Inheritance of migraine investigated by complex segregation analysis

Migraine is the most common neurological disorder, affecting about 20% of adults. The mode of inheritance was analyzed in the two main types of migraine, migraine without aura (MO) and migraine with aura (MA), by complex segregation analysis using the computer program POINTER. We included 126 probands with MO and 127 probands with MA from the general population. Firstdegree relatives and spouses were blindly interviewed by a neurological research fellow. The complex segregation analysis indicated that both MO and MA have multifactorial inheritance without generational difference.     

Inheritance of low-density lipoprotein subclass patterns: results of complex segregation analysis

Heterogeneity in the size of low-density lipoprotein (LDL) particles was used to identify two distinct patterns based on gradient gel electrophoresis analysis. These two phenotypes, LDL subclass pattern A and pattern B, were characterized by a predominance of large, buoyant LDL particles and small, dense LDL particles, respectively. The inheritance of these LDL subclass patterns was investigated in a sample of 61 healthy families including 301 individuals. LDL subclass pattern B was present in 31% of the subjects, with the prevalence varying by gender, age, and (in women) menopausal status. Complex segregation analysis suggested a major locus controlling LDL subclass patterns. The model providing the best fit to the data included a dominant mode of inheritance with a frequency of .25 for the allele determining LDL subclass pattern B and reduced penetrance for men under age 20 and for premenopausal women. Thus, the allele for the LDL subclass pattern characterized by a predominance of small, dense LDL particles appears to be very common in the population, although not usually expressed until adulthood in men and until after menopause in women. The presence of a major gene controlling LDL subclass could explain much of the familial aggregation of lipid and apolipoprotein levels and may be involved in increased risk of coronary heart disease.     

Inheritance of dermatoglyphic asymmetry in 500 Indian pedigrees: complex segregation analysis

The major aim of this study is to determine the mode of inheritance of asymmetry of quantitative dermatoglyphic traits based on principal factors through the application of complex segregation (genetic model fitting) analyses on a large ethnically homogeneous sample of 500 Indian pedigrees (2435 individuals) of two generations. By segregation analysis of the traits- PC1_FA both Mendelian and Environmental models were rejected (< 0.001) with the General model, i.e. that despite presence of significant inheritance (rejection of Environmental model), the nature of inheritance is more complex, than Mendelian one. Although a little genetic effect was observed due to familial correlations on asymmetry traits, no evidence was found of major gene contribution to be involved, but this does not contradict the notion postulated by several earlier authors that asymmetry (fluctuating) provides a measure of developmental instability in human.     

Investigation of inheritance of chronic inflammatory bowel diseases by complex segregation analysis.

OBJECTIVE--To investigate the mode of inheritance of ulcerative colitis and Crohn''s disease by complex segregation analysis. DESIGN--Cross sectional population based survey of familial occurrence of chronic inflammatory bowel disease. SETTING--Population of the Copenhagen county in 1987. SUBJECTS--662 patients in whom inflammatory bowel disease had been diagnosed before 1979, of whom 637 (96%) provided adequate information. Of 504 patients with ulcerative colitis, 54 had 77 relatives with ulcerative colitis and of 133 patients with Crohn''s disease, five had seven relatives with Crohn''s disease. MAIN OUTCOME MEASURES--Patterns of segregation of either disease as assessed by complex segregation analysis performed with the computer program POINTER. RESULTS--The analysis suggested that a major dominant gene with a penetrance of 0.20-0.26 is present in 9-13% of adult patients with ulcerative colitis. The analysis did not allow for other components in the familial aggregation. For Crohn''s disease the best fitting model included a major recessive gene with complete penetrance, for which 7% of the patients are homozygous. However, this model was not significantly different from a multifactorial model. CONCLUSIONS--The segregation pattern indicates that a major dominant gene has a role in ulcerative colitis, and suggests that a major recessive gene has a role in Crohn''s disease.     

