A confirmed association between DNA variants in CAPN9, OSM, and ITGAM candidate genes and the risk of umbilical hernia in pigs.

Umbilical hernia (UH) is one of the most prevalent defects of swine, affecting their welfare and causing considerable economic loss. The molecular mechanisms behind UH in pigs remain poorly understood. The aim of this study was to verify the association between UH and previously reported DNA variants in the CAPN9, OSM, ITGAM, and NUGGC genes. A case/control study design was applied in two different crossbred cohorts of commercial fatteners containing 412 and 171 pigs, respectively. SNPs within CAPN9, OSM, and ITGAM were analyzed using Sanger sequencing, and 10 SNPs in CAPN9, five in OSM, and two in ITGAM were identified. A structural variant in the NUGGC gene was studied by droplet-digital PCR, and an elevated copy number was detected in only a single individual. Significant differences in allele frequencies for four SNPs in CAPN9 were detected. The haplotype analysis showed the effect on the risk of UH for two genes. The CAGGA haplotype within OSM and AT haplotype in ITGAM reduced the relative risk of UH by 52% and 45%, respectively, confirming that variants in those genes are associated with the risk of UH in pigs. Moreover, the interaction between the CAPN9 haplotype and the sex of animals had also significant impact on UH risk.

The relation of local order to material properties in relaxor ferroelectrics.

Correlating electromechanical and dielectric properties with nanometre-scale order is the defining challenge for the development of piezoelectric oxides. Current lead (Pb)-based relaxor ferroelectrics can serve as model systems with which to unravel these correlations, but the nature of the local order and its relation to material properties remains controversial. Here we employ recent advances in diffuse scattering instrumentation to investigate crystals that span the phase diagram of PbMg1/3Nb2/3O3-xPbTiO3 (PMN-xPT) and identify four forms of local order. From the compositional dependence, we resolve the coupling of each form to the dielectric and electromechanical properties observed. We show that relaxor behaviour does not correlate simply with ferroic diffuse scattering; instead, it results from a competition between local antiferroelectric correlations, seeded by chemical short-range order, and local ferroic order. The ferroic diffuse scattering is strongest where piezoelectricity is maximal and displays previously unrecognized modulations caused by anion displacements. Our observations provide new guidelines for evaluating displacive models and hence the piezoelectric properties of environmentally friendly next-generation materials.

Comorbidity of bipolar I disorder and conduct disorder: a familial risk analysis.

OBJECTIVE: To investigate the association between pediatric bipolar I (BP-I) disorder and conduct disorder (CD) using familial risk analysis. METHOD: We compared diagnoses in relatives of youth in four proband groups defined by the presence or absence of BP-I and CD: (1) probands with neither CD nor BP-I (probands: N = 550; relatives: N = 1656), (2) probands with CD and without BP-I (probands: N = 40; relatives: N = 127), (3) probands with BP-I and without CD (probands: N = 197; relatives: N = 579), and (4) probands with both CD and BP-I (probands: N = 176; relatives: N = 488). All subjects were evaluated with structured diagnostic interviews, and diagnoses of relatives were made blind to the diagnoses of probands. RESULTS: Relatives of probands with BP-I disorder had high rates of BP-I, and relatives of probands with CD had high rates of CD irrespective of the comorbidity with the other disorder. Relatives of probands with the combined condition of CD and BP-I had high rates of the combined condition. CONCLUSION: The finding of cosegregation between BP-I disorder and CD is consistent with the hypothesis that the combined condition represents a distinct subtype of either disorder.

Assessing service usage and protective factors in a pediatric psychiatry clinic during the COVID-19 pandemic.

Youth with developmental and pre-existing mental health conditions have been particularly vulnerable to declines in psychological functioning during the COVID-19 pandemic. This study aimed to first, analyze service usage within an outpatient child and adolescent psychiatry clinic in the months preceding and during the COVID-19 pandemic, and second, to examine associations with potential protective factors against mental health concerns in a treatment-engaged sample. Service usage was examined using clinic billing data, and reports on protective factors were gathered via parent survey of 81 children ages 6-17 years who received mental health treatment in an outpatient psychiatry clinic during the pandemic. Protective factors were assessed at the individual, family, and community levels, and included children's use of coping strategies, parental resilience, and parents' perceived social supports. Study outcomes, including mental health concerns, mental health emergencies, pandemic-related distress, and social impact of the pandemic, were analyzed via Pearson correlations and simultaneous multiple linear regressions. Findings suggest increased service usage and child coping, parental resilience, and social connectedness as factors associated with fewer mental health concerns in youth with psychiatric concerns during the pandemic. This study lends support for expanding psychiatric services with continued use of telemedicine platforms. Further, findings suggest a mental health benefit to optimizing individual, parental, and community-based resources to enhance children's psychological functioning, particularly for youth with pre-existing mental health conditions.

