A novel missense mutation in NR0B1 causes delayed-onset primary adrenal insufficiency in adults.

A novel missense mutation (c.775T>C; p.ser259Pro) in the NROBI gene cause a late-onset adrenal insufficiency without hypogonadism.

[Psychosocial Aspects in Cardiac Rehabilitation: From Theory to Practice. A Position Paper From the Cardiac Rehabilitation Section of The European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology].

A large body of empirical research shows that psychosocial risk factors (PSRFs) such as low socio-economic status, social isolation, stress, type-D personality, depression and anxiety increase the risk of incident coronary heart disease (CHD) and also contribute to poorer health-related quality of life (HRQoL) and prognosis in patients with establishedCHD. PSRFs may also act as barriers to lifestyle changes and treatment adherence and may moderate the effects of cardiac rehabilitation (CR). Furthermore, there appears to be a bidirectional interaction between PSRFs and the cardiovascular system. Stress, anxiety and depression affect the cardiovascular system through immune, neuroendocrine and behavioural pathways. In turn, CHD and its associated treatments may lead to distress in patients, including anxiety and depression. In clinical practice, PSRFs can be assessed with single-item screening questions, standardised questionnaires, or structured clinical interviews. Psychotherapy and medication can be considered to alleviate any PSRF-related symptoms and to enhance HRQoL, but the evidence for a definite beneficial effect on cardiac endpoints is inconclusive. A multimodal behavioural intervention, integrating counselling for PSRFs and coping with illness should be included within comprehensive CR. Patients with clinically significant symptoms of distress should be referred for psychological counselling or psychologically focused interventions and/or psychopharmacological treatment. To conclude, the success of CR may critically depend on the interdependence of the body and mind and this interaction needs to be reflected through the assessment and management of PSRFs in line with robust scientific evidence, by trained staff, integrated within the core CR team.

WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome.

Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ∼500 arRP mutations in ∼20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed 'sub-clinical' renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.

An Overview of the Role of Radiotherapy in the Treatment of Small Cell Lung Cancer - A Mainstay of Treatment or a Modality in Decline?

AIMS: Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. Chemotherapy, immunotherapy and radiotherapy all play important roles in the management of SCLC. The aim of this study was to provide a comprehensive overview of the role and evidence of radiotherapy in the cure and palliation of SCLC. MATERIALS AND METHODS: The search strategy included a search of the PubMed database, hand searches, reference lists of relevant review articles and relevant published abstracts. CLINICALTRIALS: gov was also queried for relevant trials. RESULTS: Thoracic radiotherapy improves overall survival in limited stage SCLC, but the timing and dose remain controversial. The role of thoracic radiotherapy in extensive stage SCLC with immunotherapy is the subject of several ongoing trials. Current evidence supports the use of prophylactic cranial irradiation (PCI) for limited stage SCLC but the evidence is equivocal in extensive stage SCLC. Whole brain radiotherapy is well established for the treatment of brain metastases but evidence is rapidly accumulating for the use of stereotactic radiosurgery. Further studies will define the role of PCI, whole brain radiotherapy and hippocampal avoidant PCI in the immunotherapy era. CONCLUSION: Radiotherapy is an essential component in the multimodality management of SCLC. Technological advances have allowed safer delivery of radiotherapy with reduced toxicities. Discussion at multidisciplinary team meetings is important to ensure radiotherapy is considered and offered in appropriate patients.

The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis.

BACKGROUND: To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer. METHODS: Four snoRNAs, commonly used for normalisation, RNU44, RNU48, RNU43 and RNU6B, and miRNA known to be associated with pathological factors, were measured by real-time polymerase chain reaction in two patient series: 219 breast cancer and 46 head and neck squamous cell carcinoma (HNSCC). SnoRNA and miRNA were then correlated with clinicopathological features and prognosis. RESULTS: Small-nucleolar RNA expression was as variable as miRNA expression (miR-21, miR-210, miR-10b). Normalising miRNA PCR expression data to these recommended snoRNAs introduced bias in associations between miRNA and pathology or outcome. Low snoRNA expression correlated with markers of aggressive pathology. Low levels of RNU44 were associated with a poor prognosis. RNU44 is an intronic gene in a cluster of highly conserved snoRNAs in the growth arrest specific 5 (GAS5) transcript, which is normally upregulated to arrest cell growth under stress. Low-tumour GAS5 expression was associated with a poor prognosis. RNU48 and RNU43 were also identified as intronic snoRNAs within genes that are dysregulated in cancer. CONCLUSION: Small-nucleolar RNAs are important in cancer prognosis, and their use as reference genes can introduce bias when determining miRNA expression.

