Abnormal brain connectivity in first-episode psychosis : A diffusion MRI tractography study of the corpus callosum A model of disconnectivity involving abnormalities in the cortex and connecting white matter pathways may explain the clinical manifestations of schizophrenia . Recently , diffusion imaging tractography has made it possible to study white matter pathways in detail and we present here a study of patients with first-episode psychosis using this technique . We selected the corpus callosum for this study because there is evidence that it is abnormal in schizophrenia . In addition , the topographical organization of its fibers makes it possible to relate focal abnormalities to specific cortical regions . Eighteen patients with first-episode psychosis and 21 healthy subjects took part in the study . A probabilistic tractography algorithm -LRB- PICo -RRB- was used to study fractional anisotropy -LRB- FA -RRB- . Seed regions were placed in the genu and splenium to track fiber tracts traversing these regions , and a multi-threshold approach to study the probability of connection was used . Multiple linear regressions were used to explore group differences . FA , a measure of tract coherence , was reduced in tracts crossing the genu , and to a lesser degree the splenium , in patients compared with controls . FA was also lower in the genu in females across both groups , but there was no gender-by-group interaction . The FA reduction in patients may be due to aberrant myelination or axonal abnormalities , but the similar tract volumes in the two groups suggest that severe axonal loss is unlikely at this stage of the illness . Introduction Altered connectivity is likely to account for the symptoms and cognitive changes of schizophrenia -LRB- Friston and Frith , 1995 -RRB- . A disconnectivity model involving both loss of specialized cortical function and damage to connecting pathways is likely to apply to schizophrenia -LRB- Catani and ffytche , 2005 -RRB- . Imaging studies have repeatedly confirmed the presence of cortical abnormalities , especially in prefrontal and temporal heteromodal cortex -LRB- Shenton et al. , 2001 ; Bagary et al. , 2003 ; Foong et al. , 2001 -RRB- , and synaptic pathology leading to aberrant cortical circuitry has been well documented in neuropathological studies -LRB- Harrison and Weinberger , 2005 -RRB- . By comparison , the study of abnormalities in intra - and interhemispheric pathways has received much less attention , although the occurrence of schizophrenia-like symptoms has been documented in diseases involving the white matter -LRB- Walterfang et al. , 2006 -RRB- . Among these connecting pathways the corpus callosum is of special interest in schizophrenia . The corpus callosum develops into the third decade of life -LRB- Pujol et al. , 1993 -RRB- and the topographical organization of its fibers makes it possible to relate its abnormalities to specific cortical regions . Fibers of small diameter from heteromodal cortex traverse the genu -LRB- connecting prefrontal cortex -RRB- or the splenium -LRB- connecting superior temporal cortex -RRB- , and larger diameter fibers connecting unimodal motor and sensory cortex traverse the body . A model by Crow -LRB- 1998 -RRB- , based on the evolutionary aspects of language and the emergence of psychosis in man , postulated that abnormalities in callosal pathways connecting areas of the cortex asymmetrically distributed between the two hemispheres were central to schizophrenia . Since then , conventional MRI studies -LRB- Shenton et al. , 2001 -RRB- , including those in drug-naive patients with their first episode of schizophrenia -LRB- Keshavan et al. , 2002 -RRB- , have reported reduction in the size of the corpus callosum , more marked anteriorly , but shape differences in the rostral and mid area of the body containing motor and sensory fibers have also been reported -LRB- Goghari et al. , 2005 -RRB- . Similar findings have been reported by Bachmann et al. -LRB- 2003 -RRB- in a first-episode cohort that included patients with schizophreniform and schizoaffective psychoses . In addition , a longitudinal study of patients with childhood-onset schizophrenia -LRB- Keller et al. , 2003 -RRB- has suggested that a failure of normal callosal growth may result in area reductions , particularly in the splenium , by early adulthood . Other imaging studies using voxel-based analysis -LRB- Hulshoff Pol et al. , 2004 -RRB- or magnetization transfer imaging -LRB- Foong et al. , 2001 -RRB- have also reported abnormalities , predominantly in the genu . In addition Highley et al. -LRB- 1999a -RRB- , in a detailed neuropathological study , reported a decrease in axon density in all , but the rostral region of the corpus callosum in female schizophrenics compared to controls . The functional significance of the corpus callosum in schizophrenia has been well documented by studies of interhemispheric transfer of information -LRB- Innocenti et al. , 2003 -RRB- . Diffusion tensor imaging -LRB- DTI -RRB- -LRB- Basser et al. , 1994 -RRB- has made it possible to study in vivo the integrity and orientation of neural tissue by measuring water diffusion in the brain . DTI studies have used a region-of-interest -LRB- ROI -RRB- methodology and have measured the apparent diffusion coefficient -LRB- ADC -RRB- and/or fractional anisotropy -LRB- FA -RRB- , indices of white matter integrity . An early study from our group -LRB- Foong et al. , 2000 -RRB- reported reduced FA in the splenium of the corpus callosum in patients with chronic schizophrenia and similar findings have been reported by others in the splenium -LRB- Agartz et al. , 2001 -RRB- , or in the structure as a whole -LRB- Brambilla et al. , 2005 ; Ardekani et al. , 2003 ; Kubicki et al. , 2005 -RRB- . Kumra et al. -LRB- 2004 -RRB- , on the other hand , failed to find such abnormalities in a small group of patients with early-onset psychosis and the same was the case in the only available study in first-episode patients , also from our group -LRB- Price et al. , 2005 -RRB- . The clinical correlations of these corpus callosum abnormalities remain uncertain . Brambilla et al. -LRB- 2005 -RRB- reported a correlation between DTI changes in the anterior part of the corpus callosum and severity of positive symptoms , but these findings have not been confirmed in other studies . The information about the direction of diffusion encoded by the eigenvalues and eigenvectors of the diffusion tensor has been used in DTI tractography -LRB- Mori et al. , 1999 -RRB- to investigate the continuity of axonal orientation between voxels and thus to infer the paths of fiber tracts in 3 dimensions . DTI tractography has been used in studies of normal subjects -LRB- Toosy et al. , 2004 ; Parker and Alexander , 2005 ; Parker et al. , 2005 -RRB- , in patients with multiple sclerosis -LRB- Wilson et al. , 2003 -RRB- , callosal dysgenesis -LRB- Lee et al. , 2004 -RRB- and stroke -LRB- Huang et al. , 2005 -RRB- . To date only one study -LRB- Kanaan et al. , 2006 -RRB- has used tractography to study the corpus callosum in patients with chronic schizophrenia , reporting reduced FA in the genu and it also demonstrated the superiority of this method , over ROI studies , in detecting subtle abnormalities across the whole of a white matter tract . Here we present , to our knowledge , the first study of the corpus callosum -LRB- or indeed any white matter pathway -RRB- in patients with first-episode schizophrenia spectrum disorders using diffusion imaging tractography . The main aim of the study was to determine whether subtle abnormalities of interhemispheric connections could be detected using this new technique in a group of patients during the first-episode of psychosis , in whom chronicity-related factors could be excluded . We hypothesized that measures of tract coherence -LRB- FA -RRB- , in white matter traversing the genu and splenium of the corpus callosum , would be significantly reduced in the patient group compared to controls . Materials and methods The patients were recruited as part of a prospective , longitudinal study of first-episode psychosis in West London . Patients were eligible to be recruited into the study if they fulfilled the following criteria ; age between 16 and 50 years presenting with a psychotic illness for the first time and less than 12 weeks on antipsychotic medication . Patients eligible for the study were screened using the WHO Psychosis Screen -LRB- Jablensky et al. , 1992 -RRB- . The diagnosis was established using a structured interview , the diagnostic module of the Diagnostic Interview for Psychosis -LRB- DIP , Jablensky et al. , 2000 -RRB- , which includes items from the Operational Criteria Checklist for Psychosis -LRB- OPCRIT , McGuffin et al. , 1991 -RRB- and the World Health Organization Schedules for Clinical Assessment in Neuropsychiatry -LRB- SCAN , Wing et al. , 1990 -RRB- . Using these data , a computerized algorithm generates diagnoses under several classification systems including DSM-IIIR and ICD-10 . DSM-IIIR diagnoses were subsequently checked against DSM-IV criteria by separately entering OPCRIT items into OPCRIT for Windows -LRB- http://sgdp.iop.kcl.ac.uk/opcrit/ -RRB- . Exclusion criteria