Total and differential white blood cell counts,high-sensitivity C-reactive protein,and cardiovascular risk in non-affective psychoses

Schizophrenia is associated with increased cardiovascular disease morbidity and mortality. Schizophrenia is also associated with immune and inflammatory abnormalities, including aberrant blood levels of lymphocytes, cytokines and high-sensitivity C-reactive protein (hsCRP). The purpose of this study is to investigate the relationship between total and differential white blood cell (WBC) counts, hsCRP, and indices of cardiovascular disease risk in patients with schizophrenia and related non-affective psychoses. 108 inpatients and outpatients age 18–70 with non-affective psychoses and 44 controls participated in this cross-sectional study. Subjects had a fasting blood draw between 8 and 9 am for glucose, lipids, total and differential WBC counts, and hsCRP. Vital signs and medical history were obtained. Patients with non-affective psychosis had significantly higher hsCRP levels than controls (p = 0.04). In linear regression analyses, lymphocyte and monocyte counts were a significant predictor of the total-to-HDL cholesterol ratio in subjects with non-affective psychosis (p ⩽ 0.02 for each). In binary logistic regression analyses, total WBC count was a significant predictor of an elevated 10-year estimated risk of myocardial infarction and cardiovascular disease in subjects with non-affective psychosis (p ⩽ 0.03 for each). Associations between total and differential WBC counts and cardiovascular disease risk indices were stronger in males than females with non-affective psychosis. Our findings provide further evidence that measurement of total and differential WBC counts may be germane to the clinical care of patients with schizophrenia and related disorders, and support an association between inflammation and cardiovascular disease risk in these patients.     

Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder

Previous studies have revealed psychosocial and cognitive impairments in patients during depression. The primary aim of this study was to investigate whether patients with major depression (MDD) and bipolar disorder (BD) differ in psychosocial and neurocognitive profiles. A second aim was to examine whether cognitive impairments are homogeneous among depressed patients. Patients with MDD (n = 16) and BD (n = 14) were enrolled during a major depressive episode. About half of them had comorbidities, including personality, substance use, and anxiety disorders. Information was collected about symptomatology and psychosocial functioning, whereas an exhaustive neuropsychological battery was administered to assess cognition. During a depressive episode, MDD and BD patients had global psychosocial dysfunction, characterized by occupational and relational impairments. A cognitive slowing was also observed, as well as deficits related to alertness, spontaneous flexibility, sustained and divided attention. Moreover, severity of depression and cognitive functions were significantly associated with psychosocial functioning. In the case of severe mood disorders, psychosocial and neurocognitive functioning seem similar among MDD and BD patients during a depressive episode. In addition to an altered daily functioning, the neurocognitive profile was heterogeneous with regard to the nature and extent of cognitive deficits. Executive functions, as well as verbal learning and memory, were preserved better than attentional processes.     

Cognitive Impairment in Affective Psychoses: A Meta-analysis

It has recently been suggested that cognitive impairment should be included in the diagnostic criteria of schizophrenia. One of the main arguments in support of this suggestion has been the hope that cognitive impairment can help distinguish schizophrenia from bipolar disorder (BD). However, recent evidence shows that cognitive deficits occur in BD and persist beyond euthymia. Further, mood disorders with psychotic features might be expected to manifest greater cognitive impairment, which further complicates the potential to differentiate these disorders. The goal of the current meta-analysis was to examine the magnitude and characteristics of cognitive impairments in affective psychoses (AP). A systematic search of the existing literature sourced 27 studies that met the inclusion criteria. These studies compared cognitive performances of 763 patients with AP (550 BD and 213 major depressive disorder) and 1823 healthy controls. Meta-regression and subgroup analyses were used to examine the effects of moderator variables. Meta-analyses of these studies showed that patients with AP were impaired in all 15 cognitive tasks with large effect sizes for most measures. There were no significant differences between the magnitude of impairments between the BD and major depressive disorder groups. The largest effect size was found for symbol coding, stroop task, verbal learning, and category fluency, reflecting impairments in elementary and complex aspects of attentional processing, as well as learning and memory. In general, the pattern of cognitive impairments in AP was similar to reported findings in euthymic patients with BD, but relatively more pronounced.     

