Only the Arg389Gly polymorphism of the β1-adrenergic receptor gene was associated with increased risk for mild OSA in hypertensive patients . Hypertensive men carrying the Arg389Arg genotype had higher crude and age-adjusted AHI than carriers of the Arg389Gly/Gly389Gly genotypes. When adjusted also for BMI this difference became borderline significant. This difference was not observed in women. The risk of hypertension in mild OSA was associated with increasing number of Arg-alleles .The sympathetic nervous system and the adrenergic receptors play an important role in regulation of blood pressure. This study explored the associations between functional polymorphisms of the  Obstructive sleep apnea (OSA) is a disorder characterized by upper airway collapse and is common in middle-aged adults . OSA oftα2B-, β1-, and β2-adrenergic receptor genes and occurrence of OSA in hypertensive patients and occurrence of hypertension in patients with OSA in a population-based sample. The sympathetic nervous system plays an important role in regulation of blood pressure and the adrenergic receptors are important components of this system. The aim of this study was to explore the associations between functional polymorphisms of the α2A-adrenergic receptor and the α2B-adrenergic receptor are expressed in the central nervous system. Blood pressure is regulated by the opposing action of these receptors upon agonist binding. The α2A-adrenergic receptor has an inhibiting effect on the sympathetic outflow while the α2B-adrenergic receptor has an excitatory effect [α2B-adrenergic receptor gene is located on chromosome 2 in a region where several genome scans, including one from the population in the current study [The y effect . The α2nt study , have font study –14. In tnt study  and thatnt study , 17.β1-adrenergic receptor is expressed in cardiac myocytes [The myocytes  and uponβ1-adrenergic receptor gene on chromosome 10 harbors two polymorphisms with functional properties. The Ser49Gly, located in the extra cellular portion of the receptor, has been associated with variations in resting heart rate in a dose dependent way [The dent way . The othdent way . Homozygdent way  and a mident way . The homdent way  and metodent way  compareddent way , 26. Recdent way .β2-adrenergic receptor is expressed in most arteries in the body and in the heart and also in the respiratory tract. Upon agonist binding it elicits dilation of the arteries and bronchi. The β2-adrenergic receptor gene is located on chromosome 5 in an area where already in 1996 genetic variation was found to be associated with hypertension [β2-adrenergic receptor gene variants [The rtension . Linkagertension  and subsvariants  in the cvariants . Studiesvariants . In the variants . In studvariants  and withvariants .n = 1149) in the local community of Skara investigated in 1992-1993 and an age-stratified, random sample from 40 years of age from Skara population (n = 1109) that was investigated in 1993-1994 [The Skaraborg Hypertension and Diabetes Project cohort have previously been described in detail . This sa993-1994 . In 2000993-1994 , 39 or o993-1994  in 21 hy4/A1, C3/A2), two-channel electrooculography, and one-channel submental electromyography (EMG). Limb movements were monitored by tibial surface electrodes. Ventilatory monitoring included oxygen saturation (SaO2) by an oximeter probe, respiratory movements by chest and abdominal belts, nasal and oral airflow by thermistor and nasal pressure by pressure sensors. Two cotrained staff members manually scored the recordings according to a validated scoring manual [ At baseline 1992–1994 all subjects were surveyed for cardiovascular disease (CVD) risk factors using a previously published protocol . Sleep sg manual . A succeHigh molecular weight DNA was extracted from blood leukocytes according to standard techniques  and usedχ2-test and by logistic regression. Confounding from age and sex was accounted for by multivariate analyses or by stratification. Multiple logistic regressions were performed with mild OSA (OSA10) and severe OSA (OSA30) as the dependent variable and with age, sex, BMI and the α2B-adrenergic receptor, β1- and β2-adrenergic receptor polymorphisms as independent variables. Associations were expressed as odds ratio (OR) with 95 per cent confidence interval (95% CI). For the α2B-adrenergic receptor gene the II genotype was used as reference in the comparison with the ID and DD genotypes. For the β1-adrenergic receptor gene the combination of Ser49Gly and Gly49Gly was used as a reference and compared with the Ser49Ser genotype. The combination of Gly389Gly and Arg389Gly genotypes was used as reference and compared with the Arg389Arg genotype. Finally, for the β2-adrenergic receptor gene the Gly16Gly and Glu27Glu genotypes were used as references compared with the Arg16Gly and Arg16Arg and the Gln27Glu and Gln27Gln genotypes, respectively. Analyses were carried out using SPSS Base system for Macintosh 11.0 . All statistical tests were two sided. P-values less than.05 were considered statistically significant.Hypertensive and normotensive subjects were analysed separately. Continuous variables are presented as means ±  standard deviation (SD) and discrete variables as frequencies (%). Differences between means were tested by ANCOVA. Differences in proportions were tested by The clinical characteristics of the subjects are shown in α2B-adrenergic receptor gene were 15% for DD genotype, 51% for ID genotype, and 34% for the II genotype. There was no statistical difference in genotype or allele frequencies of the 301–303 I/D polymorphism in hypertensive patients with or without OSA , P = .029 and still significant when adjusted also for BMI OR 2.1 (95% CI 1.02–4.71), P = .045. In sex specific analysis the patterns were very similar in men and women; however, neither crude nor adjusted models turned out significant. In the full model we found OR 3.4 (95% CI 0.85–13.40), P = .085 in men, and 2.26 (95% CI 0.85–5.99), P = .102 in women, respectively. Hypertensive men carrying the Arg389Arg genotype had higher crude and age-adjusted AHI than carriers of the Arg389Gly/Gly389Gly genotypes. When adjusted also for BMI this difference became borderline significant. This difference was not observed in women (P = .017). In the subgroups of men with and without hypertension AHI showed a similar increasing trend, 4.0 (one subject), 27.2 ± 20.1 and 39.5 ± 27.7 events per hour, P = .065 and 16.1 ± 13.9, 21.8 ± 16.9, and 25.9 ± 23.4 events per hour, P = .33, respectively. In women no such trend was observed . The Arg389Arg genotype of the mild OSA . There wmild OSA . In a rein women . There wP = .028 and for two Arg389 alleles 5.4 (95% CI 1.4–21.2), P = .015. A test for trend adjusted for age, sex, and BMI also showed an increased OR for hypertension with increasing number of Arg389 alleles, OR 1.6, 95% CI 1.003–2.5, P = .048.In analysis including both patients with hypertension and normotensive controls subjects the frequency of hypertension versus normotension differed significantly between the different genotype carriers in subjects with mild OSA . When usNeither of the investigated polymorphisms (Arg16Gly or Gln27Glu) was associated with increased risk of OSA in hypertensive subjects or with hypertension in patients with OSA (data not shown).β1-adrenergic receptor gene and OSA in hypertensive patients. Furthermore, occurrence of hypertension increased in subjects with mild OSA with increasing number of Arg389 alleles. The Arg389Arg genotype carriers had a borderline significantly higher AHI than the Arg389Gly/Gly389Gly carriers when adjusted for age and BMI. While the current study was designed to investigate the risk of OSA in patients with hypertension, the results showing that the risk of hypertension in subjects with mild OSA was associated with the Arg389 allele are in accordance with what have been previously published on association between hypertension and the Arg389Gly polymorphism [We describe an association between the Arg389Arg genotype of the morphism . β1-adrenergic receptor is important in the adrenergic activation of the heart by increasing both the inotropic and chronotropic responses upon agonist binding. The Arg389 variant of the β1-adrenergic receptor has been found to increase both the basal and the isoprotenerol-stimulated adenylate cyclase activity compared with the Gly389 variant. Experimental hypoxia in rats is a powerful activator of the sympathetic nervous system leading to increased blood pressure [β1-adrenergic receptor that confers an increased cyclic AMP activity and has been shown to be associated with hypertension also could be associated with increased risk of OSA in hypertensive patients. The gender difference found in this study could be due to the lower impact of the genetic variants of the sympathetic nervous system in development of OSA in females compared with males; instead anatomic factors in the throat might play a greater role in females [β1-adrenergic receptor genotype carriers showed a significant difference only in males. In fact we found no difference in AHI between female hypertensive patients and controls. This suggests that hypertension plays a less important role in OSA in women than in men. One limitation of this study is the small number of subjects especially after dichotomization into hypertension and normotension. In this particular polymorphism where the Gly389Gly genotype has a low frequency the data should be interpreted with care. The pressure . This is females . The anaα2B-adrenergic receptor and the β2-adrenergic receptor) were not associated with OSA in this study population. The polymorphisms in the other adrenergic receptor genes (the α2B-adrenergic receptor gene I/D 301–303 polymorphism studied here is proposed to influence the agonist-induced desensitization of the receptor. We found no association between this polymorphism and OSA in hypertensive or normotensive individuals. One explanation might be that the α2B-adrenergic receptor acts on a level of sympathetic action that is only indirectly involved in the adrenergic response of the heart to hypoxia induced during OSA.The β2-adrenergic receptor and OSA is in accordance with the results from a cohort with high prevalence of hypertension from Germany [β1-adrenergic receptor the β2-adrenergic receptor has a similar but less pronounced effect in the heart. This difference in action could explain why the β2-polymorphisms investigated here do not seem to be of importance in development of OSA in hypertensive patients. The lack of association between polymorphisms of the  Germany  although Germany . Compareβ1-adrenergic receptor was associated with increased risk of OSA in hypertensive men and with hypertension in subjects with mild OSA. Also, in men, there was a dose dependent increase in AHI being the lowest in Gly389Gly carriers and the highest in Arg389Arg carriers. These findings highlight the role of the sympathetic nervous system in OSA and hypertension.In conclusion, the Arg389Gly polymorphism of the


