Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9.

The initial stages of pancreatic development occur early during mammalian embryogenesis, but the genes governing this process remain largely unknown. The homeodomain protein Pdx1 is expressed in the developing pancreatic anlagen from the approximately 10-somite stage, and mutations in the gene Pdx1 prevent the development of the pancreas. The initial stages of pancreatic development, however, still occur in Pdx1-deficient mice. Hlxb9 (encoding Hb9; ref. 6) is a homeobox gene that in humans has been linked to dominant inherited sacral agenesis and we show here that Hb9 is expressed at early stages of mouse pancreatic development and later in differentiated beta-cells. Hlxb9 has an essential function in the initial stages of pancreatic development. In absence of Hlxb9 expression, the dorsal region of the gut epithelium fails to initiate a pancreatic differentiation program. In contrast, the ventral pancreatic endoderm develops but exhibits a later and more subtle perturbation in beta-cell differentiation and in islet cell organization. Thus, dorsally Hlxb9 is required for specifying the gut epithelium to a pancreatic fate and ventrally for ensuring proper endocrine cell differentiation.

Thrombospondin-4, an extracellular matrix protein expressed in the developing and adult nervous system promotes neurite outgrowth.

Extracellular matrix (ECM) molecules are involved in multiple aspects of cell-to-cell signaling during development and in the adult. In nervous system development, specific recognition processes, e.g., during axonal pathfinding and synaptogenesis involve modulation and signaling by ECM components. Much less is known about their presence and possible roles in the adult nervous system. We now report that thrombospondin-4 (TSP-4), a recently discovered member of the TSP gene family is expressed by neurons, promotes neurite outgrowth, and accumulates at the neuromuscular junction and at certain synapse-rich structures in the adult. To search for muscle genes that may be involved in neuromuscular signaling, we isolated cDNAs induced in adult skeletal muscle by denervation. One of these cDNAs coded for the rat homologue of TSP-4. In skeletal muscle, it was expressed by muscle interstitial cells. The transcript was further detected in heart and in the developing and adult nervous system, where it was expressed by a wide range of neurons. An antiserum to the unique carboxyl-terminal end of the protein allowed to specifically detect TSP-4 in transfected cells in vitro and on cryostat sections in situ. TSP-4 associated with ECM structures in vitro and in vivo. In the adult, it accumulated at the neuromuscular junction and at synapse-rich structures in the cerebellum and retina. To analyze possible activities of TSP-4 towards neurons, we carried out coculture experiments with stably transfected COS cells and motor, sensory, or retina neurons. These experiments revealed that TSP-4 was a preferred substrate for these neurons, and promoted neurite outgrowth. The results establish TSP-4 as a neuronal ECM protein associated with certain synapse-rich structures in the adult. Its activity towards embryonic neurons in vitro and its distribution in vivo suggest that it may be involved in local signaling in the developing and adult nervous system.

s-cyclophilin is retained intracellularly via a unique COOH-terminal sequence and colocalizes with the calcium storage protein calreticulin.

