychiatrist (JE) assessed diagnostic status by administering a K-SADS P-IVR interview to the parent(s) and child separately . This seThe K-SADS IVR records Irritability as a symptom independent of Depressed Mood. Irritability/Anger (subjective) was added as a third primary symptom of major depression to verify whether it was synonymous to depressed mood. This allows diagnosing an "Irritable Affective Disorder" which is a RDC or DSM defined depressive disorder where irritability replaces depressed mood or pervasive anhedonia as the cardinal symptom. For this study, Minor Depression (MD) and Dysthymic Disorder (DD) are combined into a variable labeled MDDD. Additional overall diagnostic variables were created for Any Anxiety Disorder (AnyAD) and for Any Depressive Disorder (AnyDep). The four main ADHD subtypes are labeled ADDI (Inattentive ADHD), ADDH (Hyperactive ADHD), ADDC (Combined ADHD), and ADDN (ADHD NOS).Cognitive ability was quantified by reviewing reports of past IQ assessments. Children not previously tested were administered the Wechsler Abbreviated Scale of Intelligence (WASI). IQ scores are available for 241 subjects (70.5% of the sample). Socioeconomic status (SES) was calculated on 314 families (91.8%) by Hollingshead 4 factor scale . Other pChi-square with continuity correction, Fisher exact probability, or binomial tests were used to analyze observed frequency or dichotomous data. Analysis of variance was used to test mean difference among continuous variables. All analyses were two tailed. Corrections for multiple comparisons were not made as the data analysis was exploratory in nature; significant p values were set equal to or less than 0.05. All analyses were done with SPSS 15.0.The sample consists of 342 Caucasian patients all with a current diagnosis of ADHD. Within the sample there are 31 sibling pairs and 6 triple sibling groups comprising 62 and 18 patients respectively. This is approximately 24% of the sample. Twins or triplets were not included. Birth weight range was 5.5–12 lbs . IQ scores ranged from 77 to 147 . The mean SES raw score was 47.9 (SD 11.1) with a range from 18 to 66. The mean SES class was 2.0 (SD 0.9). None of these demographic parameters differed among the three main ADHD subtypes.x2 = 4.5, df = 2, p = 0.033). The sex ratios were not significantly different in other comparisons between the ADDC vs ADDH or the ADDC vs ADDI.The subject's sex and age characteristics are shown in Table Tables x2 = 7.6, df = 1, p = .004).In the sample as a whole, the most prevalent co-occurring diagnoses were Oppositional Defiant Disorder , Minor Depression/Dysthmic Disorder , and Generalized Anxiety Disorder . This pattern however varied when co-morbid patterns were considered in the three individual diagnostic groups . Among the MDDD group (n = 74), the most prevalent diagnoses were ODD , ADDC , and GAD . 32.2% of the total sample had at least one anxiety disorder. Among those with AnyAD (n = 110), the most common disorders were ADDC , GAD (52: 47.3%), and ODD (48: 43.6%). 30% (33) of the AnyAD group had MDDD. Those with ODD (n = 139) most commonly had ADDC (103: 74.1%), MDDD (48: 34.5%), and GAD (24: 17.4%). There were no significant sex differences in any of these diagnostic frequency patterns except that Separation Anxiety (SA) was more common in girls than boys , 20.8% had MDDD, 20.8% has ODD, and 18.6% had GAD. The most common diagnostic patterns in ADDH (n = 31) were ODD (41.9%), GAD (22.6%), and MDDD (19.4%). In ADDC (n = 203), the most prevalent disorders were ODD (50.7%), MDDD (22.7%), and GAD (12.3%). Within these three ADHD subtypes, MDDD and GAD were equally prevalent. However, ODD was significantly more prevalent in those with ADDC (50.7%) and ADDH (41.9%) compared to those with ADDI (20.8%). ODD was equally prevalent in those with ADDC and ADDH. Of all comorbid diagnoses, only ODD exhibited a different prevalence among the 3 ADHD subtypes.The mean number of concurrent comorbid diagnoses in the total sample is 2.1, inclusive of ADHD. 36.3% (124) had only ADHD, 33.3% (114) had ADHD with one additional disorder, 18.7% (64) had two disorders, 8.2% (28) had three disorders, 2.9% (10) had four disorders, and two patients (0.6%) had five additional disorders besides ADHD. ODD occurred alone in 51.8% (59), GAD in 13.2% (15), and MDDD in 12.3% (14) of those with one additional diagnosis. 