Directional dominance on stature and cognition in diverse human populations

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Neurological manifestations and molecular genetics of acute intermittent porphyria in North Western Russia

Acute intermittent porphyria (AIP, MIM #176000) is an inherited metabolic disease due to a partial deficiency of the third enzyme, hydroxymethylbilane synthase (HMBS, EC: 4.3.1.8), in the haem biosynthesis. Neurological symptoms during an acute attack, which is the major manifestation of AIP, are variable and relatively rare, but may endanger a patient's life. In the present study, 12 Russian and two Finnish AIP patients with severe neurological manifestations during an acute attack were studied prospectively from 1995 to 2006. Autonomic neuropathy manifested as abdominal pain (88%), tachycardia (94%), hypertension (75%) and constipation (88%). The most common neurological sign was acute motor peripheral neuropathy (PNP, 81%) often associated with neuropathic sensory loss (54%) and CNS involvement (85%). Despite heterogeneity of the neurological manifestations in our patients with acute porphyria, the major pattern of PNP associated with abdominal pain, dysautonomia, CNS involvement and mild hepatopathy could be demonstrated. If more strict inclusion criteria for biochemical abnormalities (>10-fold increase in excretion of urinary PBG) are applied, neurological manifestations in an acute attack are probably more homogeneous than described previously, which suggests that some of the neurological patients described previously may not have acute porphyria but rather secondary porphyrinuria. Screening for acute porphyria using urinary PBG is useful in a selected group of neurological patients with acute PNP or encephalopathy and seizures associated with pain and dysautonomia. Clinical manifestations and the outcome of acute attacks were used as a basis for developing a 30-score scale of the severity of an acute attack. This scale can easily be used in clinical practice and to standardise the outcome of an attack. Degree of muscle weakness scored by MRC, prolonged mechanical ventilation, bulbar paralysis, impairment of consciousness and hyponatraemia were important signs of a poor prognosis. Arrhythmia was less important and autonomic dysfunction, severity of pain and mental symptoms did not affect the outcome. The delay in the diagnosis and repeated administrations of precipitating factors were the main cause of proceeding of an acute attack into pareses and severe CNS involvement and a fatal outcome in two patients. Nerve conduction studies and needle EMG were performed in eleven AIP patients during an acute attack and/or in remission. Nine patients had severe PNP and two patients had an acute encephalopathy but no clinically evident PNP. In addition to axonopathy, features suggestive of demyelination could be demonstrated in patients with severe PNP during an acute attack. PNP with a moderate muscle weakness was mainly pure axonal. Sensory involvement was common in acute PNP and could be subclinical. Decreased conduction velocities with normal amplitudes of evoked potentials during acute attacks with no clinically evident PNP indicated subclinical polyneuropathy. Reversible symmetrical lesions comparable with posterior reversible encephalopathy syndrome (PRES) were revealed in two patients' brain CT or MRI during an acute attack. In other five patients brain MRI during or soon after the symptoms was normal. The frequency of reversible brain oedema in AIP is probably under-estimated since it may be short-lasting and often indistinguishable on CT or MRI. In the present study, nine different mutations were identified in the HMBS gene in 11 unrelated Russian AIP patients from North Western Russia and their 32 relatives. AIP was diagnosed in nine symptom-free relatives. The majority of the mutations were family-specific and confirmed allelic heterogeneity also among Russian AIP patients. Three mutations, c.825+5G>C, c.825+3_825+6del and c.770T>C, were novel. Six mutations, c.77G>A (p.R26H), c.517C>T (p.R173W), c.583C>T (p.R195C), c.673C>T (p.R225X), c.739T>C (p.C247R) and c.748G>C (p.E250A), have previously been identified in AIP patients from Western and other Eastern European populations. The effects of novel mutations were studied by amplification and sequencing of the reverse-transcribed total RNA obtained from the patients' lymphoblastoid or fibroblast cell lines. The mutations c.825+5G>C and c.770T>C resulted in varyable amounts of abnormal transcripts, r.822_825del (p.C275fsX2) and [r.770u>c, r.652_771del, r.613_771del (p.L257P, p.G218_L257del, p.I205_L257del)]. All mutations demonstrated low residual activities (0.1-1.3 %) when expressed in COS-1 cells confirming the causality of the mutations and the enzymatic defect of the disease. The clinical outcome, prognosis and correlation between the HMBS genotype and phenotype were studied in 143 Finnish and Russian AIP patients with ten mutations (c.33G>T, c.97delA, InsAlu333, p.R149X, p.R167W, p.R173W, p.R173Q, p.R225G, p.R225X, c.1073delA) and more than six patients in each group. The patients were selected from the pool of 287 Finnish AIP patients presented in a Finnish Porphyria Register (1966-2003) and 23 Russian AIP patients (diagnosed 1995-2003). Patients with the p.R167W and p.R225G mutations showed lower penetrance (19% and 11%) and the recurrence rate (33% and 0%) in comparison to the patients with other mutations (range 36 to 67% and 0 to 66%, respectively), as well as milder biochemical abnormalities [urinary porphobilinogen 47±10 vs. 163±21 mol/L, p<0.001; uroporphyrin 130±40 vs. 942±183 nmol/L, p<0.001] suggesting a milder form of AIP in these patients. Erythrocyte HMBS activity did not correlate with the porphobilinogen excretion in remission or the clinical of the disease. In all AIP severity patients, normal PBG excretion predicted freedom from acute attacks. Urinary PBG excretion together with gender, age at the time of diagnosis and mutation type could predict the likelihood of acute attacks in AIP patients.

