Cross-sectional associations between adaptive functioning and social cognitive and neurocognitive functions in adolescents with first-episode, early-onset schizophrenia spectrum disorders.

BACKGROUND: Few studies have explored associations between adaptive functioning and cognition in adolescents with early-onset schizophrenia spectrum disorders (EOS). METHODS: Adaptive functioning, cognition, positive, negative, and general symptoms were characterized in adolescents with EOS and healthy controls. A modified scale of negative, respectively, general symptoms was used. Bivariate analyses identified correlates of adaptive functioning to be included in multivariate analysis. RESULTS: Adolescents with EOS showed significant impairments of social- and neurocognitive functions (-0.86 < Cohen´s ds < -0.58) and adaptive functioning (Cohen´s d = -2.23). Visual memory, verbal working memory, processing speed, reaction time, social cognition, and modified negative and general symptoms correlated significantly with adaptive functioning. The multiple regression analysis revealed only verbal working memory as uniquely associated with adaptive functioning (explaining 22.7 % of its variance). Verbal working memory also associated significantly with adaptive functioning in the context of the nonsignificant modified negative and the significant modified general symptoms dimension. CONCLUSIONS: Adolescents with first-episode EOS had large impairments in adaptive functioning and moderate to large cognitive deficits. Verbal working memory was an important associate to concurrent adaptive functioning and may be a treatment target for trials to improve cognitive and adaptive functioning in adolescents with EOS.

Home visits in the Danish High Risk and Resilience Study - VIA 7: assessment of the home environment of 508 7-year-old children born to parents diagnosed with schizophrenia or bipolar disorder.

OBJECTIVE: The home environment provided by the caregivers of a child is an influential single factor for development and well-being. We aimed to compare the quality of the home environment of children at familial high risk of schizophrenia or bipolar disorder with population-based controls. METHODS: Danish nationwide registers were used to retrieve a cohort of 522 7-year-old children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) or none of these diagnoses (N = 200). The home environment was assessed using the Middle Childhood-Home Observation for Measurement of the Environment Inventory (MC-HOME Inventory). RESULTS: The proportion of children living in home environments that were evaluated not to meet the needs of a 7-year-old child was significantly larger in the two familial high-risk groups. This was true for 21% of the children with familial predisposition for schizophrenia and 7% of children with familial disposition for bipolar disorder. CONCLUSION: Children born to parents diagnosed with schizophrenia and to a lesser extent bipolar disorder are at an increased risk of growing up in a home environment with an insufficient level of stimulation and support. Identifying families with inadequate home environments is a necessary step towards specialized help and support to at-risk families.

Overlapping and disease specific trait, response, and reflection impulsivity in adolescents with first-episode schizophrenia spectrum disorders or attention-deficit/hyperactivity disorder.

BACKGROUND: Schizophrenia and attention-deficit/hyperactivity disorder (ADHD) are developmental disorders with shared clinical characteristics such as cognitive impairments and impulsivity. Impulsivity is a core feature of ADHD and an important factor in aggression, violence, and substance use in schizophrenia. Based on the hypothesis that schizophrenia and ADHD represent a continuum of neurodevelopmental impairments, the aim was to identify overlapping and disease specific forms of impulsivity. METHODS: Adolescents between 12 and 17 years of age were assessed with the Schedule for Affective Disorders and Schizophrenia for School-aged Children - Present and Lifetime Version. Subjects with early-onset, first-episode schizophrenia spectrum disorders (EOS) (N = 29) or ADHD (N = 29) and healthy controls (N = 45) were compared on two performance measures (Information Sampling Task, Stop Signal Task) and a subjective personality trait measure of impulsivity (Barratt Impulsiveness Scale, Version 11 (BIS-11)). RESULTS: Significantly increased reflection impulsivity was observed in ADHD but not in the EOS group. No significant response inhibition deficits (stop signal reaction time) were found in the two clinical groups. The ADHD and the EOS group showed significantly increased motor, attentional, and non-planning subtraits of impulsivity. CONCLUSIONS: Impaired pre-decisional information gathering appeared to be specific for ADHD while the information gathering was not significantly reduced in subjects with EOS. Neither the ADHD nor EOS group showed impaired response inhibition but shared increased personality subtraits of attentional, non-planning, and motor impulsivity although the latter was significantly more pronounced in ADHD. These increased subtraits of impulsivity may reflect diagnostic non-specific neurodevelopmental impairments in ADHD and EOS in adolescence.