34.2% (39) only had AnyAD co-occurring with ADHD. In those with two or more additional diagnoses (n = 104), ODD occurred in 76.9% (80), MDDD in 57.7% (60), and GAD in 35.6%, (37). If Major Depressive Disorder (MDD) and Cyclothymia (CYCLO) are also included with the MDDD cohort, ODD and Any Affective Disorder co-occur in 54 cases which are 15.8% of the entire sample but represents 51.9% (54/104) of those with 3 or more diagnoses. All affective disorders (except Cyclothymia), GAD, SA and SPD were significantly more prevalent in those with 3 or more diagnoses compared to those with only 2 diagnoses. In the pure ADHD sample (124), the rate of ADDI was 35.5%(44), ADDH 9.7%(12), and ADDC 54.8%(68). This proportional pattern of ADHD subtypes was similar to that of the remaining group with 2 or more diagnoses.Subjects with Panic Disorder (PD) were the youngest (mean age 8.0) but there were only 2 cases. Subjects with SA and ADDH were the next youngest diagnostic groups (mean age 8.5). The oldest diagnostic group was the Substance Abuse Disorder/Substance Dependence (SAB/SD) patients (mean age 16.5). Patients with SA or ADDH were significantly younger than those patients without these diagnoses. Those with SP, ADDI, ADDC, and SAB/SD were significantly older than those without these diagnoses. There were no significant age differences between the boys and girls in any diagnostic group except for the boys with SP being older than the girls with SP (12.6 vs 10.2). However, there were only two girls with SP. The ADDH group were significantly younger than either the ADDC or ADDI subjects .2 = 21.7, df = 1, p = 0.00).Given the high prevalence of ODD, the sample was dichotomized into those with or without ODD and comorbid characteristics reanalyzed. Those subjects with ODD were significantly more likely to have MDDD, SPD, ADDC and significantly less likely to have ADDI. Within the Affective Disorder group, the significant correlation with ODD was predominantly driven by DD, IDD, and IMD. 64.9% (48/74) of MDDD subjects had ODD versus 34.0% of those without MDDD  either had subjective (from the Depressive K-SADS module) or overt (from the Mania module) Irritability. This represents 19.3% of the entire sample of ADHD subjects. Only 7 subjects had concurrent subjective and overt Irritability. Irritability was significantly associated with all of the Affective Disorder subtypes. In the Anxiety Disorder group, it was significantly associated with Avoidant Disorder; and, in the Behavior Disorder group it was significantly associated with ODD and ADDC. Within the Irritable group, 66.7% (44/66) have MDDD, 71.2% (47/66) have ADDC, and 80.3% (53/66) have ODD. This specific comorbid triad  represents 10.8% (37/342) of the entire sample. 31 of these 37 cases (83.8%) are those with symptomatic Irritability. These 31 cases represent almost half of those with Irritability .Although the comorbid frequencies in this report do not reflect a naturalistic sample, these diagnostic patterns are quite similar to prior clinical studies reflecting diagnoses endorsed by both child and parent informants. This data set however includes the broadest age range and the most extensive description of concurrent comorbidity of any study which is based on summary data from both the parent and child regardless of the subject's age.rd of cases had pure ADHD. These findings are similar to those reported in the MTA study, based on parental DISC reports, in a comparable clinical cohort which reported a 31.8%, 6 month prevalence rate of pure ADHD, although from a younger age  and mixed racial sample of only ADDC subjects [Over 1/3subjects . The prosubjects . This stADDH represents less than 10% of the total sample of ADHD subjects. This rate is lower than reported epidemiological frequencies yet ADDH was still the least prevalent of the three subtypes in such samples ,23. In ax2 = 9.6, df = 1, p = 0.002,) and AnyDep  were likely paired with ADD while ODD  was more likely paired with ADDH/ADDC.ADDH and ADDC are dominated by ODD with a 49.6% 116/234) combined comorbidity rate while ADDI has a more uniform comorbid pattern among affective, anxious, and behavior