were the presence of a medical or neurological illness that might impair cognitive function including head injury and alcohol or drug dependency . Eighteen patients with an initial diagnosis of schizophrenia , schizophreniform or schizoaffective disorder took part in this study . Fifteen of these patients were interviewed again a year later to review the diagnosis , and for the remaining three , who could not be interviewed , a final diagnosis was established also a year later by compiling information from clinicians looking after the patients and by reviewing the clinical notes . Thirteen patients received a final diagnosis of schizophrenia and the remaining five received a diagnosis of schizoaffective disorder -LRB- one bipolar , two manic and two depressed subtype -RRB- . The patients had been ill for a mean of 12.6 months -LRB- SD = 19.3 months , range 0 -- 72 months -RRB- at entry into the study . The range and severity of symptoms were assessed at each time point with the Scales for the Assessment of Positive Symptoms -LRB- Andreasen , 1983 -RRB- and Negative Symptoms -LRB- Andreasen , 1981 -RRB- , The Young Mania Scale -LRB- Young et al. , 1978 -RRB- and the Hamilton Rating Scale for Depression -LRB- Hamilton , 1960 -RRB- . The onset of psychosis was established using the Symptom Onset in Schizophrenia inventory -LRB- Perkins et al. , 2000 -RRB- . Alcohol and drug use was assessed as part of the Diagnostic Interview for Psychosis -LRB- see above -RRB- and criteria for abuse and dependence were established using the Alcohol Use Scale and the Drug Use Scale -LRB- Drake et al. , 1990 -RRB- . The mean age of the patient group was 23.6 years -LRB- SD = 6.3 ; range = 17 -- 38 years -RRB- , composed of 8 males and 10 females . All patients were receiving antipsychotic medication at the time of scanning . Twenty-one healthy subjects with a mean age of 29.4 years -LRB- SD = 7.1 ; range = 16 -- 42 years -RRB- with a gender composition of 6 males and 15 females served as controls . Handedness for all subjects was assessed using the Annett scale -LRB- Annett , 1970 -RRB- as it may be associated with DTI findings in the corpus callosum -LRB- Westerhausen et al. , 2003 -RRB- . Exclusion criteria were the same as in the patient group as well as history of psychiatric illness in themselves or their first-degree relatives . See Table 1 for a description of study subjects . Permission to conduct the study was obtained from Merton , Sutton and Wandsworth , Riverside and Ealing Research Ethics Committees . All participants gave written informed consent and were paid an honorarium for their time . MRI data acquisition MRI for all subjects was obtained using a GE Signa 1.5 T scanner -LRB- General Electric , Milwaukee , WI , USA -RRB- , which underwent regular quality-control checks , using a standard quadrature head coil . Each subject had a dual-echo fast spin echo scan -LRB- TR = 2000 ms , TE1/TE2 = 19/95 ms , matrix = 256 × 192 , field of view -LSB- FoV -RSB- = 24 × 18 cm2 -RRB- , which provides both proton density and T2-weighted images . Twenty-eight 5-mm slices were collected , in an oblique-axial plane -LRB- parallel to the AC/PC line -RRB- . An axial plane , IR-SPGR sequence was also performed which obtained a series of 156 contiguous axial slices with the following parameters TE = 5.1 ms , matrix = 256 × 128 , field of view = 31 × 16 cm2 , slice thickness = 1.2 mm , TR = 14.3 ms , flip angle 20 ° , TI = 450 ms. Diffusion-weighted single-shot echo planar images -LRB- DW-EPI -RRB- were acquired in the axial plane -LRB- TE = 96 ms , FoV = 22 × 22 cm2 , matrix = 96 × 96 , slice thickness = 2.3 mm , Δ = 40 ms , δ = 34 ms , resulting in a maximum b factor of 1000 s/mm2 -RRB- . The acquisition of diffusion-weighted images was gated to the cardiac cycle using a pulse oximeter with a gating scheme optimized for diffusion imaging . Gradients for diffusion sensitization were applied in 54 non-collinear directions . Six images with no diffusion weighting -LRB- b ≈ 0 s/mm2 -RRB- were also collected for each slice , giving a total of 60 images per slice . Images were interpolated to a 128 × 128 matrix during reconstruction , yielding a final in-plane resolution of 1.72 mm . Diffusion processing and analysis The diffusion tensor was estimated for each voxel according to the method of Basser et al. -LRB- 1994 -RRB- and used to compute FA . We also used a model-selection algorithm based on the fit of spherical harmonic series to the diffusion profile -LRB- Alexander et al. , 2002 -RRB- to detect the most parsimonious description of diffusion in every voxel . Diffusion within each voxel was classified as isotropic , anisotropic with a single principal direction of diffusion , or anisotropic with more than one direction of diffusion -LRB- as in the white matter of the centrum semiovale -RRB- . The single tensor model was subsequently used for voxels characterized by isotropic diffusion or a single direction of diffusion population . The two-tensor model of diffusion , as described by Parker and Alexander -LRB- 2003 -RRB- , was used for the remaining voxels . We used a probabilistic tractography algorithm -LRB- PICo or ` probabilistic index of connectivity ' -RRB- which considers multiple pathways emanating from a seed point or region -LRB- i.e. a group of voxels in a region of interest -RRB- -LRB- Parker and Alexander , 2003 , 2005 -RRB- . Due to the presence of noise in the data , there is some uncertainty associated with the determination of the principal direction of diffusion . The algorithm accounts for this uncertainty by generating a probability density function -LRB- PDF -RRB- of fiber alignment from the diffusion model of each voxel -LRB- which in this case is either the single or the two-tensor model -RRB- . This provides voxel-wise estimates of confidence in fiber tract alignment , which are then used in the probabilistic tract-tracing procedure . Using the PDFs from a chosen seed point , streamline-based tracking is performed and repeated 10,000 times in a Monte Carlo fashion -LRB- sampling each PDF at random on each repeat -RRB- to produce tract maps that estimate the probability of connection of every voxel in the brain to a given seed point or region -LRB- Parker and Alexander , 2005 -RRB- . Streamlines were propagated using trilinear interpolation of PDFs , as suggested by Behrens et al. -LRB- 2003 -RRB- , and were terminated if curvature over the scale of a single voxel exceeded 180 ° or if the path left the brain . Seed regions were placed in the genu and splenium of the corpus callosum . The genu was defined as the most anterior point of the corpus callosum before it bends downwards and backwards in front of the septum pellucidum , and the splenium as the posterior end of the corpus callosum at its thickest part . Each seed region consisted of a six voxel rectangular shape on a single axial slice . This region size ensured that partial volume effects were completely avoided . Seed regions were placed by displaying the FA maps in three mutually orthogonal orientations using MRIcro -LRB- http://www.sph.sc.edu/comd/rorden/ -RRB- and identifying the sagittal and coronal planes in which the volumes of the genu and splenium were largest . The seed regions were placed on the axial view corresponding to the intersection of these sagittal and coronal planes . The seed region placement was the only operator-dependent step in the diffusion processing . To assess the inter-rater reliability of the method , a second , independent rater performed the seed region placement in 8 cases , using the same procedure . The voxel values of the PICo output maps for the corpus callosum range from 0 -LRB- no probability of connection -RRB- to 1 -LRB- certainty of connection -RRB- with an intensity resolution step of 0.001 representing the ratio of the number of times that voxel was reached by a streamline originating from the seed point to the total number of iterations in the Monte Carlo process . Each PICo map was thresholded at five probability values ranging from 0.001 -LRB- the lowest recorded value of probability of connection -RRB- to 0.03 , at logarithmically spaced intervals , to generate five objective binary masks -LRB- thresholded at 0.001 , 0.002 , 0.006 , 0.013 and 0.03 -RRB- . This multi-threshold approach , previously used in the study of visual pathways -LRB- Toosy et al. , 2004 -RRB- , allows with increasing degrees of certainty the reconstruction of the core of the tract , where fiber alignment should be greatest , and the exploration of the probability of connection of distant voxels to the seed point . For each threshold the mean tract volume and the mean FA were calculated for each subject . The spatial variability of the tract across each subject group was characterized as previously described -LRB- Toosy et al. , 2004 ; Parker et al. , 2005 -RRB- . Firstly the non-diffusion-weighted -LRB- b = 0 -RRB- images -LRB- inherently co-registered with PICo output images -RRB- were normalized to a stereotactic space -LRB- Montréal Neurological Institute , MNI -RRB- using the standard echo planar image template in SPM2 -LRB- Wellcome Department of Cognitive Neurology , Institute of Neurology , London , UK -RRB- running in