External barrel temperature of a small bore olympic rifle and shooting precision.

Investigations on changes in a rifle's barrel temperature during shooting in a rhythm typical for practitioners of Olympic shooting sports are presented. Walther KK300 (cal. 5.6 mm), a typical rifle often used in Olympic competitions, R50 RWS ammunition and a high speed thermographic camera were used in the study. Altair version 5 software was used to process thermal images and a stationary wavelet transform was applied to denoise signals for all the studied points. It was found that the temperature of the rifle barrel does not exceed 0.3°C after one shot whereas the total temperature increase does not exceed 5°C after taking 40 shots and does not affect the position of the hitting point on a target. In fact, contrary to popular belief, the so-called "warming shots" are not done for barrel heating but for cleaning of remnants in the barrel.

Cardiovascular assessment of asymptomatic patients with juvenile-onset localized and systemic scleroderma: 10 years prospective observation.

OBJECTIVES: The aim of the present study was non-invasive evaluation of the cardiovascular system in asymptomatic young adult patients with juvenile localized scleroderma (JLS) and juvenile systemic sclerosis (JSS). METHODS: A group of 34 consecutive children with scleroderma were prospectively observed in the study. The control group (CG) consisted of 20 healthy subjects. In each subject 12-lead electrocardiographic, echocardiographic, ECG Holter, and ambulatory blood pressure monitoring examinations were performed at the baseline visit and after 10 years. Additionally, B-type natriuretic peptide (BNP) concentrations were measured after 10 years. RESULTS: Examinations were performed in 13 patients with JLS and 15 with JSS at the final visit. Two children had died (one from each group). Four patients were alive but refused the final visit. After 10 years, a higher prevalence of ventricular extrasystoles (p = 0.01) and an elevated pulmonary arterial pressure (JLS: p = 0.04, JSS: p = 0.03) were observed in both groups, but in comparison with the controls there was no significant difference at the final visit. In JLS patients more cases of left ventricle diastolic dysfunction, hypertension, and sinus tachycardia were diagnosed at the final visit (p ≤ 0.05). More atrioventricular block episodes in both groups of scleroderma patients were observed. Over the 10 years, arterial hypertension was diagnosed in three patients from the JLS group and in two with JSS. There were no significant differences in BNP concentrations at the final visit. CONCLUSIONS: The results of the present study show that juvenile scleroderma seems to be more benign than adult-onset disease. This observational study shows subclinical, not severe, cardiac abnormalities in adult patients with juvenile-onset disease.

Extent of the frontal sinuses in the aspect of neurosurgical craniotomy approaches.

BACKGROUND: Frontal sinuses within the frontal bone can be a potential obstacle in neurosurgical approach in this region. Their unintended opening during craniotomy is not beneficial due to the risk of brain infections by bacteria inhabiting the sinus mucosa. Therefore, such opening should be avoided whenever the surgical procedure does not involve the sinus itself. The aim of the study was the morphometric analysis of the frontal sinuses based on computed tomography imaging. MATERIALS AND METHODS: The width, height, projection surface area and location of the highest and most lateral points of the sinuses were determined. RESULTS: The vertical diameter of the sinuses was found to be greater in men compared with women. The most lateral point of the sinuses was located higher in men, and in men was located higher on the left side. The results obtained may indicate that the frontal sinuses tend to be larger in men and that air cells in men extend further in the upper-lateral direction on the left side of the frontal bone. CONCLUSIONS: This may cause an increased risk of unintentional opening of the left frontal sinus during frontal craniotomy or pterional craniotomy with frontal extension.

A controlled family study of children with DSM-IV bipolar-I disorder and psychiatric co-morbidity.

