bluuebunny/crossref_metadata_2025 huggingface dataset:
Alternative sources of pluripotent stem cells: altered nuclear transfer
Authors: Condic M. L.
Published: September 2010

Abstract. Altered nuclear transfer (ANT) is one of several methods that have been suggested for obtaining pluripotent stem cells without destroying human embryos. ANT proposes to alter the nucleus of a somatic cell and/or the cytoplasm of an enucleated oocyte such that when the two are combined, they do not produce a zygote, but rather they form a cell capable of producing pluripotent stem cells without being an embryo. The ANT proposal raises the serious question of whether it is possible to know with confidence that this procedure generates a non‐embryo, rather than merely an embryo with a deficiency. Here I address the question of how embryos can be distinguished from non‐embryos using scientific criteria and apply these criteria to the two forms of ANT proposed thus far: ANT combined with oocyte‐assisted reprogramming (ANT‐OAR) or with gene deletion (ANT‐GD). I propose that the first globally coordinated event in human development, the formation of trophoblast and inner cell mass (ICM) lineages via Cdx2‐Oct3/4 mutual cross‐repression, is the earliest act of the embryo qua embryo; it is an operation intrinsic to an embryo as such, and entities lacking the power (potentia) for such an act cannot be considered embryos. Thus, I will argue that formation of trophoblast‐ICM lineages is a both necessary and sufficient criterion for determining whether ANT produces an embryo or a non‐embryonic entity.
Stem cells and neurological diseases
Authors: Hess D. C. , Borlongan C. V.
Published: September 2010

Abstract.  Cells of the central nervous system were once thought to be incapable of regeneration. This dogma has been challenged in the last decade with studies showing new, migrating stem cells in the brain in many rodent injury models and findings of new neurones in the human hippocampus in adults. Moreover, there are reports of bone marrow‐derived cells developing neuronal and vascular phenotypes and aiding in repair of injured brain. These findings have fuelled excitement and interest in regenerative medicine for neurological diseases, arguably the most difficult diseases to treat. There are numerous proposed regenerative approaches to neurological diseases. These include cell therapy approaches in which cells are delivered intracerebrally or are infused by an intravenous or intra‐arterial route; stem cell mobilization approaches in which endogenous stem and progenitor cells are mobilized by cytokines such as granulocyte colony stimulatory factor (GCSF) or chemokines such as SDF‐1; trophic and growth factor support, such as delivering brain‐derived neurotrophic factor (BDNF) or glial‐derived neurotrophic factor (GDNF) into the brain to support injured neurones; these approaches may be used together to maximize recovery. While initially, it was thought that cell therapy might work by a ‘cell replacement’ mechanism, a large body of evidence is emerging that cell therapy works by providing trophic or ‘chaperone’ support to the injured tissue and brain. Angiogenesis and neurogenesis are coupled in the brain. Increasing angiogenesis with adult stem cell approaches in rodent models of stroke leads to preservation of neurones and improved functional outcome. A number of stem and progenitor cell types has been proposed as therapy for neurological disease ranging from neural stem cells to bone marrow derived stem cells to embryonic stem cells. Any cell therapy approach to neurological disease will have to be scalable and easily commercialized if it will have the necessary impact on public health. Currently, bone marrow‐derived cell populations such as the marrow stromal cell, multipotential progenitor cells, umbilical cord stem cells and neural stem cells meet these criteria the best. Of great clinical significance, initial evidence suggests these cell types may be delivered by an allogeneic approach, so strict tissue matching may not be necessary. The most immediate impact on patients will be achieved by making use of the trophic support capability of cell therapy and not by a cell replacement mechanism.
Progenitor cells and vascular disease
Authors: Jevon M. , Dorling A. , Hornick P. I.
Published: September 2010

Abstract.  Vascular progenitor cells have been the focus of much attention in recent years; both from the point of view of their pathophysiological roles and their potential as therapeutic agents. However, there is as yet no definitive description of either endothelial or vascular smooth muscle progenitor cells. Cells with the ability to differentiate into mature endothelial and vascular smooth muscle reportedly reside within a number of different tissues, including bone marrow, spleen, cardiac muscle, skeletal muscle and adipose tissue. Within these niches, vascular progenitor cells remain quiescent, until mobilized in response to injury or disease. Once mobilized, these progenitor cells enter the circulation and migrate to sites of damage, where they contribute to the remodelling process. It is generally perceived that endothelial progenitors are reparative, acting to restore vascular homeostasis, while smooth muscle progenitors contribute to pathological changes. Indeed, the number of circulating endothelial progenitor cells inversely correlates with exposure to cardiovascular risk factors and numbers of animal models and human studies have demonstrated therapeutic roles for endothelial progenitor cells, which can be enhanced by manipulating them to overexpress vasculo‐protective genes. It remains to be determined whether smooth muscle progenitor cells, which are less well studied than their endothelial counterparts, can likewise be manipulated to achieve therapeutic benefit. This review outlines our current understanding of endothelial and smooth muscle progenitor cell biology, their roles in vascular disease and their potential as therapeutic agents.
Long‐term clinical results of autologous infusion of mobilized adult bone marrow derived CD34+ cells in patients with chronic liver disease
Authors: Levičar N. , Pai M. , Habib N. A. , Tait P. , Jiao L. R. , Marley S. B. , Davis J. , Dazzi F. , Smadja C. , Jensen S. L. , Nicholls J. P. , Apperley J. F. , Gordon M. Y.
Published: September 2010

