Impaired working speed and executive functions as frontal lobe dysfunctions in young first-degree relatives of schizophrenic patients The aim of the investigation was to detect neuropsychological markers , such as sustained and selective attention and executive functions , which contribute to the vulnerability to schizophrenia especially in young persons . Performance was assessed in 32 siblings and children of schizophrenic patients and 32 matched controls using Wisconsin Card Sorting Test , Colour-Word-Interference-Test , Trail Making Test , and d2-Concentration-Test . The first-degree relatives showed certain impairments on all four tests , in particular , slower times on all time-limited tests . These results suggest the need for more time when completing neuropsychological tasks involving selected and focused attention , as well as cognitive flexibility , as a possible indicator of genetic vulnerability to schizophrenia . Introduction Schizophrenic disorder is characterized by clinical heterogeneity and certain neurobiological alterations . The world-wide constant prevalence of schizophrenia disease suggests an genetic influence . Especially high-risk-studies have shown a broad genetic component in the traits of schizophrenia -LSB- 20 , 23 , 39 , 43 -RSB- . However , little is currently known about the nature of the transmission of inheritance . Furthermore , genetic predisposition may be clinically unexpressed . Thus , it is necessary to examine ill , stabilized or recovered patients as well as unaffected individuals who are at an increased genetic risk for schizophrenia disease . Cognitive processes are a directly expression of brain functions and especially their interactions . Thus , failured , prolonged , complicated or rigided ways of thinking in persons with a genetic risk reflect disturbed neuronal connections . Studying cognitive processes of unaffected first-degree relatives with a genetic risk for schizophrenia in comparison with healthy controls allows estimating the genetic impact of the disease on infomation-processing only if both groups were matched . Then they only differ in their genetic risk and we can lead back the differences to the impact of the genes . Various vulnerability models -LSB- 41 , 58 -RSB- and certain neuropsychological indicators of attentional and cognitive abilities such as selective attention , cognitive flexibility , inhibitory control and naming skills were examined in detail among schizophrenic patients and risk persons -LSB- 11 , 14 , 40 -RSB- . Therefore , the idea of cognitive endophenotypes is an important approach in the research of genetic risk of schizophrenia since years -LSB- 24 , 52 -RSB- . In research the Stroop Test -LRB- FWIT -RRB- , the Trail Making Test -LRB- TMT -RRB- , and the Wisconsin Card Sorting Test -LRB- WCST -RRB- , have been used especially to assess executive or higher-order functions such as working memory , cognitive adjustment and maintenance of set . However , only few studies have applied the d2-Concentration-Test -LRB- d2 -RRB- or the above-mentioned tests to a young population with a genetic risk . Some studies have determined lower WCST-scores among schizophrenic patients . These have achieved a lower percentage of correct trials , fewer completed categories , and have made more preservative errors -LSB- 16 , 47 -RSB- . Egan et al. -LSB- 10 -RSB- also determined impairments using the WCST and other tests among 193 unaffected siblings and even worse scores on these and other tests among 147 of their relatives who were patients . Further studies -LSB- 12 , 37 , 38 , 47 , 48 , 56 -RSB- also indicate a genetic component regarding impairments among relatives of schizophrenic patients as compared to relatives of other patients with affective disorders and as compared to normal controls . Stratta et al. -LSB- 53 -RSB- showed lower WCST-scores among 92 schizophrenic patients , but not among 25 first-degree relatives . Other studies were also not able to detect any change in WCST-parameters among schizotypic persons or subjects with a genetic risk -LSB- 28 , 36 -RSB- . Laurent et al. -LSB- 33 -RSB- showed deficits only in subgroups of relatives with higher rates of physical anhedonia and negative schizotypal symptoms . Therefore , the authors suggest that performance on the WCST is more likely a feature inherent to the disease process rather than an index of genetic susceptibility to the illness . WCST-deficits in schizotypic individuals -LSB- 18 , 42 -RSB- support the hypothesis that executive function deficits may precede the onset of schizophrenia or indicate cognitive impairments in schizophrenic-spectrum syndromes . Performance on the Stroop was also analyzed in detail among schizophrenic patients using various test versions . Impairments could be found repeatedly in patient groups . Nevertheless , some studies were not able to replicate these findings -LSB- 33 , 47 -RSB- . In a review of 32 studies -LSB- 19 -RSB- , inconsistent findings and the contribution of thought disorders and special components of the attention process to the Stroop-effect were emphasized . In genetic risk studies there are contradictory findings of poor performance among children , siblings and parents of schizophrenics -LSB- 4 , 9 , 33 , 47 -RSB- . Impairments on the TMT , especially in the second part , could also often be determined in schizophrenic patients -LSB- 33 , 47 , 57 -RSB- . However , only a few studies were able to demonstrate lower scores among those at genetic risk -LSB- 10 , 33 -RSB- . Some investigations showed impaired performance among schizophrenic patients or relatives on all of these tests : the Stroop , the TMT , and the WCST -LSB- 13 , 21 , 27 -RSB- . Only the investigations by Schreiber et al. -LSB- 49 -RSB- are known to have used the d2-Concentration-Test on schizophrenic patients and risk groups . On this test , patients , but not unaffected risks , performed more poorly -LRB- working speed and error rate -RRB- than did the controls . Furthermore , other tests have also shown reduced psychomotor speed and reaction time among schizophrenics -LSB- 2 , 49 -RSB- . The findings described above suggest a subtle deficit in maintained and focused attention together with a subsequent impairment of stimulus discrimination among schizophrenics and schizotypical subjects . Due to these results , we assume these impairments principally to be an expression of the disease process , personality traits or symptomatology , such as schizoid , paranoid , extraversion , or anhedonia . Among subjects with a genetic risk for schizophrenia , cognitive dysfunctions have also been repeatedly determined -LSB- 5 , 32 -RSB- . However , scores are inconsistent and display different impairment profiles -LSB- 54 -RSB- . Thus , it may be concluded that subgroups with various neurobiological and genetic profiles as well as certain symptomatology during the process of the disease can be distinguished and the vulnerable cognitive domains revealed . The aim of this study -LRB- as part of an ongoing project called `` Neurobiological and neuropsychological risk factors for schizophrenia '' ; -LSB- 30 -RSB- -RRB- is to consider the special cognitive abilities of working speed , inhibitory control , cognitive flexibility and executive functions , such as working memory , maintenance of set and naming skills using various tests among juvenile unaffected first-degree relatives of schizophrenic patients as compared to controls . Our hypothesis is that the genetic risk group of unaffected children and siblings of schizophrenics will score lower on the tests than will healthy controls . Based on frequently used tests and the results presented above , we selected the WCST , the TMT and the FWIT -LRB- Farbe-Wort-Interferenz-Test -RRB- as the German Version of the Stroop-Paradigm . A number of important studies -LSB- 5 , 11 , 14 , 32 -RSB- refer to these test when assessing cognitive functioning and neuropsychological risk indicators in schizophrenic patients and persons at high risk , because these tests make demands on cognitive processes based in the frontal lobes , a brain area vulnerable to potential antecendents of schizophrenic disorder . All of these tests are supposed to have high effect sizes for test variation with a medium level of difficulty . Additionally , we used the d2-Test because it , in particular , makes demands on concentration and discrimination between similar stimuli under high time pressure in routine tasks . Methods Subjects A total of 32 children and siblings of schizophrenic patients without any clinical manifestation of schizophrenic symptoms -LRB- mean age in years : 16.0 ; males/females : 13/19 -RRB- and 32 controls -LRB- mean age in years : 16.2 ; males/females : 13/19 -RRB- -- carefully matched for age -LRB- range from 12 to 21 years -RRB- , sex and educational level -- were examined . Additionally , in order to screen for the performance comparability of groups with respect to personal background data , the intellectual quotient was assessed using the Standard Progressive Matrices -LRB- SPM ; -LSB- 26 -RSB- according to -LSB- 37 -RSB- -RRB- . We assessed the educational level of probands and controls and also of parents of probands and controls as an indicator of their socio-economic status . Both groups did not differ significantly -LRB- Table 1 -RRB- . Demographic characteristics are summarized in Table 2 . The high-risk subjects were drawn from a sample of schizophrenic in and outpatients of the Department of Psychiatry and Child - and Adolescent Psychiatry of the University of Jena and of two additional departments of psychiatry in the county of Jena . First-degree relatives of in and outpatients were asked for participation . The controls were recruited from all school types within the German School System . We also placed an ad in the local newspaper . People were asked to participate in a high-risk study conducted by the University of Jena as part of a neuropsychological study . Since recruitment was difficult we included both children and siblings of schizophrenic patients . Although siblings are a little more likely to be taken ill at schizophrenia , the genetic risk on average is nearly the same for children and siblings -LSB- 51 -RSB- . We made up only one group for relatives , because the risk of schizophrenia is almost equal for both . The study was approved by the ethical commission of the University of Jena . All tests took place in the Department of Child and Adolescent Psychiatry in Jena . After a full explanation of the procedures to the subjects , written informed consent was obtained from the young persons and their parents . Table 1Education level of probands and controlsProbands with genetic riskControlsSchool typeLerning-Disabled School 11Secondary School1514Grammer School/Advanced Technical College/University10/313 / 2Technical College/Vocational School32Education level of the parents -LRB- always the highest qualification -RRB- Secondary School31Technical College/Vocational School1717Advanced Technical College/University1214Groups did not differ significantly Table 2Demographic characteristics of probands Demographic dataSubjectsProbands with genetic riskControlsAge -LRB- years -RRB- 16.0 ± 2.416.2 ± 2.0 Gender -LRB- male/female -RRB- 13/1913/19Intelligence -LRB- SPM-IQ -RRB- Non verbal IQ101 .6 ± 13.8100.5 ± 9.7 Data of age and intelligence as mean values ± standard deviationGroups did not differ significantly Diagnostic screening and evaluation Psychiatric status of both groups was determined according to the Schedule for Affective Disorders and Schizophrenia -LRB- SADS -RRB- or the Kiddie-SADS -LSB- 8 -RSB- by a board-certified psychiatrist or psychologist . First - or second-degree relatives of controls showing any schizophrenic symptoms were excluded , as were all probands suffering from internal or neurological disorders , schizotypical personality , affective or eating disorders , or diseases with a possible neurobiological basis , such as attentional deficit disorder or dyslexia . One subject in each group had an adjustment disorder , one had a minor depressive episode , two had social behavioral disorders without any symptoms of attentional deficit disorder , and one an enuresis . First-degree relatives showed no scores on SADS or were below threshold for diagnostic relevance . Inclusion criteria were an IQ of 70 or above according to SPM -LSB- 31 , 44 -RSB- and an age between 12 and 21 years . Neuropsychological evaluation We used the -LRB- WCST ; -LSB- 22 -RSB- -RRB- in order to examine the probands ' executive functions such as working memory and maintenance of set as well as cognitive flexibility . The probands were asked to successively place 128 response cards , showing symbols drawn in different combinations of color , form , and number , under one of four stimulus cards . After ten consecutive correct trials , the criteria according to which the response cards were selected changed . The examiner provided information only on correct or incorrect choices and the probands had to find out by themselves according to what criteria the response cards were to be placed . We evaluated the percentage of correct trials -LRB- WCST/PCT -RRB- , the percentage of perseverative errors -LRB- WCST/PPE -RRB- , and the number of completed categories -LRB- WCST/NC -RRB- . The FWIT -LSB- 1 -RSB- as a version of the Stroop-Test was used to determine general alertness , naming skills and selectivity . At first the probands were asked to read aloud a list of color names printed in black , second to name the color of strokes , and third to name the color of different colored words . This run was repeated two times and the time required for reading was assessed . Finally , we calculated time needed -LRB- FWIT/A -RRB- , naming skills -LRB- FWIT/N -RRB- , selectivity of relevant information -LRB- FWIT/S -RRB- , and number of errors on the interference task -LRB- FWIT/E -RRB- . The -LRB- TMT ; -LSB- 46 -RSB- -RRB- provides information about psychomotoric speed , cognitive flexibility and working memory . Part A of the TMT requires the subjects to connect numbers in rising sequence . For Part B of the TMT , a line is drawn to connect alternating numbers and letters , starting with the number one , and then to the letter A , also in rising sequence . We determined time required for TMT/A and TMT/B as an indicator for working speed as well as cognitive flexibility using a ratio of TMT/A and TMT/B . The d2-Concentration-Test -LRB- d2 ; -LSB- 3 -RSB- -RRB- provides information about the ability to discriminate between similar stimuli , measured by speed and accuracy of performance . The probands have to mark all `` d '' s that have two strokes within an array of 14 lines , with 20 s allowed per line . The probands must also discriminate between similar stimuli , because there are `` d '' s with one or more than two strokes , and `` p '' s with strokes . We counted the number of all scanned characters measuring the working speed -LRB- d2/GZ as the German expression for number of scanned characters -RRB- . Furthermore , the ratio of incorrectly marked characters -LRB- d2/F as the German expression for error rate -RRB- to all scanned characters -LRB- d2/GZ -RRB- as an indicator of accuracy was assessed . Results The primary aim of the data analysis was to evaluate group differences for the parameters described above and to examine connections between the variables . Therefore , we tested our hypothesis that the genetic risk group of unaffected children and siblings of schizophrenics would perform more poorly on the tests than would healthy controls . Furthermore , we assumed that relatives of schizophrenics would show a wider pattern of impairments than would healthy controls . All statistical analysis were done using SPSS software -LRB- version 10.1 -RRB- . The multivariate analysis of variance -LRB- MANOVA -RRB- showed significant differences between the group of children and siblings of schizophrenic patients and the controls for certain variables of performance , as well as a connection to age , intelligence and gender . In order to determine the normal distribution of parametric statistics for each variable , the score distributions of each group were examined using the Kolmogorov -- Smirnov-test . Homogeneity of variance of the groups was tested using the Levene Test . If there was no normal distribution , as was the case for the variables WCST/NC and TMT/F , then the non-parametric Mann -- Whitney-U-test was used to evaluate group differences . Otherwise comparisons were made using the t-test . Mean scores -LRB- ± standard deviation -RRB- are shown in Table 3 . Correlations were determined using the non-parametric Spearman -- Rank-test , with selected values shown in Table 4 . Inhomogeneous variances arose in the variables WCST/NC , WCST/PCT , and FWIT/F . The level of significance was fixed at 0.05 for all tests . Table 3Comparison of neuropsychological data between high risk and control probandsNeuropsychological variableSubjectsComparisonsRisk probands -LRB- n = 32 -RRB- Controls -LRB- n = 32 -RRB- p-valuesWCSTPCT , Percentage of correct trials77 .7 ± 10.584.0 ± 6.10.002 + PPE , Percentage of perseverative errors9 .8 ± 3.57.9 ± 2.80.010 NC , Number of complete categories5 .7 ± 0.86.0 ± 0.20.042 * FWITA , Working speed 47.6 ± 8.052.2 ± 6.30.012 N , Naming skill49 .5 ± 7.049.0 ± 8.3 nsS , Selectivity skill54 .7 ± 7.155.5 ± 8.4 nsE , Number of errors during the interference task14 .9 ± 6.39.8 ± 5.10.000 * TMTA , Time to execute TMT part A35 .3 ± 10.627.8 ± 9.90.002 B , Time to execute TMT part B83 .0 ± 32.663.0 ± 18.60.002 E , Number of errors0 .47 ± 1.020.25 ± 0.57 ns * A/B , Ratio of times of part A to B0 .462 ± 0.1670.452 ± 0.121 nsd2GZ , Number of treated signs396 .7 ± 97.7448.9 ± 92.10.016 FGZ , Rate of errors to number of treated signs3 .6 ± 2.13.1 ± 2.9 nsns , Non-siginficant differencesStatistical analysis by t-test , not Bonferoni-corrected * Non-parametric test -LRB- Mann -- Whitney-U-test -RRB- + p-values for inhomogeneous variances Table 4Selected correlations between the test variables for all probands -LRB- n = 64 -RRB- , shown as rho of Spearman-rank correlationWCSTFWITTMTD2PCTErrorsAction AGZWCSTPCT , Percentage of correct trials − 0.354 ** 0.316 * − 0.357 ** − 0.387 ** FWITErrors − 0.354 ** − 0.471 ** 0.347 ** − 0.331 ** Action , Speed of a general alertness0 .316 * − 0.471 ** − 0.416 ** 0.627 ** TMTA , Time to execute TMT part A as an inverse indicator of working speed − 0.357 ** 0.347 ** − 0.416 ** − 0.463 ** d2GZ , Number of treated signs as an indicator of working speed0 .387 ** − 0.331 ** 0.627 ** − 0.463 *** Correlation two-sited significant at the level of 0.05 ** Correlation two-sited significant at the level of 0.01 Group differences Compared to the controls , first-degree relatives of schizophrenic patients were significantly impaired in their performance on certain parts of all tests . For the WCST variables `` percentage of correct trials '' -LRB- PCT -RRB- , `` percentage of perseverative errors '' -LRB- PPE -RRB- , and `` number of complete categories '' -LRB- NCC -RRB- , the analysis showed significantly worse results in the index group . The second finding of the three tests with time-limited demands , the FWIT , TMT , and d2-test , was that subjects with a genetic risk for schizophrenia worked at a significant slower rate as compared to the controls . Even though the variance of the significant results is greater in the high-risk group , these differences are not caused by extreme values . Statistical differences between the groups could not be detected for error rate on the TMT or on the d2 , for cognitive control and flexibility or for naming skills on the FWIT -LRB- FWIT/N -RRB- . However , first-degree relatives of schizophrenic patients produced significantly more mistakes on the interference task of the FWIT as compared to their controls . Effects of age , intelligence and gender These effects were taken into account in the analysis . As generally known , intelligence and speed on the FWIT , TMT , and d2 , correct categorization on the WCST , as well as naming skills , improve with age for all probands . Intelligence correlated significantly with all measured performance except for selectivity and naming on the FWIT and for accuracy on the d2 . With regard to gender effects -LRB- for a review , see -LSB- 17 , 55 -RSB- -RRB- for all probands , females showed a significantly higher cognitive flexibility on the TMT/B . Among all probands and within the risk group , males achieved significantly higher accuracy when demands were placed on cognitive adjustment during the interference task of the FWIT . They scored significantly lower on naming skills than did the females . No gender effects were found in the control group . Relationships between variables The correlation between working speed and all time-limited tests -LRB- FWIT , TMT , d2 -RRB- was highly significant , as was the correlation between speed and the PCT during the WCST . There is a positive connection between the accuracy of the d2 and the TMT . However , only the accuracy of the interference task on the FWIT correlated to parts of the WCST scores and the working speeds on the FWIT , TMT , and d2 . While speed on the TMT is lower in the index group , there was no difference between the two groups regarding the ratio of the times required to complete the TMT/A and the TMT/B . Variable naming correlated only with general alertness on the FWIT . And selectivity on the FWIT did not correlate with any other performance variable . Additionally , we did some factor analyses to see if different cognitive test variables could reflect the same cognitive function or a general vulnerability for schizophrenia . Surprisingly , after orthogonal rotation we found three factors explaining almost 60 % of variance . But the other 4 of 7 components had `` Eigenwerte '' between 0.55 and 0.97 , so that we found almost as many factors as variables . After graphic representation , we are very cautious with an interpretation of the results of this factor analyses . Discussion This study examined the hypothesis that children and siblings of patients with schizophrenia , without a schizophrenic-spectrum disorder , show a pattern of decreased attentional and cognitive performance when compared to controls . Several findings of this study can be emphasized . First , subjects at risk for schizophrenia were slower on all three time-limited tests ; the FWIT , TMT , and d2 . These results suggest that young persons with a genetic risk need much more time to achieve the same accuracy as the controls during routine work on the d2 and the TMT/A . The correlations among working speeds for all time-limited tests indicate that these tests assess the same components of an attentional process and that this