Safety of tacrolimus 0.03% and 0.1% ointments in young children with atopic dermatitis: a 36-month follow-up study.

BACKGROUND: Topical tacrolimus is used off-label in young children, but data are limited on its use in children under 2 years of age and for long-term treatment. AIM: To compare safety differences between topical tacrolimus (0.03% and 0.1% ointments) and topical corticosteroids (mild and moderate potency) in young children with atopic dermatitis (AD). METHODS: We conducted a 36-month follow-up study with 152 young children aged 1-3 years with moderate to severe AD. The children were followed up prospectively, and data were collected on infections, disease severity, growth parameters, vaccination responses and other relevant laboratory tests were gathered. RESULTS: There were no significant differences between the treatment groups for skin-related infections (SRIs) (P = 0.20), non-SRIs (P = 0.20), growth parameters height (P = 0.60), body weight (P = 0.81), Eczema Area and Severity Index (EASI) (P = 0.19), vaccination responses (P = 0.62), serum cortisone levels (P = 0.23) or serum levels of interleukin (IL)-4, IL-10, IL-12, IL-31 and interferon-γ. EASI decreased significantly in both groups (P < 0.001). In the tacrolimus group, nine patients (11.68%) had detectable tacrolimus blood concentrations at the 1-week visit. There were no malignancies or severe infections during the study, and blood eosinophil counts were similar in both groups. CONCLUSIONS: Topical tacrolimus (0.03% and 0.1%) and topical corticosteroids (mild and moderate potency) are safe to use in young children with moderate to severe AD, and have comparable efficacy and safety profiles.

Infant and childhood growth and frailty in old age: the Helsinki Birth Cohort Study.

BACKGROUND: Evidence from life course studies highlights the importance of infant and childhood growth as risk factors for adulthood chronic diseases. METHODS: In this sub-study of the Helsinki Birth Cohort Study, we studied 1078 individuals who had both information on body size from birth to 12 years of age and who were assessed for frailty according to the Fried criteria at the mean age of 71 years. RESULTS: Greater BMI gain between 2 and 11 years in boys was associated with frailty in old age (age-adjusted RRR 2.36, 95% CI 1.21, 4.63). No similar associations were observed in girls. CONCLUSIONS: Men who were frail in old age experienced accelerated BMI gain in childhood compared with those men who were not frail. This was not observed in women, which suggests that the patterns of early growth predisposing to frailty may vary by sex.

Early life stress and frailty in old age: the Helsinki birth cohort study.

BACKGROUND: Evidence suggests that early life stress (ELS) may extend its effect into adulthood and predispose an individual to adverse health outcomes. We investigated whether wartime parental separation, an indicator of severe ELS, would be associated with frailty in old age. METHODS: Of the 972 participants belonging to the present sub-study of the Helsinki Birth Cohort Study, 117 (12.0%) had been evacuated abroad unaccompanied by their parents in childhood during World War II. Frailty was assessed at a mean age of 71 years according to Fried's criteria. RESULTS: Thirteen frail men (4 separated and 9 non-separated) and 20 frail women (2 separated and 18 non-separated) were identified. Compared to the non-separated men, men who had been separated had an increased relative risk ratio (RRR) of frailty (age-adjusted RRR 3.93, 95% CI 1.02, 15.11) that persisted after adjusting for several confounders. No associations were observed among women (RRR 0.62; 95% CI 0.13, 2.94). CONCLUSIONS: These preliminary results suggest that ELS might extend its effects not just into adulthood but also into old age, and secondly, that men may be more vulnerable to the long-term effects of ELS.

Early life determinants of frailty in old age: the Helsinki Birth Cohort Study.