Book Review: "The Interface: IBM and the Transformation of Corporate Design, 1945-1975", John Harwood, Minneapolis: University of Minnesota Press, 2011

Within the history of twentieth-century design, there are a number of well-known objects and stories that are invoked time and time again to capture a pivotal moment or summarize a much broader historical transition. For example, Marcel Breuer’s Model B3 chair is frequently used as a stand-in for the radical investigations of form and new industrial materials occurring at the Bauhaus in the mid-1920s. Similarly, Raymond Loewy’s streamlined pencil sharpener has become historical shorthand for the emergence of modern industrial design in the 1930s. And any discussion of the development of American postwar “organic design” seems incomplete without reference to Charles and Ray Eames’s molded plywood leg splint of 1942. Such objects and narratives are dear to historians of modern design. They are tangible, photogenic subjects that slot nicely into exhibitions, historical surveys, and coffee-table best sellers...

'Hero to healing' drink driving program for Indigenous communities in Far North Queensland

Issue addressed: Alcohol-related road crashes are a leading cause of the injury burden experienced by Indigenous Australians. Existing drink driving programs are primarily designed for the mainstream population. The ‘Hero to Healing’ program was specifically developed with Indigenous communities and is underpinned by the Community Reinforcement Approach (CRA). This paper reports on the formative evaluation of the program from delivery in two Far North Queensland communities. Methods: Focus groups and semistructured interviews were conducted with drink driver participants (n = 17) and other Elders and community members (n = 8) after each program. Qualitative content analysis was used to categorise the transcripts. Results: The CRA appealed to participants because of its flexible nature and encouragement of rearranging lifestyle factors, without specific focus on alcohol use. Participants readily identified with the social and peer-related risk and protective factors discussed. Cofacilitation of the program with Elders was identified as a key aspect of the program. More in-depth discussion about cannabis and driving, anger management skills and relationship issues are recommended. Conclusions: Participants’ recognition of content reinforced earlier project results, particularly the use of kinship pressure to motivate younger family members to drink drive. Study findings suggest that the principles of the CRA are useful; however, some amendments to the CRA components and program content were necessary. So what?: Treating drink driving in regional and remote Indigenous Australian communities as a community and social issue, rather than an individual phenomenon, is likely to lead to a reduction in the number of road-related injuries Indigenous people experience.

Characterization of an N6 adenine methyltransferase from Helicobacter pylori strain 26695 which methylates adjacent adenines on the same strand

Genomic sequences of Helicobacter pylori strains 26695, J99, HPAGI and G27 have revealed an abundance of restriction and modification genes. hp0050, which encodes an N6 adenine DNA methyltransferase, was cloned, overexpressed and purified to near homogeneity. It recognizes the sequence 5'-GRRG-3' (where R is A or G) and, most intriguingly, methylates both adenines when R is A (5'-GAAG-3'). Kinetic analysis suggests a nonprocessive (repeated-hit) mechanism of methylation in which HP0050 methyltransferase methylates one adenine at a time in the sequence 5'-GAAG-3'. This is the first report of an N6 adenine DNA methyltransferase that methylates two adjacent residues on the same strand. Interestingly, HP0050 homologs from two clinical strains of H. pylori (PG227 and 128) methylate only 5'-GAGG-3' compared with 5'-GRRG-3' in strain 26695. HP0050 methyltransferase is highly conserved as it is present in more than 90% of H. pylori strains. Inactivation of hp0050 in strain PG227 resulted in poor growth, suggesting its role in the biology of H. pylori. Collectively, these findings provide impetus for exploring the role(s) of this conserved DNA methyltransferase in the cellular processes of H. pylori.