may reflect a general vulnerability . On the other hand , on tasks with no time structure or constraints high risks showed a lower ability to establish , maintain or adjust a required conceptual level during the WCST . This finding suggests impaired executive functions , working memory , vigilance and cognitive flexibility , which can not be compensated by using more time , as compared to the controls . Furthermore , it is fair to assume that parameters of the prolonged and more complex tasks of the WCST measure different cognitive processes than do those of the time-limited tests . Nevertheless , there are correlations between WCST-scores and other scores , especially regarding working speed . Second , gender effects are greater within the risk group . In this group , females showed a worse selectivity , but only by making more mistakes . In contrast , females performed significantly better than males on naming skills on the FWIT . These findings support the assumption of gender-specific vulnerability markers , in particular that males with a genetic risk show vulnerability in respect to naming skills -LSB- 50 -RSB- . Third , our findings regarding cognitive flexibility and naming skills on the FWIT are not reflected in the working speed for all time-limited tasks or in the intelligence of the probands . There is no correlation between these variables . However , there are significant correlations between the accuracy of the interference task on the FWIT with both the working speed for all time-limited tasks , as well as with WCST performance . Thus , both groups needed the same time to perform the interference task on the FWIT , but the high-risk probands made more mistakes . This is an indicator of impaired selectivity in distinguishing relevant from irrelevant stimuli . The results of the TMT test can be attributed to an impaired action speed but not to a lower ability of cognitive adjustment . Thus , the results do not allow a clear comparison of selectivity and naming performance in both groups . Probably the FWIT subtests , with their demands on naming and cognitive adjustment , reflect other aspects of the attentional process as compared to other parts of the tests used . These results in first-degree relatives of schizophrenic patients without schizotypical or affective symptoms only partly confirm prior studies . Some studies show no differences on the Stroop and the WCST -LSB- 28 , 33 -RSB- . Only the scores on the WCST variables , `` completed categories , '' `` percentage of perceptual level response , '' and `` perseverative errors , '' are repeatedly lower among the genetic risks as compared to the healthy controls , especially among high-risk probands affected by symptoms such as anhedonia or those that are schizotypical -LSB- 33 , 56 -RSB- . TMT/B impairments could also be detected in groups with a genetic risk for schizophrenia -LSB- 10 , 33 -RSB- suggesting a lower cognitive flexibility , again , particularly for subjects affected by schizoid or paranoid symptoms , extraversion or anhedonia -LSB- 15 , 34 -RSB- . In contrast , we found lower working speeds on the TMT/A in the risk group , but not decreased selectivity on the ratios of the TMT subtests . However , we were able to confirm lower scores on the WCST among the risks without these special symptoms . Some methodical issues must be discussed with respect to these findings . The sample size and power , the survey , the type of relatives and of control subjects may also account for the differences and the different results as compared to other studies . One factor relates to the motivation of the probands . Since they know themselves to be members of the index group it is possible that siblings or children of patients lack confidence in their own cognitive abilities and are , thus , less motivated than those in the control group . Nevertheless , abstract-logical intelligence is equal in both groups , although these scores are not influenced by time constraints . No ceiling or floor effects could be found so it may be assumed that all tests were sufficiently difficult . Furthermore , it is especially important to note that schizophrenia is etiologically heterogeneous . The higher standard deviation on almost all test variables relates to an inhomogeneous feature in the index group . Although subjects with a clinical diagnosis of a schizotypical personality disorder -LRB- SPD -RRB- , affective or personality disorder were excluded , links to personality traits or other symptoms as described for our probands could also account for the lower scores in the risk group . We examined relatively small sample sizes . Therefore , an analysis of subgroups would not have been effective . In particular , a possible impact of the SPD dimensions could affect cognitive abilities , as suggested by the available studies of schizotypical persons . One could examine such effect by including a third group , namely patients with schizophrenic disorder . We took in consideration to include also patients into our statistical analysis in order to look for a continuum in behavioral symptoms and cognitive performances . In our case , the patients group was too heterogenous . We did not succeed in matching three parallel groups of first-degree relatives , healthy controls and patients . Therefore , our focus lies on cognitive impairments of relatives of schizophrenic patients . Especially the recruitment of adolescent patients and much more of their relatives is a fussy issue in the research of neuropsychological indicators of cognitive abilities . Nevertheless , there is a need for further neuropsychological research to evaluate the impact of subtypes of schizophrenia on cognitive abilities . The discussion concerning the variability of risk groups is also reflected in our results with respect to the contrast of trait markers versus prodromali , the sensitivity of test versions and the specificity to schizophrenic disease -LSB- 6 , 7 , 25 , 29 -RSB- . Furthermore , comparisons between the patients and their symptomatology during the course of the disease , and between subjects with genetic or symptomatical risks and controls may provide more insight into possible traits signaling vulnerability to schizophrenia . It is important to identify risk factors for schizophrenia as early as possible because of the poor prognoses for early-onset schizophrenia -LSB- 35 , 45 -RSB- . The design of the present study did not allow the analysis of such a complex issue . Effects are currently being evaluated in order to determine patterns of cognitive vulnerability of risk subgroups . However , the results from our ongoing project did confirm a link to genetic influences , because both groups were matched for age , gender and intelligence . So the differences between probands and healthy controls are due to their relationship with schizophrenic patients , respectively to the genetic vulnerability of first-degree relatives . Our results demonstrate that attentional impairments as shown by the data of the FWIT , TMT , and d2 may be a trait indicator of the disease and so , too , may deficits of cognitive adjustment and executive functions as determined by the WCST . We were able to show that starting at a young age persons at risk work more slowly in general and not only on specific interference tasks . This suggests a more easily distracted working memory even among these young subjects . Therefore , our findings support the need for future studies based on the same and similar multiple tasks in order to gather more evidence in the search to identify subgroups of vulnerable subjects .