Differential patterns of muscle modification in women with episodic and chronic tension-type headache revealed using surface electromyographic analysis

Tension-type headache (TTH) is a prototypical disorder in which muscular factors play a key role in the pathogenesis. This study was designed to understand muscular dysfunction in patients with episodic (ETTH) and chronic TTH (CTTH) using surface electromyography analysis (SEMG). Women with frequent ETTH (n = 14), CTTH (n = 14) and age-matched controls (n = 13) were recruited. SEMG data were recorded from the masseter, sternocleidomastoid, and upper trapezius muscles during maximum voluntary contraction and sustained voluntary isometric clenching, the neck flexion endurance test and shoulder elevation for 30 s. The root mean square (RMS) and median frequency (MDF) of the SEMG signal were measured throughout the test. The fatigue index, which is the MDF slope during sustained muscle contraction, decreased significantly faster in the ETTH and CTTH groups compared with that in the control (p < 0.05). The mean absolute RMS and relative percentage values at the initial and final period during sustained isometric contraction decreased significantly in the CTTH group (p < 0.05). Furthermore, headache clinical parameters (frequency and duration) were negatively correlated with the amplitude values (p < 0.05). A different muscle firing pattern or some muscle modifications in patients with CTTH may reflect reorganization of the motor-control strategy.     

Time preference of headache attack and chronotype in migraine and tension-type headache

ABSTRACT

Migraine attacks have a time preference of headache attack (TPHA). Chronotype is the propensity for an individual to sleep at a particular time during a 24-h period. However, limited evidence exists regarding the association between TPHA and chronotype in individuals with migraine or tension-type headache (TTH). The aim of the present study is to investigate TPHA and chronotype in individuals with migraine and TTH, which are two of the most common primary headaches. One hundred sixty-nine first-visit migraine and TTH participants were consecutively enrolled. Information on sleep onset time and wake up time on workdays and free days, and TPHA were investigated with a face-to-face interview using a questionnaire booklet. Chronotype was assessed, using the midpoint of sleep on free days, corrected for sleep extension on free days (MSFsc), by subtracting one-half of the average weekly sleep duration. Headache frequency per month, headache intensity, impact of headache, sleep quality, daytime sleepiness, insomnia severity, and mood status were also assessed. Time preference of headache attack was reported for 45.5% and 44.8% of participants with migraine and TTH, respectively. Migraineurs with TPHA had an earlier MSFsc than did migraineurs without TPHA (1:18 a.m. ± 282 min vs. 4:18 a.m. ± 186 min; p = .022). Among migraineurs with TPHA, a later MSFsc was associated with a later preferential time of attack (β = 1.3, 95% confidence interval [CI] = 0.6–2.1, p = .004). A later MSFsc was significantly correlated with a higher headache frequency per month among migraineurs with TPHA (β = 1.9, 95% CI = 0.3–3.4, p = .023), but was not significantly correlated among migraineurs without TPHA (β = 1.4, 95% CI ?1.7–4.4, p = .332). Among TTH participants with TPHA, MSFsc was not significantly associated with a preferential time of attack (β = ?0.2, 95% CI = ?1.0 to 0.6, p = .611). Headache frequency was not associated with MSFsc among TTH participants with TPHA (β = 0.2, 95% CI = ?1.2 to 1.6, p = .792) or among TTH participants without TPHA (β = 0.4, 95% CI = ?0.5 to 1.3, p = .354). In conclusion, approximately one-half of participants with migraine and TTH reported having TPHA. Migraineurs with TPHA had an earlier chronotype than did migraineurs without TPHA. A later chronotype was associated with increased headache frequency and a later time of attack among migraineurs with TPHA. Among participants with TTH, TPHA and headache frequency were not significantly associated with chronotype.     

A unified model for complex segregation analysis.

Various methods have been proposed for statistical inference of major genes by segregation analysis of human familial data. An attempt is made to resolve some divergences that have occurred in this context by the consideration of a unified model, with some practical applications.     