Cyclophilins (cyclosporin A-binding proteins) are conserved, ubiquitous, and abundant proteins that accelerate the isomerization of XaaPro peptide bonds and the refolding of proteins in vitro. s-Cyclophilin is a member of the cyclophilin family with unique NH2- and COOH-terminal extensions, and with a signal sequence. We now report that s-cyclophilin is retained in the cell, and that the conserved s-cyclophilin-specific COOH-terminal extension VEKPFAIAKE is sufficient to direct a secretory protein to s-cyclophilin containing structures. Antibodies to s-cyclophilin-specific peptides were produced and the location of the protein was determined by an immunocytochemical study at the light microscopic level. s-Cyclophilin colocalized with the Ca(2+)-binding protein calreticulin and, to a lesser extent, with the microsomal Ca(2+)-ATPase in the myogenic cell line L6, and with the Ca(2+)-binding protein calsequestrin in skeletal muscle. In activated platelets, s-cyclophilin immunoreactivity was detected in a ring-like structure that might correspond to the Ca(2+)-storing and -releasing dense tubular network. In spreading cells, s-cyclophilin containing vesicular structures accumulated at actin-rich protrusion sites. While s-cyclophilin consistently codistributed with Ca2+ storage site markers, the distribution of s-cyclophilin immunoreactivity was not identical to that of ER markers. To determine whether the COOH-terminal extension of s-cyclophilin was involved in its intracellular transport we added this sequence to the COOH-terminus of the secretory protein glia-derived nexin. Appropriate constructs were expressed transiently in cultured cells and proteins were detected with specific antibodies. We found that glia-derived nexin with the COOH-terminal sequence VEKPFAIAKE (but not with the control sequence GLVVMNIT) colocalized with endogenous s-cyclophilin, indicating that the sequence contained retention information. These results indicate that s-cyclophilin is a retained component of an intracellular organelle and that it may accumulate in specialized portions of the ER, and possibly in calciosomes. Because of its conserved structure, widespread distribution, and abundance s-cyclophilin may be a useful marker to study the biogenesis and distribution of ER subcompartments.

Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis.

The characteristic shapes and positions of each individual body muscle are established during the process of muscle morphogenesis in response to patterning information from the surrounding mesenchyme. Throughout muscle morphogenesis, primary myotubes are arranged in small parallel bundles, each myotube spanning the forming muscles from end to end. This unique arrangement potentially assigns a crucial role to primary myotube end regions for muscle morphogenesis. We have cloned muscle ankyrin repeat protein (MARP) as a gene induced in adult rat skeletal muscle by denervation. MARP is the rodent homologue of human C-193 (Chu, W., D.K. Burns, R.A. Swerick, and D.H. Presky. 1995. J. Biol. Chem. 270:10236-10245) and is identical to rat cardiac ankyrin repeat protein. (Zou, Y., S. Evans, J. Chen, H.-C. Kuo, R.P. Harvey, and K.R. Chien. 1997. Development. 124:793-804). In denervated muscle fibers, MARP transcript accumulated in a unique perisynaptic pattern. MARP was also expressed in large blood vessels and in cardiac muscle, where it was further induced by cardiac hypertrophy. During embryonic development, MARP was expressed in forming skeletal muscle. In situ hybridization analysis in mouse embryos revealed that MARP transcript exclusively accumulates at the end regions of primary myotubes during muscle morphogenesis. This closely coincided with the expression of thrombospondin-4 in adjacent prospective tendon mesenchyme, suggesting that these two compartments may constitute a functional unit involved in muscle morphogenesis. Transfection experiments established that MARP protein accumulates in the nucleus and that the levels of both MARP mRNA and protein are controlled by rapid degradation mechanisms characteristic of regulatory early response genes. The results establish the existence of novel regulatory muscle fiber subcompartments associated with muscle morphogenesis and denervation and suggest that MARP may be a crucial nuclear cofactor in local signaling pathways from prospective tendon mesenchyme to forming muscle and from activated muscle interstitial cells to denervated muscle fibers.

25-Hydroxyvitamin D status, light exposure and sleep quality in UK dwelling South Asian and Caucasian postmenopausal women.