Understanding diagnostic reasoning in TCM practice: tongue diagnosis.

BACKGROUND: Traditional Chinese medicine (TCM) diagnosis is a complex multifaceted process that often yields multiple differential diagnoses and subdiagnoses. OBJECTIVES: The aims of this study were to (1) understand cognitive strategies and diagnostic reasoning processes of TCM practitioners engaged in tongue diagnosis and (2) investigate TCM practitioners' diagnostic accuracy. Clinical decision making and problem solving frameworks served as a basis for this study. METHODS: Nine TCM practitioners verbalized their thinking processes via think-aloud protocols and were audiotaped while engaged in the cognitive task of tongue diagnosis. Protocol analysis was used to identify TCM diagnostic reasoning patterns. Diagnostic accuracy was assessed by participant self-report and via independent TCM expert judges. RESULTS: Protocol analysis revealed that TCM practitioners use systematic processes to arrive at diagnoses and that there were differences between novices and experts in both pre- and post-adjustments after viewing case histories. Novices tended to use more descriptors and come to the diagnoses earlier. Experts tended to use higher-level intellectual processes when coming to their diagnoses and tended to use these terms earlier in the process. Correlations between practitioner self-assessment and judges' ratings of diagnostic accuracy were noted and corollary case history information improved diagnostic accuracies. CONCLUSION: TCM practitioners use systematic reasoning patterns to determine diagnoses associated with evaluation of tongues. These processes are congruent with those observed in Western medicine whereby clinician reasoning involves a combination of analytical reasoning of domain knowledge and the use of exemplar patterns. An explicit understanding of TCM reasoning processes can inform clinical practice and education and will facilitate the development of supporting technologies and identification of best practices.

Symptom management for irritable bowel syndrome: a pilot randomized controlled trial of acupuncture/moxibustion.

The purpose of this pilot study was to assess the effect of an individualized traditional Chinese medicine (TCM) acupuncture and moxibustion (Acu/Moxa) treatment on symptom control in patients with irritable bowel syndrome (IBS) in a preliminary, randomized, sham/placebo-controlled trial. Twenty-nine men and women with IBS were randomized to either individualized Acu/Moxa (treatment group) or sham/placebo Acu/Moxa (control group). All subjects were assessed by a diagnostic acupuncturist for a TCM evaluation and individualized point prescription. Only those subjects assigned to the experimental group received the individually prescribed treatment. The diagnostic acupuncturist did not administer treatments and was blind to treatment assignments. All subjects kept a symptom diary for the duration of the study, enabling measurement of symptom frequency, severity, and improvement. The Clinical Global Impression Scale was administered preintervention to establish baseline severity and on completion of the 4-week, eight-session treatment intervention. After 4 weeks of twice-weekly Acu/Moxa treatment, average daily abdominal pain/discomfort improved whereas the control group showed minimal reduction. This between-group difference adjusted for baseline difference was statistically significant. The intestinal gas, bloating, and stool consistency composite score showed a similar pattern of improvement. The findings indicate that Acu/Moxa treatment shows promise in the area of symptom management for IBS.

Water content, raffinose, and dehydrins in the induction of desiccation tolerance in immature wheat embryos

Desiccation tolerance is initiated in wheat (Triticum aestivum L.) embryos in planta at 22 to 24 d after anthesis, at the time that the embryo water content has decreased from about 73% fresh weight (2.7 g water/g dry weight) to about 65% fresh weight (1.8 g water/g dry weight). To determine if desiccation tolerance is fully induced by the loss of a relatively small amount of water, detached wheat grains were treated to reduce the embryo water content by just a small amount to approximately 69% (2.2 g water/g dry weight). After 24 h of such incipient water loss, subsequently excised embryos were able to withstand severe desiccation, whereas those embryos that had not previously lost water could not. Therefore, a relatively small decrease in water content for only 24 h acts as the signal for the development of desiccation tolerance. Embryos that were induced into tolerance by a 24-h water loss had no detectable raffinose. The oligosaccharide accumulated at later times even in embryos of detached grains that had not become desiccation tolerant, although tolerant embryos (i.e. those that previously had lost some water) contained larger amounts of the carbohydrate. It is concluded that desiccation tolerance and the occurrence of raffinose are not correlated. Immunodetected dehydrins accumulated in embryos in planta as desiccation tolerance developed. Detachment of grains induced the appearance of dehydrins at an earlier age, even in embryos that had not been made desiccation tolerant by incipient drying. It is concluded that a small reduction in water content induces desiccation tolerance by initiating changes in which dehydrins might participate but not by their interaction with raffinose.