Testing a decades' old assumption: Are individuals with lower sensory gating indeed more easily distracted?

The sensory gating deficits in schizophrenia have been theorized to associate with increased distractibility. We explore the potential associations between sensory and sensorimotor gating and subjective and objective indices of distraction in healthy subjects. Forty healthy males were assessed with the P50 suppression and pre-pulse inhibition of the startle reflex (PPI) paradigms. Additionally, a neurocognitive test battery was administered in a cross-over design: with/without auditory distraction. Significant effects of distraction were found in response inhibition, and verbal working memory and attention. Parameters from the PPI and P50 suppression paradigms were significantly associated with the distractor effects on strategy formation, cognitive inhibition and flexibility, visual short-term memory, and the level of subjective distraction. Subjectively reported distraction was significantly associated with verbal working memory and attention as well as executive and supervisory processes. Sensory and sensorimotor gating efficiency do not reflect the effect of distraction across executive and attention functions i.e. we did not observe a generalized distractor effect. Gating only related to the effect of distraction on strategy formation, cognitive inhibition and flexibility, as well as visual short term memory. Future studies should investigate if gating deficits affect the distractibility of the same specific cognitive functions in patients with schizophrenia.

Negative symptoms mediate the relationship between neurocognition and function in individuals at ultrahigh risk for psychosis.

OBJECTIVE: Neurocognition is known to impact functioning in individuals at ultrahigh risk (UHR) for psychosis, but studies investigating potential mediators of this relationship are scarce. Building on evidence from schizophrenia spectrum disorders, the study tested whether negative symptoms and social skills act as mediators between neurocognition and functional outcome in UHR individuals. METHODS: Ultrahigh risk participants (N = 84) underwent neurocognitive testing using the Brief Assessment of Cognition in Schizophrenia. Social skills and negative symptoms were assessed using the High-Risk Social Challenge task and the Scale for the Assessment of Negative Symptoms respectively. Four instruments were used to assess overall functioning, and one instrument assessed quality of life encompassing social functioning. RESULTS: The cross-sectional analyses revealed that neurocognition was related to the measures of functioning. Negative symptoms mediated the relationship between neurocognition and four of the five measures of functioning. We did not find social skills to mediate between neurocognition and functioning. CONCLUSION: Negative symptoms appear to mediate the relationship between neurocognition and functional outcome in UHR individuals, but the finding needs to be confirmed and extended to longitudinal studies. This underscores the importance of focusing on both neurocognition and negative symptoms when aiming at improving the functional outcome of UHR individuals.

Mismatch negativity and P3a amplitude in young adolescents with first-episode psychosis: a comparison with ADHD.

BACKGROUND: Deficient mismatch negativity (MMN) has been proposed as a candidate biomarker in schizophrenia and may therefore be potentially useful in early identification and intervention in early onset psychosis. In this study we explored whether deficits in the automatic orienting and reorienting responses, measured as MMN and P3a amplitude, are present in young adolescents with first-episode psychosis (FEP) and whether findings are specific to psychosis compared to young adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: MMN and P3a amplitude were assessed in young adolescents (age 12-17 years) with either FEP (N = 27) or ADHD (N = 28) and age- and gender-matched healthy controls (N = 43). The MMN paradigm consisted of a four-tone auditory oddball task with deviant stimuli based on frequency, duration and their combination. RESULTS: Significantly less MMN was found in patients with psychosis compared to healthy controls in response to frequency and duration deviants. MMN amplitudes in the group of patients with ADHD were not significantly different from patients with psychosis or healthy controls. No significant group differences were found on P3a amplitude. CONCLUSION: Young adolescents with FEP showed impaired MMN compared to healthy controls while intermediate and overlapping levels of MMN were observed in adolescents with ADHD. The findings suggest that young FEP patients already exhibit pre-attentive deficits that are characteristic of schizophrenia albeit expressed on a continuum shared with other neuropsychiatric disorders.

Associations between social cognition, skills, and function and subclinical negative and positive symptoms in 22q11.2 deletion syndrome.

