A multi-level decomposition of variance in somatic symptom reporting in families with adolescent children

OBJECTIVES: This paper examines four different levels of possible variation in symptom reporting: occasion, day, person and family. DESIGN: In order to rule out effects of retrospection, concurrent symptom reporting was assessed prospectively using a computer-assisted self-report method. METHODS: A decomposition of variance in symptom reporting was conducted using diary data from families with adolescent children. We used palmtop computers to assess concurrent somatic complaints from parents and children six times a day for seven consecutive days. In two separate studies, 314 and 254 participants from 96 and 77 families, respectively, participated. A generalized multilevel linear models approach was used to analyze the data. Symptom reports were modelled using a logistic response function, and random effects were allowed at the family, person and day level, with extra-binomial variation allowed for on the occasion level. RESULTS: Substantial variability was observed at the person, day and occasion level but not at the family level. CONCLUSIONS: To explain symptom reporting in normally healthy individuals, situational as well as person characteristics should be taken into account. Family characteristics, however, would not help to clarify symptom reporting in all family members.

THE ROLE OF AN EXPLICIT CAUSAL FRAMEWORK IN AFFECTED SIB PAIR DESIGNS WITH COVARIATES

The affected sib/relative pair (ASP/ARP) design is often used with covariates to find genes that can cause a disease in pathways other than through those covariates. However, such "covariates" can themselves have genetic determinants, and the validity of existing methods has so far only been argued under implicit assumptions. We propose an explicit causal formulation of the problem using potential outcomes and principal stratification. The general role of this formulation is to identify and separate the meaning of the different assumptions that can provide valid causal inference in linkage analysis. This separation helps to (a) develop better methods under explicit assumptions, and (b) show the different ways in which these assumptions can fail, which is necessary for developing further specific designs to test these assumptions and confirm or improve the inference. Using this formulation in the specific problem above, we show that, when the "covariate" (e.g., addiction to smoking) also has genetic determinants, then existing methods, including those previously thought as valid, can declare linkage between the disease and marker loci even when no such linkage exists. We also introduce design strategies to address the problem.

A common ancestral glycoprotein (GP) 9 1828A>G (Asn45Ser) gene mutation occurring in European families from Australia and Northern Europe with Bernard-Soulier Syndrome (BSS)

Bernard-Soulier syndrome (BSS) is an extremely rare hereditary bleeding disorder, caused by mutations occurring in the Glycoprotein (GP) Ibalpha, GPIbbeta and GP9 genes that encode for the corresponding subunits of platelet GPIb-V-IX adhesion receptor complex. BSS has been reported in many populations, mostly behaving in an autosomal-recessive manner.While the great majority of BSS mutations are unique to a single individual or family, the GP9 1828A>G Asn45Ser mutation, which we have identified in an undocumented Australian Caucasian, has already been reported in multiple unrelated Caucasian families from various Northern and Central European countries. Haplotype analysis of 19 BSS patients from 15 unrelated Northern European families (including 2 compound heterozygote siblings from a British family previously published, and 17 1828A>G Asn45Ser homozygotes), showed that 14 of these BSS patients from 11 of the 1828A>G Asn45Ser homozygote families share a common haplotype at the chromosomal region 3' to the GP9 gene. Hence, the results suggest that the GP9 1828A>GAsn45Ser mutation in these families is ancient, and its frequent emergence in the European population is the result of a founder effect rather than recurrent mutational events. Association of the 1828A>G Asn45Ser mutation with variant haplotypes in 4 other Northern European BSS families raised the possibility of a second founder event, or rare recombinations in these families. Additional members from these 'atypical' lineages would need to be screened to resolve this question.

The influence of measles vaccination on the incidence of otosclerosis in Germany

The pathologic process of otosclerosis is characterized by an inflammatory lytic phase followed by an abnormal bone remodeling at very specific sites of predilection. There is a clear genetic predisposition with about half of all cases occurring in families with more than one affected member. Females are affected more frequently than males with an approximate 2:1 ratio. N, H, and F measles proteins as well as measles virus RNA have been demonstrated in osteoblasts, chondroblasts, and macrophages of the inflammatory phase of the disease. These observations merely show an association between measles viruses and otosclerosis. In the present study, we tried to prove that there is a causal relationship: voluntary measles vaccination has been available in Germany since 1974. In the absence of official data, we reconstructed the rate of vaccination coverage between 1974 and 2004 using information from the Robert Koch Institute (RKI, Berlin) and from the literature. From the German Federal Office of Statistics, we received the data of 64,112 patients who had been hospitalized between 1993 and 2004 and in whom otosclerosis (ICD-9: 387; ICD-10: H80) had been confirmed. We calculated the effect of measles vaccination on the incidence of hospital treatments for otosclerosis in the period from 1993 to 2004 in Germany. For this purpose, we divided the female and male otosclerosis patients treated as inpatients each year in the observation period into two age groups: those up to 25 years, who had in most cases been vaccinated (designated below as "vaccinated patients") and those over 25 years who mostly could not have been vaccinated (designated below as "unvaccinated patients"). We calculated the incidence of otosclerosis requiring inpatient treatment for the two age groups in each year in the period of observation. For external validation of the study results, the same analysis was carried out in all patients who received inpatient treatment for otitis media in the same period. Between 1993 and 2004 the incidence of hospital treatments for otosclerosis decreased to a significantly greater extent in the vaccinated patients than in the unvaccinated patients. The decline is much greater in men than in women. A comparable effect cannot be demonstrated in patients with otitis media. The results indicate that measles vaccination in Germany has resulted in a significant reduction in the number of hospital treatments for otosclerosis in the vaccinated age groups. We conclude that there is a causal relationship between measles viruses and the development of otosclerosis.