MATLAB -LRB- MathWorks , MA -RRB- . The normalization parameters thus obtained were then applied to the binary images of the tract obtained by thresholding the probability images at the level that maximized the difference in FA between patients and controls -LRB- see below -RRB- . After normalization , these images were averaged on a voxel-by-voxel basis , producing a map used to display the degree of tract overlap between subjects within each group . In order to detect the presence of ventricular enlargement in the patient group , which might affect tractography , we performed a voxel-based comparison of CSF maps between the two groups using SPM2 -LRB- Wellcome Department of Cognitive Neurology , Institute of Neurology , London , UK -RRB- . The IR-SPGR images were segmented and normalized using the iterative procedure described in Good et al. -LRB- 2001 -RRB- , thus performing first a segmentation in native space , next normalizing gray matter images using the standard a priori gray matter template available in SPM2 and applying the same normalization parameters to the whole volume . The normalized volume was then segmented again yielding white matter , gray matter and CSF probability images . Voxel values in segmented images were multiplied by the Jacobian determinants derived from spatial normalization -LRB- modulation -RRB- to provide intensity correction for induced regional volumetric changes , thus preserving within-voxel volumes that may have been altered during non-linear normalization -LRB- Ashburner and Friston , 2000 -RRB- . CSF images were also smoothed to 6 mm -LRB- Full-Width-Half-Maximum -RRB- Gaussian filter . Smoothing is required to accommodate anatomical variation between subjects and therefore results in more normally distributed data . Global CSF volumes in cm3 were also obtained by integrating the CSF image signal intensity over the whole volume for each subject . Statistical analysis Age , gender and handedness distributions in the two groups were compared using t-tests and χ2 tests . The inter-rater reproducibility of the method was tested by comparing the tract volumes obtained by the two raters . Inter-rater reliability was assessed using the coefficient of variation -LRB- CoV -RRB- , CoV = -LRB- σ / μ -RRB- × 100 % , where σ is the standard deviation and μ is the mean , with lower values indicating better reproducibility . Multiple linear regressions of mean FA were carried out to compare tract coherence in patients and controls , with gender , age and tract volume as covariates , to control for between-group differences in these covariates . To avoid spurious positive results due to multiple comparisons , the multiple regressions were carried out simultaneously for each of the five thresholds in the genu and the splenium -LRB- ten regressions -RRB- using Zellner 's seemingly unrelated regression method -LRB- Zellner , 1962 -RRB- , which yields a single significance value -LRB- from the F-statistic -RRB- of the difference between patients and controls across all ten regressions , in addition to individual values for each regression . The F-statistic is obtained by comparing the ten regressions obtained including or excluding group membership and taking into account the correlations between the residuals from all ten equations . This method also allows a test of whether region -LRB- genu or splenium -RRB- or probability thresholds modify the differences in FA between patients and controls . Similar multiple linear regressions were performed to explore gender differences in FA -LRB- when adjusting for group membership , age and tract volume -RRB- as well as age differences in FA -LRB- adjusting for group membership , gender and tract volume -RRB- . A voxel-based statistical comparison between CSF maps from patients and controls was performed in SPM2 based on the General Linear Model and Gaussian random field theory incorporating subject age and gender into this model . Results Patients were significantly younger than controls . The mean age for patients was 23.6 years and 29.4 years for controls -LRB- t = − 2.7 , df = 37 , P = 0.011 -RRB- . However , there was an age overlap between the two groups , allowing the results to be adjusted for age . There were no significant differences in gender distribution -LRB- χ2 = 0.62 , df = 1 , P = 0.43 -RRB- or handedness -LRB- χ2 = 1.81 , df = 1 , P = 0.18 -RRB- between the groups . All patients were receiving antipsychotic medication and two were on mood stabilizers at the time of the study -LRB- see Table 1 -RRB- . The average duration of treatment prior to scanning was 61 days -LRB- range 8 -- 153 days -RRB- . The coefficient of variation for the tract volume for the 8 repeated measurements performed by two raters was 1.36 % , indicating a very high inter-rater reproducibility . The tract overlap maps for the genu and splenium in patients and controls -LRB- Figs. 1 and 2 -RRB- were compared with reference maps of the corpus callosum to ascertain their anatomical validity . The estimated tract volumes in patients and controls decreased at higher connection probability thresholds as the core of the tract was progressively isolated . Conversely , FA increased with higher thresholds -LRB- Figs. 3A -- D -RRB- . The results of the multiple regression analysis comparing FA in patients and controls are shown in Table 2 . The single test of significance considering both regions of the corpus callosum at all thresholds was P ≤ 0.02 , indicating a significant difference in FA between the two groups in either region , over all thresholds . Inspection of the differences in FA at the individual thresholds indicated that the differences in FA between the groups are due to lower FA in the patient group in the genu at probability thresholds 0.006 and 0.013 , and to a lesser extent in the splenium at thresholds 0.013 and 0.03 -LRB- see Table 2 -RRB- . To examine subgroup differences in FA , we performed a regression analysis to compare the 13 schizophrenic and 5 schizoaffective patients . Both subgroups had a lower FA than controls . Results from the regression analysis revealed that in the genu , the schizoaffective group had a lower FA than the schizophrenia group -LRB- P = 0.0806 -RRB- , whereas in the splenium , the schizoaffective group had higher FA values than the schizophrenia group -LRB- P = 0.0295 -RRB- . This suggests that , although there may be subtle differences between subgroups , they differed from controls in the same direction and amalgamating the subgroups does not obscure the differences between patients and controls . We performed a separate analysis looking for gender and age differences in FA by considering patients and controls together . In the analysis of gender , a single test of significance considering all thresholds and both regions of the corpus callosum gave a P = 0.0001 . This result indicates that there are gender differences in FA irrespective of subject status . Thus FA , adjusted for group membership , was lower in females than males in the genu at thresholds 0.001 and 0.002 , but not in the splenium . There was no significant group membership-by-gender interaction -LRB- P = 0.2 -RRB- . With respect to the effects of age , there was no evidence that the difference between patients and controls in FA varied with age -LRB- P = 0.791 -RRB- for the global test over both regions -LRB- i.e. the ten equations -RRB- , after adjusting for gender and tract volume . Finally , the SPM analysis using a voxel-based comparison of CSF maps between the two groups revealed no differences between patients and controls using a family wise error correction for multiple comparisons , with f = 34.42 and no voxels as an extent threshold . This indicates that no ventricular enlargement was present in the patient group relative to controls . There was no significant difference between the global CSF volumes of patients -LRB- 287 cm3 , SD = 33.6 -RRB- and controls -LRB- 283 cm3 , SD = 51.6 -RRB- -LRB- t = − 0.85 , P = 0.40 , CI = -LSB- − 41.7 -- 17.2 -RSB- -RRB- . Discussion Our findings provide evidence of altered interhemispheric connectivity in patients with first-episode schizophrenia spectrum disorders . In the patient group , abnormal tract coherence , as measured by reduction in FA , was present in tracts traversing the genu and , to a lesser extent , in those traversing the splenium . Tract coherence , as measured by FA , was lower in females , both in patients and controls , but we failed to find a gender-by-group interaction . The genu and the anterior part of the body of the corpus callosum contain mainly connections from prefrontal cortex , cingulate and insula , and pathology in these cortical regions could result in the abnormalities of the corpus callosum described here . Similarly , a decreased thalamic input to the frontal and temporal cortex , perhaps due to excessive synaptic pruning , could also result in decreased cortical connections and hence in abnormalities in the corpus callosum -LRB- Innocenti et al. , 2003 -RRB- , but it is also possible that primary white matter abnormalities could contribute to our findings -LRB- Walterfang et al. , 2006 -RRB- . The corpus callosum develops alongside other midline structures , namely the