BACKGROUND: Identification of the early signs of schizophrenia would be a major achievement for the early intervention and prevention strategies in psychiatry. Social impairments are defining features of schizophrenia. Impairments of individual layers of social competencies are frequently described in individuals with 22q11.2 deletion syndrome (22q11.2DS), who have high risk of schizophrenia. It is unclear whether and to what extent social impairments associate with subclinical negative and positive symptoms in 22q11.2DS, and which layer of social impairments are more correlated with schizophrenia-related symptoms. The aims of this study were to conduct a comprehensive investigation of social impairments at three different levels (function, skill, and cognition) and their interrelationship and to determine to what degree the social impairments correlate to subclinical levels of negative and positive symptoms, respectively, in a young cohort of 22q11.2DS not diagnosed with schizophrenia. METHODS: The level of social impairment was addressed using questionnaires and objective measures of social functioning (The Adaptive Behavior Assessment System), skills (Social Responsiveness Scale), and cognition (The Awareness of Social Inference Test and CANTAB Emotional Recognition Task), and the presence of subclinical symptoms of schizophrenia were evaluated using the Structured Interview for Prodromal Syndromes in a cross-sectional case-control study of 29 cases and 29 controls, aged 12 to 25 years. Association between social impairment and negative and positive symptoms levels was examined in cases only. RESULTS: Subjects with 22q11.2DS were highly impaired in social function, social skills, and social cognition (p ≤ 6.2 × 10-9) relative to control peers and presented with more negative (p = 5.8 × 10-11) and positive (p = 7.5 × 10-4) symptoms. In particular, social functional and skill levels were highly associated with notably subclinical negative symptoms levels. CONCLUSIONS: This study shows strong correlations between levels of social impairments and subclinical negative and positive symptoms. However, longitudinal studies are required to show if social impairments represent early disease manifestations. If parental or self-reporting suggests severe social impairment, it should advocate for clinical awareness not only to social deficits per se but also of potential subclinical psychosis symptoms.

Obesity continues to be a major health risk for Danish seafarers and fishermen.

BACKGROUND. In addition to the well-known medical consequences of overweight, severe obesity may also constitute a safety problem on board a ship in case of an emergency. The purpose of this study was to determine the current extent of the problem of overweight among Danish seafarers and fishermen and to follow-up the situation since a previous survey. The aim was to identify the main target groups and determine the need for continuous intervention. MATERIAL AND METHODS. Data on height and weight were obtained from the mandatory health examinations of seafarers and fishermen. A total of 2,101 seafarers were included in the study. Body Mass Index (BMI) was calculated for each individual seafarer. Data from two other surveys were used as reference. RESULTS. A total of 1,379 (66%) of all tested subjects were overweight. Among the male officers and ratings, the relative risk of being overweight was 1.33 (1.25-1.38) and 1.30 (1.22-1.38), respectively. The relative risk for fishermen was 1.45 (1.25-1.66) and for maritime students and trainees 1.44 (1.25-1.66). The female seafarers had a relative risk of being overweight of 1.42 (1.23-1.65). There were a statistical significantly increased number of overweight merchant seafarers since 2001/2002. DISCUSSION. The study shows that Danish merchant seafarers have a major and significantly increasing overweight problem. Among fishermen, overweight was even more frequent. Overweight constitutes a threat not only to their health, but also to their career at sea. The larger than expected incidence of overweight among new employees in the industry provides particular cause for concern. The causes of the problem are complex and interventions need to be broad.

Phenological diversity in the interactions between winter moth (Operophtera brumata) larvae and parasitoid wasps in sub-arctic mountain birch forest.

Population cycles of the winter moth (Operophtera brumata) in sub-arctic coastal birch forests show high spatiotemporal variation in amplitude. Peak larval densities range from levels causing little foliage damage to outbreaks causing spatially extensive defoliation. Moreover, outbreaks typically occur at or near the altitudinal treeline. It has been hypothesized that spatiotemporal variation in O. brumata cycle amplitude results from climate-induced variation in the degree of phenological matching between trophic levels, possibly between moth larvae and parasitoids. The likelihood of mismatching phenologies between larvae and parasitoids is expected to depend on how specialized parasitoids are, both as individual species and as a guild, to attacking specific larval developmental stages (i.e. instars). To investigate the larval instar-specificity of parasitoids, we studied the timing of parasitoid attacks relative to larval phenology. We employed an observational study design, with sequential sampling over the larval period, along an altitudinal gradient harbouring a pronounced treeline outbreak of O. brumata. Within the larval parasitoid guild, containing seven species groups, the timing of attack by different groups followed a successional sequence throughout the moth's larval period and each group attacked 1-2 instars. Such phenological diversity within parasitoid guilds may lower the likelihood of climate-induced trophic mismatches between victim populations and many/all of their enemies. Parasitism rates declined with increasing altitude for most parasitoid groups and for the parasitoid guild as a whole. However, the observed spatiotemporal parasitism patterns provided no clear evidence for or against altitudinal mismatch between larval and parasitoid phenology.