Abstract.  Evidence is growing in support of the role of stem cells as an attractive alternative in treatment of liver diseases. Recently, we have demonstrated the feasibility and safety of infusing CD34+ adult stem cells; this was performed on five patients with chronic liver disease. Here, we present the results of long‐term follow‐up of these patients. Between 1 × 106 and 2 × 108 CD34+ cells were isolated and injected into the portal vein or hepatic artery. The patients were monitored for side effects, toxicity and changes in clinical, haematological and biochemical parameters; they were followed up for 12–18 months. All patients tolerated the treatment protocol well without any complications or side effects related to the procedure, also there were no side effects noted on long‐term follow‐up. Four patients showed an initial improvement in serum bilirubin level, which was maintained for up to 6 months. There was marginal increase in serum bilirubin in three of the patients at 12 months, while the fourth patient's serum bilirubin increased only at 18 months post‐infusion. Computed tomography scan and serum α‐foetoprotein monitoring showed absence of focal lesions. The study indicated that the stem cell product used was safe in the short and over long term, by absence of tumour formation. The investigation also illustrated that the beneficial effect seemed to last for around 12 months. This trial shows that stem cell therapy may have potential as a possible future therapeutic protocol in liver regeneration.
Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors
Authors: Yamanaka S.
Published: September 2010

Abstract.  Pluripotent stem cells, such as embryonic stem cells (ESCs), proliferate rapidly while maintaining pluripotency, namely, the ability to differentiate into various types of cells. Embryonic stem cells are promising donor sources for cell transplantation therapies. However, human ESCs are also associated with ethical issues regarding the use of human embryos and rejection reactions after allogenic transplantation. It may be possible to overcome these issues by generating pluripotent stem cells directly from a patient's somatic cells. That somatic cell nuclei acquire an embryonic stem‐like status by fusion with ESCs suggests the existence of ‘pluripotency‐inducing’ factors. Previous studies have recently shown that retrovirus‐mediated transfection with four transcription factors (Oct‐3/4, Sox2, KLF4 and c‐Myc), which are highly expressed in ESCs, into mouse fibroblasts has resulted in generation of induced pluripotent stem (iPS) cells. iPS cells are similar to ESCs in morphology, proliferation, and pluripotency, judged by teratoma formation and chimaera contribution. If iPS cells can be derived from human somatic cells, then such cells may thus lead to important drug discoveries and advances in regenerative medicine.
For the child’s sake: parents and social workers discuss conflict‐filled parental relations after divorce
Authors: Hydén
Published: September 2010

After a divorce, the former partners have to form new relationships between themselves as parents, and with their children. What does this reconstruction involve? What are the tasks facing the parents? What are the areas of conflict? This paper attempts to answer these questions. Eight initial sessions of parental mediation were chosen for the analysis. The analysis indicates that statements about the ways in which parents are entitled to their children, and vice versa, are common denominators for the transition from nuclear family parenting to post‐nuclear family parenting. In the sessions, parents dealt with this duty by fighting a battle for a place in the children’s lives. The battles were expressed in negotiations about time and place. The analysis revealed two different solutions to the problem of the parents’ entitlements. One was the creation of the homogeneous family, with one parent and the children living together in a close relationship, giving the other parent visiting rights. The other was to form a heterogeneous family, based on the idea that it is possible to build a childhood on differences and dissimilarities. Most of the conflicts originated from parents’ efforts to create homogeneous families.
Do we care? Adult mental health professionals' attitudes towards supporting service users' children
Authors: Slack Karin , Webber Martin
Published: September 2010