syndromes. ODD pervasiveness in ADDH/ADDC is further seen as it is the overwhelming comorbidity occurring in nearly 70% (51/74) of those with only one additional diagnosis. Affective and Anxious disorders only co-occur as a second diagnosis in approximately 6.8% and 23.0% respectively of the combined ADDH/ADDC subtypes with one additional diagnosis. These co-occurrence patterns between ADHD and affective, anxious and behavior disorders partially validate Angold's analysis [16/234 coThe high co-occurrence of an affective disorder with ADHD is reported in numerous settings ,26 and iThe finding that Irritability as a symptom was highly associated with MDDD and ODD is not surprising since it is part of the diagnostic domain of Affective Disorders and ODD . Angold In the present sample of 342 subjects, Irritability occurred in 20% (54/272) of the preadolescents and in 17% (12/70) of the adolescent subjects. However within the Irritable subjects themselves, 81.8% (54/66) were preadolescents. It may be that it is this concurrent comorbid triad with irritability is being over diagnosed as the prepubertal Bipolar child. This data set's exclusion of Bipolarity only adds more weight to this hypothesis. Whether this subset of ADHD patients represents an enriched future Bipolar core can only be evaluated through follow-up studies. Nonetheless, there are current reports identifying ODD and ADHD are more prevalent in youths with Irritable Bipolar NOS .This clinical sample does not represent the general population of clinically referred ADHD youths since the study required the participation of both biological parents and it was limited to Caucasians. Its comorbid patterns could diverge from ADHD youths growing up in less-intact families as well as ethnically mixed ADHD samples. However, this approach was necessitated by the primary genetic aims of this study. The young mean age also implies that many subjects have not passed through syndrome specific age of onset time frames. This was most notable in the same sex prevalence of MDDD. The sample also excluded obvious active cases of both Major Depressive and Bipolar disorders so it can not further elucidate characteristics of the Bipolar/ADHD debate.The majority of the K-SADS IVR interviews were completed by one rater which could introduce an information collection bias to this data set. Also, the K-SADS does not diagnoses learning disorders which can be co-morbid in 20–25% of ADHD subjects .rd of ADHD children have at least one additional impairing diagnosis. It is all too easy to overlook this pattern and focus treatment solely on ADHD. As noted in the MTA study, specific treatment combinations may be more efficacious in certain comorbid patterns [Almost 2/3patterns . It alsopatterns ,23.The comorbidities described here reflect that occurring within a selected ADHD sample chosen for a genetic analysis. It would be inappropriate therefore to interpret these rates suggesting they are "true" comorbid patterns in other disorders since the rate of ADHD is 100% within every diagnosis recorded in this data set.The clinician should be aware that Minor Depression/Dysthymia is common in ADHD and not be quick to dismiss dysphoric states as adverse events of stimulant treatment or the demoralization of having a significantly debilitating illness.The concurrent comorbid pattern displayed by this ADHD cohort generally corresponds with previously reported ADHD clinical samples. This suggests this data set is sufficiently representative of the ADHD clinical population to serve as a valid sample for genetic analysis. Concurrent comorbid analysis of the ADHD population may allow for a more comprehensive understanding of the vicissitude of this syndrome and assist in identifying potential endophenotypes. Phenotyping data from this study has been submitted to the NIMH repository. Genotyping data will also be submitted upon completion of study.The authors declare that they have no competing interests.JE participated in study design, subject recruitment, phenotype ascertainment, data analyses and interpretation. PJA participated in study design, data analyses and interpretation. WB participated in study design, data analyses and interpretation. All authors read and approved the final manuscript.