Retrospective analysis of 318 cases of uterine sarcoma.

A study of data from 318 cases of uterine sarcoma presenting during a 10-year period (1967-1976) is reported. All but 6 of the patients had at least a 5-year follow-up (98% 5-year follow-up). Overall 5-year survival was 31%, with the major prognostic indicator being tumour stage. Despite the tendency for mixed mesodermal tumours to present in older women with more advanced disease, survival was not statistically different to those patients with leiomyosarcomas. Thus, the propensity for tumour dissemination in leiomyosarcomas should not be underestimated. Leiomyosarcomas are less likely to present with abnormal symptoms than are other sarcomas, and their occurrence as an incidental finding on histological examination underlines the need for an adequate inspection of the intra-abdominal contents at hysterectomy. The tendency to treat all sarcomas as if they were endometrial tumours may be fallacious, and an alternative classification (such as the TNM system) may be required. Recurrence of tumour tended to be at distant sites (distant:pelvic recurrence rate 3:1). Adjuvant radiotherapy is unlikely to alter distant disease foci, and thus the development of combination chemotherapeutic regimens using agents which have shown to result in tumour response seem warranted. Such trials will need to be organised on a multicentre basis to attain statistically evaluable numbers of patients.

Aspirin for the prevention of preeclampsia in women with abnormal uterine artery Doppler: a meta-analysis.

OBJECTIVE: To determine the effectiveness of aspirin to prevent preeclampsia in women identified as high risk for preeclampsia by an abnormal second-trimester uterine artery Doppler examination. DATA SOURCES: Searches were conducted in MEDLINE, Embase, the Cochrane Controlled Trials Register, and Science Citation Index for randomized trials published from 1966 to 2000, using the following medical subject headings and key words: "aspirin," "antiplatelet*," "salicyl*," "acetylsalicyl*," "platelet aggregation inhibitors," "ultrasonography," "ultraso*," and "Doppler." STUDY SELECTION: We included all randomized trials that evaluated the effectiveness of aspirin compared with placebo or no treatment in women with an abnormal uterine artery Doppler and that reported clinically relevant perinatal and maternal outcomes. Study selection, quality assessment, and data extraction were performed in duplicate. TABULATION, INTEGRATION, AND RESULTS: There were five relevant trials. Pooling of results from these trials showed a significant benefit of aspirin in reducing preeclampsia (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.32, 0.95). The baseline risk of preeclampsia in women with abnormal uterine artery Doppler was 16%, and the number of women needed to be treated with aspirin to prevent one case of preeclampsia was 16 (95% CI 8, 316). Women on aspirin had babies who were on average 82 g heavier than controls, but this result did not reach statistical significance (weighted mean difference 81.5, 95% CI 40.27, 203.27). CONCLUSION: Uterine artery Doppler assessment identifies high-risk women in whom aspirin therapy results in a significant reduction in preeclampsia.

Management of postconization cervical stenosis by laser vaporization.

In 18 patients with symptomatic cervical stenosis after conization, laser vaporization of the stenotic segment was performed. Total relief of symptoms was achieved in 12 patients and partial relief in four. In seven cases there was no evidence of stenosis at follow-up, and in a further nine cases the degree of stenosis was less. In seven cases it was possible to visualize the squamocolumnar junction at follow-up. This had not been possible in any cases before the procedure. Vaporization using the carbon dioxide laser provides a useful conservative management technique for postconization stenosis.

Fetal and maternal outcomes in Indo-Asian compared to caucasian women with diabetes in pregnancy.