BACKGROUND: there is evidence suggesting that several chronic diseases have their origins in utero and that development taking place during sensitive periods may affect the aging process. We investigated whether early life determinants would be associated with frailty in old age. METHODS: at a mean age of 71 years, 1,078 participants belonging to the Helsinki Birth Cohort Study were assessed for frailty according to the Fried frailty criteria. Early life measurements (birth weight, length, mother body mass index [BMI] and parity) were obtained from birth, child welfare and school health records. Multinomial regression analysis was used to assess the association between early life determinants and frailty in old age. RESULTS: weight, length and BMI at birth were all inversely associated with frailty in old age. A 1 kg increase in birth weight was associated with a lower relative risk ratio (RRR) of frailty (age and sex-adjusted RRR = 0.40, 95% CI: 0.19, 0.82) compared to non-frailty. Associations persisted after adjusting for several confounding factors. Compared to cohort members in the upper middle class, those who as adults worked as manual workers or belonged to the lower middle class, were at an increased risk of frailty. CONCLUSIONS: those who were small at birth were at an increased risk of developing frailty in old age, suggesting that frailty is at least partly programmed in early life. A less privileged socioeconomic status in adulthood was associated with an increased risk of frailty in old age.

Relationship between physical activity and physical performance in later life in different birth weight groups.

There is strong evidence that physical activity (PA) has an influence on physical performance in later life. Also, a small body size at birth has been associated with lower physical functioning in older age and both small and high birth weight have shown to be associated with lower leisure time physical activity. However, it is unknown whether size at birth modulates the association between PA and physical performance in old age. We examined 695 individuals from the Helsinki Birth Cohort Study born in Helsinki, Finland between 1934 and 1944. At a mean age of 70.7 years PA was objectively assessed with a multisensory activity monitor and physical performance with the Senior Fitness Test (SFT). Information on birth weight and gestational age was retrieved from hospital birth records. The study participants were divided in three birth weight groups, that is <3000 g, 3000-3499 g and ⩾3500 g. The volume of PA was significantly associated with the physical performance in all birth weight groups. However, the effect size of the association was large and significant only in men with a birth weight <3000 g (ß 0.59; 95% confidence interval 0.37-0.81, P<0.001). Our study shows that the association between PA and physical performance is largest in men with low birth weight. Our results suggest that men with low birth weight might benefit most from engaging in PA in order to maintain a better physical performance.

Associations between family characteristics and parental empowerment in the family, family service situations and the family service system.

BACKGROUND: Parental empowerment signifies parents' sense of confidence in managing their children, interacting with services that their children use and improving child care services. High empowerment is associated with parents' resilience to demands and their confidence to make decisions and take actions that positively affect their families. Most families with children access various healthcare and education services. Professionals working in these services are therefore ideally placed to reinforce parental empowerment. However, little is known about the characteristics associated with parental empowerment within a generic sample of parents or in the context of basic child care services. AIM: The aim of this study was to assess how family characteristics are associated with maternal and paternal empowerment in the family, in service situations and in the service system. METHOD: Parental empowerment was measured among 955 parents (mothers = 571; fathers = 384) of children aged 0-9 years using the Generic Family Empowerment Scale. Family characteristics were assessed through questions on children, parents and the life situation. Associations between empowerment and family characteristics were evaluated using one-way analysis of variance and t-test. Parental empowerment was predicted by multiple linear regression analysis. RESULTS: Parents' concerns related to their parenting, such as whether they possessed sufficient skills as a parent or losing their temper with children, as well as experiences of stress in everyday life, were negatively associated with all dimensions of maternal and paternal empowerment. Both determinants were more common and more significant in empowerment than child-related problems. CONCLUSION: Promoting parental self-confidence and providing appropriate emotional and concrete support for everyday functioning may reinforce parental empowerment, thereby enhancing families' well-being and coping, as well as improving their access to required services and timely support. Finally, it may facilitate the provision of better services to all families.

Identifying microRNAs regulating B7-H3 in breast cancer: the clinical impact of microRNA-29c.