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

schizophrenia
genetic vulnerability
attention


Multifocal ERG findings in carriers of X-linked retinoschisis Purpose To determine whether retinal dysfunction in obligate carriers of X-linked retinoschisis -LRB- XLRS -RRB- could be observed in local electroretinographic responses obtained with the multifocal electroretinogram -LRB- mfERG -RRB- . Methods Nine obligate carriers of XLRS -LRB- mean age , 46.2 years -RRB- were examined for the study . Examination of each carrier included an ocular examination and mfERG testing . For the mfERG , we used a 103-scaled hexagonal stimulus array that subtended a retinal area of approximately 40 ° in diameter . The amplitudes and implicit times in each location for the mfERG were compared with the corresponding values determined for a group of 34 normally-sighted , age-similar control subjects . Results Mapping of 103 local electroretinographic response amplitudes and implicit times within a central 40 ° area with the mfERG showed regions of reduced mfERG amplitudes and delayed implicit times in two of nine carriers . Conclusions The mfERG demonstrated areas of retinal dysfunction in two carriers of XLRS . When present , retinal dysfunction was evident in the presence of a normal-appearing fundus . Multifocal ERG testing can be useful for identifying some carriers of XLRS . Introduction Juvenile X-linked retinoschisis -LRB- XLRS -RRB- is a hereditary , vitreoretinal degeneration that was initially described in 1898 by Haas -LSB- 1 -RSB- and subsequently recognized to have an X-linked recessive inheritance in 1938 by Mann and Mac Rae -LSB- 2 -RSB- . It is characterized by decreased visual acuity within the first to second decade of life and cystic-appearing lesions within the fovea -LSB- 3 -- 5 -RSB- . Approximately 50 % of patients will also show peripheral retinoschisis -LSB- 3 -- 5 -RSB- . A selective or predominant b-wave amplitude reduction on full-field electroretinogram -LRB- ERG -RRB- testing is a distinctive feature of the disease -LSB- 6 -RSB- . In other X-linked diseases , such as X-linked retinitis pigmentosa , choroideremia and X-linked ocular albinism , because of the principle of Lyonisation , which predicts a random inactivation of one X chromosome within each cell , female carriers can express some features of the diseases -LSB- 7 -- 9 -RSB- . As a rule , female carriers of XLRS do not exhibit any clinically apparent fundus abnormalities -LSB- 3 , 4 -RSB- . Isolated observations of foveal cystic-appearing lesions in female carriers from families with XLRS have been reported . There were six such female carriers noted out of a total of 13 who were examined in two different families with consanguineous marriages reported by two previous studies -LSB- 10 , 11 -RSB- . Foveal changes , described as wrinkling of the internal limiting membrane , of one eye was reported in one female XLRS carrier from a non-consanguineous marriage by Wu et al. -LSB- 12 -RSB- . One study did find that 11 out of 11 obligate carriers showed an abnormal rod-cone interaction by psychophysical testing -LSB- 13 -RSB- . Nevertheless , carrier detection of XLRS currently can most reliably be successful by identifying genetic mutations in a gene that codes for a protein referred to as retinoschisin -LRB- RS1 -RRB- -LSB- 14 , 15 -RSB- . In the current study , we evaluated the possible role of multifocal ERG -LRB- mfERG -RRB- testing as a means of detecting functional abnormalities in obligate carriers of XLRS . Methods Nine obligate carriers -LRB- eight parents , one offspring -RRB- of XLRS patients were enrolled in the study . They were selected on the basis of their availability and willingness to participate in the study . Each had at least one male family member who was diagnosed as having characteristic XLRS findings by one of the authors -LRB- GAF -RRB- . Five of the nine XLRS patients were confirmed as having the causative gene RS1 . None of the carriers had any other medical or ocular conditions that might have affected their retinal function . After each carrier was counseled regarding the study , they signed a written informed consent approved by the Institutional Review Board at the University of Illinois at Chicago . The examinations were conducted in accordance with Health Insurance Portability and Accountability Act regulations . All carriers were examined at the Department of Ophthalmology , University of Illinois at Chicago by two of the authors -LRB- GAF , LSK -RRB- . Best-corrected visual acuity -LRB- BCVA -RRB- was measured in each carrier with a Snellen projection chart . A dilated fundus examination and slit-lamp biomicroscopy of the lens and anterior segment of both eyes were performed on all carriers as were mfERG -LRB- Electro-Diagnostic Imaging , San Mateo , CA -RRB- measurements . Multiple retinal areas were stimulated to record local cone responses using a stimulus array of 103-scaled hexagons subtending a retinal area of approximately 40 ° in diameter . Each hexagon was scaled with eccentricity to obtain approximately equal amplitudes of local ERG responses -LSB- 16 -RSB- . The luminance of each hexagon was modulated according to a binary m-sequence . Individual stimulus elements were modulated between black -LRB- 0.45 cd/m2 -RRB- and white -LRB- 280 cd/m2 -RRB- for a time averaged luminance of 140.23 cd/m2 -LRB- approximately 3.8 log td -RRB- . The surround luminance was set at 140 cd/m2 . The stimulus was displayed on a black-and-white monitor driven at a frame rate of 75 Hz -LRB- Nortec , Plymouth , MN -RRB- . Each subject 's vision was optimally corrected with a refractor/camera system for the fixed viewing distance of 40 cm . To ensure equal magnification of the stimulus array , the distance between a subject 's eye and the refractor/camera was adjusted for each subject to obtain a sharp image on a control monitor . Each carrier 's pupil was dilated with 2.5 % phenylephrine and 1 % tropicamide to obtain a pupil diameter of at least 7 mm . Multifocal ERGs were recorded only for the right eye for each of the XLRS carriers . A Burian-Allen bipolar contact lens electrode -LRB- Hansen Ophthalmic Laboratories , Iowa City , IA -RRB- was used and grounded to the ipsilateral ear . Before insertion of the contact lens electrode , a carrier 's cornea was anesthetized with 0.5 % proparacaine , and the left eye was occluded . The total recording time was approximately 8 min divided into 32 segments . All carriers were required to maintain fixation during each of 14 sec segments . Segments with large eye movements , losses