Diagnostic distribution of non-traumatic upper limb disorders: vibrotactile sense in the evaluation of structured examination for optimal diagnostic criteria.

BACKGROUND: Upper limb disorders (ULDs) are common, and so are the difficulties in specific diagnoses of these disorders. Prior studies have shed light on the nerves in the diagnostic approach beside disorders related to muscles, tendons and joints (MCDs). OBJECTIVE: The study aimed to compare the distribution of upper limb disorders, and the vibration perception threshold (VPT) in different diagnostic groups according to 1) A-criteria: the SALTSA consensus criteria, including MCDs and four peripheral neuropathies, and 2) B-criteria: including MCDs and 10 different neuropathy diagnoses--re-defined in an attempt to refine diagnostic criteria of peripheral neuropathy in respect of different MCDs; and further to discuss the impact of the presented criteria. METHODS: 161 patients--recruited from 21 general practitioners--were examined by the same examiner according to the two sets of diagnostic criteria. VPT measurements were conducted in all patients. RESULTS: Three patients did not fulfill the criteria of any ULD diagnosis. A/B criteria were fulfilled for 181/183 upper limbs, respectively, out of which 29.3%/163.3% were neuropathy diagnoses alone, 23.8%/10.9% MCD alone, and 46.9%/25.7% were categorized as neuropathy in combination with MCD diagnoses. The overall agreement on presence of neuropathy was high (75%), but on focal level there was a large discrepancy. According to the A-criteria, patients with symptoms located at wrist and shoulder were primarily defined with wrist diagnoses, and only few had concomitant shoulder diagnoses. In contrast, the B-criteria primarily defined neuropathy located at the shoulder, often concomitantly with neuropathy of the radial and the median nerve at the elbow, but seldom at the wrist level. In MCDs defined by both sets of criteria--Rotator cuff syndrome and medial/lateral epicondylitis--the A-criteria defined more MCDs than the B-criteria, the B diagnoses typically constituted only a part of the A diagnoses and additionally defined neuropathy. The B-criteria showed more significant VPT findings than the A-criteria concerning the discrimination between limbs with and contralateral limbs without diagnoses as well as between diagnostic groups with and without neuropathy. CONCLUSIONS: The VPT findings suggest the B-criteria to be superior to A-criteria for differentiating between patients with and without neuropathy. This study shows that neuropathy is extensive in ULDs when specific diagnostic criteria are used. Additionally it suggests the importance of a critical revision of the current diagnostic criteria of upper limb neuropathy, and the differential diagnoses concerning the MCDs. Management and prevention is highly dependent on correct diagnoses.

Insulin-like growth factor binding protein 2 is a marker for antiestrogen resistant human breast cancer cell lines but is not a major growth regulator.

Antiestrogens target the estrogen receptor and counteract the growth stimulatory action of estrogen on human breast cancer. However, acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. To mimic acquired resistance, we have used a model system with the antiestrogen sensitive human breast cancer cell line MCF-7 and several antiestrogen resistant cell lines derived from the parental MCF-7 cell line. This model system was used to study the expression and possible involvement in resistant cell growth of insulin-like growth factor binding protein 2 (IGFBP-2). By an oligonucleotide based microarray, we compared the expression of mRNAs encoding insulin-like growth factor binding protein 1,2,3,4,5 and 6 (IGFBP-1 to -6) in the parental MCF-7 cell line to three human breast cancer cell lines, resistant to the antiestrogen ICI 182,780 (Faslodex/Fulvestrant). Only IGFBP-2 mRNA was overexpressed in all three resistant cell lines. Thus, we compared the IGFBP-2 protein expression in MCF-7 cells to nine antiestrogen resistant breast cancer cell lines, resistant to either ICI 182,780 or tamoxifen or RU 58,668 and found that IGFBP-2 was overexpressed in all nine resistant cell lines. Three of the resistant cell lines, resistant to different antiestrogens, were selected for further studies and IGFBP-2 overexpression was demonstrated at the mRNA level as well as the intra- and extracellular protein level. The objective of this study was to examine if IGFBP-2 is involved in growth of antiestrogen resistant human breast cancer cells. Therefore, IGFBP-2 expression was inhibited by antisense oligonucletides and siRNA. Specific inhibition of IGFBP-2 protein expression was achieved in MCF-7 and the three selected antiestrogen resistant cell lines, but no effect on resistant cell growth was observed. Thus, we were able to establish IGFBP-2 as a marker for antiestrogen resistant breast cancer cell lines, although IGFBP-2 was not a major contributor to the resistant cell growth.