Reducing the incidence of Low birth weight (LBW) neonates by at least one third between 2000 and 2010 is one of the major goals of the United Nations resolution "A World Fit for Children". This was a case-control study conducted between August-October 2009 in Medani Hospital, Sudan to investigate the risk factors for LBW. Cases were mothers who delivered singleton baby < 2500 gm. Controls were mothers delivered singleton baby of ≥ 2500 gm.P = 0.01) and maternal anaemia  were the main risk factor for LBW.Out of 1224 deliveries, 97 (12.6%) of the neonates were LBW deliveries. While maternal socio-demographic characteristics  and anthropometrics measurements were not associated with LBW, lack of antenatal care (OR = 5.9, 95% CI = 1.4-24.4; Thus, more care on antenatal care and nutrition may prevent LBW. Low birth weight (LBW) is an important indicator of obstetric care and health status. It continues to remain a major public health problem worldwide especially in the developing countries. LBW is an important determinant of child-hood morbidity, associated with death during infancy ,2. Reducfalciparum parasites per 200 white blood cells and double checked blindly by an expert microscopist.This was a case-control study conducted between August-October 2009 in the labour ward of Medani Hospital in Central Sudan, figure Preterm delivery was defined as labour before completed 37 weeks gestational age. Maternal anaemia was considered if her haemoglobin was < 11 g/dl. Anaemia was classified as mild (Hb: 9-10.9 gm/dl), moderate (7-8.9 gm/dl and severe anaemia (Hb: < 7 gm/dl), respectively. Neonates were weighed immediately to the nearest 50 gm and LBW considered if birth weight was less than 2500 gm.t test and χ2 test, respectively. Univariate and multivariate analyses were performed. LBW was the dependent variable, while socio-demographic characteristics and medical and obstetrics events were independent variables. P < 0.05 was considered significant. When there was discrepancy between the results of the t test, χ2 test, and the results of multivariate, the results of the multivariate analysis were taken as final.Data were entered into a computer database and were double-checked before analysis using SPSS version 13.0 . Means and proportions for the socio-demographic characteristics were compared between the 2 groups of the study using the The study received ethical clearance from the Research Board at the Faculty of Medicine, University of Khartoum, Sudan.P = 0.01] and did not attend antenatal care  in the index pregnancy. The mean (SD) of the maternal weight, height and BMI were significantly lower in the cases than in the controls. Significantly more women in case group had anaemia, 65 (67.0%) vs. 27(27.8%), P = 0.001, Table Out of 1224 singleton deliveries, 97 (12.6%) of the neonates were LBW deliveries. only 7 (7.2%) out of these 97 LBW deliveries were preterm deliveries and the rest were small for gestational age. The age and education were not different between cases and controls. In comparison with the controls, significantly more women in the case group were primipare [31 (31.9%) vs. 16(16.4%), P > 0.05. The blood films for P. falciparum malaria were positive in three sets of maternal, placental and cord P. falciparum malaria, 2 of these were in the cases and the rest (one) in the controls. One woman in the case group had placental positive blood films for malaria.Ten and 8 women in the case and control group, respectively had self reported malaria in the index pregnancy; P = 0.01) and maternal anaemia  were the main risk factor for LBW in multivariate analyses, table P = 0.01) and maternal weight  were the risk factors for LBW in univariate analyses only, table While maternal socio-demographic characteristics and anthropometrics measurement were not associated with LBW, lack of antenatal care  of LBW in this study was high like the rate of LBW that we have previously reported in Khartoum and eastern Sudan ,10 and wUnlike the previous reports from eastern and central Sudan ,10,12, mThe current study showed that anaemic women were at nine times higher risk to deliver LBW babies. This goes with the previous observations from eastern and western Sudan as well as other African countries ,8,13, whLike our previous reports in Khartoum , in the In other African countries, maternal characteristics such as marital status, age gravidity and substance abuse have been reported to be associated with prematurity . SmokingRecently, in other countries other infectious diseases namely tuberculosis and periodontal diseases were the main risk factor for low birth weight in Taiwan and in Madagascar, respectively ,20. PateIn summary, this is small sample size hospital based study and may not represent what is going on in the community. This point  may account for failure to show association between birth weight and the traditional factors like maternal age, parity, weight and height. Thus, more care on mother  nutrition and prevention of anaemia may prevent LBW in this setting.The authors declare that they have no competing interests.EME and IA carried out the study and participated in the statistical analysis and procedures. ADH, MSA and AOA coordinated and participated in the design of the study, statistical analysis and the drafting of the manuscript. All the authors read and approved the final version.