PCR amplified blaCTX-M genes were cloned and sequenced. Enterobacterial repetitive intergenic consensus (ERIC)-PCR was used for the analysis of genetic relatedness of the ESBL-producers. Risk factors for "sex-associated MDRGNB-infection status" of ulcers were assessed. Modeling was performed using Swiss-Model-Server and verified by Procheck and verify3D programmes. Discovery Studio2.0 (Accelrys) was used to prepare Ramachandran plots. Z-scores were calculated using 'WHAT IF'-package. Docking of cefotaxime with modeled CTX-M-15 enzyme was performed using Hex5.1.Seventy-seven diabetic patients having clinically infected foot ulcers were studied in a consecutive series. The E. coli isolates, 14 (27.5%) ESBL-producers were identified. Only 7 Class1 integrons, 2 blaCTX-M-15, and 1 blaTEM-1 were detected. Ceftazidime and cefotaxime resistance markers were present on the plasmidic DNA of both the blaCTX-M-15 positive strains and were transmissible through conjugation. The residues Asn132, Glu166, Pro167, Val172, Lys234 and Thr235 of CTX-M-15 were found to make important contacts with cefotaxime in the docked-complex. Multivariate analysis proved 'Glycemic control at discharge' as the single independent risk factor.Among 51 blaCTX-M-15 resistance marker in the present setting. Since the docking results proved that the amino acid residues Asn132, Glu166, Pro167, Val172, Lys234 and Thr235 of CTX-M-15 (enzyme) make important contacts with cefotaxime (drug) in the 'enzyme-drug complex', researchers are expected to duly utilize this information for designing more potent and versatile CTX-M-inhibitors.Male diabetic patients with MDRGNB-infected foot ulcers have poor glycemic control and hence they might have higher mortality rates compared to their female counterparts. Plasmid-mediated conjugal transfer, albeit at a low frequency might be the possible mechanism of transfer of  We do not claim that these 77 patients represent the entire region. Hence, similar studies from this region and across the globe that could help in updating the empirical antibiotic regimen in diabetic foot ulcers are highly recommended. We regret that we could not use bone biopsy sample in case of osteomyelitis. Bone biopsy may be traumatic to patient and is not routinely performed in our hospital. Moreover, Pellizzer et al.  have repK. pneumoniae to be approximately 37% in Latin America vs. 7% in the United States [blaCTX-M-15 among clinical isolates have also been reported earlier [blaCTX-M-15. This is in harmony with a study in which the authors detected only 3 strains out of 365 clinical isolates that were PCR-positive for blaCTX-M-15 [blaCTX-M-15 among clinical isolates [P. aeruginosa (32.8%), which is generally considered to be a rare ESBL-producer. This result was in harmony with the reports from Peshawar, Pakistan (close to North India) and even Delhi (India) which is adjacent to Aligarh. The authors of these studies have reported 35.85% and 33.6% ESBL-producers among P. aeruginosa isolates, respectively [P. aeruginosa strains made in these studies as well as ours might have been simply matters of coincidence. Class1 integrons are the most commonly found integron type in Gram-negative bacteria [int1 and sul1. None of the blaCTX-M-15 markers were found to be located within the integrons. Hence, it is confirmed that the horizontal transfer of these markers was not integron-mediated but whole plasmid-mediated in our setting. Authors have earlier reported whole plasmid-mediated transfer of blaCTX-M-15 despite the presence of integron [blaCTX-M-15 positive E. coli strains in the present study. It is important to mention here that in medical literature, not all transfer experiments were successful with ESBL-producing E. coli. In a study, 19 of 24 strains did not transfer the ESBLs [A surveillance program reported the frequency of ESBL-producing d States . Plasmid earlier . Only 2 CTX-M-15 . Howeverisolates . ESBL-prbacteria . Accordiintegron . Transcohe ESBLs . Similarhe ESBLs . The prehe ESBLs ,43.blaCTX-M-15 positive isolates displayed cefotaxime MICs up to 8 fold higher than ceftazidime MICs. The strain having a higher cefotaxime MIC displayed a higher negative binding energy as well  of CTX-M enzymes play an important role in the substrate profile for cephalosporins . But resi)    make important contacts with cefotaxime (drug) in the 'enzyme-drug complex', researchers are expected to duly utilize this information for designing more potent and versatile CTX-M-inhibitors.The following conclusions can be drawn from this study: The authors declare that they have no competing interests.SS has performed all the experiments incorporated in this manuscript. AUK has designed the problem, approved the final draft of the manuscript and was a guide throughout this study.


Age-related maculopathy (ARM) is the leading cause of blindness in the elderly. Although beneficial therapeutic strategies have recently begun to emerge, much remains unclear regarding the etiopathogenesis of this disorder. Epidemiologic studies have enhanced our understanding of ARM, but the data, often conflicting, has led to difficulties with drawing firm conclusions with respect to risk for this condition. As a consequence, we saw a need to assimilate the published findings with respect to risk factors for ARM, through a review of the literature appraising results from published cross-sectional studies, prospective cohort studies, case series, and case control studies investigating risk for this condition. Our review shows that, to date, and across a spectrum of epidemiologic study designs, only age, cigarette smoking, and family history of ARM have been consistently demonstrated to represent risk for this condition. In addition, genetic studies have recently implicated many genes in the pathogenesis of age-related maculopathy, including Complement Factor H, PLEKHA 1, and LOC387715/HTRA1, demonstrating that environmental and genetic factors are important for the development of ARM suggesting that gene-environment interaction plays an important role in the pathogenesis of this condition. Age-related macular degeneration (AMD), the late stage of age-related maculopathy (ARM), is the leading cause of blindness in white individuals over 65 years of age in the Western world –3. AccorThe burden of AMD to individuals and to society is expected to rise as a result of an increase in life expectancy, reduced birth rates, and the consequential demographic shift towards an elderly population . The incRisk factors for ARM may be classified as modifiable and nonmodifiable. Possible modifiable risk factors for ARM include smoking, body mass index, cumulative sunlight exposure, diet, alcohol consumption, and cardiovascular disease. Possible nonmodifiable risk factors for ARM include: age, family history of ARM (early and/or late), iris color, and refractive error.Any review of the literature assessing possible risk factors for ARM should comment upon the nature of the designs of the studies cited, and on the relative strengths and limitations of such designs . Cross-sThus, in this article, we review the literature germane to risk for ARM, as determined by studies of various design, including case series, cross-sectional, cohort, and case-control studies Tables and 2. Fuμm) within the macular area and/or areas of retinal pigment epithelium (RPE) changes (hyperpigmentation and/or hypopigmentation). The late stage of ARM, known as age-related macular degeneration (AMD), is characterized by at least one of the following features: geographic atrophy, RPE detachment (neovascular or nonneovascular in origin), choroidal neovascularization, with or without its sequelae . Geographical atrophy (GA) is defined as a discrete area of hypopigmentation or depigmentation or apparent absence of the RPE in which choroidal vessels are more visible than in surrounding areas, and must be at least 175 μm in diameter. Cases with minimal subretinal fibrosis and widespread surrounding atrophy were also classified as neovascular AMD, because this appearance was considered to indicate previous choroidal neovascularization , a, a237], α-tocopherol levels should be expressed in terms of its concentration within these lipoproteins . H. H252]. e of ARM , 242. Moe of ARM . HoweverHowever, the macular carotenoids are likely to be more relevant to risk for ARM than B carotene, especially since B-carotene is not found in the human neurosensory retina. Foods that are rich in lutein and zeaxanthin include leafy green vegetables, corn, green peppers, and egg yolks . Data frα- and β-carotene, γ-cryptoxanthin, and lycopene, as measured in subsamples of the Beaver Dam Eye Study and Blue Mountains Eye Study, failed to demonstrate any consistent associations with ARM . H. H234]. Aspects of pro-oxidant status that have been evaluated with respect to risk for ARM in population-based epidemiologic studies include exposure to light and dietary intake of fatty acids.Polyunsaturated fatty acids are particularly susceptible to free radical damage, and it is noteworthy that the photoreceptor membranes of both rods and cones contain a lipid bilayer . PolyunsA number of studies have investigated dietary intake of total fat, saturated fat, and polyunsaturated fat with respect to ARM . FurtherThe retina is subjected to high levels of cumulative irradiation with visible light over a lifetime. Exposure to ambient light is known to result in retinal injury, and a number of laboratory studies indicate that oxidative stress plays a role in this process . FurtherUnfortunately, it is difficult to accurately measure cumulative and lifetime exposure to visible light. The Beaver Dam Eye Study investigated how exposure to sunlight relates to prevalence and incidence (5 and 10 years) of ARM and found significant associations between extended exposure to summertime sun and the 10-year incidence of early ARM , 261. ThIt has been proposed that refractive error may be etiologically important for the development of ARM .The pathophysiologic mechanisms for any association between refractive error and ARM remain unclear. Hypermetropic eyes typically have a smaller axial length than emmetropic or myopic eyes, and have a tendency towards increased scleral thickness , 268. ThA number of case-control studies have looked at the association between hypermetropia and ARM . HoweverSimilarly, the Beaver Dam Eye Study failed to identify a relationship between refractive status and either the 5-or 10-year incidence of ARM (early or late) . In contIris color is related to skin pigmentation, and therefore a relationship, if any, between iris color and ARM must be interpreted with full appreciation of the possibility that any observed association between iris color and ARM may actually reflect ethnicity-based differences for this condition.Subjects with nonblue irides have increased tissue concentrations of melanin, and this is also evident in the choroid , 276. ItInitial case-control studies suggested that brown-colored irides were associated with a reduced risk for ARM . In 1990There is a strong correlation between hair color and iris color, thus prompting a number of researchers to investigate hair color with respect to risk for ARM. The Beaver Dam Eye Study showed that people with brown hair were less likely to develop early ARM, in the form of pigmentary abnormalities, when compared to those with blond hair , 275. InCataract and ARM are the most frequent causes of decreased vision in older people. Of the numerous cataract subtypes, the most commonly seen are nuclear sclerosis, cortical lens opacities, and posterior subcapsular cataracts. The prevalence of lens opacification rises with increasing age and may therefore have risk factors common with ARM. Alternatively, cataracts could, in theory at least, have a protective effect against ARM due to their light-absorbing properties.It has been hypothesized that cataracts may provide protection against