BACKGROUND: B7-H3, an immunoregulatory protein, is overexpressed in several cancers and is often associated with metastasis and poor prognosis. Here, our aim was to identify microRNAs (miRNAs) regulating B7-H3 and assess their potential prognostic implications in breast cancer. METHODS: MicroRNAs targeting B7-H3 were identified by transfecting two breast cancer cell lines with a library of 810 miRNA mimics and quantifying changes of B7-H3 protein levels using protein lysate microarrays. For validations we used western immunoblotting and 3'-UTR luciferase assays. Clinical significance of the miRNAs was assayed by analysing whether their expression levels correlated with outcome in two cohorts of breast cancer patients (142 and 81 patients). RESULTS: We identified nearly 50 miRNAs that downregulated B7-H3 protein levels. Western immunoblotting validated the impact of the 20 most effective miRNAs. Thirteen miRNAs (miR-214, miR-363*, miR-326, miR-940, miR-29c, miR-665, miR-34b*, miR-708, miR-601, miR-124a, miR-380-5p, miR-885-3p, and miR-593) targeted B7-H3 directly by binding to its 3'-UTR region. Finally, high expression of miR-29c was associated with a significant reduced risk of dying from breast cancer in both cohorts. CONCLUSIONS: We identified miRNAs efficiently downregulating B7-H3 expression. The expression of miR-29c correlated with survival in breast cancer patients, suggesting a tumour suppressive role for this miRNA.

Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10/Apo2L) holds promise for cancer therapy as it induces apoptosis in a large variety of cancer cells while exerting negligible toxicity in normal ones. However, TRAIL can also induce proliferative and migratory signaling in cancer cells resistant to apoptosis induced by this cytokine. In that regard, the molecular mechanisms underlying the tumor selectivity of TRAIL and those balancing apoptosis versus survival remain largely elusive. We show here that high mRNA levels of PLAU, which encodes urokinase plasminogen activator (uPA), are characteristic of cancer cells with functional TRAIL signaling. Notably, decreasing uPA levels sensitized cancer cells to TRAIL, leading to markedly increased apoptosis. Mechanistic analyses revealed three molecular events taking place in uPA-depleted cells: reduced basal ERK1/2 prosurvival signaling, decreased preligand decoy receptor 2 (DcR2)-death receptor 5 (DR5) interaction and attenuated recruitment of DcR2 to the death-inducing signaling complex upon TRAIL challenge. These phenomena were accompanied by increased FADD and procaspase-8 recruitment and processing, thus guiding cells toward a caspase-dependent cell death that is largely independent of the intrinsic apoptosis pathway. Collectively, our results unveil PLAU mRNA levels as marker for the identification of TRAIL-responsive tumor cells and highlight a key role of uPA signaling in 'apoptosis versus survival' decision-making processes upon TRAIL challenge.

The validity and reliability of the Finnish Family Empowerment Scale (FES): a survey of parents with small children.

BACKGROUND: The Family Empowerment Scale (FES) is a widely used instrument which measures the parents' own sense of their empowerment at the level of the family, service system and community. It was originally developed for parents of children with emotional disabilities. AIM: The aims of this study were to evaluate the validity and reliability of the Finnish FES and to examine its responsiveness in measuring the empowerment of parents with small children. METHODS AND PARTICIPANTS: The English FES was translated into Finnish using back translation and modified so as to be generic and convenient for all families. The construct, convergent, discriminant and concurrent validities, reliability and responsiveness of the Finnish FES were examined. Participants (n = 955) were the parents of children aged 0-9 years who had been selected using stratified random sampling. RESULTS: Confirmatory factor analysis proved that the Finnish FES had three subscales based on the original FES. Convergent and discriminant validities confirmed and supported the same construct. The relationship between parents' participation and empowerment was tested for concurrent validity. As in previous FES studies, the participating parents were more empowered, which supported the concurrent validity. The reliability of the Finnish FES proved acceptable for both parents. The Finnish FES could also discriminate the responses of the parents. Participation in the activities organized by the family service system influenced parents' perceptions of empowerment more than did their background characteristics. CONCLUSIONS: The Finnish FES is a valid and reliable instrument and it is suitable for measuring the empowerment of parents. However, it is necessary to consider how the FES would identify in the best way the parents who perhaps need some help.

Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent in selectively killing tumor cells. However, TRAIL monotherapy has not been successful as many cancer cells are resistant to TRAIL. Chemotherapeutic agents, such as doxorubicin have been shown to act synergistically with TRAIL, but the exact mechanisms of actions are poorly understood. In this study, we performed high-throughput small interfering RNA screening and genome-wide gene expression profiling on doxorubicin-treated U1690 cells to explore novel mechanisms underlying doxorubicin-TRAIL synergy. The screening and expression profiling results were integrated and dihydroorotate dehydrogenase (DHODH) was identified as a potential candidate. DHODH is the rate-limiting enzyme in the pyrimidine synthesis pathway, and its expression was downregulated by doxorubicin. We demonstrated that silencing of DHODH or inhibition of DHODH activity by brequinar dramatically increased the sensitivity of U1690 cells to TRAIL-induced apoptosis both in 2D and 3D cultures, and was accompanied by downregulation of c-FLIPL as well as by mitochondrial depolarization. In addition, uridine, an end product of the pyrimidine synthesis pathway was able to rescue the sensitization effects initiated by both brequinar and doxorubicin. Furthermore, several other cancer cell lines, LNCaP, MCF-7 and HT-29 were also shown to be sensitized to TRAIL by brequinar. Taken together, our findings have identified a novel protein target and its inhibitor, brequinar, as a potential agent in TRAIL-based combinatorial cancer therapy and highlighted for the first time the importance of mitochondrial DHODH enzyme and pyrimidine pathway in mediating TRAIL sensitization in cancer cells.

Leukocyte telomere length and its relation to food and nutrient intake in an elderly population.

BACKGROUND/OBJECTIVES: Shorter leukocyte telomere length (LTL) is associated with several chronic diseases, but only a few studies have assessed the association between dietary factors and LTL. Our objective was to study the association between fats, fruits, vegetables and LTL in a cross-sectional study design. We hypothesized that intakes of fruits and vegetables would be positively associated with LTL and that intakes of fats, and especially saturated fatty acids (SFAs), would be negatively associated with LTL. SUBJECTS/METHODS: LTL was measured by quantitative real-time polymerase chain reaction in 1942 men and women aged 57-70 years from the Helsinki Birth Cohort Study. We assessed the whole diet by a validated semiquantitative 128-item food-frequency questionnaire. RESULTS: In general, there were only a few significant results. However, total fat and SFA intake (P=0.04 and 0.01, respectively) were inversely associated with LTL in men adjusting for age and energy intake. In women, vegetable intake was positively associated with LTL (P=0.05). Men consuming the most butter and least fruits had significantly shorter telomeres than those consuming the lowest amounts of butter and highest amounts of fruits (P=0.05). We found no association between LTL and body mass index, waist-hip ratio, smoking, physical activity or educational attainment. CONCLUSIONS: In this cross-sectional study of elderly men and women, there were only a few statistically significant effects of diet, but in general they support the hypothesis that fat and vegetable intakes were associated with LTL.

Search for clastogenic factors in the plasma of locally irradiated individuals.