There are three childhood disruptive behavior disorders (DBDs), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). The most common comorbid disorder in ADHD is ODD. DSM-IV describes three ADHD subtypes: predominantly inattentive type (ADHD-IA), predominantly hyperactive-impulsive type (ADHD-HI), and combined type (ADHD-C). Prior work suggests that specific candidate genes are associated with specific subtypes of ADHD in China. Our previous association studies between ADHD and functional polymorphisms of COMT and MAOA, consistently showed the low transcriptional activity alleles were preferentially transmitted to ADHD-IA boys. Thus, the goal of the present study is to test the hypothesis that COMT Val158Met and MAOA-uVNTR jointly contribute to the ODD phenotype among Chinese ADHD boys.171 Chinese boys between 6 and 17.5 years old  with complete COMT val158met and MAOA-uVNTR genotyping information were studied. We used logistic regression with genotypes as independent variables and the binary phenotype as the dependent variable. We used p < 0.05 as the level of nominal statistical significance. Bonferroni correction procedures were used to adjust for multiple comparisons.Our results highlight the potential etiologic role of COMT in the ADHD with comorbid ODD and its predominately inattentive type in male Chinese subjects. ADHD with comorbid ODD was associated with homozygosity of the high-activity Val allele, while the predominantly inattentive ADHD subtype was associated with the low-activity Met allele. We found no evidence of association between the MAOA-uVNTR variant and ADHD with comorbid ODD or the ADHD-IA subtype.Our study of attention deficit hyperactivity disorder comorbid oppositional defiant disorder and its predominately inattentive type highlights the potential etiologic role of COMT for ADHD children in China. But we failed to observe an interaction between COMT and MAOA, which suggests that epistasis between COMT and MAOA genes does not influence the phenotype of ADHD-IA with comorbid ODD in a clinical sample of Chinese male subjects. To confirm our findings further studies with a larger number of subjects and healthy controls are needed. The three childhood disruptive behavior disorders (DBDs), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), are characterized by developmentally extreme and impairing levels of distractibility, hyperactivity, impulsivity, hostility, and aggression . They acDSM-IV for ADHD describes three subtypes: predominantly inattentive type (ADHD-IA), predominantly hyperactive-impulsive type (ADHD-HI), and combined type (ADHD-C), each with different characteristics and correlates . AlthougBecause there is evidence that the covariation between ADHD, ODD, and CD is largely due to shared genetic influences ,13, it iMonoamine neurotransmitters in the brain, including dopamine (DA), noradrenalin (NE), and serotonin (5-HT), are metabolized by two key enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). These two enzymes are of interest in the study of aggressive behavior in both animals and human subjects.The human COMT gene on 22q11 contains a functional polymorphism Val158Met) affecting the activity of the enzyme at body temperature ,15. The 8Met affeP = 0.01), and also the inattentive subtype of ADHD in boys (P = 0.02). Zhang et al. found no association between MAOA-uVNTR and ADHD among boys comorbid with ODD.The gene for monoamine oxidase A (MAOA) maps to Xp11.23. The longer repeats  of a functional polymorphism in the promoter region of the MAOA gene consists of 30-bp upstream repeats (MAOA-uVNTR). The long alleles have been shown to affect the transcription of the gene three to four times more efficiently than the shorter 3R allele ,22. StudSince our previous association studies between ADHD clinical phenotypes and these two functional polymorphisms consistently showed the low transcriptional activity alleles were preferentially transmitted to the inattentive subtype of ADHD in boys, and because these polymorphisms are all involved in the probable etiology of externalizing behaviors, the goal of the present study is to test the hypothesis that COMT Val158Met and MAOA-uVNTR jointly contribute to the phenotype of ADHD-IA with comorbid oppositional defiant disorder (ODD) in a clinical sample of Chinese male subjects.ADHD cases were recruited from the child psychiatric clinics at Peking University Institute of Mental Health. Those families who gave consent to participate in the study underwent the assessment process. The study was approved by the Ethics Committee of the Health Science Center, Peking University. To be included in the study, children had to meet three criteria: 1) meet Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for ADHD meet Dia, and (3)Consensus diagnoses were made according to the Clinical Diagnostic Interviewing Scale (CDIS) , a strucThe intelligence quotient (IQ) of subjects was assessed using the Chinese-Wechsler Intelligence Scale for Children (C-WISC), a revised edition of the Wechsler Intelligence Scale for Children-Revised (WISC-R), which was standardized by Gong and Cai .Genomic DNA was extracted from whole venous blood using the protein-depositing method. The COMT val158met (rs4680) was genotyped under conditions previously described . The MAOWe used logistic regression with genotypes as