There is a lack of research into 25-hydroxyvitamin D (25(OH)D) status, light exposure and sleep patterns in South Asian populations. In addition, results of research studies are conflicting as to whether there is an association between 25(OH)D status and sleep quality. We investigated 25(OH)D status, self-reported and actigraphic sleep quality in n = 35 UK dwelling postmenopausal women (n = 13 South Asians, n = 22 Caucasians), who kept daily sleep diaries and wore wrist-worn actiwatch (AWL-L) devices for 14 days. A subset of n = 27 women (n = 11 South Asian and n = 16 Caucasian) also wore a neck-worn AWL-L device to measure their light exposure. For 25(OH)D concentration, South Asians had a median ± IQR of 43.8 ± 28.2 nmol/L, which was significantly lower than Caucasians (68.7 ± 37.4 nmol/L)(P = 0.001). Similarly, there was a higher sleep fragmentation in the South Asians (mean ± SD 36.9 ± 8.9) compared with the Caucasians (24.7 ± 7.1)(P = 0.002). Non-parametric circadian rhythm analysis of rest/activity patterns showed a higher night-time activity (L5) (22.6 ± 14.0 vs. 10.5 ± 4.4; P = 0.0008) and lower relative amplitude (0.85 ± 0.07 vs. 0.94 ± 0.02; P < 0.0001) in the South Asian compared with the Caucasian women. More South Asians (50%) met the criteria for sleep disorders (PSQI score >5) than did Caucasians (27%) (P = 0.001, Fishers Exact Test). However, there was no association between 25(OH)D concentration and any sleep parameter measured (P > 0.05) in either ethnic group. South Asians spent significantly less time in illuminance levels over 200 lx (P = 0.009) than did Caucasians. Overall, our results show that postmenopausal South Asian women have lower 25(OH)D concentration than Caucasian women. They also have higher sleep fragmentation, as well as a lower light exposure across the day. This may have detrimental implications for their general health and further research into sleep quality and light exposure in the South Asian ethnic group is warranted.

Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity.

The homeobox gene Hb9, like its close relative MNR2, is expressed selectively by motor neurons (MNs) in the developing vertebrate CNS. In embryonic chick spinal cord, the ectopic expression of MNR2 or Hb9 is sufficient to trigger MN differentiation and to repress the differentiation of an adjacent population of V2 interneurons. Here, we provide genetic evidence that Hb9 has an essential role in MN differentiation. In mice lacking Hb9 function, MNs are generated on schedule and in normal numbers but transiently acquire molecular features of V2 interneurons. The aberrant specification of MN identity is associated with defects in the migration of MNs, the emergence of the subtype identities of MNs, and the projection of motor axons. These findings show that HB9 has an essential function in consolidating the identity of postmitotic MNs.

Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation.

The patterning of skeletal muscle is thought to depend upon signals provided by motor neurons. We show that AChR gene expression and AChR clusters are concentrated in the central region of embryonic skeletal muscle in the absence of innervation. Neurally derived Agrin is dispensable for this early phase of AChR expression, but MuSK, a receptor tyrosine kinase activated by Agrin, is required to establish this AChR prepattern. The zone of AChR expression in muscle lacking motor axons is wider than normal, indicating that neural signals refine this muscle-autonomous prepattern. Neuronal Neuregulin-1, however, is not involved in this refinement process, nor indeed in synapse-specific AChR gene expression. Our results demonstrate that AChR expression is patterned in the absence of innervation, raising the possibility that similarly prepatterned muscle-derived cues restrict axon growth and initiate synapse formation.

The organ donor crisis: the missed organ donor potential from the accident and emergency departments.

The critical shortage of cadaveric donor organs for transplant purposes is a worldwide concern. The disparity between the number of cadaveric organs donated for transplant purposes and those patients awaiting transplant operations continues to widen. This article reports on the findings of an audit of deaths undertaken in 10 accident and emergency (A&E) departments in North Thames region, UK. The audit itself was borne out of informal anecdotal accounts from colleagues working in the A&E department who suggested that there was a potential pool of organ and tissue donors that were not being realized. The article discusses how those audit findings helped shape the current A&E education strategy in the North Thames region. The result has been that the North Thames region has seen a dramatic increase in the number of referrals from the A&E departments, resulting in solid organ transplantation. Although the results are very encouraging, the program is still very much in its infancy and a long way from the desired 100% referral rate. In order to maximize the number of organs from the potential donor pool, the transplant community needs to focus more attention toward donation from the A&E departments.

Class, paid employment and family roles: making sense of structural disadvantage, gender and health status.