A preliminary analysis of EMG variance as an index of change in EMG biofeedback treatment of tension-type headache

The effectiveness of EMG biofeedback training for tension headache has been well established. Previous studies evaluating changes in an average EMG activity score from pre- to posttreatment have not consistently found a relationship between a reduction in average EMG activity and headache improvement at posttreatment. The current study is a preliminary analysis of the utility of EMG variance as another possible mechanism of change. Frontalis EMG average activity and variances from 6 chronic tension-type headache sufferers who demonstrated significant improvement in headache activity at posttreatment (at least 70%) and 6 chronic tension-type headache sufferers who did not demonstrate improvement (less than 30%) were examined across 6 sessions of biofeedback treatment. The improved group demonstrated larger time-specific EMG variance in relation to mean EMG amplitudes during all treatment sessions. A dramatic decline in time-specific variance was observed during the later treatment sessions for improved participants; this pattern was not observed in the group who demonstrated little or no improvement. Results from the current study suggest that the inclusion of both average EMG activity and EMG variance may provide a more comprehensive measure to evaluate possible physiological changes responsible for improvement in headache activity following EMG biofeedback training.     

Inheritance and segregation of exogenous genes in transgenic cotton

Three transgenic cotton varieties (lines) were chosen for the study of inheritance and segregation of foreign Bt (Bacillus thuringiensis toxin) andtfdA genes in cotton. The transformed cotton varieties CCRI 30 and NewCott 33B expressing the BtcryIA gene, and cotton line TFD expressing thetfdA gene were crossed with CCRI 19, CCRI 12 and Lumian 6. The results confirm inheritance and segregation of (i) the exogenous Bt gene in transgenic CCRI 30 and NewCott 33B, governing resistance to bollworm, and (ii) the exogenoustfdA gene in transgenic TFD, governing resistance to the herbicide 2,4-D. Both resistance characters were governed by a single dominant nuclear gene, and were not affected by cytoplasm. Our data support the conclusion that foreign traits encoded by single genes are inherited and expressed in Mendelian fashion in cotton. Our results also indicate that a practical backcross breeding program could be used to develop cotton cultivars combining one or more resistance traits from foreign and native gene sources.     

Inheritance pattern of tetraploid Dioscorea alata and evidence of double reduction using microsatellite marker segregation analysis

Recent studies have shown that the basic chromosome number of the three major edible yams, Dioscorea alata, Dioscorea rotundata and Dioscorea trifida, is x?=?20, and that the clones with 2n?=?40 chromosomes are diploids. D. alata breeding programmes were limited to the production of diploid hybrids until 2006, when the tetraploids (2n?=?80) were found to be fertile and polyploid hybrids were produced by conventional hybridisation. However, the nature of the polyploidy (autotetraploidy or allotetraploidy) was not known in D. alata tetraploid clones. In the present study, the inheritance pattern of simple sequence repeat markers was determined in a tetraploid progeny using a Bayesian approach and by examining double reduction events. Results obtained confirm the autotetraploid nature of the 2n?=?80 clones of D. alata.     

Protein-protein interaction investigated by steered molecular dynamics: the TCR-pMHC complex

We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered, which only differ by the mutation of a single amino acid on the peptide; one is a strong agonist that produces T cell activation in vivo, while the other is an antagonist. We investigate the interaction mechanism from a large number of unbinding trajectories by analyzing van der Waals and electrostatic interactions and by computing energy changes in proteins and solvent. In addition, dissociation potentials of mean force are calculated with the Jarzynski identity, using an averaging method developed for our steering scheme. We analyze the convergence of the Jarzynski exponential average, which is hampered by the large amount of dissipative work involved and the complexity of the system. The resulting dissociation free energies largely underestimate experimental values, but the simulations are able to clearly differentiate between wild-type and mutated TCR-pMHC and give insights into the dissociation mechanism.     

Diurnal variation of tension-type headache intensity and exacerbation: An investigation using computerized ecological momentary assessment