BACKGROUND: To estimate the spectrum of familial risk for psychopathology in first-degree relatives of children with unabridged DSM-IV bipolar-I disorder (BP-I). METHOD: We conducted a blinded, controlled family study using structured diagnostic interviews of 157 children with BP-I probands (n=487 first-degree relatives), 162 attention deficit hyperactivity disorder (ADHD) (without BP-I) probands (n=511 first-degree relatives), and 136 healthy control (without ADHD or BP-I) probands (n=411 first-degree relatives). RESULTS: The morbid risk (MR) of BP-I disorder in relatives of BP-I probands (MR=0.18) was increased 4-fold [95% confidence interval (CI) 2.3-6.9, p<0.001] over the risk to relatives of control probands (MR=0.05) and 3.5-fold (95% CI 2.1-5.8, p<0.001) over the risk to relatives of ADHD probands (MR=0.06). In addition, relatives of children with BP-I disorder had high rates of psychosis, major depression, multiple anxiety disorders, substance use disorders, ADHD and antisocial disorders compared with relatives of control probands. Only the effect for antisocial disorders lost significance after accounted for by the corresponding diagnosis in the proband. Familial rates of ADHD did not differ between ADHD and BP-I probands. CONCLUSIONS: Our results document an increased familial risk for BP-I disorder in relatives of pediatric probands with DSM-IV BP-I. Relatives of probands with BP-I were also at increased risk for other psychiatric disorders frequently associated with pediatric BP-I. These results support the validity of the diagnosis of BP-I in children as defined by DSM-IV. More work is needed to better understand the nature of the association between these disorders in probands and relatives.

One-year follow-up of clinical and inflammatory parameters in children allergic to grass pollen receiving high-dose ultrarush sublingual immunotherapy.

BACKGROUND: In a previous double-blind placebo-controlled study, we analyzed a high-dose sublingual immunotherapy (SLIT) ultrarush protocol in asthmatic children monosensitized to grass pollen. In the present open-label study, we assessed the effect of SLIT on symptom score and nonspecific bronchial hyperreactivity in the same cohort followed for 1 subsequent year. METHODS: The study population comprised 35 children who were enrolled in our previous study. Placebo-treated patients were switched to active treatment; therefore, SLIT was administered for a further year to all patients. SLIT was considered effective if it reduced the severity of clinical symptoms and decreased the use of symptomatic medication. The effect of SLIT on nonspecific bronchial hyperreactivity (methacholine challenge test) was also measured. RESULTS: The symptom scores for asthma and rhinitis and medication score remained unchanged in the group who continued SLIT. We also observed further significant improvement in the results of the methacholine challenge test during the third year of treatment. CONCLUSIONS: High-dose ultrarush SLIT reduced the severity of allergic symptoms in the first 2 grass pollen seasons but continuously improved bronchial hyperreactivity in children with asthma, suggesting that SLIT should be continued despite the lack of further improvement in clinical symptoms.

Efficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollen.

BACKGROUND: Although sublingual immunotherapy (SLIT) has been used with increasing frequency, the data on the efficacy of SLIT in pediatric asthma are limited. AIM: The aim of our study was to evaluate the efficacy and the safety of high-dose SLIT given pre-seasonally and co-seasonally in an ultra-rush scheme in children with bronchial asthma allergic to grass pollen. METHODS: Fifty children with asthma, aged 6-17, sensitive to grass pollen, participated in the 2-year prospective, randomized, double-blind, placebo-controlled trial, to investigate the efficacy and safety of SLIT (Staloral 300 IR, Stallergenes SA, 25 microg major allergens) as a standardized extract of five grass pollen with ultra-rush induction. RESULTS: SLIT significantly improved asthma symptom scores (41% vs. placebo group), reduced nasal symptoms (25% vs. placebo group) and the use of rescue medications (10% vs. placebo group), improved forced expiratory volume in 1 s, but had no effect on ocular symptoms, nasal hyper-reactivity, peak expiratory flow and forced expiratory volume between 25% and 75% of vital capacity. Serum levels of immunoglobulin E and IgG4 did not change after SLIT. After the second season of SLIT, an improvement in bronchial hyperresponsiveness was observed; however, compared with placebo, this effect was not significant. Among all subjects in SLIT group, predominantly local reactions have been recorded in 59% of subjects in the first year of treatment and in 35% in the second. CONCLUSIONS: Our study indicated that high-dose ultra-rush, co-seasonal SLIT given for 2 years, was safe and reduced a multiple symptom-medication score.