The impact of parental mental health is well known, but children's very existence may fail to be recognized by adult mental‐health services. This study aimed to explore attitudes of mental‐health professionals in one outer London borough regarding support needs of mental‐health service users' children to highlight potential barriers to identifying or meeting their support needs. All statutory mental‐health teams in the borough participated in a cross‐sectional survey. The response rate was 62.8% (n = 94) out of 150. The sample consisted of a diverse range of professionals from both inpatient and community settings. The main finding was that practitioners were overwhelmingly in favour of supporting children. However, attitudes and practices were significantly associated with profession, setting and whether the respondent was a care coordinator. Demographic characteristics or experience was not associated with attitudes. Perceived barriers to supporting children are highlighted. In particular, the mental‐health professionals in our sample considered supporting children important but did not necessarily consider it their role to do so. Training is required to raise awareness about this issue.
Strengthening the parent–child relationship: a review of family interventions and their use in medical settings
Authors: Johnson G. , Kent G. , Leather J.
Published: September 2010

The quality of family functioning is important for both psychological well‐being and physical health. This review describes family interventions that aim to improve the strength of the parent–child relationship and considers ways in which these approaches can be applied to physical health care. This review first describes the development of family therapy in dealing with children's behavioural and emotional difficulties. As shown in psychotherapeutic settings, parenting skills can affect children's emotional well‐being and ability to control their own conduct. Intervention strategies that focus on developing the ability of parents to provide a benign and nurturing parenting style are considered. The review then considers how the principles of family therapy can be applied to settings where physical health is the central issue. In medical settings, families are not only affected by medical interventions but they can also serve to facilitate or hinder clinical effectiveness. Illustrations of how these interventions can be applied in medical settings are provided. Although a practising clinician will need training in using family therapy techniques, it may be possible to recruit a family therapist to help in particular cases.
One month after diagnosis: quality of life, coping and previous functioning in siblings of children with cancer1
Authors: Houtzager B. A. , Grootenhuis M. A. , Hoekstra‐Weebers J. E. H. M. , Last B. F.
Published: September 2010

Background  The aim of the present study is to describe the quality of life (QoL) of siblings of children with cancer and to predict it according to their health before the diagnosis of cancer in the ill child and their ways of coping with the illness.

Methods  Participants were 83 siblings from 56 families – 46 girls and 37 boys, aged 7–18. The assessment took place 1 month to 8 weeks after the diagnosis of cancer in the ill child. The siblings’ QoL was assessed with the TNO‐AZL children's quality of life questionnaire (TACQOL). Coping strategies were assessed with the Cognitive Coping Strategies Scale for siblings (CCSS‐s). Physical problems and eating and sleeping problems that existed before the ill child was diagnosed were determined in a structured interview with the parents.

Results  A substantial number of siblings reported impaired cognitive and emotional QoL compared to the reference group. School‐aged siblings (7–11 years) reported more trouble with motor functioning than peers. The coping strategy ‘predictive control’ (maintaining positive expectations regarding the illness) positively predicted siblings’ QoL. The presence of health problems before diagnosis was negatively associated with siblings’ QoL. Older siblings reported more negative emotions, while girls reported lower social QoL and reliance on ‘interpretative control’ (trying to understand the illness) was associated with fewer positive emotions.

Conclusions  During the first 2 months after the diagnosis of cancer in a brother or sister, siblings have relatively lower QoL than peers. Health problems that existed before diagnosis may be a predictor of later adjustment problems. Positive expectations about the course of the illness appear to protect siblings from distress. Information about the illness is a delicate issue that requires parental guidance.
The relationship between maternal self‐efficacy and parenting practices: implications for parent training
Authors: Sanders M. R. , Woolley M. L.
Published: September 2010

The present study examined the relationship between maternal self‐efficacy, dysfunctional discipline practices and child conduct problems. Specifically, three levels of self‐efficacy, global, domain and task‐specific self‐efficacy, were assessed in mothers of 2‐ to 8‐year‐old children with conduct problems (clinic group, n = 45) and non‐clinic mothers from the community (non‐clinic group, n = 79). Measures of global, domain and task‐specific self‐efficacy were completed by mothers. Clinic mothers reported significantly lower self‐efficacy than non‐clinic mothers for all but one of the parenting tasks assessed. Both groups of mothers reported lowest self‐efficacy for similar parenting tasks. In the sample as a whole self‐efficacy measures were significant predictors of maternal discipline style after controlling for other parent, child and risk factors. Of the self‐efficacy variables behavioural self‐efficacy was the best predictor of mothers discipline style. The findings support the importance of developing parenting strategies that enable parents to generalize their parenting skills to a diverse range of diverse parenting contexts both in the home and in the community.
The impact of childhood chronic neurological diseases on Greek families
Authors: Tzoufi M. , Mantas Ch. , Pappa S. , Kateri M , Hyphantis T. , Pavlou M. , Mavreas V. , Siamopoulou‐Mavridou A.
Published: September 2010

Background  Although the impact of childhood chronic neurological diseases (CND) on patients’ psychological well‐being has been increasingly addressed, little attention has been given to the influence of these conditions on family members and family functioning. The purpose of the present study was to investigate the family characteristics of Greek children suffering from CND.