ARM by absorbing blue light, and thus reducing oxidative damage to the retina –284. HowAs sunlight has been putatively implicated in the pathogenesis of ARM, the possibility that cataract surgery results in increased risk of ARM has been postulated. Indeed, ophthalmologists often observe the development of neovascular AMD shortly following cataract surgery. Such a hypothesis has prompted lens manufacturers to incorporate a blue-light filter into the intraocular lens. However, the benefit of such blue-filtering intraocular lenses has yet to be established , 282. CaEarly population-based epidemiological studies have reported inconsistent findings on the relationship between cataract and ARM . Cross-sHowever, these limitations have been addressed in more recent studies. In 1994, the Beaver Dam Eye Study published evidence indicating that nuclear sclerosis was associated with an increased prevalence of early ARM, but not of late ARM , 274. ThEvidence for a relationship between cataract surgery and ARM is, however, more consistent . A singlIn conclusion, the relationship between cataract and cataract surgery and AMD has been the subject of much debate over recent years. With regard to cataract and ARM, some studies show cataract to be negatively associated with ARM, others having equivocal results. With regard to cataract surgery and ARM, some studies show it to be beneficial in AMD patients, whereas others show cataract extraction to have deleterious effects and result in progression of disease. At this time however, it is not possible to draw reliable conclusions from the available data to determine whether cataract surgery is beneficial or harmful in people with AMD. Physicians will have to make practice decisions based on best clinical judgment until appropriate studies are conducted and reported.The association, if any, between alcohol consumption and ARM has been investigated in a number of studies.Alcohol has been shown to have both harmful and beneficial effects with respect to a number of conditions, and may exert deleterious effects by interfering with cellular defense mechanisms against oxidative processes , 290.However, investigation of the association between alcohol and cardiovascular disease has also revealed a number of mechanisms whereby alcohol may actually exert beneficial effects. Putative mechanisms leading to a protective effect of alcohol include increased HDL cholesterol, decreased platelet aggregation , 290, anInitial evidence from the Beaver Dam Eye Study revealed that consumption of beer in the past year was associated with an increased prevalence of pigmentary changes at the macula, and of neovascular AMD  285]. H. H285]. Other studies have also investigated the effects of total alcohol consumption with respect to age related maculopathy. Cross-sectional data from the Reykjavik Eye Study found that current alcohol consumption was associated with decreased risk of drusen formation, and increased risk of pigmentary changes, at the macula , 35. TheThe association between use of certain medications and risk of ARM has been investigated in a number of population-based epidemiologic studies .Certain medications, such as chloroquine and chlorpromazine, are well known to have toxic effects on the human retina . It is bA review of studies investigating the relationship between ARM and hormone replacement therapy and lipid-lowering agents has already been discussed.The Beaver Dam Eye Study investigated the association, if any, between medication use and the 5-year incidence of early ARM . There wβ-blockers, and a reduced risk of early ARM amongst users of hormone replacement therapy and tricyclic antidepressants. However, it should be emphasized that these latter findings were of borderline significance.Due to the difficulties and limitations in the studies designed to investigate associations between medication usage and ARM, data from the Beaver Dam Eye Study, the Blue Mountains Eye Study, and the Rotterdam Study has been pooled . This poIntake of caffeine has been shown to have a vasoconstrictive effect on the retinal capillary circulation at the macula , thus prARM can also be considered to be part of a global aging process, as well as a specific disease entity. In this context, markers of frailty or biologic aging may be relevant to risk for ARM. Such markers include gait-time, handgrip strength, peak expiratory flow rate, and the ability to stand from a sitting position without using the arms. The Beaver Dam Eye Study has examined the relationship between these markers and ARM , and theMeaningful comment on risk for ARM has been greatly facilitated by a large number of studies of varying design that have been published over the last twenty years. Our review of case series, large-scale population-based studies, cohort, cross-sectional, and case-control studies strongly indicate that age, tobacco use, and family history of ARM represent indeed the risk for this condition. Further, there is a growing body of evidence that cataract surgery and obesity also represent risk for ARM, especially the neovascular form of this disease. However, population-based epidemiologic studies have failed to consistently demonstrate associations between ARM and a myriad of other potential risk factors. It should be noted that the low prevalence of late ARM in the general population makes the detection of relationships with potential risk factors for its development particularly difficult in the context of population-based studies. Moreover, identification of relationships may also be confounded where disease expression is strongly determined by genetic background. Indeed, our recently enhanced understanding of the genetic basis of ARM will inform the design and interpretation of future studies attempting to investigate risk for ARM, and the role of gene-environment interaction in the etiopathogenesis of this condition.Archives of Ophthalmology, Survey of Ophthalmology, American Journal of Ophthalmology, Ophthalmology, British Journal of Ophthalmology, and Investigative Ophthalmology and Visual Sciences were regularly reviewed throughout the period of writing. The following key words, and combinations thereof, were used to perform the initial search: age-related maculopathy, agerelated macular degeneration, risk factors, epidemiology, family history, smoking, cardiovascular disease, inflammation, oxidative stress, cataract, iris color, refractive error, and alcohol. References for this review were identified through a comprehensive systematic literature search of the electronic MEDLINE database (1966–2008) using the Pubmed search service. Further articles, abstracts, and textbook references generated from reviewing the bibliographies of the initial search were selectively included. To ensure the up-to-date nature of our review article, current issues of


Because developmental constraints on variation are expected to act by influencing trait correlations, studies of modularity offer promising approaches that quantify and summarize patterns of trait relationships. Modules, highly-correlated and semi-autonomous sets of traits, are observed at many levels of biological organization, from genes to colonies. The evolutionary significance of modularity is considerable, with potential effects including constraining the variation of individual traits, circumventing pleiotropy and canalization, and facilitating the transformation of functional structures. Despite these important consequences, there has been little empirical study of how modularity influences morphological evolution on a macroevolutionary scale. Here, we conduct the first morphometric analysis of modularity and disparity in two clades of placental mammals, Primates and Carnivora, and test if trait integration within modules We used both randomization methods and direct comparisons of landmark variance to compare disparity in the six cranial modules identified in previous studies. The cranial base, a highly-integrated module, showed significantly low disparity in Primates and low landmark variance in both Primates and Carnivora. The vault, zygomatic-pterygoid and orbit modules, characterized by low trait integration, displayed significantly high disparity within Carnivora. 14 of 24 results from analyses of disparity show no significant relationship between module integration and morphological disparity. Of the ten significant or marginally significant results, eight support the hypothesis that integration within modules constrains morphological evolution in the placental skull. Only the molar module, a highly-integrated and functionally important module, showed significantly high disparity in Carnivora, in support of the facilitation hypothesis.This analysis of within-module disparity suggested that strong integration of traits had little influence on morphological evolution over large time scales. However, where significant results were found, the primary effect of strong integration of traits was to constrain morphological variation. Thus, within Primates and Carnivora, there was some support for the hypothesis that integration of traits within cranial modules limits morphological evolution, presumably by limiting the variation of individual traits. Morphological IntegrationThe correlated evolution of traits, whether due to genetic, developmental, or functional interactions, has been a rich source of study for decades. Early researchers identified “functional components” to systems such as the cranium Measurements of trait variation and covariation, the tendency for traits to vary in a coordinated manner, have shown that there are significant differences in the relationships among traits and, in some cases, have demonstrated that some traits are linked by strong correlations, while others show little or no correlation For morphologists and paleontologists, this emergence of studies of phenotypic modularity is particularly important, because the quantitative methods used to identify modularity can be applied equally to living, extinct or rare taxa. Moreover, the concept of evolutionary modularity is tied to the genotype-phenotype map, with most studies of modularity and integration having focused on the relationships among modules observed in genetic, developmental, and morphological systems Modularity is thought to affect evolution in several ways. When considering the evolution of a single module, the most important feature is the integration of within-module traits. Strong correlations among traits potentially limit the variation of any individual trait Modularity itself also evolves, and new modularity may arise by the parcellation or fragmentation of one large group of traits into smaller groups by the severing of interactions bridging the two new groups In this regard, there have been several studies conducted on the relationship between overall cranial shape and variation in an individual module, primarily on basicranial interactions in hominids A recent study demonstrated that patterns of cranial phenotypic modularity are strongly conserved across placental mammals Here, we use these observed differences in the cranial modules to address one aspect of modularity's influence on morphological evolution: how the magnitude of trait integration influences the disparity of individual modules. Disparity measures the morphological divergence among taxa and is a measure of the variety of organisms, rather than simply their numbers constraint and facilitation. As shown in constraint). Correspondingly, the