Neurocognitive impairment in unaffected siblings of youth with bipolar disorder.

BACKGROUND: There is growing evidence for the familiality of pediatric bipolar disorder (BPD) and its association with impairments on measures of processing speed, verbal learning and 'executive' functions. The current study investigated whether these neurocognitive impairments index the familial risk underlying the diagnosis. METHOD: Subjects were 170 youth with BPD (mean age 12.3 years), their 118 non-mood-disordered siblings and 79 non-mood-disordered controls. Groups were compared on a battery of neuropsychological tests from the Wechsler Intelligence Scales, the Stroop Color Word Test, the Wisconsin Card Sorting Test (WCST), the Rey-Osterrieth Complex Figure (ROCF), an auditory working memory Continuous Performance Test (CPT) and the California Verbal Learning Test-Children's Version (CVLT-C). Measures were factor analyzed for data reduction purposes. All analyses controlled for age, sex and attention-deficit/hyperactivity disorder (ADHD). RESULTS: Principal components analyses with a promax rotation yielded three factors reflecting: (1) processing speed/verbal learning, (2) working memory/interference control and (3) abstract problem solving. The CPT working memory measure with interference filtering demands (WM INT) was only administered to subjects aged > or =12 years and was therefore analyzed separately. BPD youth showed impairments versus controls and unaffected relatives on all three factors and on the WM INT. Unaffected relatives exhibited impairments versus controls on the abstract problem-solving factor and the WM INT. They also showed a statistical trend (p=0.07) towards worse performance on the working memory/interference control factor. CONCLUSIONS: Neurocognitive impairments in executive functions may reflect the familial neurobiological risk mechanisms underlying pediatric BPD and may have utility as endophenotypes in molecular genetic studies of the condition.

Replacements of Pro86 in phage T4 lysozyme extend an alpha-helix but do not alter protein stability.

To investigate the relation between protein stability and the predicted stabilities of individual secondary structural elements, residue Pro86 in an alpha-helix in phage T4 lysozyme was replaced by ten different amino acids. The x-ray crystal structures of seven of the mutant lysozymes were determined at high resolution. In each case, replacement of the proline resulted in the formation of an extended alpha-helix. This involves a large conformational change in residues 81 to 83 and smaller shifts that extend 20 angstroms across the protein surface. Unexpectedly, all ten amino acid substitutions marginally reduce protein thermostability. This insensitivity of stability to the amino acid at position 86 is not simply explained by statistical and thermodynamic criteria for helical propensity. The observed conformational changes illustrate a general mechanism by which proteins can tolerate mutations.

Sex differences in associations between white matter microstructure and gonadal hormones in children and adolescents with prenatal alcohol exposure.

Despite accumulating evidence from animal models demonstrating that prenatal alcohol exposure (PAE) results in life-long neuroendocrine dysregulation, very little is known on this topic among humans with fetal alcohol spectrum disorders (FASD). We expected that alterations in gonadal hormones might interfere with the typical development of white matter (WM) myelination, and in a sex-dependent manner, in human adolescents with FASD. In order to investigate this hypothesis, we used diffusion tensor imaging (DTI) to assess: 1) whether or not sex moderates the impact of PAE on WM microstructure; and 2) how gonadal hormones relate to alterations in WM microstructure in children and adolescents affected by PAE. METHODS: 61 youth (9 to 16 yrs.; 49% girls; 50% PAE) participated as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). DTI scans and passive drool samples were obtained to examine neurodevelopmental associations with testosterone (T) and dehydroepiandrosterone (DHEA) levels in boys and girls, and estradiol (E2) and progesterone (P) levels in girls. Tract-based spatial statistics were utilized to generate fractional anisotropy (FA) and mean diffusivity (MD) for 9 a priori WM regions of interest (ROIs). RESULTS: As predicted, alterations in FA were observed in adolescents with PAE relative to controls, and these differences varied by sex. Girls with PAE exhibited lower FA (Inferior fronto-occipital and Uncinate fasciculi) while boys with PAE exhibited higher FA (Callosal body, Cingulum, Corticospinal tract, Optic radiation, Superior longitudinal fasciculus) relative to age-matched controls. When gonadal hormone levels were examined in relation to DTI measures, additional group differences in FA were revealed, demonstrating that neuroendocrine factors are associated with PAE-related brain alterations. CONCLUSIONS: These findings provide human evidence that PAE relates to sex-specific differences in WM microstructure, and underlying alterations in gonadal hormone function may, in part, contribute to these effects. Determining PAE-effects on neuroendocrine function among humans is an essential first step towards developing novel clinical (e.g., assessment or intervention) tools that target hormone systems to improve on-going brain development among children and adolescents with FASD.