Methods  A total of 52 parents of children with CND were studied by using the Family Environmental Scale (FES), the Family Burden Scale, the General Health Questionnaire (GHQ‐28) and a questionnaire on the knowledge of their children's illness, their coping strategies and their satisfaction with our services. During the same period, 30 parents of hospitalized children for common paediatric illnesses completed the FES. In both groups social and demographic features were registered. Appropriate statistical processes were applied to compare the above‐mentioned family groups and to study the differences between the families of children with epilepsy (n = 37) and the families of children with other CND (n = 15).

Results  Parents of children with CND discuss their problems less freely, talk less openly around home, score highly on FES subscale of Conflict and, pay more attention to ethical and religious issues and values. Furthermore, the families of children with other CND were more burdened regarding the financial state and the health status of other family members in comparison with families of children with epilepsy. In addition, families of children with epilepsy were more involved in social and recreational activities, appeared to be more knowledgeable on the availability of help in critical conditions and were more satisfied with rendered medical services, in comparison with families of children with other CND.

Conclusion  These preliminary findings provide important information concerning the special characteristics of Greek families of children suffering from CND, which may prove especially helpful in organizing specific support services.
Motor skills in adolescents with low birthweight
Authors: Reading Richard
Published: September 2010

Background  Minor motor problems have been reported in low birthweight children, but few studies have assessed motor skills in adolescents.

Objective  To examine the prevalence of motor problems in adolescents with low birthweight.

Methods  Fifty‐four very low birthweight (VLBW: birth weight ≤1500 g), 59 term small for gestational age (SGA: birthweight <10th centile), and 83 control (birthweight ≥10th centile at term) children were assessed with the movement assessment battery for children (Movement ABC) at the age of 14 in a population‐based study.

Results  One in four VLBW children [odds ratio (OR) 9.3, 95% confidence interval (CI) 2.5–34.5] and one in six SGA children (OR 4.7, 95% CI 1.2–18.4) had motor problems compared with controls (3.7%). There were no sex differences in motor problems in the VLBW group, and the increased risk was consistent across the continuum of the Movement ABC. For SGA children, the increased risk of motor problems was particularly in manual dexterity in boys.

Conclusion  VLBW and SGA adolescents have increased risk of motor problems compared with control children.
Open‐label use of placebos in the treatment of ADHD: a pilot study
Authors: Sandler A. D. , Bodfish J. W.
Published: September 2010

Background This study examined short‐term efficacy, side effects and acceptability of a placebo treatment procedure designed to maintain children with attention deficit hyperactivity disorder (ADHD) on 50% of their usual stimulant dose.

Methods An open‐label prospective crossover trial was conducted in 26 children with ADHD, ages 7–15 years, stable on stimulant therapy, followed at a community‐based developmental paediatrics ADHD clinic. Subjects were randomly assigned to one of two orders of experimental conditions: (1) baseline (100%) dose (1 week), then 50% dose (1 week), then 50% dose + placebo (1 week), or (2) baseline (100%), then 50% dose + placebo, then 50% dose. The inert nature of the placebo was fully disclosed to parent and child. Treatment was open‐label for child, parents and physician, but single blind for teachers. Main outcome measures included weekly IOWA Conners parent and teacher rating scales, the Pittsburgh side effects rating scale (PSERS) and the Clinical Global Impressions (CGI) scale.

Results Parent IOWA showed ADHD behaviour tended to remain the same when the dose of stimulant medication was reduced with placebo but to deteriorate when the dose was reduced without placebo. There were no significant differences between conditions on the Teacher IOWA. PSERS scores were higher at baseline than on 50% dose. On the CGI, there was a significant difference (P = 0.004) between the 50% dose and the 50% + placebo conditions. Individual subject analysis showed that eight subjects met criteria for responder.

Conclusions Results indicate that the open‐label placebo treatment was acceptable and efficacious in the short term for some children.
Demographic, socioeconomic, and attitudinal associations with children's cycle‐helmet use in the absence of legislation
Authors: Reading Richard
Published: September 2010

.
 
Lang I.A.
(
2007
)

,
13
,
355
–
358
.
 
DOI: 10.1136/ip.2007.015941.
Increased risk of injury in children with developmental disabilities
Authors: Reading Richard
Published: September 2010

.
 
Lee L.C.,
Harrington R.A.,
Chang J.J. &
Connors S.L.
(
2007
)

,
ePub
.
 
DOI: 10.1016/j.ridd.2007.05.002.
Does amblyopia affect educational, health, and social outcomes? Findings from 1958 British birth cohort
Authors: Reading Richard
Published: September 2010

.
 