Cognitive deficits and levels of IQ in adolescent onset schizophrenia and other psychotic disorders

Cognitive deficits have been found to be prevalent in early onset schizophrenia. Whether these deficits also characterise other early onset psychotic disorders to a similar degree is unclear, as very few comparative studies have been done. The primary purpose of this study was to compare the profile and severity of cognitive impairments in first-episode early onset psychotic patients who received the schizophrenia diagnosis to those diagnosed with other non-organic, non-affective psychotic disorders. The secondary purpose was to examine whether the profile of cognitive deficits, in terms of intelligence, executive functions, memory, attention and processing speed was global or specific. First-episode psychotic adolescents (N = 39) between the ages 11 and 17 years were included, 18 of whom were diagnosed with schizophrenia, and 21 with other non-organic, non-affective psychoses, using ICD-10 criteria. A healthy control group (N = 40) was included, matched on gender and age. Cognitive functions were assessed using WISC-III/R, the CANTAB battery, WCST, Trail Making B, fluency tasks, and Buschke's selective reminding task. A similar profile and level of impairment was found on measures of attention, executive functions, reaction time, and memory in the schizophrenic and psychotic adolescent groups. However, analyses of WISC-III factor profiles suggested that early onset schizophrenia patients may have more global IQ deficits than non-organic, non-affective psychoses when examined recently after illness onset. Compared to the deficits of adult schizophrenia described in the literature, the results suggest relatively spared simple reaction times in early onset patients.     

Neuregulin 1 and age of onset in the major psychoses

Genetic vulnerability to psychiatric illness extends across major psychiatric illness. Neuregulin 1 (NRG1) is a large gene on chromosome 8p, that has been identified as a susceptibility factor in bipolar disorder and schizophrenia. In particular, a core at risk haplotype has received considerable attention for a putative role in the pathophysiology of the major psychoses (schizophrenia and bipolar disorder). This core haplotype can be represented by three markers 478B14-848, 420M9-1395, and SNP8NRG221533. We genotyped 312 families with bipolar probands, and 120 families with schizophrenia probands. Association of the core haplotype was tested for with age-at-onset and with three phenotypes: major psychosis, schizophrenia, and bipolar disorder. Neither age of onset (P = 0.893) nor the major psychosis phenotype (P = 0.374) was associated with the core haplotype in the overall sample. Ours was the first study to investigate the NRG1 core haplotype with age of onset of major psychoses, and despite our preliminary negative findings, this area deserves further investigation.     

Course of intelligence deficits in early onset, first episode schizophrenia: a controlled, 5-year longitudinal study

Only few prospective longitudinal studies have assessed the course of intelligence deficits in early onset schizophrenia (EOS), and these have used different age appropriate versions of Wechsler Intelligence Scales and age appropriate norms. The post-psychotic development of intelligence in EOS has predominantly been characterized as relatively stable in these studies. However, comparisons of IQs from different test versions based on the different norms may not permit unequivocal interpretations. The objective of the current study was to compare the development of intelligence in EOS patients (N = 10) from their first psychotic episode to 5 years of post onset with that of healthy controls (N = 35) and patients who at baseline had been diagnosed with other non-affective psychoses (N = 8). The same version of a Wechsler Intelligence Scale was administered at both baseline and follow-up assessments, and the same norms were used to derive IQs at baseline and follow-up. Significantly smaller change in mean full scale intelligence quotient (FSIQ) was found in diagnostically stable EOS patients compared with healthy controls during the follow-up period. However, no statistically significant difference in mean FSIQ change was observed between patients with EOS and patients with other non-affective psychoses, although this result must be interpreted with caution due to the small sample sizes. The results suggest abnormally slow acquisition of new intellectual information and skills in EOS patients during the first 5 years after full clinical presentation.     

Dysfunctional Attitudes and Perfectionism and Their Relationship to Anxious and Depressive Symptoms in Boys with Autism Spectrum Disorders

In spite of increasing interest in cognitive behaviour therapy for emotional disorders in children with autism spectrum disorders (ASD), little research has explored the relevance of the cognitive model in this population. This study explores dysfunctional attitudes and perfectionism in boys with ASD and the relationship with anxious and depressive symptoms. Compared to a typically developing group (n = 42), boys with ASD (n = 41) endorsed more dysfunctional attitudes and reported higher emotional symptoms. The relationship between emotional and cognitive variables was weak in both groups, although in the ASD group dysfunctional attitudes were significantly associated with reported obsessive–compulsive symptoms. Reasons for elevated dysfunctional attitudes in the ASD group are discussed and the roles of cognitive inflexibility and social impairments are explored.     