low correlations in the “weak” modules should exert little control on the variation of individual traits, allowing high morphological disparity to evolve. If it is instead correct that modularity promotes morphological evolution via coordinated transformations of sets of traits (facilitation), then the high correlations in the “strong” modules should promote trait variation, resulting in high morphological disparity, while “weak” modules should show low disparity , the orbit and zygomatic-pterygoid modules showed significantly high disparities (both with p = .01), but the molar group also displayed marginally significantly high disparity p = .03; , Fig. 3.In analyses where disparity from one of the three “strong” modules was compared to a distribution generated from random sets of landmarks drawn only from a combined set of “weak” modules, and vice versa (Disparity B), results were generally concordant with those for Disparity A , Fig. 3.In the last series of analyses, direct comparisons of landmark variances of each module from a single Procrustes superimposition of all cranial landmarks, Carnivora showed marginally significant differences in landmark variance across modules , while Primates showed extremely significant differences across modules (p<0.001). In Primates, Mann-Whitney tests showed that this reflects primarily the significantly low landmark variances in the basicranial region and high landmark variances in the vault , Fig. 3.The constraint hypothesis predicts that “strong” modules, sets of highly-correlated traits, should display low morphological disparity. In contrast, the facilitation hypothesis predicts that strong modules show display high morphological disparity. Likewise, regions of the skull with little to no integration of traits in most taxa (“weak” modules) should, or more conservatively, could display high disparity under the constraint hypothesis or low disparity under the facilitation hypothesis. Within these two clades of placental mammals, there was some support for the hypothesis that integration of landmarks within cranial modules limits morphological evolution, presumably by limiting the variation of individual landmarks, but most results did not support a significant relationship between integration and morphological disparity.The orbit, zygomatic-pterygoid, and cranial vault are the most weakly-integrated regions of the cranium, with low mean within-module correlations in both Carnivora and Primates and little to no correlation among landmarks in many individual species. In Carnivora, these three “weak” modules displayed significantly higher disparity than that of randomly-generated sets of traits in five out of six analyses  or low landmark variance (Primates and Carnivora) in the basicranial region, and high disparity (Carnivora) or high landmark variance (Primates and Carnivora) in the vault regions, Primates did not show high disparity in the molar regions. As noted above, this difference in the disparity of the molar region likely reflects greater dietary diversity in carnivorans. While there may well be commonalities to the relationship between modularity and morphological disparity across mammalian clades, there are also significant differences related to selection pressures, ecology, and even life history. Preliminary analyses of marsupial crania, for example, display a markedly different pattern of module disparity that that reported here for placentals. Future analyses of modularity's influence on morphological evolution should continue to test the relationship between modularity and disparity to establish whether the patterns shared by Primates and Carnivora can be applied to more distantly related clades.Of course, a complete view of modularity should not only examine the effects of integration within modules on module disparity, but also how the parcellation of a system into modules influences the morphological evolution of the entire system. To address that question, two approaches are possible. An empirical approach would require two or more clades, each with markedly different patterns of modularity in homologous systems, to compare morphological disparities across the entire system. For example, to address how the cranial modules that have been identified in placentals influence the evolution of the entire skull, one would need to compare other large clades with different patterns of cranial modularity, including different numbers of modules. Unfortunately, such an empirical approach is not possible with the three extant mammal clades because Marsupialia and Monotremata do not fulfill those requirements. Marsupials have the same general pattern of cranial modularity as placentals The topic of modularity has proven to be a rich source of novel ideas on the evolutionary process. Studies of how organisms are organized, and how this organization can dictate the course of evolution, have revolutionized evolutionary biology and provided an unexpectedly successful way of bridging scales of evolutionary study, from genetics to development to macroevolution. In this study, we have attempted to make one small step towards testing one of the most provocative hypotheses concerning the modular design of organisms: that modularity increases evolvability. If strong relationships among parts of an organism limit their variation, then breaking those relationships is crucial to maintaining the ability of organisms to vary and evolve with changing circumstances over time. However, strong relationships among functionally or developmentally-linked parts are also essential to maintain. These relationships are known to change, although they are relatively conserved across large clades This study represents only a first pass at the question, and the models we assess here are the simplest possible, providing a starting point for more complicated scenarios and a basic methodology for testing those with empirical data. Because of the limitations discussed in detail above, we were unable to test how changes in modularity influence disparity. However, we were able to test how differences in integration influence morphological disparity, and our results show that, for the most part, there is no simple relationship between integration and disparity. Nonetheless, the results that were significant tended to support the constraint hypothesis, that integration limits variation, and thus morphological evolution, within modules.The majority of results show that there is no simple rule or straightforward model for the influence of modularity on morphological evolution. In some cases, high integration within modules may well promote changes across the entire module, rather than impeding any change. These effects are not mutually exclusive, and high integration may well limit one kind of change while facilitating another. However, it is possible that one effect dominates over the course of evolutionary history, and empirical data is essential to determining if that is in fact the case, or if both are equally balanced over time. This study suggests that, while the total number of significant results is relatively limited, high integration constrains morphological evolution more often than it facilitates it. If this result is supported in future studies with empirical data, then it would support the idea that increasing modularity, specifically the parcellation of units into smaller subunits, may well promote evolvability by circumventing the restrictions on trait variation imposed by high integration. By breaking the bonds between traits, increasing modularity frees traits to vary independently of each other, potentially resulting in higher morphological variation and, ultimately, greater morphological evolution.In conclusion, the results of the current analysis of within-module disparity suggested that strong integration of landmarks has little influence on morphological evolution across large time scales. However, where significant results were found, the primary effect of strong integration of landmarks was to constrain morphological variation and thus morphological evolution in the placental mammal cranium. This result was supported by separate analysis of two long-diverged orders, suggesting that it is likely to be a general pattern for placental mammals. Analyses incorporating other placental mammalian clades, particularly the more basal clades Afrotheria and Xenarthra, are necessary to establish its applicability to all placental mammals. As noted above, preliminary analysis of marsupials suggests a different pattern of cranial disparity, perhaps related to the markedly different reproductive strategies of the two therian clades.Although most studies of modularity discuss its potential influence on morphological evolution (most intriguingly by increasing “evolvability”), there have been very few empirical studies of this effect, particularly at the macroevolutionary scale. Most studies of modularity to date have focused on bridging genetics, development, and morphology, which has provided a solid foundation for broad-scale studies and produced many provocative hypotheses on modularity's evolutionary significance. With large comparative morphometric studies increasingly possible through improvements in computing and imaging, it is hoped that more studies will focus on testing modularity's influence on morphological evolution. The study presented here provides a first step in this promising direction of research.Data were gathered from 141 specimens, representing 77 species . Most spGeometric morphometric analysis of 41 3-D landmarks , Fig. 1 To measure disparity, all specimens were first aligned with generalized least squares Procrustes superimposition n landmarks were drawn from the full dataset and aligned with GLS Procrustes superimposition, where n is the number of landmarks in the module being tested. The disparities were calculated for each of the 10,000 configurations, as described above. Analyses were also conducted in which “strong” modules  were compared to disparities generated from random sets of landmarks pulled only from the “weak” modules , and vice versa (Disparity B). Similarly to Disparity A, the constraint hypothesis would predict that strong modules would have significantly lower disparities than observed in random sets of landmarks from weak modules, and that weak modules would have significantly higher disparities than observed in random sets of landmarks from strong modules. Analyses were conducted separately for Primates and Carnivora.Because modules had different numbers of landmarks , their rAdditionally, a single Procrustes superimposition of all landmarks was conducted, after which landmarks were divided into the six modules. Sample variance was calculated for each landmark, and differences in landmark variances were compared across modules with a non-parametric Kruskal-Wallis test. Pairwise comparisons of modules were also conducted with non-parametric Mann-Whitney tests, with a Bonferroni correction used to account for multiple comparisons. Lastly, all landmarks were grouped into two bins, based on membership in a “strong” module or a “weak” module, and a Mann-Whitney test was used to test for differences in landmark variances between the two bins.Table S1List of species used in analyses.(0.08 MB DOC)Click here for additional data file.Table S2Landmarks used in analyses and module affiliations. ACR, acronyms for landmarks, shown in (0.04 MB DOC)Click here for additional data file.