Rahi J.S.,
Cumberland P.M. &
Peckham C.S.
(
2006
)

,
332
,
820
–
825
.
 
DOI: 10.1136/bmj.38751.597963.AE.

Objective  To determine any association of amblyopia with diverse educational, health, and social outcomes in order to inform current debate about population screening for this condition.

Design, setting, and participants  Comparison of 8432 people with normal vision in each eye with 429 (4.8%) people with amblyopia (childhood unilateral reduced acuity when tested with correction and unaccounted for by eye disease) from the 1958 British birth cohort, with respect to subsequent health and social functioning.

Results  No functionally or clinically significant differences existed between people with and without amblyopia in educational outcomes, behavioural difficulties or social maladjustment, participation in social activities, unintended injuries (school, workplace, or road traffic accidents as driver), general or mental health and mortality, paid employment, or occupation based social class trajectories.

Conclusions  It may be difficult to distinguish, at population level, between the lives of people with amblyopia and those without, in terms of several important outcomes. A pressing need exists for further concerted research on what it means to have amblyopia and, specifically, how this varies with severity and how it changes with treatment, so that screening programmes can best serve those who have the most to gain from early identification.
Development of a new assessment of time processing ability in children, using Rasch analysis
Authors: Janeslätt G. , Granlund M. , Alderman I. , Kottorp A.
Published: September 2010

Background Children with disabilities like ADHD, Autism or Intellectual Disabilities may have problems with everyday functioning related to time management and hence there is a need to develop systematic methods for evaluation of the ability to understand and use time information. The purpose of this study was to examine aspects of construct validity of a new instrument, KaTid, for assessing time processing ability (TPA) in children.

Methods Data from 144 typically developing, 5–10‐years‐old typically developing children, were analysed with Rasch analysis. Instruments used were the KaTid, a self‐rating scale measuring autonomy in daily routines and a parent scale measuring daily time management.

Results Fifty‐one items in KaTid, initially defined in three subcategories: time perception, time orientation and time management, all demonstrated acceptable goodness‐of‐fit to a Rasch model, indicating evidence of internal scale validity. Performance of the children on the KaTid also provided evidence for validity in response processes and that it may discriminate among children with different levels of TPA. Relationships between the KaTid measures and the parents' ratings of the child's daily time management indicated further evidence of construct validity.

Conclusions The results of this study supports evidence of construct validity in the KaTid when used with typically developing 5–10 years‐old children. Further research is needed to evaluate the validity of KaTid in children with known time processing difficulties.
Development of a Children's Trust in General Physicians Scale
Authors: Rotenberg K. J. , Cunningham J. , Hayton N. , Hutson L. , Jones L. , Marks C. , Woods E. , Betts L. R.
Published: September 2010

Background  Researchers have developed scales assessing adults' trust beliefs in physicians and found that those are associated with measures of health behaviour and physical health. The purpose of the research was to develop a Children's Trust in General Physicians Scale (CTGPS) and examine its relation to health behaviour: adherence to medical regimes.

Methods  The participants were 128 children (68 girls and 60 boys) in Study 1 and 198 children (105 girls and 93 boys) in Study 2 who attended years 5 and 6 of elementary school in UK (mean ages = 10 years and 10 months and 10 years and 7 months respectively). The children completed the nine‐item CTGPS and reported their trust in doctors and (in Study 2) adherence to medical regimes. Parents also reported those behaviours.

Results  Principal components analysis and confirmatory factor analysis of the CTGPS yielded the expected three factors: Honesty, Emotional and Reliability. The CTGPS had acceptable internal consistency and, as evidence for its validity, was associated with reported trust in doctors. The results from Study 2 confirmed that the CTGPS was associated with adherence to medical regimes.

Conclusion  A CTGPS was developed that is associated with adherence to medical regimes.
Obesity in looked after children: is foster care protective from the dangers of obesity?
Authors: Hadfield S. C. , Preece P. M.
Published: September 2010

Background  Obesity in all age groups of children has become an increasing concern in recent years. Children looked after by the Local Authority (LA) should be protected from health problems while being accommodated. These studies assess the effect on weight of looked after children (LAC) in the care of a Midlands County Council.

They assess the frequency of obesity or overweight problems in looked after children following receipt into care and review changes in body mass index (BMI) while in the care of the LA.

Method  The height and weight measurements of all 106 children who had statutory health assessments while in the care of the LA between 1 January 2004 and 30 December 2004 were used to calculate their BMI. The data were plotted onto standard Growth Foundation charts and the International Obesity Task Force Paediatric cut‐offs were determined to distinguish overweight and obese children and young people.

The date that the child had come into the care system and the number of moves of placement was obtained for each child from the social care. This was related to the total group and the overweight group of looked after children.