independent variables and the binary phenotype as the dependent variable. We used p < 0.05 as the level of nominal statistical significance. Bonferroni correction procedures were used to adjust for multiple comparisons.There were 171 Chinese boys between 6 and 17.5 years old  with complete COMT val158met and MAOA-uVNTR genotyping information. ADHD-IA accounted for 53.2% of the sample, ADHD-C 39.8%, and ADHD-HI 7.0%. Many ADHD children also met diagnostic criteria for other disorders: 32.7% had comorbid ODD, 6.4% had comorbid CD, 13.4% had an emotional disorder, 13.5% had a tic disorder, 10.5% had an affective disorder, and 32.2% had a learning disability (LD).P > 0.05). The numbers of subjects in each group are showed in table For the COMT Val158Met polymorphism, 171 ADHD boys were successfully genotyped. The allele frequencies were: Val allele 66.1%, Met 33.9%. The genotype frequencies were: valval 42.7%, ValMet 46.8%, MetMet 10.5%. For the MAOA-uVNTR, 185 ADHD boys were successfully genotyped. The 1, 2 and 5 R alleles of MAOA-uVNTR were rare. Therefore, four individuals who carried them  were excluded. Since the MAOA gene is X-linked, males had only one allele. The alleles were grouped as 3R and 4R in the males for statistical analyses. The allele frequencies were: 3R allele 69.6%, 4R 30.4%. The genotype distributions of the COMT and MAOA gene polymorphism were in Hardy-Weinberg equilibrium (2 = 5.46. p = 0.019). No statistically significant group differences were found for MAOA-uVNTR  isoform predominates in most assayed tissues [Catechol- tissues , while a tissues . Althoug tissues . However tissues ,16-36,15 tissues . Mesocor tissues ,38. Ther tissues -42. Ther tissues ,17, whic tissues .The PFC has also been implicated in the etiology of aggressive and antisocial behavior in children . In the We found no evidence of association between the MAOA-uVNTR variant and ADHD with comorbid ODD or the ADHD-IA subtype in contrast with previous studies, in which the short variant was found to be associated with impulsivity, aggression, and ADHD with concurrent conduct disorder ,51.There were several limitations to this study that bear comment and suggest future directions. First, the major limitation of the study is the small number of individuals with the subtypes of ADHD. Our results, although nominally significant, were not significant after correcting for multiple comparisons. Larger samples, closer to 1000 are needed for more definitive results ,53. SecoIn summary, our study of attention deficit hyperactivity disorder comorbid oppositional defiant disorder and its predominately inattentive type highlights the potential etiologic role of COMT in a Chinese sample. But we failed to observe an interaction between COMT and MAOA, which suggests that epistasis between COMT and MAOA does not influence the phenotype of ADHD-IA with comorbid ODD in a clinical sample of Chinese male subjects. To confirm our findings further studies with a larger number of subjects and healthy controls are needed.The authors declare that they have no competing interests.QJQ and JL contributed equally to this work, they recruited the subjects, made consensus clinical diagnoses, analyzed the data and drafted the manuscript. YFW designed the study and assisted with proof-reading of the manuscript. LY and LLG also recruited the subjects and provided the data necessary for the analysis. SVF revised manuscript critically and assisted with proof-reading of the manuscript. All authors have read and given final approval of the final manuscript.


Atomoxetine is FDA-approved as a treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6 years to adult. Among pediatric clinical trials of atomoxetine to date, six with a randomized, double-blind, placebo-controlled design were used in this meta-analysis. The purpose of this article is to describe and compare the treatment response and tolerability of atomoxetine between younger children (6–7 years) and older children (8–12 years) with ADHD, as reported in these six acute treatment trials.Data from six clinical trials of 6–9 weeks duration were pooled, yielding 280 subjects, ages 6–7 years, and 860 subjects, ages 8–12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-diagnosed ADHD. Efficacy was analyzed using the ADHD Rating Scale-IV (ADHD-RS), Conners' Parent Rating Scale-revised (CPRS-R:S), and the Clinical Global Impression of ADHD Severity (CGI-ADHD-S).Atomoxetine was superior to placebo in both age categories for mean (SD) change in ADHD-RS total, total T, and subscale scores; 3 CPRS-R:S subscales; and CGI-ADHD-S from baseline. Although there were no significant treatment differentials between the age groups for these efficacy measures, the age groups themselves, regardless of treatment, were significantly different for ADHD-RS total , total T , and subscale scores , as well as the CGI-ADHD-S score . Although few subjects discontinued from either age group due to adverse events, a significant treatment-by-age-group interaction was observed for abdominal pain , vomiting , cough , and pyrexia .Atomoxetine is an effective and generally well-tolerated treatment of ADHD in both younger and older children as assessed by three recognized measures of symptoms in six controlled clinical trials.Not Applicable. Attention-deficit/hyperactivity disorder (ADHD) is characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity . In ordeThe preschool and early years of school are times of rapid growth and development in children. Failing to identify and treat ADHD early can allow impaired functioning to persist in multiple domains throughout critical periods of development. Preschool children with ADHD are at greater risk for behavioral, academic, social, and family difficulties relative to their unaffected counterparts. In a study of 94 preschool children, those with ADHD had already demonstrated a difference in behavioral ratings that was two standard deviations greater than the control group . By the Even with growing awareness of the potential impairments of ADHD in early childhood, limited data exist regarding its treatment in young children. For example, despite being one of the largest and most influential studies of pediatric psychopharmacology to date, the Multimodal Treatment Study of Children with ADHD (MTA)  did not Atomoxetine (ATX), a selective noradrenergic reuptake inhibitor, is a non-stimulant medication approved for the treatment of ADHD in patients 6 years of age through adulthood. No known controlled studies of non-stimulant medications for young children with ADHD have been completed to date, although a small open label 8-week study of ATX in 5- and 6-year old children with ADHD was recently conducted by Kratochvil, et al. . In thisAllen and Michelson  describeThis report is based upon a meta-analysis of 6 randomized, double-blind, placebo-controlled studies of ATX that were conducted in the United States  between Subjects were assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and Lifetime Versions (KSADS-PL) , a semi-Although learning disabilities were not exclusionary, subjects were required to be of normal intelligence (IQ ≥ 80) as assessed by one of the following means: four subtests  of the Wechsler Intelligence Scale for Children-3rd Edition (WISC-III) , the fulFor each subject, a parent or guardian provided written informed consent to participate and the child provided written assent, prior to receiving any study treatment or undergoing any study procedure. These studies met all federal and local regulatory requirements and were conducted in accordance with the ethical standards of each investigative site's institutional review board and the Helsinki Declaration of 1975, as revised in 2000 ) final ATX doses were 1.47 mg/kg/day and 1.39 (0.38) mg/kg/day for younger children, and 1.44 mg/kg/day and 1.37 (0.40) mg/kg/day for older children. The difference in final dose was not statistically significant. Rates of study completion were similar between the two groups .Reasons for discontinuation for subjects receiving ATX or PBO did not significantly differ within age groups, with the exception of discontinuation due to lack of efficacy. Patients who received PBO had a significantly higher rate of study discontinuation due to lack of efficacy for both younger  and older  children. Conversely, incidence of study discontinuation due to AEs was not significantly different between treatment groups in younger  versus older  children. However, a significant differential treatment effect was observed between the age groups (p = .015).Treatment-emergent AEs reported by at least 5% of patients are presented in Table Atomoxetine was associated with a statistically significant increase in mean (SD) pulse rate for both younger  and older  subjects. Similarly, a statistically significant treatment-group difference in systolic blood pressure  and diastolic blood pressure  was observed for older children, but not for younger children. There was no significant treatment-by-age-group interaction observed for either pulse rate, systolic or diastolic blood pressure. For mean (SD) weight change from baseline to endpoint, a statistically significant decrease in weight was observed for children taking ATX compared with PBO in both age groups . In addition, a significant differential treatment effect between the age groups was observed for mean weight change (p = .004). There were no significant differences between the age groups or significant treatment-by-age-group interaction for mean (SD) corrected QT interval (Fridericia's method) , and no clinically meaningful differences in laboratory measures.ADHD is a disorder that, by definition, presents at a young age and generally persists for years with continuing treatment often recommended. Limited information, however, exists regarding the safety and efficacy of pharmacotherapy for ADHD in children under the age of 8. The current analysis takes advantage of the growing database from multiple clinical trials of ATX to examine differences in response and tolerability in younger (6–7 years) versus older (8–12 years) children with ADHD. In the absence of trials specifically designed to examine these outcomes in young children treated with ATX, this meta-analysis may be the only available means of systematically assessing the effects of this medication, which is used with increasing frequency in this patient population.As anticipated, ATX was effective in reducing core symptoms of ADHD in both age groups. There was a statistically significant improvement compared with placebo for both age groups in all but one of the efficacy measures. Combining data from ATX and PBO patients, significant