The OR of prostate carcinoma for men with BMI ⩽25 kg m−2 was 1.74 , compared with men with higher BMI (>25 kg m−2). Other significant risk factors associated with the disease included higher income , physical activity , being married  and coffee consumption . Stratified analysis also showed that the consumption of fish/shellfish had an adverse association for men with higher BMI. This study suggests that the intake of the low fat local vegetarian food has a protective effect against prostate carcinoma for thin men in this study population.In a case–control study in a veterans hospital in Taiwan, we compared 237 histology-confirmed prostate carcinoma cases with 481 controls, frequency matched by age, for their consumption of vegetarian food, namely soybean products, rice, wheat protein and other vegetables. The multivariable logistic regression analysis showed a significant association with such food (odds ratio (OR)=0.67, 95% confidence interval (CI)=0.47, 0.94). This beneficial effect presented for men with body mass index (BMI) ⩽25 kg m Diet has been associated with cancers of the prostate, colorectum, breast and other sites . Althougvs 118.2 per 100 000 in men in the US in 1992–1996 , Department of Ophthalmology (38.5%) and other departments (21.0%).With the consent of the subjects, interviews were conducted in person by trained interviewer using standard questionnaires while the participants were in hospital. Adapted from a previous pilot study  are most likely to consume this type of food. Other lay people also consume this local vegetarian food, particularly for breakfast, but may include milk and/or eggs, such as preserved eggs (thousand-year eggs in lay language) or boiled salted eggs.The major items of physical activities in the questionnaire included leisure-time exercises, work or leisure-time hobbies such as gardening, yard work, carpentry and other domestic chores requiring physical exertion. These were scored and then categorised as sedentary, low, moderate or high.vs ⩾70 years) based on the age of cases and controls at diagnosis. In this study, participants were mainly veterans (83%). Since the tumorigenesis may have association with the body weight, body mass indexes (BMI) values taken 1 year prior to the interview about the disease and at ages 40–45 years were used in the data analysis and also grouped into two levels (>25 vs ⩽25 kg m−2) based on the normal BMI range for Taiwanese males. Physical activity was considered as the combination of work and exercises and was classified into two levels (low/moderate vs high).The data analyses began with distributions of responses and risk factors to estimate differences in cases and controls. For the comparison of age, subjects were grouped into two groups  and 95% confidence interval (CI). Significant variables identified from the univariate analyses were included as covariates in multivariable logistic regression models. With age and BMI being included, the downward stepwise modelling was used to determine the best predictors of risk for prostate carcinoma. The least significant variables were deleted one at a time. The final model was derived based on significance testing. Data were analysed using SAS for Windows Version 8.0 .P=0.02).More than half of the subjects were aged 70 years or older and approximately 64 percent of participants were retired. Compared with controls, cases had higher education, higher rate of marriage, more children, higher proportion of religious affiliation and a higher family income . Cases avs 55.3%; OR=0.66, 95%, CI=0.48, 0.91). Although a larger percentage of cases drank tea and milk than controls, these differences were not significant either.There were no significant differences between cases and controls in the consumption of most dietary beverage variables . Cases cRisk factors for prostate carcinoma that remained significant following multivariate conditional logistic regression without interaction terms were higher income, pursuing physical activities, being married, drinking coffee and partaking of folk style vegetarian food . Men witThe present case–control study found prostate carcinoma to be negatively associated with the consumption of Taiwanese folk style vegetarian food and BMI, but positively associated with income, being married, coffee consumption and physical activities. Different from other studies .The protective effect of the vegetarian meals against the development of prostate carcinoma in this study is consistent with findings in some other studies on the consumption of selected vegetables. Those studies suggest that increased consumption of green leafy vegetables, soybean products, lentils and peas, and tomatoes are associated with decreased prostate carcinoma risk . One of Some limitations to the present study should be considered. First, recall bias is a drawback in case–control studies. The use of hospital-based controls could decrease differences in health consciousness between cases and controls although using hospital-based controls may also minimise the effect of risk factors. Second, the use of semiquantitative food frequency to quantify diet may not reveal the precise effect of risk factors such as meat and fat consumption. However, its use is very convenient for the elderly with little or no education who must recall the contents of their diet. On the other hand, the folk vegetarian food termed as ‘Zhai’ or ‘Sue’ food in Taiwan is easily recalled and counted by lay people regardless of educational levels. Third, due to the use of a binary analysis regarding all risk factors, we might have missed potentially important information such as a dose response. The use of semiquantified data restricts our ability to stratify data into multiple levels. It is also likely that subjects may have under-reported their exposure status, but such bias would likely be similar in both cases and controls.This case–control study showed that prostate carcinoma cases were more likely to occur in educated individuals who engaged in more physical activities and had a lower body mass index. The seemingly protective effect related to the increased intake of folk vegetarian food with very low fat content is particularly significant for thin men.


P = 0.03). Alcohol consumption was unrelated to risk, but there was a significant trend with years of smoking (P = 0.015). A protective effect of aspirin consumption was confined to the English centres . Comparison with a parallel study of adenocarcinoma indicated a common protective effect of a healthy diet but otherwise distinct risk factors. © 2001 Cancer Research Campaign http://www.bjcancer.comOesophageal cancer rates in women in the UK are more than 3 times higher than in most other European populations. A population-based matched case–control study of histologically confirmed squamous cell carcinoma of the oesophagus in women was carried out in 4 regions in England and Scotland. Interviews were carried out in hospital or at home and topics included: smoking; alcohol; tea and coffee consumption; medical and obstetric history; and diet. Response rates were 62% for cases and 65% for first-chosen controls. There were 159 case–control pairs. Significant results were found for: eating salads (odds ratio (OR) 0.42, 95% CI 0.20–0.92 in the highest quartile of consumption) and a light (as distinct from no) breakfast  were protective; quantity of tea was a risk factor and there was a significant positive trend with temperature at which hot drinks were consumed (


We studied the effect of dietary factors and a variety of other risk factors on the development ofcholelithiasis through a case control study.        The study involved 96 cases and 118 age and sex matched controls. All cases and controls wereinterviewed with regard to a variety of risk factors and frequency of consumption of over 100 fooditems. Analysis was done both by chi square and a multiple logistic regression model. From all thedietry factors the only ones that showed a positive statistically signficantly (p<0.05) association wasconsumption of animal fat as expressed by eating all visible fat on the meat and using butter on thetable. Interestingly high consumption of olive oil had a negative (protective) association with thedisease. A negative association was also found with smoking and holding a job demanding hardlabor.