Genetic maps of the proximal half of chromosome arm 2L of Drosophila melanogaster

Drosophila mutants have played an important role in elucidating the physiologic function of genes. Large-scale projects have succeeded in producing mutations in a large proportion of Drosophila genes. Many mutant fly lines have also been produced through the efforts of individual laboratories over the past century. In an effort to make some of these mutants more useful to the research community, we systematically mapped a large number of mutations affecting genes in the proximal half of chromosome arm 2L to more precisely defined regions, defined by deficiency intervals, and, when possible, by individual complementation groups. To further analyze regions 36 and 39-40, we produced 11 new deficiencies with gamma irradiation, and we constructed 6 new deficiencies in region 30-33, using the DrosDel system. trans-heterozygous combinations of deficiencies revealed 5 additional functions, essential for viability or fertility.

Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia

PURPOSE: The transcription factor CCAAT/enhancer binding protein-alpha (CEBPA) is crucial for normal myeloid differentiation. Mutations in the CEBPA gene are found in subsets of patients with acute myeloid leukemia (AML). Recently, three families were reported in whom several family members had germline CEBPA mutations and subsequently developed AML. Whereas familial AML is considered a rare event, the frequency of CEBPA germline mutations in AML is not known. PATIENTS AND METHODS: In this study, we screened 187 consecutive AML patients for CEBPA mutations at diagnosis. We detected 18 patients (9.6%) with CEBPA mutations. We then analyzed remission samples and constitutive DNA from these patients. RESULTS: We found that two (11.1%) of 18 AML patients with CEBPA mutations carried a germline N-terminal frameshift CEBPA mutation. Interestingly, additional members in the families of both of these patients have been affected by AML, and the germline CEBPA mutations were also observed in these patients. Additional somatic mutations in AML patients with germline CEBPA mutations in the two families comprised in-frame C-terminal CEBPA mutations in two patients, two nonsilent CEBPA point mutations in one patient, and monosomy 7 in one patient. CONCLUSION: This study shows, for the first time to our knowledge, that germline CEBPA mutations are frequently observed among AML patients with CEBPA mutations. Including the families with germline CEBPA mutations reported previously, additional somatic CEBPA mutations represent a frequent second event in AML with germline CEBPA mutations. Our data strongly indicate that germline CEBPA mutations predispose to AML and that additional somatic CEBPA mutations contribute to the development of the disease.

Epidemiological survey of 214 families with bladder exstrophy-epispadias complex

PURPOSE: We sought to identify causative nongenetic and genetic risk factors for the bladder exstrophy-epispadias complex. MATERIALS AND METHODS: A total of 237 families with the bladder exstrophy-epispadias complex were invited to participate in the study, and information was obtained from 214 families, mainly from European countries. RESULTS: Two families showed familial occurrence. Male predominance was found among all subgroups comprising epispadias, classic bladder exstrophy and cloacal exstrophy, with male-to-female ratios of 1.4:1, 2.8:1 and 2.0:1, respectively (p = 0.001). No association with parental age, maternal reproductive history or periconceptional maternal exposure to alcohol, drugs, chemical noxae, radiation or infections was found. However, periconceptional maternal exposure to smoking was significantly more common in patients with cloacal exstrophy than in the combined group of patients with epispadias/classic bladder exstrophy (p = 0.009). Only 16.8% of mothers followed the current recommendations of periconceptional folic acid supplementation, and 17.6% had started supplementation before 10 weeks of gestation. Interestingly, in the latter group mothers of patients with cloacal exstrophy were more compliant with folic acid supplementation than were mothers of the combined group of patients with epispadias/classic bladder exstrophy (p = 0.037). Furthermore, mothers of children with cloacal exstrophy knew significantly more often prenatally that their child would have a congenital malformation than did mothers of children with epispadias/classic bladder exstrophy (p <0.0001). CONCLUSIONS: Our study corroborates the hypothesis that epispadias, classic bladder exstrophy and cloacal exstrophy are causally related, representing a spectrum of the same developmental defect, with a small risk of recurrence within families. Embryonic exposure to maternal smoking appears to enforce the severity, whereas periconceptional folic acid supplementation does not seem to alleviate it. There is a disproportional prenatal ultrasound detection rate between severe and mild phenotypes, possibly due to the neglect of imaging of full bladders with a focus on neural tube defects.