Deficient maturation of aspects of attention and executive functions in early onset schizophrenia

The few existing long-term, neuropsychological follow-up studies of early onset schizophrenia (EOS) patients have reported relative stability in some cognitive functions but abnormal developmental trajectories in verbal memory, set shifting, aspects of attention, and speed of information processing throughout late adolescence into early adulthood. The current 5-year follow-up study compared the development of specific cognitive functions in EOS patients (N = 17) from the time of first-episode to chronic phase with that of healthy controls (N = 38) and secondarily to patients with other early onset, non-organic, non-affective psychoses (EOP) (N = 11). Speed of processing of executive functions, set shifting, and attention improved significantly in the healthy controls and reflected continuous functional maturation during late adolescence and early adulthood. The developmental progression of attention and set shifting but not speed of processing of executive functions was significantly subnormal in EOS patients. Other specific cognitive functions that had attained functional maturity in the healthy controls before or around the time of the baseline assessment showed normal development in EOS patients during the follow-up period, indicating stable cognitive deficits. These results suggest post-onset developmental deficits in two out of the three aspects of attention and executive functions that have protracted maturational trajectories and that overlap the age of onset of EOS. No significant difference in the development of any specific cognitive function was found between the EOS and EOP group.     

Activities of daily living,social functioning and their determinants in persons with psychotic disorder

ObjectiveThe determinants of everyday functioning in persons with psychotic disorder have not been widely studied in community dwelling samples. Our aim was to investigate limitations in everyday functioning among subjects with psychotic disorders in a population-based study.MethodEveryday functioning was assessed in a nationally representative sample of 7112 persons aged 30+ using interviewer observations and self-reports, while verbal fluency and memory were also measured. Diagnostic assessment of DSM-IV psychotic disorders was based on SCID interview and case-note data. Lifetime-ever diagnoses of psychotic disorder were classified into schizophrenia (n = 61), other non-affective psychotic disorders (ONAP) (n = 79) and affective psychoses (n = 45).ResultNon-affective psychotic disorder was significantly associated with limitations in everyday functioning, as well as with deficits in verbal fluency and memory. Negative symptoms, depression, age, gender, verbal memory deficits, and reduced visual acuity were predictors of limitations in everyday functioning even after controlling for sociodemographic factors and chronic medical conditions, and difficulties in social functioning were also related to expressive speech problems.ConclusionPersons with schizophrenia and ONAP have significantly more problems in everyday functioning than the general population. One significant predictor of problems was reduced visual acuity, which at least in some situations could be easily corrected.     

White-matter hyperintensities in first-episode psychosis

BACKGROUND: White-matter hyperintensities have been associated with both schizophrenia and mood disorders, particularly bipolar disorder, but results are inconsistent across studies. AIMS: To examine whether white-matter hyperintensities are a vulnerability marker for psychosis or are specifically associated with bipolar disorder. METHOD: T(2)-weighted magnetic resonance imaging data were acquired in 129 individuals with first-episode psychosis (either affective or non-affective psychoses) and 102 controls who were randomly selected from the same geographical areas. Visual white-matter hyperintensity ratings were used for group and subgroup comparisons. RESULTS: There were no statistically significant between-group differences in white-matter hyperintensity frequency or severity scores. No significant correlations were found between white-matter hyperintensity scores and duration of illness, duration of untreated psychosis, or severity of psychotic, manic or depressive symptoms. CONCLUSIONS: White-matter hyperintensities are not associated with vulnerability to psychosis in general, or specifically with affective psychoses. Further, first-episode psychosis investigations using more quantitative methods are warranted to confirm these findings.     

Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Facial Affect Recognition in Schizophrenia

ObjectiveFacial affect recognition, a basic building block of social cognition, is often impaired in schizophrenia. Poor facial affect recognition is closely related to poor functional outcome; however, neither social cognitive impairments nor functional outcome are sufficiently improved by antipsychotic drug treatment alone. Adjunctive repetitive transcranial magnetic stimulation (rTMS) has been shown to enhance cognitive functioning in both healthy individuals and in people with neuropsychiatric disorders and to ameliorate clinical symptoms in psychiatric disorders, but its effects on social cognitive impairments in schizophrenia have not yet been studied. Therefore, we evaluated the effects of sham-controlled rTMS on facial affect recognition in patients with chronic schizophrenia.MethodInpatients (N = 36) on stable antipsychotic treatment were randomly assigned to double-blind high-frequency (10 Hz) rTMS or sham stimulation for a total of ten sessions over two weeks. In the verum group, each session consisted of 10 000 stimuli (20 trains of 5 s) applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. Facial affect recognition was assessed before (T0) and after (T1) the ten sessions.ResultsFacial affect recognition improved significantly more after rTMS (accuracy change: mean = 8.9%, SD = 6.0%) than after sham stimulation (mean = 1.6%, SD = 3.5; Cohen's d = 1.45). There was no correlation with clinical improvement.ConclusionOur results indicate that prefrontal 10 Hz rTMS stimulation may help to ameliorate impaired facial affect recognition in schizophrenia.     

Depressive syndrome in major psychoses: a study on 1351 subjects

The aim of this study was to investigate depressive symptomatology across distinct major psychiatric disorders. A total of 1351 subjects affected by major depressive disorder (MDD = 389), bipolar disorder (BP = 511), delusional disorder (DD = 93) and schizophrenia (SKZ = 358) were included in our study. Subjects were assessed using the Operational Criteria for Psychotic Illness checklist (OPCRIT). The most frequently represented depressive symptoms in MDD were Loss of energy/tiredness, Loss of pleasure, Poor concentration, and Sleep disorders. Compared with MDD, BP had higher occurrences of Agitated activity, Excessive sleep, and Increased appetite and/or Weight gain, as well as lower Loss of pleasure. In our sample, 32.3% and 26.8% of DD and SKZ, respectively, had quite consistent depressive symptomatology, with at least four or more depressive symptoms. The most common depressive symptoms were Sleep disorders, Poor concentration and Loss of energy/Tiredness, followed by Psychomotor symptoms in SKZ only. Excessive self-reproach, Suicidal ideation, and Appetite and/or Weight changes were more specific to mood disorders. Finally, compared with SKZ, DD suffered from more depressive symptoms and had more severe depressive symptomatology. A quite consistent level of depressive symptomatology is therefore present in subpopulations of delusional and schizophrenic subjects other than in affective subjects. We identified some symptoms that are common across all major psychoses and symptoms that are more specific to each group.     

Association of adolescent catatonia with increased mortality and morbidity: Evidence from a prospective follow-up study

This paper examined outcomes among youth with catatonic syndrome and determined whether the characteristics suggesting the relevance of chronic catatonic schizophrenia (CCS) at index episode remained stable at follow-up. From 1993 to 2004, 35 individuals aged 12 to 18 years were prospectively admitted for management of catatonic syndrome and followed up after discharge. Mean duration from discharge to follow-up was 3.9 years (range 1–10). Four patients were lost to follow-up. Among the remaining 31 subjects (mean age = 19.5 years, range 15–26), life-time diagnosis using the Diagnostic Interview for Genetic Studies was unchanged in 28 patients, and included schizophrenia (all subtypes; N = 20), major depressive episode (N = 5), bipolar disorder type I (N = 4) and brief psychotic episode (N = 2). Mortality (all-cause Standardized Mortality Ratio = 6266; 95% CI = 1181–18,547) and morbidity were severe, with 3 deaths (including 2 suicides), 6 patients presenting with a causal organic condition and 14 subjects needing continuous psychiatric care. All males in the study (N = 8) who had chronic catatonic schizophrenia at the index episode still had chronic catatonic signs at follow-up.Catatonia is one of the most severe psychiatric syndromes in adolescents. It is associated with a 60-fold increased risk of premature death, including suicide, when compared to the general population of same sex and age. This increased risk of premature death remains higher than the one measured in former adolescent psychiatric patients (all-cause SMR = 221; 95% CI = 156–303; Engqvist and Rydelius, 2006), or in schizophrenia irrespective to age and subtype (all-cause SMR = 157; 95% CI = 153–160; Harris and Barraclough, 1998).     