Reactive oxygen species generated by hyperglycaemia modify structure and function of lipids, proteins and other molecules taking part in chronic vascular changes in diabetes mellitus (DM). Low activity of scavenger enzymes has been observed in patients with DM. Protective role of scavenger enzymes may be deteriorated by oxidative stress. This study was undertaken to investigate the association between gene polymorphisms of selected antioxidant enzymes and vascular complications of DM.Significant differences in allele and genotype distribution among T1DM, T2DM and control persons were found in SOD1 and SOD2 genes but not in CAT gene . Serum SOD activity was significantly decreased in T1DM and T2DM subjects compared to the control subjects . SOD1 and SOD2 polymorphisms may affect SOD activity. Serum SOD activity was higher in CC than in TT genotype of SOD2 gene  and higher in AA than in CC genotype of SOD1 gene . Better diabetes control was found in patients with CC than with TT genotype of SOD2 gene. Significantly different allele and genotype frequencies of SOD2 gene polymorphism were found among diabetic patients with macroangiopathy and those without it. No difference was associated with microangiopathy in all studied genes.The results of our study demonstrate that oxidative stress in DM can be accelerated not only due to increased production of ROS caused by hyperglycaemia but also by reduced ability of antioxidant defense system caused at least partly by SNPs of some scavenger enzymes. H2O2 isysosomes .We still have to elucidate the fact that some patients with DM develope vascular complications but this cannot be seen in the others with the same level of disease control . We haveCuZnSOD also called SOD1, EC 1.15.1.1 is one of the cellular defense systems for oxidative insults . The incTotal of 120 T1DM, 306 T2DM and control group of 140 healthy subjects without family history of diabetes were examined in this study. Diagnosis of T1DM and T2DM was based on WHO/ADA definition of diabetes (1999), healthy subjects don't meet the criteria for the diagnosis of DM. They were in good health and namely free of any comorbidities often associated with DM, especially with T2DM  and other endocrine disorders. Microangiopathy was confirmed by ophthalmoscopy or by the presence of peripheral neuropathy  in 167 patients who did not have any evidence of macrovascular disease from the clinical picture . Patients were excluded from this group in the case of suspection on autonomic neuropathy made from physical examination . 66 subjects had macrovascular complications manifested by ischaemic heart disease (diagnosis was based on ECG or coronarography), ischemic disease of the lower limbs (diagnosis was based on angiography of lower limbs arteries) or had history of stroke . The remaining 161 diabetic patients were free of any complications. Clinical and laboratory characteristics are shown in Tab. Venous blood samples were drawn after an overnight fasting. Plasma (Li-Heparine) glucose, creatinine were measured in central biochemistry laboratory. Serum total cholesterol, HDL-cholesterol and triglycerides (TG) were measured by automated enzymatic methods on Hitachi analyzer, LDL cholestrol was calculated according to Friedewald formula. HbA1c was measured by high-performance liquid chromatography. Superoxide dismutase activity was determined spectrophotometrically by xanthine/xanthine oxidase system by Genesys 5 spectrophotometer, USA. The method is based on the reaction described by McCord and Fridovich . SOD act9 /l) by sodium dodecylsulphate (SDS) lysis by ammonium acetate extraction and ethanol precipitation. Determination of the SOD and CAT polymorphisms was achieved by PCR-RFLP analysis. Details are shown in Tab. Blood was extracted from the peripheral blood (5–10 ml) and genomic DNA was prepared from leucocytes  test. Comparison of continuous variables (HbA1c) among the SOD genotypes was performed with the use of analysis of variance (ANOVA). A logistic regression analysis was performed to evaluate the interaction between the genotypes and other variables in relation to the prevalence of macro- or microangiopathy. In this analysis, the dependent variable was the presence or absence of vascular complication. Independent variables included in this analysis were BMI, age, present HbA1c level, type of diabetes, duration of diabetes, SOD activity and genotype. P values < 0.05 were considered as significant. The laboratory data are expressed as means ± SD. The analysis was performed using programme Statistica 6.0 (StatSoft). Testing for deviation from Hardy-Weinberg equilibrium (HWE) was performed and all the observed genotype frequencies were in agreement with HWE.Age, BMI and duration of diabetes were compared between studied groups using Student's Serum SOD activity was significantly decreased in T1DM  and in T2DM patients  compared to the control subjects , both p < 0,01. Differences between T1DM and T2DM in SOD activity were not found statistically significant . No gender or age influence on its activity was found in diabetic patients or healthy subjects. Difference in SOD activity between diabetic patients and healthy subjects is probably accountable not only by genotype background but also by various effects in terms of diabetes, e.g. enzyme glycation.The lower serum SOD activity was found in patients (T1DM and T2DM) with macrovascular complications  than in those with microvascular complications , p < 0,01 or without any vascular complications , p < 0,05.The AA genotype was the most common observed in the healthy subjects followed by the AC genotype, whereas the AC was more common than the AA genotype in T1DM and T2DM patients Tab. . SignifiThe TT genotype  was the most common in both T1DM and T2DM patients, CT genotype was the most common in healthy subjects whereas the CC genotype (Ala/Ala) was the rarest one in all groups Tab. . The allWe found no statistically significant differences between frequencies in alleles of CAT SNP between diabetic patients and healthy subjects p = 0,294) Tab. . Control Tab. . CDiabetes control expressed by glycated haemoglobin values was poorer in TT genotype  of SOD2  than in CC genotype (Ala/Ala) of SOD2 , p < 0,05.No effect of SNP in SOD1 gene on diabetes control was found. Glycated haemoglobin was 6,7 ± 1,4; 95%CI: 5,41–6,23 in T1DM and 6,9 ± 1,4; 95%CI: 5,48–6,09 in T2DM, both in AA genotype of SOD1 gene and 6,59 ± 1,22, 95%CI: 5,08–6,24 in T1DM and 6,61 ± 1,51; 95%CI: 5,02–6,05 in T2DM, both in CC genotype of SOD1 gene, with p = 0,124.Similar findings were made in CAT gene. Glycated haemoglobin was 6,14 ± 1,11; 95% CI: 6,06–6,57 in T1DM and 6,50 ± 0,85; 95%CI: 6,32–7,25 in T2DM, both in AA genotype of CAT and 6,19 ± 1,32, 95% CI: 6,09–6,60 in T1DM and 6,61 ± 0,54; 95%CI: 6,45–7,05 in T2DM, both in TT genotype of CAT gene, with p = 0,249.Significantly different genotype frequencies of SNPs were found in diabetic patiens (T1DM and T2DM) with macroangiopathy (MA+) in SOD1 and SOD2 genes. When compared these with CC genotype vs. AC and AA genotypes of SOD1: OR (odds ratio) was 1.73; 95% CI 1.45–5.37 with p < 0,05, CC genotype (Ala/Ala) vs. CT  and TT  genotypes of SOD2: OR was 0,62; 95%CI 0,58–0,90 with p < 0,01. When compared AA genotype vs. AT and TT genotypes of CAT: OR was 1.05; 95%CI 0,78–1,13, p = 0,851.Macroangiopathy was associated with significantly higher frequency of C allele in SOD1 gene , lower frequency of C alelle (Ala) in SOD2 gene  whereas no such distribution was found in CAT gene, p = 0,594.No differences in genotype frequencies were associated with microangiopathy (MI+). When compared these with CC genotype vs. AC and AA genotypes in SOD1: OR was 0,91; 95%CI 0.74–1.32 with p = 0.783, CC genotype (Ala/Ala) vs. CT  and TT  genotypes in SOD2: OR was 0,96; 95% CI 0.52–1.38 with p = 0.852 and AA genotype vs. AT and TT genotypes in CAT: OR 1,04 95%; CI 0,37–1,26 with p = 0,814. No statistically significant differences in allele frequencies were found in all SNPs of the studied genes in the patients with microangiopathy when compared with patients without vascular complications . Frequencies of genotypes ranged according to presence of vascular complications in both types of diabetes mellitus are showed in Fig. We found negative correlation between serum superoxide dismutase activity (SOD) in both types of diabetes mellitus and the values of glycated haemoglobin (HbA1c %) Fig. , as wellAssociation of the SOD1, SOD2 and CAT polymorphism, BMI, age, duration of diabetes, sex, type of diabetes and SOD activity as independent variables with the presence of microangiopathy or macroangiopathy as dependent variables was performed using a logistic regression model. This analysis indicated that SOD1 and SOD2 genotypes are significantly associated with macroangiopathy. Another variables significantly associated p < 0,05) with angiopathy were HbA1c, SOD activity and duration of diabetes. No independent contribution has been demonstrated for age, sex, BMI and the type of diabetes.  appears to be a minor determinant of carotid atherosclerosis . The AlaOur results are indicative of potential effect of A/C SNP in SOD1 gene on enzyme activity. It is known that deficiency in SOD1 results in increased levels of vascular superoxide and peroxynitrite and impaired endothelium-dependent relaxation in both large arteries and microvessels  and causWe found no statistically significant differences in distribution of CAT alleles in studied SNP and no impact of this SNP on the presence of vascular complications and the level of glycated haemoglobin. Hypocatalasaemic patients were found to have higher plasma levels of homocysteine and lower levels of folate , suggestThe study inconsistency in the association between genotypes and DM or cardiovascular disease is partly due to limits of conventional cross-sectional and retrospective case-control studies because selection bias have to be considered and the statistical analysis might have failed to demonstrate any significant differences. Large differences among ethnic populations are known in the distribution of genotypes which could be the reason for differences in studies.The presented findings show that the genotype distribution of the SOD1 and SOD2 in patients with diabetes mellitus can differed from nondiabetic individuals. We are conscious of the limitation of this study with relatively small sample size in comparison with wide epidemiological studies, especially by providing subgroup analysis within the group with diabetes mellitus. Nevertheless the results of small studies with similar conclusions may spark off suquent research. Genetic background may be at least partly associated with disease control of diabetes and consequently enzyme activities protecting against oxidative stress. Vascular disorders like atherosclerosis are then the results of combined genetic and metabolic changes.AP-1: activated protein 1; AGE: advanced glycation endproducts; BMI: body mass index; CAT: catalase; JNK: c-Jun N- terminal kinase; CT: computer tomography; 95% CI: confidence interval 95%; ECG: electrocardiography; ERK: 1/2 extracellular signal regulated kinase; HbA1c: glycated haemoglobin; HDL: high density lipoprotein; LDL: low density lipoprotein; NFκB: nuclear factor kappa B; PKC: proteinkinase C; ROS: reactive oxygen species; RFLP: restriction fragment lenght polymorphism; SOD: superoxide dismutase; TG: triacylglycerol; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus.The author(s) declares that they have no competing interests.MF drafted the manuscript, participated in design of the study, performed the statistical analysis, carried out the molecular genetic, participated in the sequence alignment. JS conceived of the study, participated in its design and coordination and helped to draft the manuscript. JH carried out the enzyme activities