fornix , hippocampus , septum and cingulate cortex , and developmental or maturational abnormalities involving the corpus callosum are also likely to affect these structures known to play a role in schizophrenia . Our diffusion-MRI-based tractography -LRB- PICo -RRB- used a probabilistic approach that takes into account branching , crossing and merging of tract fibers and this represents an advantage over previous deterministic approaches that do not take these anatomical features into consideration -LRB- Kanaan et al. , 2006 -RRB- . In addition the use of different probability thresholds and simultaneous multiple regression analysis -LRB- Zellner , 1962 -RRB- has allowed us to demonstrate evidence , from a single statistical test , that there is some difference in tract coherence between patients and controls and to explore the characteristics of the core of the tract in the genu and the splenium . The group differences in FA become more apparent at intermediate probability thresholds in the genu when fiber alignment in the core of the corpus callosum is greatest and aberrant branching that could have artificially reduced FA -LRB- Jones et al. , 2005 -RRB- less likely . The high inter-rater reliability in the placement of the seed points also suggests that the differences in FA between patients and controls are likely to be illness-related rather than artifactual . The same applies to the effects of gender and age , known to affect FA -LRB- Price et al. , 2005 ; Jones et al. , 2005 -RRB- , that were statistically controlled for in our study as our groups were not closely age matched . Antipsychotic medication may have played a role in reducing FA , although it seems unlikely that medication effects could fully account for the differences between the groups in first-episode patients who had been exposed to medication for short periods . Moreover , others -LRB- Flynn et al. , 2003 -RRB- have found no correlation between the presence of white matter abnormalities in first-episode psychosis and exposure to antipsychotic medication . The possible effect of mood stabilizers in explaining our results is likely to be negligible as they were used in only 2 patients . The gender difference in tract coherence that we found in our subjects , particularly in the genu , supports our previous results in a different sample of first-episode patients and controls using a region-of-interest methodology -LRB- Price et al. , 2005 -RRB- and is in keeping with the lower anisotropy in normal females than males reported by Westerhausen et al. -LRB- 2003 -RRB- . Gender dimorphism and maturational differences are likely to be relevant in explaining this finding . Dubb et al. -LRB- 2003 -RRB- , in an MRI study of normal subjects , found a larger genu and smaller splenium in men compared with women and attributed the differences to different hormonal influences , to enhanced motor coordination in men -LRB- interhemispheric connections crossing the genu -RRB- and to greater bihemispheric representation of language in women -LRB- tracts crossing the splenium -RRB- . Adult maturational changes in the corpus callosum , with a peak in the third decade of life , would further accentuate these differences . The differences in age between the two groups are a limitation of the study , although we tried to circumvent the problem using age as a covariate . The precise neuropathological correlates of FA abnormalities remain to be fully elucidated . Axonal membranes are considered to be the main determinant of anisotropy in neural tissue , and pathological or experimental models of axonal degeneration have lead to reductions in FA . Myelin abnormalities are also responsible for changes in FA , although their contribution may be less important than those of axons or axonal membranes -LRB- Beaulieu , 2002 -RRB- . In our study the lower FA in the white matter tracts traversing the corpus callosum may be due , in addition to myelin abnormalities , to differences in axonal membranes , alterations in axonal packing density , mean axonal diameter -LRB- for example due to a bias towards axons of greater or lesser diameter in one or other group -RRB- or a less coherent fiber alignment in the patient group . The similar tract volumes we found in patients and controls may suggest that severe axonal loss is unlikely at this early stage of the illness . On the other hand , the greater variance in genu tract volumes in the patient group suggests that there may be more branching -LRB- i.e. less coherence or alignment -RRB- in the core of the tract . We have also excluded the possibility that our findings could be related to ventricular enlargement in the patient group . The study of patients with first-episode psychosis has the advantage of minimizing the effects of chronicity and lengthy exposure to medication , on the other hand , such patients are diagnostically heterogeneous and this is one of the shortcomings of our study and it remains uncertain whether the changes in corpus callosum described here are a core neuropathological abnormality common to all psychosis or are only present in a subgroup of patients . Support for the former accrues from the study of Bachmann et al. -LRB- 2003 -RRB- who reported similar findings in a heterogeneous group of patients with first-episode psychosis . In addition , there is evidence to suggest that corpus callosum abnormalities are also present in patients with bipolar disorder -LRB- Brambilla et al. , 2003 , 2004 -RRB- and other DTI studies looking at ROIs in frontal white matter , although not specifically at the corpus callosum , have reported low FA in a mixed group of patients with first-episode psychosis -LRB- Szeszko et al. , 2005 -RRB- and in those with first-episode mania -LRB- Adler et al. , 2006 -RRB- . There is also evidence that oligodendrocyte and myelination genes may be downregulated both in schizophrenic and affective psychosis -LRB- Tkachev et al. , 2003 ; Iwamoto et al. , 2005 -RRB- . It is also likely that the abnormalities described here may also be present in other connecting tracts , as suggested by the neuropathological findings of Highley et al. -LRB- 1999b -RRB- in the anterior commissure , and the results of DTI imaging studies -LRB- Kubicki et al. , 2005 -RRB- . Our study suggests that the schizophrenia and schizoaffective subgroups may be heterogeneous based on FA , but both these groups differ from controls in the same direction of FA change . An intriguing possibility , in need of further study , is that genetic variability within schizophrenia may be associated with specific patterns of brain morphology including variations in the size and structure of the corpus callosum -LRB- Agartz et al. , 2006 -RRB- . Our findings also demonstrate that tractography is capable of detecting subtle pathological abnormalities in patients with psychosis early in the disease that may go undetected using other DTI methods -LRB- Price et al. , 2005 ; Kanaan et al. , 2006 -RRB- . Tractography is likely to have a role in future psychosis research , in elucidating connections between relevant cortical regions and in giving specific information about white matter abnormalities and their evolution over time .

O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

corpus callosum
diffusion tensor imaging
tractography

pico, probabilistic index of connectivity


Growth hormone axis in chronic kidney disease Chronic kidney disease -LRB- CKD -RRB- in children is associated with dramatic changes in the growth hormone -LRB- GH -RRB- and insulin-like growth factor -LRB- IGF-1 -RRB- axis , resulting in growth retardation . Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality . Renal failure is a state of GH resistance and not GH deficiency . Some mechanisms of GH resistance are : reduced density of GH receptors in target organs , impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription -LRB- JAK/STAT -RRB- signaling , and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins -LRB- IGFBPs -RRB- . Treatment with recombinant human growth hormone -LRB- rhGH -RRB- has been proven to be safe and efficacious in children with CKD . Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height , the final adult height is still significantly below the genetic target . Growth retardation may persist after renal transplantation due to multiple factors , such as steroid use , decreased renal function and an abnormal GH -- IGF1 axis . Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth . Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 -LRB- rhIGF-1 -RRB- , recombinant human IGFBP3 -LRB- rhIGFBP3 -RRB- and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD . Learning objectives : To review the normal growth pattern in childhood and its alteration in chronic kidney disease . To understand the mechanisms believed to be responsible for growth failure in chronic kidney disease . To understand the new evidence supporting therapy for growth failure in chronic kidney disease . To identify targets for future therapies for treatment of growth retardation in chronic kidney disease . Introduction Growth retardation is a common result of chronic kidney disease -LRB- CKD -RRB- in childhood . Children with CKD fail to achieve the final adult height consistent with their genetic potential -LSB- 1 -RSB- . Data from the North American Pediatric Renal Trials and Collaborative Studies -LRB- NAPRTCS -RRB- 2005 database revealed that 36.9 % of children with CKD had statutory growth impairment . Even though the growth failure was correlated with the degree of renal impairment , those with mild reduction of glomerular filtration rate -LRB- GFR -RRB- also exhibited short stature . Children were short at initiation of dialysis , with younger age associated with more severe growth failure and little improvement in height standard deviation score -LRB- SDS -RRB- . The mean height deficit for all renal failure patients was − 1.85 -LRB- less than the third percentile of their healthy peers -RRB- at transplantation . This deficit was greater for male patients and for younger subjects . Those below age 6 years benefited most from transplantation in demonstrating acceleration in linear growth . For subjects aged 6 -- 12 years , the linear growth remained stable , and those older than 12 years of age had no increase in their height deficit score -LSB- 2 -- 4 -RSB- . Despite advances in medical care , growth failure in CKD is associated with increased morbidity and mortality . Furthet al. demonstrated from the United States Renal Data System -LRB- USRDS -RRB- database that patients with severe-to-moderate growth failure had increased hospitalization rates and increased risk of death -LSB- 5 -RSB- . Growth retardation is assessed by the SDS or height deficit score , which measures the patient 's height in comparison with that of unaffected children of similar age . Wong et al. demonstrated that , among pediatric patients on dialysis or after transplantation , each SDS decrease in height was associated with an increase in death by 14 % -LSB- 6 -RSB- . Alteration of normal growth patterns in CKD Linear growth is unique to childhood . Complex biological processes are responsible for maintaining normal growth . Infancy is the fastest growing period of childhood ; one-third of the total growth occurs in the child 's first 2 years of life , and this is mainly nutrient dependant . This growth is markedly decreased in congenital CKD , with the greatest height deficit occurring in the child 's first year of life , especially during the first 4 months -LSB- 7 -RSB- . Thus , the earlier the onset of kidney disease , the more severe the growth disturbance . Additional factors affecting growth are inadequate protein and calorie intake , water and electrolyte losses in polyuric and salt wasting conditions , anemia , metabolic acidosis , renal osteodystrophy , and resistance to hormones mediating growth . Early nutritional intervention and prevention of metabolic deficits of renal failure can preclude the development of growth failure in this period . Conservative treatment -LRB- no use of growth hormone -RRB- in pre-dialysis patients from birth to 3 years , revealed a favorable growth rate , with height velocity at 22.2 cm/year , 10.9 cm/year and 7.6 cm/year for each year , respectively , all of which were higher than the lower two standard deviation scores -LSB- 5 -RSB- . Further discussion of these factors is beyond the scope of this article . During the mid-childhood period , a constant growth rate of 5 -- 7 cm/year is demonstrated , mainly under the control of growth hormone -LRB- GH -RRB- and thyroid hormone . Children with congenital CKD grow at the percentile achieved at the end of 2 years of life . Even though one of the most important predictors of growth impairment is the degree of renal insufficiency , significant short stature has been seen at all levels of renal function -LSB- 3 , 7 -RSB- . At the onset of puberty , the growth hormone/insulin-like growth factor -LRB- GH/IGF -1 -RRB- axis is activated by small increases in estrogen and testosterone in girls and boys , respectively . The onset of puberty is delayed in adolescents with CKD ; peak height velocity is delayed by approximately 2.5 years . The pubertal growth spurt is delayed , shortened and associated with a reduced growth velocity . The pubertal height gain is about 65 % of that seen in healthy children without CKD and is likely due to the shortened growth spurt -LSB- 1 -RSB- . These effects of delayed puberty in CKD are mediated by a loss of the normal pulsatile hypothalamic release of the gonadotropin-releasing hormone -LRB- GnRH -RRB- . GH and IGF axis Growth hormone is the key endocrine regulator of postnatal growth -LRB- Fig. 1 -RRB- -LSB- 8 -RSB- . The anterior pituitary secretes growth hormone in a pulsatile manner stimulated by the growth hormone releasing hormone -LRB- GHRH -RRB- and inhibited by somatostatin . GH mediates its somatotropic actions directly and mainly through IGF-1 . Ghrelin , a growth hormone-releasing peptide expressed in the stomach and hypothalamus , is involved in hormonal and nutritional regulation of GH release -LSB- 9 -RSB- . Fig. 1GH/IGF - 1 axis in CKD : deranged somatotropic axis in chronic renal failure . The GH/IGF-I axis in CRF is changed markedly , compared with the normal axis shown here . In CRF the total concentrations of the hormones in the GH/IGF-I axis are not reduced , but there is reduced effectiveness of endogenous GH and IGF-I , which probably plays a major role in reducing linear bone growth . The reduced effectiveness of endogenous IGF-I likely is due to decreased levels of free , bioactive IGF-I as levels of circulating inhibitory IGF-binding proteins -LRB- IGFBPs -RRB- are increased . In addition , less IGF-I is circulating in the complex with acid labile subunit -LRB- ALS -RRB- and IGFBP-3 as a result of increased proteolysis of IGFBP-3 . Together , these lead to decreased IGF-I receptor activation and a decreased feedback to the hypothalamus and pituitary . Low free IGF-I and high IGFBP-1 and IGFBP-2 levels probably contribute to reduced renal function and lead to reduced stature . The direct effects of GH on bone , which are poorly understood , also are blunted . Reprinted from -LSB- 8 -RSB- with permission Growth hormone and the IGF-1 axis play a major role in growth failure in CKD . Random fasting serum levels of GH are normal or increased in children and adults with CKD , depending on the extent of renal failure . The half-life of GH is prolonged , due to decreased metabolic clearance secondary to decreased functional renal mass in proportion to the degree of renal dysfunction . A high normal calculated GH secretion rate and amplified number of GH secretory bursts have been reported in pre-pubertal children with end-stage renal disease , likely due to attenuated IGF-1 feedback -LSB- 8 -RSB- . This has led to the concept of GH insensitivity or resistance in uremia . Pubertal patients with advanced CKD have a reduced GH secretion rate , indicating altered sensitivity of somatotropic hormones to the stimulatory effects of sex steroids -LSB- 10 -RSB- . GH resistance GH receptors One mechanism for GH resistance is a reduced density of GH receptors in target organs . Determination of the concentration of serum growth hormone binding protein -LRB- GHBP -RRB- , which is a cleaved product of the GH receptor , may be used to assess GH receptor density in tissues , particularly liver , since GHBP is derived mainly , but not exclusively , from the liver . GHBP is low in children and adults with CKD and proportionate to the degree of renal dysfunction . Serum GHBP correlates with both spontaneous growth rate and response to GH therapy , and it is an indirect indicator of sensitivity to both exogenous and endogenous GH -LSB- 11 , 12 -RSB- . However , there is controversy as to the reliability of serum GHBP level as a marker of GH receptor levels in specific tissues -LSB- 13 -RSB- . Janus kinase/signal transducer and activator of transcription signaling Another mechanism for GH resistance in uremia is a defect in post-receptor GH-activated Janus kinase/signal transducer and activator of transcription -LRB- JAK/STAT -RRB- signaling -LRB- Fig. 2 -RRB- -LSB- 14 -RSB- . GH action is mediated by the binding of GH to the growth hormone receptor -LRB- GHR -RRB- , resulting in its dimerization and the auto-phosphorylation of the tyrosine kinases , Janus kinase 2 -LRB- JAK2 -RRB- , which , in turn , stimulates phosphorylation of signaling proteins , STAT proteins STAT1 , STAT3 and STAT5 . Upon activation , these STAT proteins translocate to the nucleus and activate GH-regulated genes . An intact JAK2-STAT5b signaling pathway is essential for GH stimulation of IGF-1 gene expression . In uremia , a defect in the post-receptor GH-activated JAK2 signal transducer and STAT transduction is described as one of the mechanisms of GH resistance -LSB- 14 -RSB- . Fig. 2Growth hormone-mediated JAK/STAT signal transduction . GH activates several signaling pathways via JAK2 , including the JAK/STAT pathway -LSB- 22 , 23 -RSB- . Binding of GH to its receptor -LRB- GHR -RRB- activates JAK2 , which then self-phosphorylates . This is followed by phosphorylation of the GHR and , subsequently , STAT 1a , STAT 3 , STAT 5a , and STAT 5b , members of a larger family of cytoplasmic transcription factors . These phosphorylated STATs form dimers that enter the nucleus , where they bind