Insular cortex morphometry in first-episode schizophrenia-spectrum patients: Diagnostic specificity and clinical correlations

Evidence so far indicates that the consistent association between insular cortex abnormalities and schizophrenia is already present at early phases of the illness. In the present investigation we aimed to study the specificity of insular structural abnormalities in schizophrenia by using region-of-interest morphometry to assess insular cortex morphological characteristics in the same heterogeneous sample of schizophrenia-spectrum patients. The 225 subjects, comprising 82 schizophrenia patients, 36 schizophreniform disorder patients and 24 patients with nonschizophrenic non-affective psychoses, and 83 healthy individuals were investigated. Magnetic resonance imaging brain scans (1.5 T) were obtained and images analysed to evaluate insular cortex morphometric variables. The main resulting measurements were for insular gray matter volume and cortical surface area. The contribution of sociodemographic and clinical characteristics was controlled. Patients with schizophrenia-spectrum disorders did not significantly differ from controls in the insular cortex morphometric variables evaluated (all P’s > 0.11). Clinical variables were not significantly related with insular morphological changes. Noteworthy is the fact that none of the group morphological measurements varied significantly by gender or hemisphere. Neither did we find significant differences when patients with schizophrenia and with other non-affective psychoses were compared. Contrary to our initial hypotheses, we were unable to demonstrate significant morphometric anomalies in a large and heterogeneous sample of patients with a first-episode of schizophrenia-spectrum disorders.     

Performance-based assessment of functional skills in severe mental illness: results of a large-scale study in China

Performance-based assessments of everyday living skills have been shown to be highly correlated with cognitive functioning in schizophrenia and bipolar disorder, as well as being predictive of deficits in real-world outcomes such as independent living and employment. In this study, we expand our assessments of impairments in everyday living skills to China, evaluating people with schizophrenia, bipolar disorder, and major depression, and comparing their performance to that of healthy controls. Samples of people with schizophrenia (n = 272), bipolar disorder (n = 61), major depression (n = 50), and healthy controls (n = 284) were examined with the Chinese version of the UCSD performance-based assessment, brief version (UPSA-B). Performance was compared across the groups and the association between age, gender, educational attainment, marital status, and UPSA-B scores was evaluated. When the performance on the UPSA was compared across the groups, with education as a covariate, significant effects of both diagnosis (F = 86.3, p < .001) and education were found (F = 228.3, p < .001). Sex and age did not contribute significantly when age and education were considered. Post-hoc comparisons revealed that total UPSA-B scores were lowest in the schizophrenia patients, followed by the patients with major depression. Patients with bipolar disorder did not differ from the healthy comparison subjects on overall performance. Scores for all groups were lower than previously reported in western samples (e.g., HC mean = 64). While diagnostic differences in UPSA-B scores are similar to those previously seen in western samples, the education effect is considerably more substantial. These data suggest that in developing countries educational attainment may be strongly associated with levels of adaptive outcomes and the utilization and interpretation of functional capacity measures be adjusted accordingly.     

A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia

The severity and profile of cognitive dysfunction in first episode schizophrenia and psychotic affective disorders were compared before and after antipsychotic treatment. Parallel recruitment of consecutively admitted study-eligible first-episode psychotic patients (30 schizophrenia, 22 bipolar with psychosis, and 21 psychotic depression) reduced confounds of acute and chronic disease/medication effects as well as differential treatment and course. Patient groups completed a neuropsychological battery and were demographically similar to healthy controls (n = 41) studied in parallel. Prior to treatment, schizophrenia patients displayed significant deficits in all cognitive domains. The two psychotic affective groups were also impaired overall, generally performing intermediate between the schizophrenia and healthy comparison groups. No profile differences in neuropsychological deficits were observed across patient groups. Following 6 weeks of treatment, no patient group improved more than practice effects seen in healthy individuals, and level of performance improvement was similar for affective psychosis and schizophrenia groups. Although less severe in psychotic affective disorders, similar profiles of generalized neuropsychological deficits were observed across patient groups. Recovery of cognitive function after clinical stabilization was similar in mood disorders and schizophrenia. To the extent that these findings are generalizable, neuropsychological deficits in psychotic affective disorders, like schizophrenia, may be trait-like deficits with persistent functional implications.     