Efficacy of 12 weeks supplementation of a botanical extract-based weight loss formula on body weight, body composition and blood chemistry in healthy, overweight subjects--a randomised double-blind placebo-controlled clinical trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of composite extracts in reducing weight, as the main outcome measure. Secondary measures of the study were body composition change. DESIGN: Randomised, double blind, placebo-controlled clinical trial. SETTING: Tertiary university clinic. SUBJECTS: hundred and five subjects, 5 of them withdrawn consent, 2 drop-outs not related to study preparation. INTERVENTION: two tablet per meal concept supposed to generate a "psychological" therapy-like approach during 12 weeks supported by measured physical activity. The tablets 1 (one hour before meals, comprises extracts of Asparagus, Green tea, Black tea, Guarana, Mate and Kidney beans) and 2 (taken half an hour after meals, comprises extracts of Kidney bean pods, Garcinia cambogia, and Chromium yeast) are taken twice daily with two main meals. RESULTS: A significant change of the Body Composition Improvement Index (BCI) was observed in the active extract group compared to placebo (p = 0.012). Weight, BMI, waist-to-hip ratio was not statistically different between groups. Body fat loss was greater in active group (p = 0.011) compared to placebo. A weight loss parameter corrected for exercise was introduced and found to be higher in active group (p = 0.046) than in placebo, meaning that the formula was more efficacious, due to a concurrently performed exercise program--a recommended strategy for life style modification. CONCLUSIONS: A significant change of the Body Composition Improvement Index and the decrease in body fat was statistically significant in active extract subjects compared to placebo. A change in some outcome measures like: weight, BMI failed to produce significant difference between groups.

Protein flexibility and adaptability seen in 25 crystal forms of T4 lysozyme.

The structures of various mutants of T4 lysozyme have been determined in 25 non-isomorphous crystal forms. This provides an unusually diverse data base to compare the structures and dynamics of a closely related set of proteins in different crystal packing environments. In general, the more tightly packed crystals diffract better than those that are highly hydrated although the wild-type crystal form is an exception. The ability of the protein to form a relatively open but stable lattice may help explain why many of the mutants crystallize in this form. In different crystalline environments, the lysozyme molecules associate with 2-fold, 3-fold, 4-fold, and 5-fold symmetry, as well as with various types of screw associations. A "back-to-back" dimeric association, and a "head-to-tail" 2(1) screw association, are especially common, each occurring in more than half a dozen crystal forms. The 4-fold and 5-fold modes of association are closely related and provide an example of quasi-equivalent association as envisaged by Caspar and Klug. In different crystal environments the lysozyme molecules display a range of over 50 degrees in the hinge-bending angle between the amino and carboxy-terminal domains. Large variations in the hinge-bending angle are observed not only for lysozymes with mutations in the hinge region, but for molecules with mutations far from this site. This suggests that hinge-bending is an intrinsic property of the lysozyme molecule and is not an artifact due to mutation. As the hinge-bending angle increases about 15 degrees beyond that seen in wild-type there is a distinct conformations change in the side-chains of five residues in the hinge-bending region. Changes in the backbone are localized near residues 13, 59 and 80, but do not include significant changes in (phi, psi). Comparison of the different structures indicates that crystal contacts perturb the backbone structure of the protein by 0.2 to 0.5 A. These perturbations are of the same magnitude for helices and beta-sheet strands, suggesting that protein structures can be defined and maintained equally well by hydrogen-bonding (i.e. strand-strand) or by non-hydrogen-bonding (i.e. helix-helix) interactions. The discrepancies between the lysozyme structures in different crystallographic environments are in line with other comparisons of independently determined protein crystal structures. They suggest that protein structures in general are subject to low energy changes in conformation of 0.2 to 0.5 A.(ABSTRACT TRUNCATED AT 400 WORDS)

Cumulative site-directed charge-change replacements in bacteriophage T4 lysozyme suggest that long-range electrostatic interactions contribute little to protein stability.