In studies reported in the 1960s and in several investigations since, plasma from irradiated individuals was shown to induce chromosomal aberrations when transferred into normal blood cultures. In the present study, the aim was to investigate the occurrence of these clastogenic factors (CF) using markers representing DNA damage produced in reporter lymphocytes that are treated with plasma from locally exposed individuals. Blood plasma was obtained from clinical patients with benign conditions before and after they had received radiation to small treatment volumes. Three patient groups were studied: (I) marginal resected basal cell carcinoma, (II) painful osteoarthritis of the knee, and (III) painful tendinitis of the elbow or the heel. Patients in each treatment group obtained the same fractionated treatment regimen, ranging from a total dose of 40 Gy (8 × 5 Gy, 2 factions/week) to a very small volume (1-3.5 cm³) in group I to a total dose of 6 Gy (6 × 1 Gy, 2 fractions/week) for groups II and III (treatment volumes 800-1150 cm³ and 80-160 cm³, respectively). The presence of CF in the plasma was investigated through cytogenetic (chromosomal aberrations, micronuclei) assays and kinetics of early DNA damage (γ-H2AX foci) in reporter cells. With the experimental settings applied, local radiation exposure had no apparent effect on the induction of CF in patient plasma; no deviations in chromosomal aberrations or micronucleus or focus induction were observed in reporter cells treated with postexposure plasma with respect to pre-exposure samples when the mean values of the groups were compared. However, there was a large interindividual variation in the plasma-induced DNA-damaging effects. Steroid treatment of patients was demonstrated to be the most influential factor affecting the occurrence of plasma factors; plasma from patients treated with steroids led to significant reductions of γ-H2AX foci and reduced numbers of chromatid aberrations in reporter cells. In addition to the locally exposed patients, newly obtained plasma samples from three radiological accident victims exposed in 1994 were examined. In contrast to the patient data, a significant increase in chromosomal aberrations was induced with plasma from two accident victims.

HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation.

Malignant glioma is the most common brain tumor with 16,000 new cases diagnosed annually in the United States. We performed a systematic large-scale transcriptomics data mining study of 9783 tissue samples from the GeneSapiens database to systematically identify genes that are most glioma-specific. We searched for genes that were highly expressed in 322 glioblastoma multiforme tissue samples and 66 anaplastic astrocytomas as compared with 425 samples from histologically normal central nervous system. Transcription cofactor HES6 (hairy and enhancer of split 6) emerged as the most glioma-specific gene. Immunostaining of a tissue microarray showed HES6 expression in 335 (98.8%) out of the 339 glioma samples. HES6 was expressed in endothelial cells of the normal brain and glioma tissue. Recurrent grade 2 astrocytomas and grade 2 or 3 oligodendrogliomas showed higher levels of HES6 immunoreactivity than the corresponding primary tumors. High HES6 mRNA expression correlated with the proneural subtype that generally has a favorable outcome but is prone to recur. Functional studies suggested an important role for HES6 in supporting survival of glioma cells, as evidenced by reduction of cancer cell proliferation and migration after HES6 silencing. The biological role and consequences of HES6 silencing and overexpression was explored with genome-wide analyses, which implicated a role for HES6 in p53, c-myc and nuclear factor-κB transcriptional networks. We conclude that HES6 is important for glioma cell proliferation and migration, and may have a role in angiogenesis.

Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines.

Predicting the impact of microRNAs (miRNAs) on target proteins is challenging because of their different regulatory effects at the transcriptional and translational levels. In this study, we applied a novel protein lysate microarray (LMA) technology to systematically monitor for target protein levels after high-throughput transfections of 319 pre-miRs into breast cancer cells. We identified 21 miRNAs that downregulated the estrogen receptor-alpha (ERalpha), as validated by western blotting and quantitative real time-PCR, and by demonstrating the inhibition of estrogen-stimulated cell growth. Five potent ERalpha-regulating miRNAs, miR-18a, miR-18b, miR-193b, miR-206 and miR-302c, were confirmed to directly target ERalpha in 3'-untranslated region reporter assays. The gene expression signature that they repressed highly overlapped with that of a small interfering RNA against ERalpha, and across all the signatures tested, was most closely associated with the repression of known estrogen-induced genes. Furthermore, miR-18a and miR-18b showed higher levels of expression in ERalpha-negative as compared with ERalpha-positive clinical tumors. In summary, we present systematic and direct functional evidence of miRNAs inhibiting ERalpha signaling in breast cancer, and demonstrate the high-throughput LMA technology as a novel, powerful technique in determining the relative impact of various miRNAs on key target proteins and associated cellular processes and pathways.