Novel chloride channel mutations leading to mild myotonia among Chinese

We describe two Chinese families with a mild form of the myotonia congenita due to novel chloride channel (ClCN1) mutations. In one case, heterozygous I553F and H555N mutations were found. The patient shared the I553F mutation with his healthy father, and his mother had a history of mild myotonia when she was younger. In another family, autosomal dominant myotonia congenita was due to a L844F change. The physiological effects of the mutations were examined by using the two-electrode voltage-clamp technique after expression of the channels in Xenopus oocytes. All mutations drastically shifted the voltage required for half-maximal activation, more under conditions mimicking the homozygous situation, than under conditions mimicking the heterozygous situation. The larger effect was seen in the compound heterozygous situation combining the I553F and the H555N mutations. Our data suggest that myotonia congenita caused by CLCN1 mutations in Chinese have similar variable features to those found in the West.

The Role of Fraternal Organisation in Migration and Informal Labour Organisations in Mining Communities: Cornwall, the Keweenaw, and California Compared

During the second half of the nineteenth century fraternal and benevolent associations of numerous descriptions grew and prospered in mining communities everywhere. They played an important, but neglected role, in assisting transatlantic migration and movement between mining districts as well as building social capital within emerging mining communities. They helped to build bridges between different ethnic communities, provided conduits between labour and management, and networked miners into the non-mining community. Their influence spread beyond the adult males that made up most of their membership to their wives and families and provided levels of social and economic support otherwise unobtainable at that time. Of course, the influence of these organisations could also be divisive where certain groups or religions were excluded and they may have worked to exacerbate, as much as ameliorate, the problems of community development. This paper will examine some of these issues by looking particularly at the role of Freemasonry and Oddfellowry in Cornwall, Calumet, and Nevada City between 1860 and 1900. Work on fraternity in the Keweenaw was undertaken in Houghton some years ago with a grant from the Copper Country Archive and has since been continued by privately funded research in California and other Western mining states. Some British aspects of this research can be found in my article on mining industrial relations in Labour History Review April 2006

Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing

PURPOSE: The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. METHODS: In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. RESULTS: This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3'-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. CONCLUSIONS: RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families.

WATER ACCESS AND MAINTENANCE IN KARONGA, MALAWI

This report is a case study of how Mwangalala community accesses water and how that access is maintained. Mwangalala community is located in the northern tip of Karonga district in Malawi, Africa. The case study evaluates how close the community is to meeting target 10 of the Millennium Development Goals, sustainable access to safe drinking water, and evaluates the current water system through Human Centered Design’s criteria of desirability, feasibility, and viability. It also makes recommendations to improve water security in Mwangalala community. Data was collected through two years of immersive observation, interviews with 30 families, and observing two wells on three separate occasions. The 30 interviews provided a sample size of over 10% of the community’s population. Participants were initially self-selected and then invited to participate in the research. I walked along community pathways and accepted invitations to join casual conversations in family compounds. After conversing I asked the family members if they would be willing to participate in my research by talking with me about water. Data collected from the interviews and the observations of two wells were compared and analyzed for common themes. Shallow wells or open wells represented the primary water source for 93% of interview participants. Boreholes were also present in the community, but produced unpalatable water due to high concentrations of dissolved iron and were not used as primary water sources. During observations 75% of community members who used the shallow well, primarily used for consumptive uses like cooking or dinking, were females. Boreholes were primarily used for non-consumptive uses such as watering crops or bathing and 77% of the users were male. Shallow wells could remain in disrepair for two months because the repairman was a volunteer, who was not compensated for the skilled labor required to repair the wells. Community members thought the maintenance fee went towards his salary, so did not compensate the repairman when he performed work. This miscommunication provided no incentive for the repairman to make well repairs a priority, and left community members frustrated with untimely repairs. Shallow wells with functional pumps failed to provide water when the water table levels drop during dry season, forcing community members to seek secondary or tertiary water sources. Open wells, converted from shallow wells after community members did not pay for repairs to the pump, represented 44% of the wells originally installed with Mark V hand pumps. These wells whose pumps were not repaired were located in fields and one beside a church. The functional wells were all located on school grounds or in family compounds, where responsibility for the well’s maintenance is clearly defined. Mwangalala community fails to meet Millennium Development goals because the wells used by the community do not provide sustainable access to safe drinking water. Open wells, used by half the participants in the study, lack a top covering to prevent contamination from debris and wildlife. Shallow well repair times are unsustainable, taking longer than two weeks to be repaired, primarily because the repair persons are expected to provide skilled labor to repair the wells without compensation. Improving water security for Mwangalala can be achieved by improving repair times on shallow wells and making water from boreholes palatable. There are no incentives for a volunteer repair person to fix wells in a timely manner. Repair times can be improved by reducing the number of wells a repair person is responsible for and compensating the person for the skilled labor provided. Water security would be further improved by removing iron particulates from borehole water, thus rendering it palatable. This is possible through point of use filtration utilizing ceramic candles; this would make pumped water available year-round.