Bacteriophage T4 lysozyme is a basic molecule with an isoelectric point above 9.0, and an excess of nine positive charges at neutral pH. It might be expected that it would be energetically costly to bring these out-of-balance charges from the extended, unfolded, form of the protein into the compact folded state. To determine the contribution of such long-range electrostatic interactions to the stability of the protein, five positively charged surface residues, Lys16, Arg119, Lys135, Lys147 and Arg154, were individually replaced with glutamic acid. Eight selected double, triple and quadruple mutants were also constructed so as to sequentially reduce the out-of-balance formal charge on the molecule from +9 to +1 units. Each of the five single variant proteins was crystallized and high-resolution X-ray analysis confirmed that each mutant structure was, in general, very similar to the wild-type. In the case of R154E, however, the Arg154 to Glu replacement caused a rearrangement in which Asp127 replaced Glu128 as the capping residue of a nearby alpha-helix. The thermal stabilities of all 13 variant proteins were found to be fairly similar, ranging from 0.5 kcal/mol more stable than wild-type to 1.7 kcal/mol less stable than wild-type. In the case of the five single charge-change variants, for which the structures were determined, the changes in stability can be rationalized in terms of changes in local interactions at the site of the replacement. There is no evidence that the reduction in the out-of-balance charge on the molecule increases the stability of the folded relative to the unfolded form, either at pH 2.8 or at pH 5.3. This indicates that long-range electrostatic interactions between the substituted amino acid residues and other charged groups on the surface of the molecule are weak or non-existent. Furthermore, the relative stabilities of the multiple charge replacement mutant proteins were found to be almost exactly equal to the sums of the relative stabilities of the constituent single mutant proteins. This also clearly indicates that the electrostatic interactions between the replaced charges are negligibly small. The activities of the charge-change mutant lysozymes, as measured by the rate of hydrolysis of cell wall suspensions, are essentially equal to that of the wild-type lysozyme, but on a lysoplate assay the mutant enzymes appear to have higher activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Structural and thermodynamic analysis of the packing of two alpha-helices in bacteriophage T4 lysozyme.

Packing interactions in bacteriophage T4 lysozyme were explored by determining the structural and thermodynamic effects of substitutions for Ala98 and neighboring residues. Ala98 is buried in the core of T4 lysozyme in the interface between two alpha-helices. The Ala98 to Val (A98V) replacement is a temperature-sensitive lesion that lowers the denaturation temperature of the protein by 15 degrees C (pH 3.0, delta delta G = -4.9 kcal/mol) and causes atoms within the two helices to move apart by up to 0.7 A. Additional structural shifts also occur throughout the C-terminal domain. In an attempt to compensate for the A98V replacement, substitutions were made for Val149 and Thr152, which make contact with residue 98. Site-directed mutagenesis was used to construct the multiple mutants A98V/T152S, A98V/V149C/T152S and the control mutants T152S, V149C and A98V/V149I/T152S. These proteins were crystallized, and their high-resolution X-ray crystal structures were determined. None of the second-site substitutions completely alleviates the destabilization or the structural changes caused by A98V. The changes in stability caused by the different mutations are not additive, reflecting both direct interactions between the sites and structural differences among the mutants. As an example, when Thr152 in wild-type lysozyme is replaced with serine, the protein is destabilized by 2.6 kcal/mol. Except for a small movement of Val94 toward the cavity created by removal of the methyl group, the structure of the T152S mutant is very similar to wild-type T4 lysozyme. In contrast, the same Thr152 to Ser replacement in the A98V background causes almost no change in stability. Although the structure of A98V/T152S remains similar to A98V, the combination of T152S with A98V allows relaxation of some of the strain introduced by the Ala98 to Val replacement. These studies show that removal of methyl groups by mutation can be stabilizing (Val98----Ala), neutral (Thr152----Ser in A98V) or destabilizing (Val149----Cys, Thr152----Ser). Such diverse thermodynamic effects are not accounted for by changes in buried surface area or free energies of transfer of wild-type and mutant side-chains. In general, the changes in protein stability caused by a mutation depend not only on changes in the free energy of transfer associated with the substitution, but also on the structural context within which the mutation occurs and on the ability of the surrounding structure to relax in response to the substitution.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum tumor necrosis factor alpha receptors p55/p75 ratio and ovarian cancer detection.