Translocator protein (18 kDa) (TSPO) as a therapeutic target for anxiety and neurologic disorders

Earlier studies suggested more severe overall cognitive impairments in deficit versus non-deficit schizophrenia; however, the specific contribution of different cognitive domains to this overall cognitive impairment remains unclear. The purpose of this study was to compare the two subtypes in general cognitive functioning as well as in individual cognitive domains using the composite score approach. One hundred and forty-three patients fulfilling the criteria for the deficit syndrome were compared with 123 patients diagnosed with non-deficit schizophrenia. Neurocognitive functioning was assessed by a neuropsychological test battery measuring the domains of sustained vigilance/attention, working memory, short-term memory, verbal memory, cognitive flexibility, and ideation fluency. Using the raw neuropsychological measures, we calculated a global index of cognitive impairment and domain-specific composite z-scores. Association between these composite scores and the deficit syndrome was examined by logistic regression analysis. After adjusting for relevant covariates including sex, age, education, smoking, and antipsychotic dose, results indicated a significant increase in the likelihood of deficit syndrome as a function of global (OR = 5.40; 95% CI 3.02–9.65) as well as domain-specific impairments (OR > 2 for all individual domains except for short-term memory). Cognitive flexibility was an independent predictor (OR = 2.92; 95% CI 1.47–5.80), whereas other cognitive domains demonstrated no unique contribution to the general cognitive impairment. Patients with deficit schizophrenia suffer from a more severe degree of neurocognitive impairment, which is qualitatively similar to the dysfunction seen in non-deficit schizophrenia. However, our results indicate that cognitive flexibility is specifically impaired in deficit versus non-deficit patients and may therefore represent a core feature of this subtype.     

Neuropsychological abnormalities in schizophrenia and major mood disorders: Similarities and differences

The past 20 years have been witness to a growing knowledge base of research highlighting the critical importance of cognition in understanding functional status and outcome in schizophrenia. This work has led to an increased emphasis on identifying and evaluating treatments that enhance cognition in schizophrenia, with the hope that this would translate into a better quality of life and improved outcome for patients. At the same time, this research has raised new questions about the specificity of cognitive impairments to schizophrenia and the degree to which similar cognitive impairments may be present in other disorders that can involve psychotic symptoms (eg, schizoaffective disorder, bipolar disorder, and psychotic major depression). This article provides a brief overview of work comparing cognitive function across the nonaffective and affective psychoses and highlights areas of similarity and dissimilarity in the role cognition plays in these disorders.     

Total and differential white blood cell counts,high-sensitivity C-reactive protein,and the metabolic syndrome in non-affective psychoses

The metabolic syndrome is highly prevalent in patients with schizophrenia, and is associated with a state of chronic, low-grade inflammation. Schizophrenia is also associated with increased inflammation, including aberrant blood levels of pro-inflammatory cytokines and high-sensitivity C-reactive protein (hsCRP). The purpose of this study is to investigate the relationship between total and differential white blood cell (WBC) counts, hsCRP, and the metabolic syndrome in patients with schizophrenia and related non-affective psychoses. Fifty-nine inpatients and outpatients age 18–70 with non-affective psychotic disorders and 22 controls participated in this cross-sectional study. Subjects had a fasting blood draw between 8 and 9 am for glucose, lipids, total and differential WBC counts, and hsCRP. Vital signs and anthropometric measures were obtained. Patients with non-affective psychosis and the metabolic syndrome had significantly higher total WBC counts, monocytes, and hsCRP levels than patients without the metabolic syndrome (p ⩽ 0.04 for each). In binary logistic regression analyses, after controlling for potential confounding effects of age, race, sex, age at first hospitalization for psychosis, parental history of diabetes, smoking, and psychotropic medications, total WBC count, monocytes, and hsCRP were significant predictors of metabolic syndrome in patients (p ⩽ 0.04 for each). hsCRP was also a significant predictor of increased waist circumference and triglycerides in patients (p ⩽ 0.05 for each). Our findings suggest that measurement of total and differential WBC counts and hsCRP blood levels may be germane to the clinical care of patients with schizophrenia and related disorders, and support an association between inflammation and metabolic disturbance in these patients.