Antiestrogen-resistant human breast cancer cells require activated protein kinase B/Akt for growth.

Development of acquired resistance to antiestrogens is a major clinical problem in endocrine treatment of breast cancer patients. The IGF system plays a profound role in many cancer types, including breast cancer. Thus, overexpression and/or constitutive activation of the IGF-I receptor (IGF-IR) or different components of the IGF-IR signaling pathway have been reported to render breast cancer cells less estrogen dependent and capable of sustaining cell proliferation in the presence of antiestrogens. In this study, growth of the antiestrogen-sensitive human breast cancer cell line MCF-7 was inhibited by treatment with IGF-IR-neutralizing antibodies. In contrast, IGF-IR-neutralizing antibodies had no effect on growth of two different antiestrogen-resistant MCF-7 sublines. A panel of antiestrogen-resistant cell lines was investigated for expression of IGF-IR and either undetectable or severely reduced IGF-IR levels were observed. No increase in insulin receptor substrate 1 (IRS-1) or total PKB/Akt (Akt) was detected in the resistant cell lines. However, a significant increase in phosphorylated Akt (pAkt) was found in four of six antiestrogen-resistant cell lines. Overexpression of pAkt was associated with increased Akt kinase activity in both a tamoxifen- and an ICI 182,780-resistant cell line. Inhibition of Akt phosphorylation by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin or the Akt inhibitor SH-6 (structurally modified phosphatidyl inositol ether liquid analog PIA 6) resulted in a more pronounced growth inhibitory effect on the antiestrogen-resistant cells compared with the parental cells, suggesting that signaling via Akt is required for antiestrogen-resistant cell growth in at least a subset of our antiestrogen-resistant cell lines. PTEN expression and activity was not decreased in cell lines overexpressing pAkt. Our data demonstrate that Akt is a target for treatment of antiestrogen-resistant breast cancer cell lines and we suggest that antiestrogen-resistant breast cancer patients may benefit from treatment targeted to inhibit Akt signaling.

Sequential versus combined treatment of human breast cancer cells with antiestrogens and the vitamin D analogue EB1089 and evaluation of predictive markers for vitamin D treatment.

Development of resistance to antihormonal therapy is a major problem in the treatment of breast cancer patients. Metastatic tumors, which progress after a period of response to treatment, often respond to second line endocrine treatment, but eventually develop estrogen independent growth. Vitamin D analogues are promising new drugs, using alternative mechanisms to inhibit growth of breast cancer cells. The sensitivity to antiestrogens and vitamin D analogues has been proposed to be inverse, indicating that the sensitivity to vitamin D analogues might increase after development of antiestrogen resistance and vice versa. In this study, the inverse sensitivity between antiestrogens and the vitamin D analogue EB1089 was examined in antiestrogen and vitamin D resistant breast cancer cell lines. The majority of the investigated antiestrogen resistant cell lines had increased sensitivity to treatment with the vitamin D analogue EB1089. In addition, growth of a vitamin D resistant cell line was more inhibited by the pure antiestrogen ICI 182,780 than the growth of the parental cells, indicating that the compounds may be used sequentially. An association between the expression level of the vitamin D receptor (VDR) and EB1089 sensitivity was observed, suggesting that VDR is a possible predictive marker for response to vitamin D treatment. Valuation of Bcl-2 gene expression may be useful in combination with VDR to predict the outcome of treatment with EB1089. Furthermore, we observed a synergistic growth inhibition and an abrogated development of resistance upon combined treatment with ICI 182,780 and EB1089. Therefore, antiestrogens and vitamin D analogues may also be used as combined treatment for breast cancer patients in the future.

Long-term sickness absence - risk indicators among occupationally active residents of a Danish county.