assessment. ZL carried out the molecular genetic, participated in the sequence alignment. MJ helped with the coordination of the study, participated in the genetic part of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The aim of the present study was to investigate the role of these LOXL1 variants in a Central European cohort of Caucasian patients with XFG.Exfoliation syndrome (XFS) is characterized by an accumulation of abnormal extracellular material in the anterior part of the eye that frequently leads to increased intraocular pressure and glaucomatous optic neuropathy. Recently, two non-synonymous polymorphisms . Odds ratios of 52.1  and 14.67 (95% CI: 3.81–56.2), respectively, were calculated for the two high-risk haplotypes GG and TG compared to the haplotype GA.The frequency of allele G of LOXL1 polymorphisms and XFG and extend our knowledge to a Central European population.Our data confirm the previously reported association between  Various family-based studies reported a higher frequency of XFS among relatives of patients with XFS -8. Furthlysyl oxidase-like protein 1 gene  conferring increased risk for the development of XFS and XFG (rs1048661 and rs3825942) [rs 1048661 induces an amino acid change from arginine to leucine at position 141 (R141L) whereas rs3825942 induces an amino acid change from glycine to asparagine at position 153 (G153D).Most importantly, a recent genome-wide association study from Icelandic and Swedish patients with XFS and XFG found two common non-synonymous single nucleotide polymorphisms in exon 1 of the LOXL1 variants in a Central European cohort of Caucasian origin.So far, the potential role of these polymorphisms has not yet been determined in a Central European population. Therefore, our study was set to investigate the aforementioned One hundred sixty-seven unrelated patients with XFG and 170 control subjects were enrolled in the present retrospective case-control study. All study participants were Caucasians from the same geographical area in the southern part of Austria. Participants were seen at the Department of Ophthalmology, Medical University of Graz, Graz, Austria between May 2003 and April 2007 and gave informed, written consent before enrollment. The study was conducted in accordance with the National Gene Technology Act of Austria and the guidelines of the local ethics committee.Patients with XFG underwent slit lamp biomicroscopy in mydriasis, testing for best corrected visual acuity, Goldmann applanation tonometry, gonioscopy, pachymetry, and standard automated perimetry  or – in cases of profoundly decreased visual acuity – Goldmann perimetry. Control subjects underwent slit lamp biomicroscopy in mydriasis, Goldmann applanation tonometry, and testing for best corrected visual acuity. Optic discs in all participants were assessed by glaucoma specialists (C.F. and G.M.).XFG was defined by the presence of typical exfoliation material on the anterior lens capsule, an intraocular pressure of at least 22 mmHg before initiation of a pressure-lowering therapy, an open anterior chamber angle, optic disc changes characteristic for glaucoma , visual field defects characteristic for glaucoma , and the absence of conditions leading to secondary glaucoma.Control subjects showed biomicroscopically no evidence of exfoliation material on the anterior capsule of the lens and no morphological damage indicative for open-angle or angle closure glaucoma. Control subjects were admitted to our department for cataract surgery.LOXL1 R141L polymorphism, a 179 base-pair segment containing the polymorphic site was amplified by polymerase chain reaction using forward primer 5′-GCC GTC GGG GAC AGC A-3′ and reverse primer 5′-TAG TTC TCG TAC TGG CTG ACG AA-3′. Amplified products were digested with restriction enzyme SmaI . The 141R allele was cut into two fragments of 151 and 28 base pairs whereas the 141L allele remained uncut. Fragments were separated on 2.5% agarose gels and visualized by use of ethidium bromide.Genomic DNA was extracted from peripheral blood lymphocytes by standard techniques and stored at –70 °C until genotype determination. For genotyping of the LOXL1 G153D polymorphism was determined by a 5′-exonuclease assay  using forward primer 5′-ACC TCC GTC TCC CAG CAA-3′, reverse primer 5′-TGC TGG CGA AGG CCG AAG-3′, LOXL1–153G-probe VIC-CGG AGC CCC CGT G-NFQ, and LOXL1–153D-probe FAM-AGG CGG AGT CCC CGT-NFQ . The assay was performed according to the manufacturer’s instructions, and end-point fluorescence was measured in a lambda Fluoro 320 plus plate reader  using excitation/emission filters of 485/530 nm and 530/572 nm, respectively. The data were exported into Excel format and depicted and analyzed as a scatter plot.The 2 test. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated by logistic regression. The criterion for statistical significance was p≤0.05. The Hardy–Weinberg (HW) equilibrium has been calculated using HW Diagnostics-Version 1.beta . Statistical analysis was done using the SPSS statistical package  and haplotype analysis was done using Haploview 4.0 [Descriptive statistics were used to calculate frequencies and percentages of discrete variables. Continuous data are given as mean±standard deviation (SD). Means were compared using the Mann–Whitney test. Proportions of groups were compared by the χview 4.0 .2, a mean intraocular pressure of 26.0±11.2 mmHg, and a mean cup disc ratio of 0.80±0.16 in the worse eye.The present study comprised 167 patients with XFG  and 170 control subjects . The mean age of patients with XFG was 75.7 years (range 50.3–91.6 years), and the mean age of control subjects was 77.1 years (range 58.9–92.7 years). Patients with XFG had a mean deviation of 13.0±6.9 decibel (dB), a mean loss of variance of 36.7±21.5 dBrs1048661 and 94.1% for rs3825942. The observed genotype distributions did not deviate from those predicted by the Hardy–Weinberg equilibrium. rs1048661 and rs3825942 in patients with XFG and control subjects. In both polymorphisms, the prevalence of the GG genotype as well as the frequency of allele G was significantly higher in patients with XFG than in control subjects. An odds ratio of 2.69 (95% CI: 1.59–4.54) was calculated for allele G of rs1048661. For allele G of rs3825942, an odds ratio of 37.29 (95% CI: 6.35–218.02) was calculated.The success rate of genotyping was 93.5% for The two variants are in strong linkage disequilibrium (D’=1.0), and only three possible haplotypes were observed in our cohort . Comparers1048661. For allele G of rs3825942, positive likelihood ratio and negative likelihood ratio were 1.22 and 0.03, respectively.Positive likelihood ratio and negative likelihood ratio were 1.26 and 0.47, respectively, for allele G of elastin and lysyl oxidase-like protein 2 has been suggested as candidate susceptibility genes [Mainstay of the pathogenesis of exfoliation syndrome is the accumulation of pathognomonic fibrils in the anterior segment of the eye as well as in extraocular locations . These fty genes .LOXL1 variants and XFG. Beside the original study from Thorleifsson and coworkers [LOXL1 polymorphisms in XFS and XFG have been performed [rs1048661 and rs3825942 found in the present study were remarkably similar to four of these studies [rs1048661 was detected in patients with XFG while frequency of allele G in rs3825942 was found to be 100% in their study [rs1048661 and rs3825942 was 84.1% and 99.4%, respectively, pointing towards significant differences in the prevalence of rs1048661 among different ethnicities.The present study being the first in a Central European population confirms the strong association between oworkers  that incerformed ,15-21. T studies -16 while studies -20. Thisrs1048661) and 1.22 and 0.03 , respectively, genetic testing for XFG based solely on these polymorphisms of LOXL1 can not be recommended.With positive and negative likelihood ratios of 1.26 and 0.47 (allele G of LOXL1 polymorphisms in a Central European population of Caucasian origin. As other genetic or environmental factors are likely to be involved in the pathogenesis of XFG, further studies are warranted.In conclusion, the results of our study demonstrate the importance of the


Twin and family studies indicate that genetic influences play an important part in the aetiology of all of these disorders, yet progress in identifying genes has been slow. One way forward is to cut loose from conventional clinical criteria for diagnosing disorders and to focus instead on measures of underlying cognitive mechanisms. Psychology can inform genetics by clarifying what the key dimensions are for heritable phenotypes. However, it is not a one-way street. By using genetically informative designs, one can gain insights about causal relationships between different cognitive deficits. For instance, it has been suggested that low-level auditory deficits cause phonological problems in SLI. However, a twin study showed that, although both types of deficit occur in SLI, they have quite different origins, with environmental factors more important for auditory deficit, and genes more important for deficient phonological short-term memory. Another study found that morphosyntactic deficits in SLI are also highly heritable, but have different genetic origins from impairments of phonological short-term memory. A genetic perspective shows that a search for  Several developmental disorders are of particular theoretical interest to psychologists because they are characterized by fairly selective impairments in specific domains of functioning. In developmental dyslexia In this paper, I consider what we know about causes of such disorders at two levels of description. Part 1, “How psychology can inform genetics”, focuses on studies of aetiology: genetic and environmental factors that are associated with developmental disorders. In Part 2, “How genetics can inform psychology”, attention shifts to their underlying cognitive basis. I focus mainly on SLI, but also briefly allude to relevant work on dyslexia and autism.When neuro-imaging first became widely available, people were surprised to find remarkably little evidence of focal brain damage in children with specific developmental disorders. As As is discussed below, it is now widely accepted that inherited brain anomalies, rather than acquired brain damage, are a key factor in the aetiology of developmental dyslexia, SLI, and autistic disorder. We understand very little about how genetic variations can lead to abnormal brain development, but it is conceivable that, by affecting processes such as neuronal migration, neurotransmitter activity, programmed cell death, synaptic connectivity, or myelination, they result in a brain that functions in a nonoptimal fashion.The bulk of the evidence for genetic aetiology of developmental disorders comes from behavioural studies adopting a genetically informative design. Such studies consider how far observed similarities between individuals  are correlated with their genetic similarity (similarities in their genotypes). At the simplest level, one can do family studies to see whether a disorder is more common in first-degree relatives (parents and siblings) of an affected child than in first-degree relatives of unaffected children. Such studies are not watertight, however, because relatives typically share environments as well as genes. A more satisfactory design is the twin study, which capitalizes on the fact that there are two different processes that can lead to twinning: Splitting of a fertilized ovum will lead to genetically identical or monozygotic (MZ) twins, whereas fertilization of two ova around the same time will lead to fraternal or dizygotic (DZ) twins, whose genetic similarity is equivalent to that seen in other siblings. Although media attention focuses on studies of twins reared apart, one does not need to use such rare cases to