OBJECTIVE: Early ovarian cancer detection is still very difficult and patients are mostly in advanced stages, with obvious influence on poor prognosis. METHOD: Fifty-one ovarian cancer patients and 16 healthy controls had the serum concentrations of TNF alpha receptor p55, p75 and CA-125 measured prospectively and preoperatively. RESULT: Mean concentrations of TNF alpha receptor p55, p75 and CA-125 in patients with ovarian cancer were higher than in controls. The ratios of p55 and p75 receptor in ovarian cancer and controls were 0.73+/-0.38 and 0.55+/-0.06 respectively. The areas under ROC curve in detecting malignancy (all FIGO stages) were 0.73, 0.65, 0.88 and 0.85 for p55, p75, p55/p75 ratio and CA-125 respectively. The areas under ROC curve in detecting stage I of ovarian cancer were 0.52, 0.60, 0.84 and 0.66 for p55, p75, p55/p75 ratio and CA-125 respectively. CONCLUSION: Serum TNF alpha p55/p75 ratio showed promising value in ovarian cancer detection.

Evaluation of soluble tumour necrosis factor alpha receptors p55 and p75 in ovarian cancer patients.

PURPOSE: Evaluation of serum TNFalpha receptor 1 (p55) and 2 (p75) concentrations preoperatively in patients with ovarian masses. METHODS: Estimation by ELISA assay in 51 women with ovarian cancer and 16 healthy controls. Mean values and correlations with CA-125, tumour volume index, morphological score, pathological finding and cytoreduction were estimated. RESULTS: Mean concentrations of p55 and p75 in cancer patients were 2006 +/- 1030 pg/ml and 2849 +/- 1092 pg/ml, respectively, whereby for controls 1323 +/- 291 pg/ml and 2386 +/- 475 pg/ml, respectively. The area under the ROC curve for CA-125, p55 and p75 for cancer (FIGO Stages I-IV) were: 0.85 (95% CI 0.75-0.92), 0.73 (95% CI 0.60-0.83) and 0.65 (95% CI 0.50-0.77), respectively. Serum p55 correlated with morphological ultrasound score and CA-125 but not with FIGO stage, tumour grade or tumour volume index. No correlations of p75 with these parameters were observed. CONCLUSION: Estimation of p55 and p75 provide little information in ovarian cancer patients and have poor detecting power.

Parsing the association between bipolar, conduct, and substance use disorders: a familial risk analysis.

BACKGROUND: Bipolar disorder has emerged as a risk factor for substance use disorders (alcohol or drug abuse or dependence) in youth; however, the association between bipolar disorder and substance use disorders is complicated by comorbidity with conduct disorder. We used familial risk analysis to disentangle the association between the three disorders. METHODS: We compared relatives of four proband groups: 1) conduct disorder + bipolar disorder, 2) bipolar disorder without conduct disorder, 3) conduct disorder without bipolar disorder, and 4) control subjects without bipolar disorder or conduct disorder. All subjects were evaluated with structured diagnostic interviews. For the analysis of substance use disorders, Cox proportional hazard survival models were utilized to compare age-at-onset distributions. RESULTS: Bipolar disorder in probands was a risk factor for both drug and alcohol addiction in relatives, independent of conduct disorder in probands, which was a risk factor for alcohol dependence in relatives independent of bipolar disorder in probands, but not for drug dependence. The effects of bipolar disorder and conduct disorder in probands combined additively to predict the risk for substance use disorders in relatives. CONCLUSIONS: The combination of conduct disorder + bipolar disorder in youth predicts especially high rates of substance use disorders in relatives. These findings support previous results documenting that when bipolar disorder and conduct disorder occur comorbidly, both are validly diagnosed disorders.