The British tradition of analysing differences in health has been dominated by class, with women belatedly entering this debate. The American tradition has been dominated by role analysis, with women's health considered primarily in terms of their marital, parental and employment roles, with recent research coming to contradictory conclusions. Research in both traditions has reached an impasse. This paper uses a sample of over 25,000 men and women from the 1985 and 1986 British General Household Survey to show how both traditions need to be reformulated and integrated. The ways in which family roles are associated with women's health status is determined by material circumstances, but the material circumstances cannot be captured by occupational class alone. Participation in the labour market and consumption divisions, in the form of housing tenure, are crucial additional indicators of structural disadvantage. Standardised limiting long-standing illness ratios and multivariate logit analysis confirm that occupational class and paid employment are the most important attributes associated with health status for women and men. Family roles are important for women; women without children and previously married women have particularly poor health status especially those not in paid employment and living in local authority housing.

Comparing inequalities in women's and men's health: Britain in the 1990s.

Data on over 20,000 women and men aged 20-59 are analysed from the British General Household Survey for 1991 and 1992, showing the importance of separately analysing educational qualifications, occupational class and employment status for both women and men. Own occupational class and employment status are the key structural factors associated with limiting long-standing illness, but educational qualifications are particularly good predictors of women's self-assessed health. Class inequalities in health are less pronounced among women who are not in paid work. Women's limiting long-standing illness relates solely to their own labour market characteristics, whereas self-assessed health relates to wider aspects of women's everyday lives, including their household material conditions, and for married women, their partner's occupational class and employment status. Men's unemployment has adverse consequences for the health of their wives, which occurs through the mechanism of the family living in disadvantaged material circumstances. Women's labour market position and role in the family have undergone substantial changes since the 1970s. Approaches to measuring inequalities in women's health need to reflect changes in women's employment participation and changes in marital status and living arrangements.

The role of the receptionist in general practice: a 'dragon behind the desk'?

The power and influence of receptionists in general practice has been the subject of little research. We argue that the structural position of receptionists and the nature of primary medical care give receptionists a potential discretionary role in determining access to the general practitioner. A major criterion for access is the imputed urgency of the patient's condition, which frequently involves the receptionist making a medical assessment based on only a brief verbal exchange. The paper draws on interviews with a sample of over 1000 adults about their experiences of the reception process in general practice. The receptionist's role in the following areas is examined; delay in obtaining appointments, asking the reason for surgery consultations and home visits, reducing the number of home visits by suggesting patients attend the surgery, putting patients through to speak to the doctor on the telephone and giving health advice. Patients who have experienced receptionists as an active intermediary are more likely to report interaction difficulties with receptionists. The survey data lend support to two major findings: (1) that as practices become larger and more complex receptionists operate with more rigid rules, leading to greater hostility expressed by patients towards reception staff; and (2) parents with dependent children and young adults express more antagonism, because they are more likely to experience the receptionist as a 'gatekeeper' with whom they need to negotiate to see a doctor for acute care for themselves or for their children.

Inequalities in women's and men's ill-health: Britain and Finland compared.

This paper examines inequalities in ill-health among men and women in Britain and Finland, using national survey data from the mid-1980s. Age-standardised illness ratios are compared followed by multivariate logistic regression analyses. The degree of social inequality in ill-health for women and men is greater in Finland than in Britain. British employed women in each class report less limiting long-standing illness than their Finnish counterparts. A major difference between the two countries is the poor health of British housewives. We relate these differences to societal variations in the participation of women in paid employment. In Finland women participate fully in paid work, whereas in Britain women are more likely to be full-time housewives or part-time employees. Unlike Finland, state provisions do not support the economic independence of British women. Structural variables, encapsulated by occupational class and employment status' are the primary factors associated with men's ill-health in Britain and Finland and also with Finnish women's ill-health. The difference between British and Finnish women is striking: class is associated with ill-health amongst women in both countries, but housing tenure and family roles are additional factors only among British women. In Britain, previously married women have particularly poor health. Our findings suggest that in a society such as Britain where paid employment is not universal for women, women's family roles and housing quality are associated with ill-health, but this is not the case in Finland, where women's participation in the labour market is near universal.