Maternal and fetal complications are increased when pregnancy is complicated by diabetes, and this may be further influenced by racial and cultural differences. We examined fetal and maternal outcomes in Indo-Asian and Caucasian women attending the same antenatal diabetes service to see if there were any differences. Women with diabetes mellitus (type 1, type 2 and gestationally-acquired disease) complicating pregnancy, registered at the combined diabetes/antenatal clinic of this University teaching hospital over the period 1990-1998 were included. Fetal outcomes examined were miscarriage <24 weeks, stillbirths, neonatal deaths up to 28 days of life, perinatal mortality, congenital malformations and size for gestational age. Maternal outcomes examined were rates of caesarean section and vaginal deliveries, and number of pre-term deliveries <37 completed weeks of gestation. Outcomes for Indo-Asian and Caucasian women were similar, with a take-home baby rate of 96% and 92%, respectively. There was no perinatal mortality in Indo-Asian women, who were more likely to have a vaginal delivery and less likely to have a baby large for gestational age. Pregnancies complicated by type 2 diabetes in both groups pose the greatest threat to a successful pregnancy outcome. Indo-Asian and Caucasian women attending the same antenatal diabetes service have comparable outcomes. Attendance for pre-pregnancy care needs to be encouraged to combat the high early pregnancy loss and congenital malformation rate identified, particularly in those with type 2 disease, irrespective of ethnicity.

Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women's physical and psychological health needs.

OBJECTIVES: To develop, implement and test the cost-effectiveness of redesigned postnatal care compared with current care on women's physical and psychological health. DESIGN: A cluster randomised controlled trial, with general practice as the unit of randomisation. Recruited women were followed up by postal questionnaire at 4 and 12 months postpartum and further data collected from midwife and general practice sources. SETTING: Thirty-six randomly selected general practice clusters in the West Midlands Health Region, UK. PARTICIPANTS: All women expected to be resident within recruited practices for postnatal care were eligible for inclusion. Attached midwives recruited 1087 women in the intervention and 977 in the control practice clusters. INTERVENTIONS: The systematic identification and management of women's health problems, led by midwives with general practitioner contact only when required. Symptom checklists and the Edinburgh Postnatal Depression Scale (EPDS) were used at various times to maximise the identification of problems, and individual care and visit plans based on needs. Evidence-based guidelines were used to manage needs. Care was delivered over a longer period. MAIN OUTCOME MEASURES: Women's health at 4 and 12 months, assessed by the Physical and Mental Component Scores (PCS and MCS) of the Short-Form 36 (SF-36) and the EPDS. Women's views about care, reported morbidity at 12 months, health service usage during the year, 'good practice' indicators and health professionals' views about care were secondary outcomes. RESULTS: At 4 and 12 months postpartum the mean MCS and EPDS scores were significantly better in the intervention group and the proportion of women with an EPDS score of 13+ (indicative of probable depression) was significantly lower relative to controls. The physical health score (PCS) did not differ. Health service usage was significantly less in the intervention group as well as reported psychological morbidity at 12 months. Women's views about care were either more positive or did not differ. Intervention midwives were more satisfied with redesigned care than control midwives were with standard care. Intervention care was cost-effective since outcomes were better and costs did not differ substantially. CONCLUSIONS: The redesigned community postnatal care led by midwives and delivered over a longer period, resulted in an improvement in women's mental health at 4 months postpartum, which persisted at 12 months and at equivalent overall cost. It is suggested that further research should focus on: the identification of postnatal depression through screening; whether fewer adverse longer term effects might be demonstrated among the children of the women who had the intervention care relative to the controls; testing interventions to reduce physical morbidity, including studies to validate measures of physical health in postpartum women. Further research is also required to investigate appropriate postnatal care for ethnic minority groups.

Placental-type alkaline phosphatase in pregnancy and malignancy plasma: specific estimation using a monoclonal antibody in a solid phase enzyme immunoassay.