to specific DNA sequences and activate their target genes , IGF-1 and some suppressors of cytokine signaling -LRB- SOCS -RRB- . Deletion of STAT5 expression leads to retarded body growth , and STAT5b is required for GH-mediated IGF-1 gene expression . In renal failure phosphorylation of JAK2 and the downstream signaling molecules STAT5 , STAT3 , and STAT1 is impaired , as are the nuclear levels of phosphorylated STAT proteins . This important cause of uremic GH resistance may result , in part , from up-regulation of SOCS2 and SOCS3 expression with suppressed GH signaling and also from increased protein tyrosine phosphatase activity , with enhanced dephosphorylation and deactivation of the signaling proteins . Reprinted from -LSB- 14 -RSB- with permissionThe JAK2/STAT pathway is regulated , among other factors , by suppressor of cytokine signaling -LRB- SOCS -RRB- proteins , which is induced by GH . These proteins bind to JAK2 and inhibit STAT phosphorylation -LSB- 15 -RSB- . Up-regulation of SOCS has been described in inflammatory states and may play a similar role in CKD -LSB- 16 -RSB- . IGF and IGFBP Daughaday et al. proposed the somatomedin hypothesis : GH leads to an increase in IGF-1 -LRB- formerly called somatomedin -RRB- c -RRB- from the liver , which , in turn , reaches the growth plate to mediate its action -LSB- 17 -RSB- . However , it was later demonstrated that all the effects of GH are not mediated through IGF-1 . Also , the liver is not the only source of IGF-1 , and it is produced in other tissues . Circulating IGF-1 mainly derived from the liver acts as an endocrine hormone . IGF-1 produced locally acts as a paracrine/autocrine hormone . The majority of circulating IGF in the serum exists as a 150 kDa complex , including the IGF molecule , IGF binding protein 3 -LRB- IGFBP3 -RRB- and the acid labile subunit -LRB- ALS -RRB- . IGF-1 gene knockout in mice results in miniature mice that die soon after birth . Knock-out of IGF-1 in the liver alone results in relatively normal sized mice with a 75 % reduction in circulating IGF-1 levels , suggesting that local IGF-1 may be more important for body growth than liver IGF-1 -LSB- 18 -RSB- . ALS knock-out mice also exhibit relatively normal growth and development , despite a 65 % reduction in circulating IGF-1 levels . Disruption of both liver IGF-1 and ALS genes results in 85 -- 90 % reduction in circulating IGF-1 levels and significant reduction in linear growth , suggesting that a threshold concentration of IGF-1 is necessary for normal growth -LSB- 19 -RSB- . IGF-1 is the predominant IGF during the rapid growth period of puberty . The levels of IGFs -LRB- IGF-1 and IGF-2 -RRB- are normal in pre-terminal renal failure . In end-stage renal disease IGF-1 level is normal or decreased and levels of IGF binding proteins -LRB- IGFBP -RRB- are increased , thus resulting in a net decrease in IGF bioactivity . Free IGF-1 is decreased in proportion to renal failure -LSB- 20 , 21 -RSB- . IGF-1 is an anabolic hormone ; it binds to the IGF-1 receptor -LRB- IGF-1R -RRB- at the α subunit , where it activates tyrosine kinase intrinsic to the IGF-1Rβ subunit . In experiments with rats with CKD , skeletal muscles show decreased serum levels of IGF-1 and IGF-1 mRNA , while IGF-1R mRNA and IGF-1R numbers are increased , with normal binding affinity . However , there is resistance to post-receptor signal transduction ; both auto-phosphorylation of the IGF-1R tyrosine kinase and activity of the IGF-1R tyrosine kinase to the exogenous insulin receptor substrate-1 -LRB- IRS-1 -RRB- , a natural substrate for IGF-1 receptor tyrosine kinase , are diminished in skeletal muscle of CKD rats . These abnormalities may account for the resistance of IGF-1 to protein turnover in skeletal muscles in CKD -LSB- 22 -RSB- . IGFs are transported in plasma bound to IGF binding proteins -LRB- IGFBPs -RRB- , which are responsible for extending their half-life and controlling their bioavailability . There are six different IGFBPs , based on their respective amino acid sequence . Of the IGFs in the serum , 75 % circulate as a ternary complex bound to IGFBP3 and another subunit , acid labile subunit -LRB- ALS -RRB- , to form major 150 kDa complexes . This acts as a reservoir and can not cross the endothelial barrier . Some 20 -- 25 % of IGFs are present as smaller binary complexes with other IGFBPs forming the minor complex -LRB- 35 kDa -RRB- -LSB- 23 -RSB- . Approximately 97 % of IGF is bound ; 1 % of IGF-1 is in a free bioactive form . In healthy children there is a 25 % excess of IGFBPs over IGF , while , in pre-terminal renal failure , IGFBPs are 150 % in excess of IGFs , and in end-stage renal disease they are 200 % in excess , thus reducing the bioavailability of IGF -LSB- 21 -RSB- . IGFBP3 is the most abundant of all the binding proteins . IGFBP3 and IGFBP5 are similar in many aspects ; structurally , they are both closely related , both potentiate IGF action and are up-regulated by GH . The serum level of intact IGFBP3 is normal in CKD , while the fragmented fraction -LRB- 29 kDa -RRB- is increased but has a reduced affinity for peptides -LSB- 24 -RSB- . IGFBP5 level is not altered , but it exists mostly in the fragmented form.Intact IGFBP1 , IGFBP2 , IGFBP4 and IGFBP6 are elevated in CKD in relation to the degree of renal dysfunction -LSB- 25 -RSB- . IGFBP1 , IGFBP2 and IGFBP6 are growth inhibitors of IGF-dependant proliferation of chondrocytes . Increased levels of IGFBP1 and IGFBP2 have been shown to correlate negatively with height -LSB- 26 -RSB- . Ulinski et al. analyzed serum levels of IGFBP4 and IGFBP5 in 89 CKD patients . There was a fourfold increase in IGFBP4 , while IGFBP5 was not significantly increased . IGFBP4 level was inversely correlated with glomerular filtration rate and standard height . IGFBP5 level was positively correlated with standard height -LSB- 25 -RSB- . Ghrelin Ghrelin is a newly discovered , 28-amino acid peptide , with growth hormone releasing properties -LSB- growth hormone secretagogue -LRB- GHS -RRB- -RSB- , expressed most abundantly in the stomach and also in smaller quantities by pancreatic islet cells and hypothalamus . Ghrelin levels are increased by fasting , cholinergic stimulation , estrogen and recombinant hIGF-1 , and are decreased by food intake -LSB- 27 -RSB- . Ghrelin has been shown to increase the release of GH which is amplified by co-administration of GHRH , and acts at the level of the hypothalamus and pituitary . The role of ghrelin in the growth abnormalities in CKD has yet to be defined . Treatment with recombinant human growth hormone Studies in the past have shown that therapy with recombinant human growth hormone -LRB- rhGH -RRB- in CKD is safe and efficacious , and that it increases growth rate and improves standardized height -LSB- 28 , 29 -RSB- . Haffner et al. studied the effect of growth hormone treatment on final adult height of children with CKD -LRB- Fig. 3 -RRB- -LSB- 1 -RSB- . In contrast to the controls that had persistent growth failure , children treated with rhGH demonstrated sustained catch-up growth . In treated children the standardized height increased from baseline to a mean final adult height of 1.6 ± 1.2 SD below normal , while , in untreated control children , it decreased from baseline to a mean final adult height of 2.1 ± 1.2 SD below normal . Of the children treated with rhGH , 65 % reached a final adult height within the normal range , although it was significantly below the genetic target -LSB- 1 -RSB- . Fig. 3Growth hormone treatment in chronic kidney disease : change from initially predicted adult height at baseline in 38 children -LRB- 32 boys and six girls -RRB- with chronic renal failure who received growth hormone treatment compared with 50 control children with chronic renal failure who did not receive growth hormone , according to gender . Values are means ± SD . Asterisks indicate significant differences from the previous period -LRB- P < 0.001 -RRB- and daggers indicate significant differences from the children who were not treated with growth hormone -LRB- P < 0.001 -RRB- . Reprinted from -LSB- 1 -RSB- with permission Poor growth outcomes after renal transplantation are associated with corticosteroid use , persistent CKD and abnormalities in the GH-IGF-1 axis . The use of rhGH after transplantation leads to catch-up growth associated with increase in IGF-1 levels -LSB- 26 -RSB- . Using the NAPRTCS database of 513 renal transplant recipients receiving rhGH , Fine and Stablein demonstrated that final adult height was superior in rhGH treated patients compared to controls . Allograft function and graft failure rates were similar in both groups , with no increase in adverse events -LSB- 30 -RSB- . RhGH treatment in renal failure is associated with an elevation in serum free IGF-1 -LSB- 31 -RSB- . RhGH increases IGFBP3 , IGFBP4 , and IGFBP5 , decreases IGFBP1 and has no effect on IGFBP2 and IGFBP6 . RhGH also increases IGFBP4 , but does not correlate with change in height SDS , since most of the IGFBP4 in serum is fragmented -LSB- 25 , 31 -RSB- . RhGH-mediated increase in IGFBP3 , IGFBP5 and ALS results in increased ternary complexes and correlates positively with the increment in height SDS -LSB- 31 -RSB- . Among the growth-promoting effects of treatment with rhGH in CKD are anabolic effects , demonstrated by increase in body weight and mid-arm muscle circumference . The recommended dose approved for treatment of growth failure in CKD is 0.35 mg/kg per week -LRB- 28 IU/m2 per week -RRB- -LSB- 3 -RSB- . Targets for future therapy : Treatment with recombinant IGF-1 The GH resistance associated with CKD may be amenable to treatment with recombinant human IGF-1 -LRB- rhIGF-1 -RRB- . In children with GH-receptor deficiency or GH-inactivating antibodies , rhIGF-1 treatment resulted in a modest increase in growth velocity and height SDS , although less than that expected with rhGH -LSB- 32 -RSB- . In addition , short-term administration of rhIGF-1 has been shown to increase glomerular filtration rate and renal plasma flow in patients with end-stage renal disease and in healthy subjects . Vijayan et al. demonstrated sustained improvement in renal function in a 31-day randomized , double-blinded , placebo-controlled trial of 15 patients with advanced CKD , who had received intermittent doses of rhIGF-1 -LSB- 33 -RSB- . One reason for the use of IGF-1 treatment in CKD is that while patients are GH sufficient , they are GH resistant . Therefore , rhIGF-1 may be more beneficial than GH as therapy in CKD and merits further investigation as an agent for treatment of growth failure and improvement in renal function in CKD -LSB- 34 -RSB- . Combined use of rhGH and rhIGF-1 Animal studies have shown that the combined use of rhGH and rhIGF-1 has an independent and additive effect . While whole-body growth in uremic rats was similar with treatment with either agent , an additive effect on longitudinal growth and anabolism was demonstrated when both agents were administered together -LSB- 35 -RSB- . Combined use of rhIGF-1 and rhIGFBP3 One of the concerns with the use of rhIGF-1 in children with normal GH production is that rhIGF-1 may suppress endogenous GH , IGFBP3 and ALS production , which may have a detrimental effect on growth . The other adverse effect of the use of rhIGF-1 observed in GH receptor-deficient patients is hypoglycemia , due to low levels of IGFBP3 and increased level of free IGF-1 available for binding to insulin receptors -LSB- 32 -RSB- . Both these effects can be reduced by the combined use of rhIGF-1 and rhIGFBP3 -LSB- 36 -RSB- . IGFBP displacers At least two different IGF-1 analogs have been made , which have an affinity for IGFBPs but have no effect on IGF receptors , thus `` displacing '' IGF-1 from IGFBPs and elevating free IGF-1 levels . Animal studies in hypophysectomized rats and dwarf dw/dw rats treated with IGFBP displacers demonstrated increased kidney size , improved renal function , and the stimulation of weight gain and bone growth . This effect was enhanced when treatment with IGFBP displacers was combined with rhIGF-1 -LSB- 37 -RSB- . Conclusion This review of the literature lends support to the concept that CKD is associated with GH `` resistance '' . Despite adequate treatment with rhGH and improvement in catch-up growth , children with CKD display a final adult height that is often below the genetic target . The potential for newer therapies with rhIGF-1 , combined use of rhGH and rhIGF-1 , combined use of rhIGF-1 and rhIGFBP3 or IGFBP displacers to improve both the short and long term outcomes in the treatment of the disturbances in the GH/IGF -1 axis in CKD awaits future investigations .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I B O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I B O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O

insulin-like growth factor
chronic kidney failure


Nonpalpable testes : is there a relationship between ultrasonographic and operative findings ? Background Ultrasonography -LRB- US -RRB- as a diagnostic tool in the work-up of boys with nonpalpable testes -LRB- NPT -RRB- is still controversial . Introduction Failure of testicular descent is a common childhood anomaly , being seen in 0.8 -- 2 % of full-term and 18 -- 30 % of premature boys . In undescended testes -LRB- UDT -RRB- the testis fails to migrate into the processus vaginalis , failing to reach the scrotum at 35 weeks of gestation . It is unilateral in 60 -- 70 % of cases . Approximately 20 % of UDT are nonpalpable on physical examination -LSB- 1 -RSB- . There are four possible explanations for this phenomenon . First , the testis may be situated in the scrotum or inguinal canal , but is too small or there is too much subcutaneous adipose tissue . Second , the testis is located inside an open processus vaginalis in the inguinal canal and may be intermittently inguinal and abdominal in position . Third , it is in a true abdominal position ; and fourth , the testis is lacking -LSB- 2 -RSB- . The literature reports that nearly half of viable nonpalpable testes -LRB- NPT -RRB- are in an abdominal position and 5 % are in the inguinal canal . The remaining 45 % are atrophic or absent , mostly as a result of in utero spermatic cord torsion and are located abdominally , inguinally or scrotally -LSB- 3 , 4 -RSB- . Experienced paediatric surgeons can accurately diagnose UDT by repeated and meticulous palpation of the scrotal and inguinal region . Since palpation is quite subjective , the diagnosis mostly depends on the examiner 's experience and ability -LSB- 2 -RSB- . Currently there is controversy as to the step to take when clinical examination fails to identify a testis . Further exploration might be done by means of laparoscopy or by noninvasive methods such as ultrasonography -LRB- US -RRB- , CT , MRI , venography or arteriography -LSB- 3 , 5 , 6 -RSB- . Of these , US is the imaging method of choice in children because it is noninvasive and does not use ionizing radiation . Furthermore , it is cheap and widely available -LSB- 7 -RSB- . When NPT is correctly diagnosed there is consensus on the need for early treatment , as this may decrease the risk of testicular cancer -LSB- 8 -- 12 -RSB- and fertility problems -LSB- 13 -- 15 -RSB- . We performed a study aimed at assessing the value of US in the diagnostic work-up of NPT , and to this end evaluated the relationship between preoperative US data and operative findings . Materials and methods During a 7-year period , 880 boys referred to the Department of Paediatric Surgery , Erasmus MC-Sophia Children 's Hospital , Rotterdam , underwent primary surgery for UDT . US was performed in 137 of these children with 156 NPT . Prior to US the patients were clinically examined by a general practitioner , a paediatrician , a urologist or , in most cases , by a paediatric surgeon . Clinical examination by a paediatric surgeon was with the boy in the supine position , the lower half of the body undressed . The examiner placed the index finger and thumb of the right hand on either side of the inguinal canal , thus preventing testes lying distally from the inguinal canal from withdrawing into the inguinal region during palpation of the scrotum . With the examiner standing on the right side of the patient , the inguinal region was then examined with the fingertips of a warm left hand . If there seemed to be no palpable testis , an attempt was made to empty the inguinal canal by carrying out an ironing movement with the fingertips stroking in the direction of the scrotum . This may reveal a palpable testis at the level of the exit of the inguinal canal , immediately shooting back deep into the inguinal canal . If no testis could be located at all , the perineum , the base of the penis and the thigh were closely examined to exclude an ectopic testis . US was performed using an Ultramark 9 HDI unit -LRB- Advanced Technology Laboratories , Bothell , Wash. -RRB- with a high-frequency , broadband , 7 -- 10-MHz linear array transducer or a Philips ATL HDI 5000 unit , also with a high-frequency , broadband , 5 -- 12-MHz linear array transducer . US was performed by eight different paediatric radiologists . After US all boys were clinically re-examined by a paediatric surgeon and again on the operating table when under anaesthesia . Subsequently , all boys underwent surgery and testicular position and other operative findings were assessed intraoperatively . Depending on the US results for NPT different operative procedures were used . Laparoscopy was usually performed when US could not identify a testis . In the presence of a viable abdominal testis , a one - or two-stage orchiopexy was performed . Anorchia was diagnosed when a blind-ending vas deferens was identified . When the vas deferens and testicular vessels entered the internal inguinal ring the procedure was completed by an inguinal exploration . When a viable testis was found , orchiopexy was performed . When a nubbin -LRB- vanished testis -RRB- or an atrophic testis was found , this was excised for pathological examination . Inguinal exploration was usually performed when US did show an inguinal testis . When a viable testis was found , orchiopexy was performed . A viable testis was defined as having a volume according to age -LSB- 16 -RSB- . All US findings were compared with intraoperative findings . Results Eligible for this study were 137 boys with 156 NPT . Excluded from analysis were