Gender differences in health in later life: the new paradox?

This paper examines gender differences in health, based on data from over 14,000 men and women aged 60 and above from 3 years of the British General Household Survey, 1992-1994. There is little difference between the sexes in the reporting of self-assessed health and limiting longstanding illness, but older women are substantially more likely to experience functional impairment in mobility and personal self-care than men of the same age. These findings persist after controlling for the differential social position of men and women according to their marital status, social class, income and housing tenure. The results reveal a paradox in health reporting among older people; for a given level of disability, women are less likely to assess their health as being poor than men of the same age after accounting for structural factors. Older women's much higher level of functional impairment co-exists with a lack of gender difference in self-assessed health.

Gender and inequalities in health in later life.

Little research attention has been given to examining inequalities in the health of elderly women and men, in spite of their high use of health services and the importance of health to maintaining independence in later life. This paper uses data from the British General Household Survey to analyse the variation in health of elderly women and men by class and material circumstances. Two measures of health are used; self-assessed health and functional disability. Elderly women assess their own health less positively than men, and are seriously disadvantaged compared to men in terms of functional disability. Class based on the individual's own previous main occupation is strongly associated with the two measures of health for elderly women and men at all ages. For elderly women, an 'individualistic' approach, using the woman's own last occupation, is compared with the 'conventional' approach of measuring class, which for married women uses their husband's last occupation and for other women their own last occupation. Using the two approaches makes little difference to the strength of association between class and health. Elderly women and men who live in advantaged material circumstances, in terms of income, car ownership and housing tenure, report significantly better health, after controlling for age and class. Level of functional disability is influenced by previous position in the labour market but not current material circumstances. Although elderly women suffer greater morbidity than elderly men, structural inequalities in health are equally pronounced for women and men in later life.

Health inequalities in early adulthood: a comparison of young men and women in Britain and Finland.

Several studies have recently reported that social class differences in ill-health during adolescence are almost non-existent or invisible. The aims of this comparative study of two different welfare states are first, to compare whether the relationship between social class and health is similar among young men and women at different age groups in these two welfare states; second, to examine at what age social class differences in self-reported health and illness among young adults emerge in these two countries; and third, to find out whether class of origin (i.e. parental social class) or class of destination (i.e. individual's achieved social class) have greater explanatory power in studies of health among young adults. We used comparable nationally representative interview surveys from Britain and Finland. The British data is derived from the General Household Survey for 1988 and 1989, and the Finnish data from the 1986 Level of Living Survey. We analysed five year age groups between 16 and 39 years in Britain (N = 16,626) and 15 and 39 years in Finland (N = 5950). Two health indicators (limiting long-standing illness and self-assessed health), and several indicators for social class were compared. The best discriminator of differences in ill-health among young adults both in Finland and Britain was education. Social class differences by own occupation (achieved class) emerged soon after the age of 20 among men and women in both countries and strengthened with increasing age. There was a weaker but consistent association with class of origin in both countries. Housing tenure is strongly associated with young adults' health in Britain but not Finland.(ABSTRACT TRUNCATED AT 250 WORDS)

Women's lung cancer mortality, socio-economic status and changing smoking patterns.

Mortality data from the OPCS Longitudinal Study were used to determine whether the conventional classification of married women by their husband's occupation under-estimates the extent of social differences in lung cancer among this group. Differences existed for social class measures but alternatives based on housing tenure and car access defined socio-economic differences wider than any other previously recorded for England and Wales: married women living in rented housing and without a car were two and a half times as likely to die from lung cancer than those in owner occupied housing with access to a car. In 1957 and 1974 mothers of children included in the 1958 cohort study showed parallel socio-economic differences in smoking patterns as well as in uptake and cessation rates. Data from the General Household Survey for 1982 similarly suggest that cigarette smoking is more sharply differentiated using household rather than occupational measures of class. This suggests that wide differences in mortality are likely to persist through the eighties and beyond.