Detection of low frequency external electronic identification devices using commercial panel readers.

The ability of a commercially available panel reader system to read International Standards Organization-compliant electronic identification devices under commercial dairy conditions was examined. Full duplex (FDX-B) and half-duplex (HDX) low frequency radio-frequency identification external ear tags were utilized. The study involved 498 Holstein cows in the final 6 wk of gestation. There were 516 total electronic identification devices (n = 334 HDX and n = 182 FDX-B). Eighteen FDX-B were replaced with HDX during the study due to repeated detection failure. There were 6,679 HDX and 3,401 FDX-B device detection attempts. There were 220 (2.2%) unsuccessful and 9,860 (97.8%) successful identification detection attempts. There were 9 unsuccessful detection attempts for HDX (6,670/6,679 = 99.9% successful detection attempts) and 211 unsuccessful detection attempts for FDX-B (3,190/3,401 = 93.8% successful detection attempts). These results demonstrate that this panel system can achieve high detection rates of HDX devices and meet the needs of the most demanding management applications. The FDX-B detection rate was not sufficient for the most demanding applications, requiring a high degree of detection by panel readers. The lower FDX-B rate may not be inherent in the device technology itself, but could be due to other factors, including the particular panel reader utilized or the tuning of the panel reader.

The role of sequence variations within the genes encoding collagen II, IX and XI in non-syndromic, early-onset osteoarthritis.

OBJECTIVE: We sought to determine whether sequence variations in cartilage collagen genes are associated with primary, early-onset osteoarthritis (OA). METHODS: The cartilage collagen genes, COL2A1, COL9A1, COL9A2, COL9A3, COL11A1 and COL11A2, were screened for sequence variations in 72 Finnish probands and one US family with primary early-onset hip and/or knee OA. In addition, allelic association studies were performed using six to 12 common polymorphisms from each gene by genotyping 72 OA patients and 103 controls. RESULTS: Altogether 239 sequence variations were found, of which 16 were not present in the controls. Seven of the unique variations, four in COL11A1, two in COL11A2 and one in COL2A1, were studied further, because they resulted in the substitution of conserved amino acids or were predicted to affect mRNA splicing. Co-segregation of a sequence variation and the phenotype was found in all four families available for study. Association analysis failed to identify any common predisposing alleles. CONCLUSIONS: Early-onset OA demonstrates locus and allelic heterogeneity since the identified variations were in three different collagen genes and each of the six probands had a different mutation. It is also possible that some OA cases represent the mild end of the chondrodysplasia phenotypic spectrum. The major susceptibility alleles in this form of OA, however, remain to be identified.

Differential expression patterns of matrix metalloproteinases and their inhibitors during development of osteoarthritis in a transgenic mouse model.

OBJECTIVE: To characterise the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during degeneration of articular cartilage in a transgenic Del1 mouse model for osteoarthritis. METHODS: Northern analysis was used to measure mRNA levels of MMP-2, -3, -8, -9, -13, and -14, and TIMP-1, -2, and -3 in total RNA extracted from knee joints of transgenic Del1 mice, harbouring a 15 amino acid deletion in the triple helical domain of the alpha1(II) collagen chain, using their non-transgenic littermates as controls. Immunohistochemistry was used to study the presence of cleavage products (neoepitopes) of type II collagen, and the distribution of MMP-13 and TIMP-1 in degenerating cartilage. RESULTS: Each of the MMP and TIMP mRNAs analysed exhibited distinct expression patterns during development and osteoarthritic degeneration of the knee joint. The most striking change was up regulation of MMP-13 mRNA expression in the knee joints of Del1 mice at the onset of cartilage degeneration. However, the strongest immunostaining for MMP-13 and its inhibitor TIMP-1 was not seen in the degenerating articular cartilage but in synovial tissue, deep calcified cartilage, and subchondral bone. The localisation of type II collagen neoepitopes in chondrocytes and their pericellular matrix followed a similar pattern; they were not seen in cartilage fibrillations, but in adjacent unaffected cartilage. CONCLUSION: The primary localisation of MMP-13 and TIMP-1 in hyperplastic synovial tissue, subchondral bone, and calcified cartilage suggests that up regulation of MMP-13 expression during early degeneration of articular cartilage is a secondary response to cartilage erosion. This interpretation is supported by the distribution of type II collagen neoepitopes. Synovial production of MMP-13 may be related to removal of tissue debris released from articular cartilage. In the deep calcified cartilage and adjacent subchondral bone, MMP-13 probably participates in tissue remodelling.