Result  Looked after children are more likely to be overweight and obese compared with standard norms, and there are a number of children (35%) whose BMI increases once in care.

Outcome  Looked after care did not protect a child from the national problem of increasing weight gain and obesity.
BIO AND IMMUNO‐ACTIVITY OF FSH IN SERUM AFTER INTRAMUSCULAR INJECTION OF HIGHLY PURIFIED URINARY HUMAN FSH IN NORMAL MEN
Authors: JOCKENHÖVEL F. , FINGSCHEIDT U. , KHAN S. A. , BEHRE H. M. , NIESCHLAG E.
Published: September 2010

The pharmacokinetics of a human FSH preparation widely used in clinical practice was evaluated in healthy male volunteers whose endogenous FSH was suppressed by 19‐nortestosterone injections. 9‐7 h following intramuscular injection of 150 IU FSH the mean immunoreactive peak concentration over baseline was 3–8 IU/1. Injection of 450 IU FSH led to a mean immunoreactive peak level of 10‐4 IU/1 at 9‐8 h. Mean half‐life was 24‐6 h (150 IU FSH) and 36‐2 h (450 IU FSH). Serum bioFSH concentrations were suppressed below the detection limit after injection of the 19‐nortestosterone and rose to preinjection levels after administration of FSH. Mean bioactive peak level for the 450 IU FSH was 7‐3 IU/1 FSH at 7‐4 h. The half‐life of bioFSH was calculated to be 13‐4 h and is considerably shorter than the half‐life of immunoFSH. Serum inhibin levels were suppressed by 19‐nortestosterone and did not change significantly after injection of the FSH preparation, suggesting that the FSH dose was insufficient to elicit this biological response. It is concluded that the currently used dose regimen for the treatment of male hypogonadism is inadequate for maintenace of serum bioFSH levels in the normal range.
EFFECTS OF LUTEINIZING HORMONE, INSULIN, INSULIN‐LIKE GROWTH FACTOR‐I AND INSULINLIKE GROWTH FACTOR SMALL BINDING PROTEIN 1 IN THE POLYCYSTIC OVARY SYNDROME
Authors: CONWAY GERARD S. , JACOBS H. S. , HOLLY J. M. P. , WASS J. A. H.
Published: September 2010

This study explores the clinical and endocrine implications of hyperinsulinae‐mia in the polycystic ovary syndrome (PCOS). Oral glucose tolerance tests were performed on 34 lean and 19 obese women with PCOS and on 13 lean women with normal ovaries. Insulin measurements were compared with basal gonado‐trophins, androgens, insulin‐like growth factor‐I (IGF‐I) and insulin‐like growth factor binding protein 1 (IGFBP‐1). Unselected lean women with PCOS were found to have fasting hyperinsulinaemia and the raised serum insulin concentrations were associated with menstrual disturbance and hyperandro‐genaemia. In addition, serum insulin concentrations in lean women with PCOS correlated positively with serum IGF‐I and negatively with serum IGFBP‐I concentrations. Ovarian stimulation by insulin appears to be independent of luteinizing hormone (LH) and is an important feature in 30% of lean women with PCOS.
PYRIDOSTIGMINE DOES NOT REVERSE DEXAMETHASONE‐INDUCED GROWTH HORMONE INHIBITION
Authors: DEL BALZO P. , SALVATOR R. , CAPPA M. , GERTNER J. M.
Published: September 2010

Glucocorticoids inhibit the growth hormone (GH) response to a variety of stimuli, including GH‐releasing hormone (GHRH) in vivo, but they increase GHRH‐stimulated GH secretion when added, in vitro, to animal and human pituitary cells. This discrepancy has led to the hypothesis that glucocorticoids act in vivo by increasing somatostatin secretion from the hypothalamus. To examine this hypothesis, we used a cholinergic drug, pyridostigmine (PD), which reduces hypothalamic somatostatin secretion. Eight normal volunteers were studied. They underwent four tests: (1) GHRH test; (2) Dex + GHRH (GHRH test after treatment the night before, with dexamethasone (Dex)); (3) PD + GHRH; (4) Dex + PD + GHRH. Dex significantly inhibited the GH response to GHRH expressed as area under the GH/time curve (AUC, μug/1/ min) (mean ± SEM = 895‐2 ± 196‐6 vs 1970‐9 ± 600‐1, P < 005). PD significantly increased the AUC of GH secretion in PD + GHRH compared with GHRH alone (3541‐2 + 571‐3 vs 1970‐9 + 600‐1, P<001) but by no means restored completely the normal GH response to GHRH, when given to Dex‐pretreated subjects. Furthermore, the mean AUC of Dex + PD + GHRH was significantly lower than that of PD + GHRH (1621‐7±500‐6 vs 3541‐2 + 571‐3, P<0–01), demonstrating that Dex continues to exert its inhibitory effect on GH secretion in the presence of PD. These results suggest that glucocorticoid‐induced GH inhibition does not act solely through an increase in hypothalamic somatostatin secretion.
Hypoparathyroidism—a long‐term follow‐up experience with 1α‐vitamin D3 therapy
Authors: Halabe A. , Arle R. , Mimran D. , Samuel R. , Liberman U. A.
Published: September 2010