two with Müllerian inhibitory factor deficiency syndrome , implying abnormal testis position . The ages of the remaining 135 boys ranged from 4 weeks to 16.2 years . Of the remaining 152 NPT , 70 were left-sided , 48 right-sided and 17 bilateral . Four patients -LRB- four NPT -RRB- had been referred to the radiologist by a general practitioner and 24 patients -LRB- 30 NPT -RRB- by a paediatrician . Most patients , 107 with 118 NPT , were first diagnosed by a paediatric surgeon before being referred to the radiologist . All boys were seen by a paediatric surgeon after the US examination for re-examination and to discuss therapy determined by the US findings . With knowledge of the US results , 28 % of the NPT previously diagnosed as not palpable now appeared to be palpable . Three of the four NPT -LRB- 75 % -RRB- in patients first seen by a general practitioner were palpable when re-examined by a paediatric surgeon , as was the case for 18 of 30 NPT -LRB- 60 % -RRB- referred by a paediatrician . Of the NPT first examined by a paediatric surgeon , 18 % were palpable on re-examination with knowledge of the US results . US was able to locate 103 of 152 NPT -LRB- 68 % -RRB- : 16 were found in the abdomen and 87 in an inguinal position ; therefore 49 could not be found . Comparing the US results with the surgical findings , there was a 100 % positive predictive value -LRB- PPV -RRB- for the 16 abdominal testes seen on US ; all were indeed found abdominally . Nevertheless , 14 viable abdominally located testes were missed by US . At surgery , all these testes were found in the lower abdomen -- on the iliopsoas muscle , in the pelvis , or close to the internal inguinal ring . US located 87 inguinal testes , 84 of which were indeed found in the inguinal region -LRB- 97 % PPV -RRB- ; the other three were viable and found intraabdominally . Thirty-five of the NPT were defined as small , atrophic or vanished at operation . Ultimately , US failed to locate 49 NPT . Nevertheless , 16 of these at surgery appeared to be viable , with 14 located intraabdominally and two in the inguinal region . Two atrophic testes were found in the abdomen . A further 22 atrophic testes were found inguinally or scrotally . Anorchia was present in nine boys . In summary , 92 -LRB- 85 % -RRB- of the 108 NPTs defined as viable at operation were located by US . While nearly all viable inguinal testes -LRB- 74/76 -RRB- were correctly located by US , only half of the viable abdominal testes -LRB- 16/33 -RRB- were seen on US . The relevant data are summarized in Fig. 1 . Fig. 1Ultrasound findings in 152 nonpalpable testes in relation to findings at operative exploration Discussion Over the years , a wide range of investigations -- from vascular techniques and imaging techniques to laparoscopy -- have been used in detecting NPT -LSB- 17 -RSB- . Inguinal exploration used to be the standard surgical approach for nonpalpable testes . If the testis was not found at or below the internal inguinal ring , the procedure was extended to the abdomen . Laparoscopy has gained greater acceptance in diagnosing and treating NPT . Cortesi et al. -LSB- 18 -RSB- first reported its use in 1976 in an 18-year-old adolescent . While diagnostic laparoscopy is highly sensitive in detecting NPT -LSB- 1 , 2 , 19 , 20 -RSB- , it carries an approximately 1 % risk of major or minor operative complications . Furthermore , the long-term incidence of peritoneal adhesions following laparoscopic procedures in children is approximately 10 % -LSB- 4 , 21 -RSB- . The literature is far from unanimous on the usefulness of US in UDT . Some authors recommend US for its feasibility and potential to settle the subsequent operative procedure -LSB- 7 , 21 -- 27 -RSB- . Others are sceptical because they found poor outcome for NPT , and because US does not exclude the necessity for laparoscopy -LSB- 3 , 28 -- 30 -RSB- . Most of the studies included only small groups of patients -LSB- 24 -- 26 , 28 , 30 -RSB- . Not all studies investigated only NPT ; some included all UDT -LSB- 26 , 27 , 30 -RSB- . Most studies compared US results with findings during the operative procedure -LSB- 3 , 7 , 21 , 22 , 26 -- 29 -RSB- , others compared CT and/or MRI with US -LSB- 23 -- 25 , 30 -RSB- in relation to the operative procedure . The most relevant conclusions of these studies are summarized in Table 1 . Table 1Review of the literature on the use of US in boys with NPT -LRB- n.a. not applicable , because all testes were ` true ' NPT -RRB- ReferenceStudy designTestes -LRB- n -RRB- Located by USLocated `` true '' NPTAccuracy of US -LRB- % -RRB- aPredictive value of US -LRB- % -RRB- aRe-examinationRemarksAdvice in NPTPositiveNegativeTestes palpablePrevious examiner -LSB- 22 -RSB- Retrospective/medical charts5528/55 -LRB- 51 % -RRB- n.a. 8410067n . a. -- US -LSB- 29 -RSB- Prospective/cohort6237/62 -LRB- 60 % -RRB- n.a. 761000n . a.Vanished not included in accuracy and predictive valuesLaparoscopy -LSB- 3 -RSB- Retrospective/medical charts6612/66 -LRB- 18 % -RRB- 0/21 -LRB- 0 % -RRB- 18b100b0b45/66 -LRB- 68 % -RRB- Referring physician82 % US ordered by referring physician ; 93 % US performed elsewhereLaparoscopy -LSB- 23 -RSB- Retrospective/medical charts170111/170 -LRB- 65 % -RRB- n.a. 72b100b19bn . a. -- US -LSB- 21 -RSB- Prospective/cohort7448/74 -LRB- 65 % -RRB- 16/29 -LRB- 55 % -RRB- 65b100b0b45/74 -LRB- 61 % -RRB- Referring physicianOnly nubbins palpable on re-examinationUS -LSB- 24 -RSB- Prospective/cohort2113/21 -LRB- 62 % -RRB- n.a. 769250n . a.US twice and blind to physical examinationUS → MRI -LSB- 30 -RSB- Retrospective/medical charts225/12 -LRB- 42 % -RRB- 3/7 -LRB- 43 % -RRB- 581002913/22 -LRB- 59 % -RRB- Referring physician -- Laparoscopy -LSB- 7 -RSB- Prospective/cohort4545/45 -LRB- 100 % -RRB- 6/8 -LRB- 75 % -RRB- 9393 -- 36/45 -LRB- 80 % -RRB- Referring physicianPhysical examination and US blind to each otherUS -LSB- 26 -RSB- Prospective/cohort3817/38 -LRB- 45 % -RRB- 1/18 -LRB- 6 % -RRB- 6188381/21 -LRB- 5 % -RRB- ExpertUS blind to physical examinationUS if obese20/41 -LRB- 49 % -RRB- Referring physician -LSB- 28 -RSB- Prospective/cohort142/14 -LRB- 14 % -RRB- n.a. 211008n . aSurgery blind to USLaparoscopy -LSB- 27 -RSB- Prospective/cohort6961/69 -LRB- 88 % -RRB- 4/12 -LRB- 33 % -RRB- 9910088n . aUS -LSB- 25 -RSB- Prospective/cohort2315/23 -LRB- 65 % -RRB- n.a. 919175n . a.US and CT blind to each otherUSaAccuracy and predictive values were -LRB- re -RRB- calculated : negative surgical exploration/absent testes were counted as true negative and testicular remnants / `` nubbins '' as false negative.bAbsent testes and atrophic testes grouped ; number of absent testes not -LRB- exactly -RRB- mentioned in article -LRB- calculated as false negative -RRB- . An important message emerging from these articles is the very high PPV of US and the importance of thorough examination by a physician with experience in small genital examination . More than two-thirds of testes of referred patients were palpable on examination by experienced physicians . Many US investigations could have been avoided if patients had first been referred to an expert . The -LRB- paediatric -RRB- radiologist 's experience is also vital and US should be undertaken in the hospital where further treatment will be given . US remains the modality of choice in our centre because we value its noninvasiveness , child-friendliness and cost-effectiveness . It also facilitates planning the correct surgical procedure -LRB- Fig. 2 -RRB- -LSB- 7 , 29 -RSB- . Fig. 2Flow chart representing the diagnostic and therapeutic approach in boys with NPT In summary , we found 97 % sensitivity of US for viable inguinal testes and 48 % sensitivity for viable abdominal testes . When US located a testis it was also found at that site during surgery in 97 % of NPT -LRB- PPV 97 % -RRB- . In our study , only three viable testes were not located correctly , being in the inguinal canal at US and within the abdomen at surgery . This can be explained by the fact that there was a patent internal inguinal ring with a mobile testis . More than two-thirds of NPT could be localized with US . Approximately one-third of NPT that were not found with US appeared to be viable at surgery . Of 34 testes considered nonpalpable by a general practitioner or paediatrician , 21 -LRB- 62 % -RRB- were palpable on re-examination by a paediatric surgeon after US . In contrast , of 118 testes considered nonpalpable by a paediatric surgeon , only 21 -LRB- 18 % -RRB- were palpable on re-examination . Conclusion We feel our results underpin the importance of referring boys with a presumed NPT to a physician with expertise in genital examination of small children . This will avoid unnecessary US investigations . Furthermore , we recommend US for all boys with NPT diagnosed by an experienced physician -LRB- Fig. 2 -RRB- . The findings would then determine the subsequent operation : diagnostic and/or therapeutic laparoscopy for all NPT with negative US , or intraabdominal testes located by US . In addition , we recommend inguinal exploration whenever US demonstrates an inguinal testis .

B B O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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