Development and validation of scales to measure organisational features of acute hospital wards.

In order to make comparisons between wards and explain variations in outcomes of nursing care, there is a growing need in nursing research for reliable and valid measures of the organisational features of acute hospital wards. This research developed The Ward Organisational Features Scales (WOFS); each set of six scales comprising 14 subscales which measure discrete dimensions of acute hospital wards. A study of a nationally representative sample of 825 nurses working in 119 acute wards in 17 hospitals, drawn from seven Regional Health Authorities in England provides evidence for the structure, reliability and validity of this comprehensive set of measures related to: the physical environment of the ward, professional nursing practice, ward leadership, professional working relationships, nurses' influence and job satisfaction. Implications for further research are discussed.

Integrating nonemployment into research on health inequalities.

An increasing proportion of the population is not currently employed; health inequalities research should include these people in analyses. Labor market position is the key determinant of health in Western societies; it is essential to clarify the independent effects of the three main components of labor market position: educational qualifications, occupational class, and employment status. These issues are addressed using national data from the British General Household Survey for 1991-1992 and two measures of ill-health: limiting long-standing illness and self-reported health. Occupational class is a stronger predictor than educational qualifications of measures of ill-health for men and long-term illness for women. When employment status is included in the models, the class gradient is weakened, suggesting that omitting the nonemployed from class analyses will produce a seeming weakening of class inequalities in health. The analyses show that class inequalities in health are somewhat greater for nonemployed than employed men, but weaker for nonemployed than employed women. In spite of older people having left the labor market many years earlier, class based on their previous occupation continues to have a major effect on their health. Class should be the primary variable in analyses of inequalities in health, and all groups of the nonemployed should be analyzed using their last main occupation.

Understanding income inequalities in health among men and women in Britain and Finland.

The aims of this study were to investigate whether the relationship between income and self-perceived health is similar for men and women in two contrasting welfare states, Britain and Finland; whether the relationship between income and health is accounted for by employment status, education, and occupational social class; and whether the association differs when using alternative ways of measuring income: gross individual and net household equivalent income. Among British and Finnish men, low household and low individual income were related to poor health, even after adjusting for employment status, education, and social class. The adjusted relationship between individual income and health was stronger for British than Finnish men. Among British and Finnish women, net household equivalent income was strongly related to health, but after adjusting for employment status, education, and social class this relationship became weaker for British women and practically disappeared for Finnish women. For British women the association between income and health differed strongly depending on the income measure used; gross individual income had almost no effect on health. These results indicate that the association between health and income has no threshold in the sense that only people in poverty have poorer health than others. In further studies of income and health, household equivalent income should be used as the principal measure of income with adjustments for employment status, and men and women should be studied separately.

Use of health services by children and young people according to ethnicity and social class: secondary analysis of a national survey.

OBJECTIVE: To assess whether equity is achieved in use of general practitioner, outpatient, and inpatient services by children and young people according to their ethnic group and socioeconomic background. DESIGN: Secondary analysis of the British general household survey, 1991-94. SUBJECTS: 20 473 children and young people aged between 0 and 19 years. MAIN OUTCOME MEASURES: Consultations with a general practitioner within a two week period, outpatient attendances within a three month period, and inpatient stays during the past year. RESULTS: There were no significant class differences in the use of health services by children and young people, and there was little evidence of variation in use of health services according to housing tenure and parental work status. South Asian children and young people used general practitioner services more than any other ethnic group after controlling for socioeconomic background and perceived health status, but the use of hospital outpatient and inpatient services was significantly lower for children and young people from all minority ethnic groups compared with the white population. CONCLUSIONS: Our results differ from previous studies, which have reported significant class differences in use of health services for other age groups. We found no evidence that children and young people's use of health services varied according to their socioeconomic status, suggesting that equity has been achieved. A child or young person's ethnic origin, however, was clearly associated with use of general practitioner and hospital services, which could imply that children and young people from minority ethnic groups receive a poorer quality of health care than other children and young people.