OBJECTIVE Previous studies have suggested that alpha‐D3 therapy can cause deterioration in renal function. We have, therefore, examined the long‐term effect of 1α‐hydroxyvitamin D3 (alpha‐D3) administration upon renal function in hypoparathyroid patients.

DESIGN This is a prospective long‐term follow‐up study of alpha‐D3 administration on hypoparathyroid patients at a mean daily dose of 1 μg (range 0.5–2.5 μg) during a total of 2040 patient‐months.

PATIENTS Seventeen unselected patients (14 females and 3 males), two with primary and 15 with post‐surgical hypoparathyroidism.

RESULTS The significant effect of alpha‐D3 on serum and urinary calcium was achieved during the first week of treatment and remained stable at the same range during the close follow‐up of 2040 patient‐months. No significant change was observed in the serum creatinine during the whole follow‐up period. During follow‐up, five women developed hypercalcluria and one patient developed hypercalcaemia that disappeared when the dose of the drug was reduced or discontinued.

CONCLUSIONS From our study we concluded that alpha‐D3 is a safe and effective drug in the long‐term therapy of hypoparathyroid patients.
Pharmacokinetics and metabolic effects of growth hormone injected subcutaneously in growth hormone deficient patients: thigh versus abdomen
Authors: Laursen Torben , Jørgensen Jens O. L. , Christiansen Jens S.
Published: September 2010

OBJECTIVE The absorption of insulin following subcutaneous (s.c.) injection is faster in the abdomen than the thigh. We therefore studied the effect of changing the site of injection on the absorption and metabolic effects of human growth hormone.

DESIGN AND MEASUREMENTS in a cross‐over study human GH (Norditropin) was injected s.c. in the thigh or abdomen in random order. Ultrasonography of the thigh and abdomen was performed in order to evaluate the thickness of the s.c. tissue. After each treatment period (4 weeks), serum profiles of GH, IGF‐I, IGF binding proteins 1 and 3 (IGFBP‐1 and IGFBP‐3), glucose, insulin, non‐esterified fatty acids (NEFA), glycerol, 3‐hydroxy‐butyrate, alanine, lactate and glucagon were measured for 37 hours after GH injection (3 IU/m2 at 1900 hour).

PATIENTS Nine GH deficient patients (five males, four females).

RESULTS The mean (± SEM) thickness of the s.c. tissue (mm) was higher on the abdominal site (9·35 ± 1·38 (thigh), and 22·61 ± 2·19 (abdomen), P<0·001). Mean (±SEM) integrated levels (area under the curves (AUC) divided by time) of GH (mU/l) were identical: 5·54 ± 0·70 (thigh) versus 5·48 ± 0·64 (abdomen) (P = 0·91). AUC (mU/l) for the initial 6 hours were, however, significantly different (14·10 ± 3·76 (thigh) and 19·02 ± 3·18 (abdomen), P = 0·02). Maximal serum concentration (Cmax) (mU/l) 23·18 ± 3·86 (thigh) and 29·66 ± 4·78 (abdomen) (P = 0·19) was achieved faster (Tmax) following injection in the abdomen. Tmax (hours) was 5·89 ± 0·41 (thigh) and 4·26 ± 0·49 (abdomen) (P<0·002). Mean IGF‐I levels (μg/l) were unaffected by GH injection sites (355 ± 60 (thigh) and 365 ± 63 (abdomen), P = 0·61). Mean IGFBP‐3 levels (μg/l) were significantly different (2100 ± 143 (thigh), and 2350 ± 176 (abdomen), P = 0·05). Mean levels of IGFBP‐1, insulin, glucose, lipid intermediates, metabolites and glucagon were not significantly different.

CONCLUSIONS Human GH was absorbed faster when injected s.c. In the abdomen as compared with the thigh, despite the thicker s.c. tissue on the abdomen. Apart from higher IGFBP‐3 levels after s.c. injections in the abdomen, similar metabolic effects of GH were obtained with the two injection sites.
Octreotide administration, under particular temporal conditions, enhances the responses of growth hormone to growth hormone‐releasing hormone in normal subjects
Authors: Valcavl Roberto , Zinl Michele
Published: September 2010

OBJECTIVE Somatostatin not only inhibits basal and GHRH‐stimulated GH secretion but might also enhance pituitary GH responsivity to GHRH under different temporal conditions. We investigated whether octreotide, a long‐acting somatostatin analogue, has any positive actions on GHRH‐induced GH release in normal human subjects.