of fixation , or blinks were discarded and re-recorded . The raw data were filtered at a bandpass of 10 to 300 Hz , amplified at a gain of 100,000 -LRB- Astro-Med/Gass model CP11 amplifier -RRB- , and digitized at 1200 Hz . Each local response was isolated by a cross correlation between the m-sequence and response cycle according to the VERIS algorithm . The amplitude -LRB- a-scale -RRB- and implicit time -LRB- t-scale -RRB- of all local -LRB- first-order -RRB- mfERG responses were derived using the algorithm of Hood and Li -LSB- 17 -RSB- . For the current analysis , raw waveforms were exported from the VERIS 3.0 for each of the 34 -LRB- 15 male , 19 female -RRB- age-similar -LRB- 30 -- 79 years -RRB- normally sighted control subjects . Artifact reject and averaging with neighbors were turned off . Template wave forms were constructed for each hexagon from the average of all the control subjects ' data . These averaged templates were fitted using a least-squares fitting procedure to each control subject 's data by stretching horizontally -LRB- timing -RRB- and vertically -LRB- amplitude -RRB- . For each hexagon , the a-scale values were then averaged across all normal subjects and standard deviations calculated . This was also done separately for the t-scale values . Each carrier 's data were then fit by the control templates and the resulting values for the a-scale and t-scale were plotted for each hexagon . For the a-scale , a number less than one indicates an amplitude lower than for the average control subjects and for the t-scale , a number greater than one indicates a timing delayed compared to the average control subjects . The statistical probability of each value was calculated using the control subjects mean and ± 3 standard deviations -LRB- SD -RRB- for the a-scale and t-scale respectively and at each hexagon . The grey hexagons indicate > 3 SD above the normal mean . For the 99.7 % confidence level -LRB- grey hexagons -RRB- five control subjects had one abnormal amplitude and two subjects had two abnormal grey hexagons on the a-scale . For implicit time , six control subjects had one abnormal grey hexagon and two had two abnormal grey hexagons . Therefore , for this analysis , any carrier exhibiting a total of three or more grey hexagons were considered abnormal . A black hexagon indicated that a measurable signal could not be detected from the noise level . None of the 34 control subjects had any hexagons that were depicted as black . We used a criterion of two or more black hexagons for a carrier as highly likely to represent a local abnormality . Results The nine XLRS carriers ranged in age from 23 -- 70 years , with a mean age of 46.2 years . All showed a normal exam of the anterior segment of the eye , including the lens . Visual acuity was 20/25 or better in each eye . None showed any fundus abnormalities . These findings are summarized in Table 1 . Seven of the nine obligate carriers were observed to have varying degrees , from mild to moderate , of situs inversus of their temporal retinal vessels . In ocular situs inversus , the temporal vessels leave the optic disc directed towards the nasal retina before making a sharp temporal turn . The fundus photograph for Carrier # 1 with situs inversus is shown in Fig. 1 . In a study of fundus findings for XLRS patients , situs inversus was observed in 32 % of patients with XLRS -LSB- 18 -RSB- . To our knowledge , situs inversus of the retinal vessels has not been emphasized as a possible finding in carriers of XLRS . Table 1The age , visual acuity for the right eye -LRB- OD -RRB- and left eye -LRB- OS -RRB- and fundus findings for each of the X-linked retinoschisis carriersCarrierAge -LRB- years -RRB- VA ODVA OSFundus findings13520/1520/15Mild situs inversus OU24720/2020/20Normal OU32320/2020/20 − 1Normal OU45320/2020/20Mild situs inversus OU54820/2520/20Situs inversus OU65820/2020/20Situs inversus OU73920/2020/20Mild situs inversus OU84320/20 − 220/20Situs inversus inferior vein OS , anomalous branching OS > OD97020/20 − 220/20 − 2Anomalous branching OU , situs inversus superior artery OD , inferior artery OSFig . 1Fundus photograph of XLRS carrier # 1 demonstrating situs inversus of the retinal veins Two of nine carriers demonstrated a mosaic pattern of statistically significant amplitude reductions -LRB- Figs. 2a , 3a -RRB- and implicit time delays -LRB- Figs. 2b , 3b -RRB- . The actual mfERG tracings and hexagon analysis for these two carriers are shown in Figs. 2 and 3 . Fig. 2Multifocal electroretinogram -LRB- mfERG -RRB- results of X-linked retinoschisis -LRB- XLRS -RRB- carrier # 8 exhibiting a mosaic pattern of retinal dysfunction . MfERG amplitudes -LRB- a -RRB- and implicit times -LRB- b -RRB- for the right eye . In this figure , as in figure 3 , the white hexagons show regions falling within 2 standard deviations -LRB- SD -RRB- of the normal mean . The grey hexagons represent locations that are more than 3 SD from the normal mean while the black hexagons indicate a non-measurable response . MfERG waveform traces are illustrated below -LRB- c -RRB- Fig. 3Multifocal electroretinogram -LRB- mfERG -RRB- results of XLRS carrier # 3 exhibiting a mosaic pattern of retinal dysfunction . MfERG amplitudes -LRB- a -RRB- and implicit times -LRB- b -RRB- for the right eye . MfERG waveform traces are illustrated below -LRB- c -RRB- Discussion Our findings support the conclusion that the presence of a functional abnormality on mfERG testing , in the absence of other causes for retinal dysfunction in a female at risk , should suggest the presence of a carrier state for XLRS , which could then be further confirmed by genetic testing . However , a normal mfERG result would not , by itself , rule out the carrier state . Piao and co-workers -LSB- 19 -RSB- showed that mfERG cone-mediated responses were more impaired centrally than in the more peripheral retina in their study of seven male patients with XLRS . They also observed a higher frequency of delayed implicit times than reduced amplitudes in their patients . We did not observe either of these features in our two carriers . The presence of situs inversus of the retinal vessels in a female from a family with XLRS is also suggestive of the carrier state . Our findings on mfERG testing demonstrate the effect of Lyonisation on retinal function in carriers of XLRS . A similar finding on mfERG testing was observed in carriers of X-linked retinitis pigmentosa -LSB- 20 -RSB- . Multifocal ERG testing may be a useful technique for the detection and monitoring of localized retinal dysfunction in some carriers of XLRS .