Fertility in Namibia : Changes in fertility levels in North-Central Namibia 1960-2001, including an assessment of the impact of HIV

The aim of this study was to estimate the development of fertility in North-Central Namibia, former Ovamboland, from 1960 to 2001. Special attention was given to the onset of fertility decline and to the impact of the HIV epidemic on fertility. An additional aim was to introduce parish registers as a source of data for fertility research in Africa. Data used consisted of parish registers from Evangelical Lutheran congregations, the 1991 and 2001 Population and Housing Censuses, the 1992 and 2000 Namibia Demographic and Health Surveys, and the HIV sentinel surveillances of 1992-2004. Both period and cohort fertility were analysed. The P/F ratio method was used when analysing census data. The impact of HIV infection on fertility was estimated indirectly by comparing the fertility histories of women who died at an age of less than 50 years with the fertility of other women. The impact of the HIV epidemic on fertility was assessed both among infected women and in the general population. Fertility in the study population began to decline in 1980. The decline was rapid during the 1980s, levelled off in the early 1990s at the end of war of independence and then continued to decline until the end of the study period. According to parish registers, total fertility was 6.4 in the 1960s and 6.5 in the 1970s, and declined to 5.1 in the 1980s and 4.2 in the 1990s. Adjustment of these total fertility rates to correspond to levels of fertility based on data from the 1991 and 2001 censuses resulted in total fertility declining from 7.6 in 1960-79 to 6.0 in 1980-89, and to 4.9 in 1990-99. The decline was associated with increased age at first marriage, declining marital fertility and increasing premarital fertility. Fertility among adolescents increased, whereas the fertility of women in all other age groups declined. During the 1980s, the war of independence contributed to declining fertility through spousal separation and delayed marriages. Contraception has been employed in the study region since the 1980s, but in the early 1990s, use of contraceptives was still so limited that fertility was higher in North-Central Namibia than in other regions of the country. In the 1990s, fertility decline was largely a result of the increased prevalence of contraception. HIV prevalence among pregnant women increased from 4% in 1992 to 25% in 2001. In 2001, total fertility among HIV-infected women (3.7) was lower than that among other women (4.8), resulting in total fertility of 4.4 among the general population in 2001. The HIV epidemic explained more than a quarter of the decline in total fertility at population level during most of the 1990s. The HIV epidemic also reduced the number of children born by reducing the number of potential mothers. In the future, HIV will have an extensive influence on both the size and age structure of the Namibian population. Although HIV influences demographic development through both fertility and mortality, the effect through changes in fertility will be smaller than the effect through mortality. In the study region, as in some other regions of southern Africa, a new type of demographic transition is under way, one in which population growth stagnates or even reverses because of the combined effects of declining fertility and increasing mortality, both of which are consequences of the HIV pandemic.

A Model for Creating Strategic Alliances. A Study of Inter-firm Cooperation in the North European ICT Sector

In this study, it is argued that the view on alliance creation presented in the current academic literature is limited, and that using a learning approach helps to explain the dynamic nature of alliance creation. The cases in this study suggest that a wealth of inefficiency elements can be found in alliance creation. These elements can further be divided into categories, which help explain the dynamics of alliance creation. The categories –combined with two models brought forward by the study– suggest that inefficiency can be avoided through learning during the creation process. Some elements are especially central to this argumentation. First, the elements related to the clarity and acceptance of the strategy of the company, the potential lack of an alliance strategy and the elements related to changes in the strategic context. Second, the elements related to the length of the alliance creation processes and the problems a long process entails. It is further suggested that the different inefficiency elements may create a situation, where the alliance creation process is –sequentially and successfully– followed to the end, but where the different inefficiencies create a situation where the results are not aligned with the strategic intent. The proposed solution is to monitor and assess the risk for inefficiency elements during the alliance creation process. The learning, which occurs during the alliance creation process as a result of the monitoring, can then lead to realignments in the process. This study proposes a model to mitigate the risk related to the inefficiencies. The model emphasizes creating an understanding of the other alliance partner’s business, creating a shared vision, using pilot cooperation and building trust within the process. An analytical approach to assessing the benefits of trust is also central in this view. The alliance creation approach suggested by this study, which emphasizes trust and pilot cooperation, is further critically reviewed against contracting as a way to create alliances.