A solid-phase enzyme immunoassay has been developed using a monoclonal antibody with specificity only for the placental-type alkaline phosphatase isoenzyme (Pl-ALP). This assay is uniquely sensitive, having a lower limit of detection of 0.1 U/l (approximately 0.07 micrograms/l) Pl-ALP. All plasma samples from healthy non-pregnant individuals had undetectable Pl-ALP levels whereas, in pregnancy, a wide range (0-400 U/l) of Pl-ALP levels was noted for 208 maternal plasma samples from 12 weeks gestation to term. There was no significant difference in circulating Pl-ALP levels between severe pre-eclamptic and normal pregnancy. Low levels of Pl-ALP (0.1-4.7 U/l) were found in 31 of 217 plasmas from human malignancies. Within these, 23 of 65 (35%) histologically-proven ovarian carcinoma patients were positive.

Analysis of nicotine and cotinine in the hair of hospitality workers exposed to environmental tobacco smoke.

The purpose of this study was to determine if hair nicotine and cotinine levels reflect relative exposure to environmental tobacco smoke (ETS) in subjects who worked in the hospitality industry, where public smoking was permitted. Hair samples from 26 subjects were analyzed by gas chromatograph/mass spectrometry techniques for nicotine and cotinine. An exposure gradient was shown for nicotine but not cotinine. Among nonsmokers, those working in bars where there are no public smoking restrictions had the highest hair nicotine levels, which were close to levels found in smokers. Nicotine measured in hair is useful as a biological marker for exposure to ETS from multiple sources. Bar workers in particular are exposed to high levels of ETS, which may adversely affect the health of nonsmokers.

Heart rate variability in healthy term newborns: the contribution of respiratory sinus arrhythmia.

Cardiorespiratory interactions in healthy full term newborns were investigated. Spectral analysis was used on heart rate and breathing data from 22 neonates 2-5 days old to reveal coincident frequencies in the breathing and heart rate variability (HRV) spectra, thus identifying respiratory sinus arrhythmia (RSA). The spectral description of HRV in healthy term newborns revealed a consistent and distinct RSA feature, with a mean contribution of over 30%. The contribution of RSA to HRV was dependent on breathing frequency and absolute RSA power. The mechanisms that produce this cardiorespiratory interaction are considered to be functionally active in the healthy term neonate.

The interaction between cervix and corpus uteri in the generation of intra-amniotic pressure in labour.

Theoretically, the response of the cervix to myometrial activity should affect the intra-amniotic pressure waveform. Clinical assessment of cervical response, in 80 induced labours, has been correlated with various waveform parameters. More abrupt and more rapid rises in intra-amniotic pressure are associated with the non-responding cervix. The clinical implications are discussed.

Management of severe, early pre-eclampsia: is conservative management justified?

A retrospective analysis was performed to assess the fetal and maternal benefits of allowing women presenting with severe pre-eclampsia between 24 and 32 weeks to continue their pregnancy following treatment of their hypertension. Cases presenting in Oxford (conservative management) and in Birmingham (stabilisation and early intervention) were compared. Patients were considered to require treatment when their systolic blood pressure was > or = 170 mmHg systolic or > or = 110 mmHg diastolic, associated with at least 1+ proteinuria and hyperuricaemia. We compared gestation at delivery, birth weight and neonatal complications for each group, and any maternal morbidity. There were 28 patients in each group. Gestational age at delivery was significantly less in the group managed by early intervention. Those women managed conservatively gained a mean of 9.5 days (range 2-26 days; P < 0.05), and their birthweight was significantly greater (P < 0.05). There was a significant difference between the length of stay in the neonatal intensive care unit between the 2 groups (P < 0.05), the babies of those women managed conservatively staying a mean of 7.4 days less. There were fewer neonatal complications in those cases managed conservatively, the number of newborns with 1 or more complications in the early intervention group being 18 (64.3%), compared with 8 (28.6%) in the expectant management group (P = 0.0001). All of the women in the group managed by early intervention recovered with no severe complications. However, those women managed conservatively had a higher incidence of HELLP (2 cases) and ELLP syndrome (2 cases), 1 case requiring temporary renal dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

The aetiology and clinical significance of the sinusoidal fetal heart-rate pattern; two case reports.

Two cases are presented in which sinusoidal heart-rate (SHR) patterns were recorded antenatally. In the first case the pattern was associated with severe maternal exertion and prolonged exposure to freezing temperatures. The pattern returned to normal within an hour of maternal recovery. The second case was associated with fetal death due to high-output cardiac failure associated with a large liver haemangioma. A hypothesis is proposed to link the aetiology for this heart-rate pattern which would explain these, and previously reported cases.