gain useful information from a twin study. Twins growing up together will resemble one another, insofar as they are subject to many of the same environmental influences, including prenatal as well as postnatal factors. However, if similarity between two members of a twin pair is greater for MZ than for DZ twins, this points to a role of genes. When considering developmental disorders, we can assess the degree of concordance between twins  in both MZ and DZ twins, to get estimates of the relative roles of genetic and environmental factors in the aetiology. Studies adopting this approach have found high estimates of heritability for autism  and SLI the gene for any of these disorders: They are heterogeneous, and such genes as exist are likely to act in a probabilistic fashion, in interaction with other genetic and environmental factors.With the advent of fast-throughput genetic sequencers, a sense of optimism was generated that we would quickly move on to identify risk genes for developmental disorders. However, progress has been surprisingly slow. Identifying genes that are implicated in disorder is not a single-step procedure. Typically, one first uses a method known as linkage analysis to home in on a region that is likely to harbour relevant genes. Linkage analysis relies on the fact that the closer together two bits of DNA are, the greater the likelihood they will be inherited together. Some stretches of DNA do not contain genes and are highly variable from one individual to another. These can act as “markers”, allowing one to identify whether a portion of DNA has been inherited from the mother or the father. One starts with a set of siblings, both of whom have a disorder. Then for a pair of alleles at a given locus, one can work out whether zero, one, or two alleles in siblings are “identical by descent” (IBD)—that is, inherited from the same parent see . The obsOne reason why progress in the genetics of developmental disorders is slow may be because most genetic studies rely on textbook descriptions of disorders to define the phenotype. These typically specify in rather broad terms the impairments that have to be present to merit a diagnosis, together with exclusionary factors. So, for instance, SLI is diagnosed in a child whose language development lags significantly behind nonverbal development, and there is no obvious causal factor or other medical diagnosis such as hearing loss, neurological disease, or autistic disorder. This kind of diagnosis can be useful in identifying those who require special services, but it does not yield a homogenous group of children. On the one hand, it will include children with diverse difficulties in areas such as syntax, semantics, phonology, and pragmatics. On the other hand, it may exclude a child with significant language deficits because an arbitrary IQ cut-off is not met. Furthermore, although textbook definitions imply discrete disorders, the boundaries between conditions are often fuzzy—for example, SLI can be hard to distinguish from dyslexia  and fromIdentification of subtypes of disorder is one way forward, but it is not the complete solution. Rather than subdividing a disorder into ever more selective subgroups, we may sometimes need to do the opposite and consider adopting a broader conceptualization of the phenotype. The idea is not that we should simply lump together individuals with diverse clinical profiles, but rather that we should move away from a focus solely on clinical “disease” categories and develop instead more quantitative measures of underlying processes— so-called “endophenotypes” .The value of this approach was demonstrated to me when I conducted a twin study of SLI , in whic2g, will lead to twin dissimilarity. Nonshared environment includes measurement error as well as longer term idiosyncratic influences on the child . If performance on nonword repetition were determined solely by e2g then regardless of Twin A's score, we would predict that Twin B would score at the population mean. Now consider the hypothetical situation where performance on nonword repetition is determined solely by environmental factors shared by both twins—for example, the amount of language input they received from parents. Environmental factors that are common to both twins, or c2g, make twins similar to one another, so, if such factors exert a large effect, when Twin A has a low score, we predict that Twin B will also have a low score. The effect of c2g will be the same, regardless of whether twins are MZ or DZ. Finally, consider the situation where genes, or heritable factors (h2g), are the only important influence on poor nonword repetition performance. Because MZ twins are genetically identical, if MZ Twin A has a low score, we predict that MZ Twin B will have an equally low score. However, DZ twins have, on average, 50% of segregating genes in common.2g, c2g, and e2g, and our goal is to estimate the relative contribution of each of these in explaining the observed variance. 2g) was close to 1.0, suggesting that genes play a major role in causing deficient phonological short-term memory (STM). These striking results from behavioural analysis have led to the inclusion of nonword repetition as a phenotypic index in molecular genetic studies. Strong linkage has been found to a site on chromosome 16 . Estimates of genetic influence (h2g) were negligible. This was a surprising result, in the light of much higher heritability estimates for dyslexia obtained by other researchers  was smaller than that seen for CNRep (η2 = .289), and the pattern of ART errors suggested a general auditory problem, rather than a deficit specific to brief or rapid sounds. DeFries–Fulker analysis was used to analyse the heritability of deficits on both measures and yielded remarkably clear-cut results: As in the r = .603) and DZ (r = .493) twins. This pattern shows that the ART is adequately reliable  and is compatible with the test being affected by environmental influences common to both twins. In a subsequent analysis  on the ART, the CNRep, neither, or both. The main difference between the four groups on our other language measures was in severity of language impairment, rather than pattern of strengths and weaknesses see . The impr = .35 after adjusting for age, IQ, and sex) between ART and CNRep, if they are not part of the same causal pathway? One possibility is that this is due to ascertainment bias: If children with A + B are more likely to have a diagnosis than children with either A or B alone, then if we pick a sample that is overrepresentative of those with a diagnosis, we see more cases than usual who have the A + B profile. Another possibility is that individuals with a genetic liability to SLI gravitate toward environments that do not favour the development of auditory processing skills in their children. They may, for instance, have less money to spend on music lessons.Why, then, should we see a modest correlation . The twin sample was a subset of children from the Twins Early Development Study ; two thi2 = .10) but the data suggested that this might be because of articulatory difficulties. We derived a measure that was intended to act as a purer index of phonological STM by using a regression equation to compute the mismatch between the score obtained with three- to five-syllable nonwords and that predicted from the two-syllable score. This phonological STM score did a better job than the raw nonword repetition total at discriminating children in the “language risk” group from the “low risk” group (η2 = .15), and it was significantly heritable (h2g = .61) on DeFries–Fulker analysis.The CNRep was less good at discriminating children with language difficulties than it had been in older children .The Rice–Wexler subtests were combined to give a single index of verb inflections. This was highly skewed, consistent with the extended optional infinitive theory, which maintains that most children have mastered this aspect of grammar by 4 years of age. The skewing does not affect results from DeFries–Fulker analysis and may indeed be a useful indicator of a major gene effect . Heritabp < .01. The fact that both measures were significantly heritable suggests that this lack of agreement is not readily explained by poor test reliability, as an unreliable test would simply show up on DeFries–Fulker analysis as having a large e2g term. To investigate the extent of aetiological overlap between the measures, a bivariate extension of DeFries–Fulker analysis was used. This involves predicting the score of twin B on test Y from the score of twin A on text X, after scaling both measures appropriately  were significantly, albeit weakly, correlated, when the twin analysis suggested that they had different origins. As with the previous work, one interpretation is in terms of additive risk factors; children with a double deficit may be more likely to have clinically significant language problems and hence find their way into a study such as this. Given that both of the measures were heritable, another possibility is that there may be assortative mating for language disorder, so that parents with either kind of impairment tend to have children together. To test this idea we would need to assess parents directly.Overall, these two twin studies  demonstrdisproving causation. Quite simply, if one can find a child who has grammatical deficits in the absence of auditory impairment, then this is evidence that the grammatical deficits are not caused by auditory impairment , but a more interesting possibility is that probabilistic associations between deficits are telling us something about causality. Most readers will agree that smoking causes lung cancer. We are willing, when arguing about the aetiology of this physical disease, to think of smoking as a risk factor that increases the risk of lung cancer, while accepting that the association between cause and disease is probabilistic, rather than deterministic. It would be a serious mistake to dismiss any role for smoking in causing lung cancer, because Uncle Fred smoked all his life and lived to a ripe old age, or Auntie Susan never smoked but died from lung cancer.A recurring finding in developmental disorders is that underlying deficits can be dissociated, but when they co-occur the disorder is more severe and more likely to be detected. In the case of SLI we found that weak phonological STM and auditory impairment were aetiologically as well as phenotypically dissociable, but when both deficits occurred together, the child was particularly likely to receive a clinical diagnosis. In a similar vein, syntactic and phonological impairments were genetically distinct and were often dissociated, but it was the children with both problems who had the most severe language difficulties . Such results suggest that children's language development is generally resilient in the face of a specific cognitive deficit, but that where two or more such deficits occur together, their effect is additive, and the chances increase that language learning will break down.Similar arguments have been put forward in the domains of developmental dyslexia and autism. For dyslexia, Autistic disorder is diagnosed on the basis of there being a triad of impairments affecting socialization, communication, and restricted interests/behaviour, but there is growing awareness that these areas of impairment can be dissociated from one another in children who fall short of meeting diagnostic criteria e.g., , and thothe cause of dyslexia or SLI. As In sum, cognitive studies of developmental disorders have often embraced parsimony and have looked for a single necessary and sufficient “cause” of disorders such as dyslexia, SLI, and autism. I suggest that this approach has led to theoretical stagnation, with much pointless debate about whether, for instance, auditory perceptual deficits are