age group differences were observed for ADHD-RS total and subscale scores, as well as the CGI-ADHD-S score, in which older children demonstrated significantly greater improvement compared with younger children.While generally well-tolerated by both younger and older children with ADHD, ATX treatment in the 6- to 7-year-olds resulted in higher rates of upper abdominal pain, decreased appetite, vomiting, and somnolence compared with PBO, while 8- to 12-year-olds experienced higher rates of decreased appetite, somnolence, irritability, and fatigue. There were also statistically significant increases in pulse and decreases in weight for both younger and older children on ATX treatment compared with PBO. Increases in systolic and diastolic blood pressures in the older children and decreased weight in the younger children, although statistically significant, were not judged as clinically significant. Nonetheless, increases in mean pulse and blood pressures, while not generally clinically significant in this study, are enough to warrant monitoring when utilizing ATX to treat pediatric patients. The laboratory and ECG values revealed no safety concerns, including no evidence of hepatotoxicity. These data support the current guidelines of monitoring children clinically while on ATX treatment without obtaining baseline or ongoing laboratory or ECG evaluations unless a specific clinical presentation is cause for concern .This analysis is limited by the relatively short duration of the 6 studies. Patients were treated for 6 to 9 weeks with either once or twice-daily ATX. Target doses (approximately 1.2–1.5 mg/kg) were achieved over a range of a few days to more than two weeks, depending upon the study. Therefore, maximum benefit from ATX may not have been achieved by all subjects during the treatment period, as total time on target dose may have been insufficient. Procedural variations in timing of doses, titration, duration of the study, and methods of collecting vital signs may have limited the ability to combine and/or interpret the data. Additionally, the omission of a teacher-rated efficacy measure may limit this study's application to a school-based setting.The long-term safety and efficacy of ATX in young children cannot be determined by the results of this analysis. However, a previous study demonstrated atomoxetine to be effective and generally well-tolerated in 6- and 7-year-olds over a period of up to two years .The data presented here suggest that the ADHD symptoms of children 6–7 years old improve with ATX treatment, with a more effective overall response compared with that seen in children 8–12 years old. The side effect profile of ATX differed slightly in the younger versus older children, with few study discontinuations from either group due to AEs. These data are important in making clinicians aware that, in general, the response and tolerability of ATX treatment did not vary significantly between these two age groups. However, the potential for these differences must be taken into account when assessing the risk/benefit relationship of the medication and making treatment decisions. Atomoxetine use may warrant additional care and surveillance when treating younger children, about whom we have very limited information. Further research is warranted, particularly to examine atomoxetine long-term safety and efficacy, in the treatment of young children with ADHD.ADHD: attention-deficit/hyperactivity disorder; ADHD-RS: ADHD Rating Scale-IV; AE: adverse event; ANCOVA: analysis of covariance; ANOVA: analysis of variance; ATX: atomoxetine; CGI-ADHD-S: Clinical Global Impression of ADHD Severity; CPRS-R:S: Conners' Parent Rating Scale-revised; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ES: effect size; FDA: (U.S.) Food and Drug Administration; IQ: intelligence quotient; KSADS-PL: Kiddie Schedule for Affective Disorders and Schizophrenia for School-aged Children, Present and Lifetime Versions; LOCF: last-observation-carried-forward; LS: least-squares; MPH: methylphenidate; MTA: Multimodal Treatment Study of Children with ADHD; ODD: oppositional defiant disorder; OR: odds ratio; PATS: Preschool ADHD Treatment Study; PBO: placebo; SD: standard deviation; WISC-III: Wechsler Intelligence Scale for Children-3rd Edition.Dr. Kratochvil: Honoraria/Consultant, Research Support, and/or Speakers Bureau: Cephalon, Eli Lilly, McNeil, Abbott, Pfizer, Shire, Somerset, AstraZeneca. Ms. Milton is an employee and shareholder of Eli Lilly and Company. Ms. Vaughan has no competing interests to report. Dr. Greenhill: Honoraria/Consultant, Research Support, and/or Speakers Bureau: Celltech, Cephalon, Eli Lilly, Janssen, McNeil, Medeva, Novartis Corporation, Noven, Otsuka, Pfizer, Sanofi, Shire, Solvay, Somerset, Thompson Advanced Therapeutics Communications.CJK participated in the design of the study, and contributed to the drafting and review of the manuscript. DRM participated in the design of the study, performed the statistical analysis, and contributed to the drafting and review of the manuscript. BSV and LLG contributed to the drafting and review of the manuscript. All authors substantially contributed to the drafting of the manuscript, revising it critically for important intellectual content, and have read and given final approval of the version to be submitted for publication.