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

multifocal electroretinography
x-linked retinoschisis


Reconstituted HDL infusion restores endothelial function in patients with type 2 diabetes mellitus To the Editor : HDL-cholesterol is inversely correlated with cardiovascular events in all major epidemiological studies -LSB- 1 -RSB- . HDL-increasing strategies have demonstrated that HDL-cholesterol increase is associated with decreased cardiovascular risk in high-risk individuals such as patients with type 2 diabetes -LSB- 2 -RSB- . Endothelial dysfunction , a hallmark of type 2 diabetes patients , has been shown to predict future cardiovascular events -LSB- 3 -RSB- . Therefore , we investigated the effect of reconstituted HDL -LRB- rHDL -RRB- on endothelial function measured both acutely -LRB- 4 h after infusion -RRB- and 7 days after infusion in type 2 diabetes patients . Control volunteers were measured only at baseline and 4 h after infusion . Seven non-smoking patients with type 2 diabetes -LRB- four men and three women , BMI 24.4 ± 1.6 kg/m2 -RRB- and seven matched control volunteers -LRB- four men and three women , BMI 22.9 ± 1.8 kg/m2 -RRB- were enrolled . Inclusion criteria for type 2 diabetes patients were : -LRB- 1 -RRB- fasting glucose > 7.0 mmol/l ; -LRB- 2 -RRB- no insulin therapy ; and -LRB- 3 -RRB- triacylglycerol and LDL-cholesterol levels < 2.0 and < 3.5 mmol/l , respectively . Matched control individuals were volunteers who were recruited via advertisements . The presence of macrovascular disease -LRB- ECG abnormalities , abnormal ankle -- brachial index or a history of cardiovascular events -RRB- served as exclusion criteria . Female participants were postmenopausal and not using hormone replacement therapy . The study protocol was performed at least 4 weeks after discontinuation of vasoactive medication , including ACE inhibitors , angiotensin receptor blockers and non-steroidal anti-inflammatory drugs . None of the patients or control volunteers used lipid-lowering medication . The Internal Review Board of the Academic Medical Center approved the study and all individuals gave written informed consent . Vascular function was assessed using venous occlusion strain-gauge plethysmography -LRB- EC-4 ; Hokanson , Washington , DC , USA -RRB- -LSB- 4 -RSB- . Forearm blood flow -LRB- FBF -RRB- , expressed as ml min − 1 100 ml − 1 forearm tissue volume -LRB- FAV -RRB- , was measured simultaneously in both arms . FBF responses to cumulative doses of the endothelium-dependent vasodilator serotonin -LRB- Sigma , Poole , UK ; 0.6 , 1.8 and 6 ng 100 ml − 1 FAV min − 1 -RRB- , the endothelium-independent vasodilator sodium nitroprusside -LRB- SNP ; Spruyt Hillen , IJsselstein , the Netherlands ; 6 , 60 , 180 and 600 ng 100 ml − 1 FAV min − 1 -RRB- , and the competitive inhibitor of endothelial nitric oxide -LRB- NO -RRB- synthase NG-monomethyl-l-arginine -LRB- l-NMMA ; Kordia , Leiden , the Netherlands ; 50 , 100 , 200 and 400 μg 100 ml − 1 FAV min − 1 -RRB- were measured . Agents were administered intra-arterially for 6 , 4 and 8 min at each dose , respectively . Average FBF values of the measurement -LRB- cannulated -RRB- and control arm were obtained from the last six measurements of each measurement period . The three different infusion blocks proceeded after a 15 min rest period or until FBF had returned to baseline . The ratio of flow in the infused measurement -LRB- M -RRB- and non-infused control -LRB- C -RRB- arm was calculated for each recording -LRB- M/C ratio -RRB- . The average value of the M/C ratio was calculated from these four to six M/C ratios , thus providing an internal control by excluding systemic factors from influencing the results -LSB- 5 -RSB- . Subsequently , a venous catheter was inserted in the contralateral arm for administration of rHDL -LRB- CSL-111 ; CSL Bioplasma , Parkville , VIC , Australia -RRB- at a dose of 80 mg/kg body weight over a period of 4 h. Subsequently , the infusion blocks were repeated . Blood samples were drawn from the individuals after a 12 h overnight fast , and at 4 h and 7 days after rHDL infusion . Descriptive statistics between the two groups were compared by two-tailed independent Student 's t tests or non-parametric tests , depending on skewedness of the data . Analysis of measurements for individuals between baseline and 4 h as well as baseline and 7 days after rHDL infusion was performed by two-way ANOVA for repeated measures with Bonferroni correction . Infusion of rHDL was well tolerated and no adverse events were recorded . Characteristics of type 2 diabetes patients and control volunteers during each measurement are listed in Table 1 . Baseline FBFs were not significantly different between type 2 diabetes patients and control individuals -LRB- Table 1 -RRB- . Intra-arterial infusion of serotonin increased FBF in a dose-dependent manner in both groups -LRB- see Fig. 1a -RRB- . At baseline , the FBF response to serotonin was attenuated in type 2 diabetes compared with control volunteers -LRB- M/C ratio in type 2 diabetes : 1.5 ± 0.2 vs controls : 2.5 ± 0.3 ; p < 0.05 -RRB- . Four hours after rHDL infusion in type 2 diabetes , FBF response to serotonin increased significantly -LRB- M/C ratio to 1.9 ± 0.2 ; p < 0.05 compared with baseline -RRB- . rHDL infusion had no significant effect on serotonin-induced vasodilation in control volunteers . In type 2 diabetes , 7 days after rHDL infusion serotonin responses had returned to baseline values -LRB- 7 days , 1.5 ± 0.2 -RRB- . At baseline , the maximal vasoconstrictor response to L-NMMA was blunted in type 2 diabetes compared with control volunteers -LRB- M/C ratio controls 0.6 ± 0.1 vs type 2 diabetes 1.0 ± 0.2 ; p < 0.05 , Fig. 1b -RRB- . After rHDL infusion , the L-NMMA response improved in type 2 diabetes compared with baseline -LRB- 0.7 ± 0.1 ; p < 0.05 -RRB- . Although not significant , 7 days after rHDL infusion there still was a tendency towards improvement in type 2 diabetes -LRB- M/C ratio 0.8 ± 0.1 compared with baseline -RRB- . rHDL infusion had no effect on L-NMMA response in control individuals . Finally , SNP responses were lower in type 2 diabetes vs control individuals at baseline -LRB- M/C ratio in type 2 diabetes , 3.0 ± 0.6 vs control individuals , 5.3 ± 0.7 ; p < 0.05 , Fig. 1c -RRB- and rHDL infusion had no effect on SNP responses . Fig. 1Change in M/C ratio after stimulation with the endothelium-dependent vasodilator serotonin -LRB- a -RRB- , NO inhibitor L-NMMA -LRB- b -RRB- and the endothelium-independent vasodilator SNP -LRB- c -RRB- before -LRB- white circles -RRB- and 4 h -LRB- black circles -RRB- and 7 days -LRB- diamonds -RRB- after rHDL infusion in type 2 diabetes patients as well as in control volunteers -LRB- before , white triangle ; after 4 h , black triangle -RRB- . bp < 0.05 for type 2 diabetes patients compared with control individuals and ap < 0.05 for changes after rHDL within type 2 diabetes patients . Data are means ± SEMTable 1Clinical characteristics of type 2 diabetes patients and control volunteers Type 2 diabetes patients -LRB- n = 7 -RRB- Control volunteers -LRB- n = 7 -RRB- Baseline4 h7 daysBaseline4 hWaist circumference -LRB- cm -RRB- 101 ± 5 90 ± 6 † Metabolic syndrome6/7 0/7 Systolic BP -LRB- mmHg -RRB- 148 ± 12146 ± 11143 ± 7135 ± 16138 ± 12Diastolic BP -LRB- mmHg -RRB- 78 ± 1379 ± 1382 ± 883 ± 985 ± 8Heart rate -LRB- beats per min -RRB- 65 ± 967 ± 966 ± 1261 ± 964 ± 8Total cholesterol -LRB- mmol/l -RRB- 5.6 ± 0.46.5 ± 1.45.4 ± 1.35.3 ± 0.46.7 ± 1.3LDL-cholesterol -LRB- mmol/l -RRB- 2.9 ± 0.63.3 ± 1.13.1 ± 1.03.0 ± 0.73.9 ± 1.2HDL-cholesterol -LRB- mmol/l -RRB- 1.1 ± 0.22.7 ± 0.7 * 1.6 ± 0.61.2 ± 0.32.5 ± 0.4 * ApoA-I -LRB- g/l -RRB- 1.2 ± 0.12.8 ± 0.4 * 1.5 ± 0.31.2 ± 0.22.7 ± 0.4 * Triacylglycerol -LRB- mmol/l -RRB- 1.5 ± 0.41.6 ± 0.61.6 ± 0.50.8 ± 0.3 † 1.8 ± 1.3 * Glucose -LRB- mmol/l -RRB- 8.3 ± 1.26.8 ± 1.77.3 ± 1.35.2 ± 0.4 † 4.9 ± 0.2 hsCRP -LRB- mg/l -RRB- 3.5 ± 1.64.4 ± 1.73.6 ± 0.81.0 ± 0.9 † 1.8 ± 1.1 ASAT -LRB- U/l -RRB- 22.5 ± 2.520.4 ± 4.022.4 ± 4.320.2 ± 1.821.4 ± 2.7 ALAT -LRB- U/l -RRB- 31.2 ± 6.926.0 ± 9.727.8 ± 8.714.9 ± 1.7 † 15.6 ± 3.2 Basal FBF -LRB- ml 100 ml − 1 FAV min − 1 -RRB- 4.1 ± 2.03.7 ± 0.83.9 ± 1.32.6 ± 0.92.8 ± 0.7 Values are means ± SD * p < 0.05 compared with baseline within one group ; † p < 0.05 between type 2 diabetes and control volunteers ALT , alanine aminotransferase ; ASAT , aspartate aminotransferase ; hsCRP , high-sensitivity C-reactive protein In conclusion , the present study confirms that basal and stimulated NO bio-availability is reduced in type 2 diabetes patients compared with control volunteers . Besides hyperglycaemia-induced reactive oxygen radical formation , other components of type 2 diabetes-associated dyslipidaemia such as small dense LDL are known to influence endothelial function in type 2 diabetes -LSB- 3 , 6 -RSB- . Moreover , the high prevalence of metabolic syndrome in our patients is in line with previously published data -LSB- 7 -RSB- . rHDL resulted in a significant improvement of endothelial function within several hours in type 2 diabetes patients . More importantly , there was still a tendency towards improved NO availability 7 days after infusion , at a time when apolipoprotein A-I -LRB- ApoA-I -RRB- increase had largely disappeared . Acute HDL-increasing strategies are actively being pursued for further reducing cardiovascular burden -LSB- 8 -RSB- , and thus far the lack of selective and potent HDL-increasing drugs has limited the success of the HDL-cholesterol increase concept . Our reported beneficial effects of ApoA-I infusion may lend further support to the development of ApoA-I-increasing strategies , also for patients with type 2 diabetes .

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

therapy
type 2 diabetes mellitus
vascular function