A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity.

Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.

What do women want? Women's experiences of infertility treatment.

Finnish women's experiences of infertility treatment were investigated by examining their satisfaction and dissatisfaction, and their most positive and negative experiences with the treatment. Three hundred and forty four (16%) out of the 2,189 women respondents to a 1994 postal survey (response rate 74%) had experienced difficulties in having a baby. Two-thirds had sought medical help, generally from private gynaecologists. Less than half of the women were satisfied with the infertility treatment, expressing less satisfaction than is generally found among health care clients. Dissatisfied women were more often 35-39 years of age, in treatment during the study period, in treatment in public clinics and not successful in having a baby. However, about one-third of the women were unsure about or did not give their opinion in regard to satisfaction. The subsequent birth of a baby was the most common reason for satisfaction. The most positive treatment experience was respectful, empathic and personal care from the doctor. Unsatisfactory encounters with health care personnel were the main reasons for dissatisfaction and were most often cited as the most negative treatment experience. This dissatisfaction could reflect relatively young and healthy women's assertive attitudes toward infertility care services in the context of the intimacy and vulnerability of childlessness.

Identification of a novel common genetic risk factor for lumbar disk disease.

CONTEXT: Lumbar disk disease (LDD) is one of the most common musculoskeletal diseases, with a prevalence of about 5%. A tryptophan (Trp) allele (Trp2) was recently discovered in the COL9A2 gene that is associated with dominantly inherited LDD but is only present in about 4% of Finnish patients with LDD. OBJECTIVE: To determine if other collagen IX gene sequence variations play a role in the pathogenesis of LDD. DESIGN AND SETTING: Case-control study conducted from February 1997 to May 1998 at university hospitals in Finland. PARTICIPANTS: A total of 171 individuals with LDD (evaluated clinically and by magnetic resonance imaging or computed tomography) and 321 controls without LDD (186 healthy individuals, 83 patients with primary osteoarthritis, 31 with rheumatoid arthritis, and 21 with chondrodysplasias). MAIN OUTCOME MEASURES: Frequencies of sequence variations covering the entire coding sequences and exon boundaries of the collagen IX genes, COL9A1, COL9A2, and COL9A3, which code for the alpha1, alpha2, and alpha3 chains of the protein, detected by conformation-sensitive gel electrophoresis and confirmed by sequencing, compared between individuals with and without LDD. RESULTS: Mutation analysis of all 3 collagen IX genes resulted in identification of an Arg103-->Trp (arginine-->tryptophan) substitution in the alpha3 chain (Trp3 allele). The frequency of the Trp3 allele was 12.2% in LDD cases, excluding 7 individuals who were carriers of the previously identified Gln326-->Trp (glutamine-->tryptophan) substitution in the alpha2 chain (Trp2 allele), and was 4.7% among controls. The difference in the frequency was statistically significant (P =.000013). Presence of at least 1 Trp3 allele increases risk of LDD about 3-fold. CONCLUSION: This study led to the identification of a novel common genetic risk factor for LDD, confirming that genetic risk factors likely play a significant role in LDD.