This study aims to identify risk factors and their prevalence in long-term sickness absence. The study is designed as a case-referent study which comprises 481 participants who have experienced a sickness absence lasting >10 weeks and a reference group of 1326 individuals in active employment. Multivariate analysis identified the following significant risk factors for men: (i) age >50 years [odds ratio (OR) = 2.4]; (ii) short period of education (OR = 2.3); (iii) unemployment within the last 3 years (OR = 1.7); (iv) heavy-duty work (OR = 2.1); (v) monotonous, repetitive work (OR = 1.7); (vi) lack of job satisfaction (OR = 2.1); and (vii) much back pain during the last 3 years (OR = 2.1). The following risk factors were identified for women: (i) leaving school without graduation (OR = 2.6); (ii) unemployment within the last 3 years (OR = 1.5); (iii) heavy-duty work (OR = 2.8); (iv) lack of influence on own job situation (OR = 2.1); and (v) much back pain within the last 3 years (OR = 1.8). It is concluded that the identification of working environment risk factors constitutes a case for improvement of the working environment which may be instrumental in reducing long-term sickness absence.

[Nerve affection in connection with bloodletting I. A rare, but potentially serious complication]. / Nervepåvirkning ved blodtapning I. En sjaelden, men potentielt alvorlig komplikation.

Based on clinical experiences and a review of the literature we describe venepuncture of blood donors complicated by an affection of the peripheral nerves secondary to an arterial or venous lesion. Such complications are rare but potentially disabling and should be known in blood banks and clinical departments to which these patients are referred. Blood donors should be offered optimal and early diagnostics, which appear to be a prerequisite for treatment of donors complaining of pain of neuropathic character extending beyond the puncture site. Recognition of the complication opens options for prevention.

[Nerve affection in connection with bloodletting II. Four case reports]. / Nervepåvirkning ved blodtapning II. Fire sygehistorier.

Four blood donors with persistent pain and dysfunction of the upper extremity after venepuncture are presented. Physical examinations identified median nerve-affections in all and additionally a varying involvement of other nerves in the elbow region. Such complications appear to have developed following to a vascular lesion. They are rare but potentially disabling and should be known in blood banks and clinical departments to which these patients are referred.

[Asthma caused by methylene-diphenyl-diisocyanate cast in a nurse]. / Asthma forårsaget af methylen-diphenyl-diisocyanat-gips hos en sygeplejerske.

A case of a 35 year-old female nurse without atopic disposition is presented. For one year (1990-1991), she worked in an emergency room, applying synthetic casts containing MDI 0-3 times daily. She developed rhinitis, itchy eyes and nightly wheezing, during employment in the emergency room, with subsequent serious asthma attacks in 1992 and 1996. Just before the last attack, the patient's husband had used insulation foam containing MDI. A specific bronchial provocation test was performed with MDI-based synthetic cast material. The patient developed an asthma attack after seven hours, with a 48% drop in FEV1, suggesting that MDI is the causative agent.

Conserved residues and their role in the structure, function, and stability of acyl-coenzyme A binding protein.

In the family of acyl-coenzyme A binding proteins, a subset of 26 sequence sites are identical in all eukaryotes and conserved throughout evolution of the eukaryotic kingdoms. In the context of the bovine protein, the importance of these 26 sequence positions for structure, function, stability, and folding has been analyzed using single-site mutations. A total of 28 mutant proteins were analyzed which covered 17 conserved sequence positions and three nonconserved positions. As a first step, the influence of the mutations on the protein folding reaction has been probed, revealing a folding nucleus of eight hydrophobic residues formed between the N- and C-terminal helices [Kragelund, B. B., et al. (1999) Nat. Struct. Biol. (In press)]. To fully analyze the role of the conserved residues, the function and the stability have been measured for the same set of mutant proteins. Effects on function were measured by the extent of binding of the ligand dodecanoyl-CoA using isothermal titration calorimetry, and effects on protein stability were measured with chemical denaturation followed by intrinsic tryptophan and tyrosine fluorescence. The sequence sites that have been conserved for direct functional purposes have been identified. These are Phe5, Tyr28, Tyr31, Lys32, Lys54, and Tyr73. Binding site residues are mainly polar or charged residues, and together, four of these contribute approximately 8 kcal mol-1 of the total free energy of binding of 11 kcal mol-1. The sequence sites conserved for stability of the structure have likewise been identified and are Phe5, Ala9, Val12, Leu15, Leu25, Tyr28, Lys32, Gln33, Tyr73, Val77, and Leu80. Essentially, all of the conserved residues that maintain the stability are hydrophobic residues at the interface of the helices. Only one conserved polar residue, Gln33, is involved in stability. The results indicate that conservation of residues in homologous proteins may result from a summed optimization of an effective folding reaction, a stable native protein, and a fully active binding site. This is important in protein design strategies, where optimization of one of these parameters, typically function or stability, may influence any of the others markedly.