ABSTRACT: BackgroundsTension-type headache is a common psychosomatic disease. However, diurnal variation of headache is yet to be clarified, perhaps due to the lack of an appropriate method to investigate it. Like other painful diseases, it would be helpful to know if there is diurnal variation in tension-type headaches, both for managing headaches and understanding their pathophysiology. The aim of this study was to determine if there is diurnal variation in the intensity and exacerbation of tension-type headache. METHODS: Patients (N = 31) with tension-type headache recorded for one week their momentary headache intensity several times a day and their acute headache exacerbations using a watch-type computer as an electronic diary (computerized ecological momentary assessment). Multilevel modeling was used to test the effects of time of day on momentary headache intensity and on the occurrence of acute exacerbations. RESULTS: A significant diurnal variation in momentary headache intensity was shown (P = 0.0005), with the weakest headaches in the morning and a peak in the late afternoon. A between-individual difference in the diurnal pattern was suggested. On-demand medication use was associated with a different diurnal pattern (P = 0.025), suggesting that headache intensity decreases earlier in the evening in subjects who used on-demand medication, while headache subtype, prophylactic medication use, and sex were not associated with the difference. The occurrence of acute headache exacerbation also showed a significant diurnal variation, with a peak after noon (P = 0.0015). CONCLUSIONS: Tension-type headache was shown to have a significant diurnal variation. The relation to pathophysiology and psychosocial aspects needs to be further explored.     

Interrelatedness of 5S RNA sequences investigated by correspondence analysis

Summary Correspondence analysis (a form of multivariate statistics) applied to 74 5S ribosomal RNA sequences indicates that the sequences are interrelated in a systematic, nonrandom fashion. Aligned sequences are represented as vectors in a 5N-dimensional space, where N is the number of base positions in the 5S RNA molecule. Mutually orthogonal directions (called factor axes) along which intersequence variance is greatest are defined in this hyperspace. Projection of the sequences onto planes defined by these factorial directions reveals clustering of species that is suggestive of phylogenetic relationships. For each factorial direction, correspondence analysis points to regions of importance, i.e., those base positions at which the systematic changes occur that define that particular direction. In effect, the technique provides a rapid determination of group-specific signatures. In several instances, similarities between sequences are indicated that have only recently been inferred from visual base-to-base comparisons. These results suggest that correspondence analysis may provide a valuable starting point from which to uncover the patterns of change underlying the evolution of a macromolecule, such as 5S RNA.     

Complex segregation analysis of hypospadias

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1000 male births. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis. Low birth weight is known to be an important risk factor for hypospadias, but several observations speak in favour of genetic factors as well. In order to delineate the relative contribution of the genetic factors behind hypospadias, we performed a complex segregation analysis of 2005 pedigrees in Sweden. The probands were ascertained through the departments of paediatric surgery and departments of plastic surgery and urology in Sweden where boys with hypospadias undergo surgery. In 7% of the ascertained families one or more additional cases of hypospadias were present. The complex segregation analysis showed a heritability of 0.99 and evidence for multifactorial inheritance. The results suggest that hypospadias might be due to monogenic effects in a small proportion of the families, but that there is a multifactorial cause for the majority of the cases.     

The structure of the fluorophosphate-pyruvate kinase complex investigated by 31P relaxation rate studies

The interaction of fluorophosphate with muscle pyruvate kinase was investigated by ³¹P nuclear relaxation rate measurements. The fluorophosphate samples were highly purified and were first monitored by ¹⁹F and ³¹P relaxation rate measurements in the formation of the binary FPO₃-Mn complex. The results of the binary complex demonstrated that FPO₃^2? binds in the first coordination sphere of Mn²⁺ via the oxygen atoms but not via the fluorine. The enzyme experiments were designed under conditions where a significant fraction of the ligand is in the ternary enzyme-Mn-FPO₃ complex. These studies demonstrate that the ³¹P relaxation rate of bound FPO₃ ($\text{1}\text{T}{}_{\mathrm{<mtext>1</mtext><mtext>m</mtext>}}\text{= 1.58 ± 0.05 × 10}{}^5\text{s}{}^{\mathrm{?1}}$) is consistent with the binding of this ligand in the first coordination sphere of enzyme-bound Mn²⁺ with an elongated Mn-O-P distance ($\text{r}{}_{\mathrm{<mtext>Mn-P</mtext>}}\text{= 3.3 ± 0.2}\text{A}\text{?}$). Such a structure is demonstrated in the ternary enzyme-Mn-FPO₃ complex, in the complex containing HCO₃^?, and in the complex also containing HCO₃^? and ADP. The data further substantiate the binding of phosphoenolpyruvate analogs in the first coordination sphere of pyruvate kinase-bound Mn²⁺.