A physical mechanism for North Atlantic SST influence on the Indian summer monsoon

A link between the Atlantic Multidecadal Oscillation (AMO) and multidecadal variability of the Indian summer monsoon rainfall is unraveled and a long sought physical mechanism linking Atlantic climate and monsoon has been identified. The AMO produces persistent weakening (strengthening) of the meridional gradient of tropospheric temperature (TT) by setting up negative (positive) TT anomaly over Eurasia during northern late summer/autumn resulting in early (late) withdrawal of the south west monsoon and persistent decrease (increase) of seasonal monsoon rainfall. On inter-annual time scales, strong North Atlantic Oscillation (NAO) or North Annular mode (NAM) influences the monsoon by producing similar TT anomaly over Eurasia. The AMO achieves the interdecadal modulation of the monsoon by modulating the frequency of occurrence of strong NAO/NAM events. This mechanism also provides a basis for explaining the observed teleconnection between North Atlantic temperature and the Asian monsoon in paleoclimatic proxies. Citation: Goswami, B. N., M. S. Madhusoodanan, C. P. Neema, and D. Sengupta (2006), A physical mechanism for North Atlantic SST influence on the Indian summer monsoon

Pragmatismi poliittisena filosofiana. Yksilö ja yhteisö John Deweyn ajttelussa

John Dewey (1859-1952) oli yhdysvaltalainen filosofi, pedagogi ja julkinen keskustelija, jonka ajattelu on merkittävästi vaikuttanut pragmatismina tunnetun filosofisen suuntauksen kehittymiseen. Tässä Pro gradu -tutkielmassa tarkastellaan Devveyn poliittista filosofiaa ja ajattelua. Tarkoituksena on selvitellä, millaista on Devveyn poliittinen filosofia ja voiko hänen pragmatistinen poliittinen filosofiansa tarjota jotain mielenkiintoista myös tämän päivän poliittisen filosofian kentälle. Tutkielmassa tarkastellaan Devveyn esittämää kritiikkiä klassista liberalismia ja individualismia kohtaan, Devveyn omaa poliittisen filosofian projektia sekä sen kohtaama kritiikkiä ja arvioidaan Devveyn poliittista filosofiaa yleisesti. Tarkastelun kohteena ovat muun muassa Devveyn käsitykset yksilöstä, valtiosta, demokratiasta, vallasta ja tiedosta. Ensisijaisena lähteenä tutkielmassa on Devveyn koottujen teosten sarja vuosilta 1882-1953, ennen kaikkea 1920-30-lukujen tuotanto. Lisäksi lähteenä on useita tuoreita artikkeleita sekä kommentaareja. Keskeisin löytö tutkielmassa on, että Devveyn poliittisen filosofian oleellinen piirre on "anti-essentialismi", eli huomion siirtäminen pois jostain oletetuista yksilöiden ja ryhmien olemuksista tai sisäisestä luonnosta niiden välisiin suhteisiin ja näiden ilmauksiin. Tähän liittyen Devveyn poliittisen filosofian keskeiseksi lähtökohdaksi osoittautuu perinteisen yksilö-yhteisö jaottelun kyseenalaistaminen. Tutkielma tarjoaa laajan katsauksen Devveyn poliittiseen ajatteluun sekä pragmatistiseen poliittiseen filosofiaan.

Vertical thermal structure of the atmosphere during active and weak phases of convection over the north Bay of Bengal: Observation and model results

Owing to the lack of atmospheric vertical profile data with sufficient accuracy and vertical resolution, the response of the deep atmosphere to passage of monsoon systems over the Bay of Bengal. had not been satisfactorily elucidated. Under the Indian Climate Research Programme, a special observational programme called 'Bay of Bengal Monsoon Experiment' (BOBMEX), was conducted during July-August 1999. The present study is based on the high-resolution radiosondes launched during BOBMEX in the north Bay. Clear changes in the vertical thermal structure of the atmosphere between active and weak phases of convection have been observed. The atmosphere cooled below 6 km height and became warmer between 6 and 13 km height. The warmest layer was located between 8 and 10 km height, and the coldest layer was found just below 5 km height. The largest fluctuations in the humidity field occurred in the mid-troposphere. The observed changes between active and weak phases of convection are compared with the results from an atmospheric general circulation model, which is similar to that used at the National Centre for Medium Range Weather Forecasting, New Delhi. The model is not able to capture realistically some important features of the temperature and humidity profiles in the lower troposphere and in the boundary layer during the active and weak spells.