DESIGN The study consisted of three protocols. At 0800 hours, after fasting overnight, all subjects received 1 μg/kg GHRH l.v. bolus at 0 minutes. In each protocol, either octreotide (200 μg s.c.) or placebo were given respectively 8, 12, or 16 hours prior to GHRH challenge.

SUBJECTS Three groups of eight normal volunteers (four female and four male in each group), aged 18–35 years, were randomly assigned to each protocol.

MEASUREMENTS Growth hormone was measured by IRMA. Samples for GH assay were taken at −30 and 0 minutes and then at 15‐minute intervals up to 120 minutes.

RESULTS When placebo or octreotide were administered 8 hours before GHRH, peak GH levels were respectively (mean ± SE, mU/l) 56·2 ± 16·6 and 60·8 ± 11·4 (NS). Also, when placebo or the somatostatin analogue were administered 16 hours prior to GHRH, peak GH levels were comparable (61·0 ± 7·4 vs 58·8 ± 7·4, NS). However, in the group receiving placebo or octreotide 12 hours prior to GHRH, the GH responses to GHRH were clearly enhanced by octreotide administration (peak GH levels, mU/l, 55·6 ± 21·6 vs 104·0 ± 17·4, P < 0·02). This enhancement of GH responses was observed in all subjects.

CONCLUSIONS Octreotide administration did not affect GH responses to GHRH when given either 8 or 16 hours prior to GHRH. However, octreotide enhanced GHRH‐induced GH release when administered 12 hours prior to GHRH. It thus appears that, under particular temporal conditions, octreotide may act positively on GH secretion in man.
Pulsatile gonadotrophin‐releasing hormone therapy in patients with pituitary tumours treated by surgery and irradiation
Authors: Park Ki Hyun , Park Won II , Lee Byung Seok , Song Chan Ho , Huh Kap Bum , Lee Hyun Chul , Chung Sang Sup , Kim Gwl Eon
Published: September 2010

OBJECTIVE Pulsatile administration of GnRH for induction of ovulation is effective for women with idiopathic hypogonadotrophic hypogonadism. We were interested to assess the pituitary‐ovarian response to pulsatile GnRH infusion and the therapeutic effectiveness of restoring ovulation in a group of hypogonadotrophic women previously treated with surgery and irradiation to pituitary tumours.

PATIENTS The group of patients comprised 15 hypogonadotrophic women, aged 29–40 years (mean 32·4 years), who had undergone transsphenoidal adenomectomy or craniotomy and irradiation with a total of 4500–5400 cGy in 25 fractional doses divided over 5–6 weeks. The time interval from irradiation to study was 6·3 ± 2·0 years (mean±SD).

TREATMENT A single bolus GnRH (100 μg) test and pulsatile infusion of GnRH were performed to assess the pituitary gonadotrophin reserve and induce ovulation. We tried to correlate the pituitary response with characteristics of intracranial lesions on computerized tomography findings. We undertook ovarian biopsy in one patient who falled to respond to gonadotrophin therapy and pulsatile infusion of GnRH.

RESULTS Twelve women (80%) showed evidence of ovulation in response to pulsatile GnRH treatment and five subsequently became pregnant. Four of 12 ovulators were previous non‐ovulators to exogenous gonadotrophin therapy. There was no correlation between pituitary response and character of lesions based on computerized tomography findings. A patient who failed to respond to either gonadotrophin or pulsatile infusion of GnRH had premature ovarian failure on ovarian histology.

CONCLUSIONS The functional reserve capacity of pituitary gonadotrophs may remain less impaired by tumour encroachment, pituitary surgery or irradiation than had previously been thought. This holds promise for ovulation induction in hypogonadotrophic patients who had been treated with surgery and irradiation for pituitary tumours.
Phase‐shifts in melatonin, 6‐sulphatoxymelatonin and alertness rhythms after treatment with moderately bright light at night
Authors: Deacon Stephen J. , Arendt Josephine
Published: September 2010

OBJECTIVES Shift work and rapid travel across several time zones leads to desynchronization of internal circadian rhythms from the external environment and from each other with consequent problems of behaviour, physiology and performance. Field studies of travellers and shift workers are expensive and difficult to control. This investigation concerns the simulation of such rhythm disturbance in a laboratory environment. The main objectives are to assess the ability of controlled exposure to moderately bright light and darkness/sleep to delay circadian rhythms in volunteers without environmental isolation and, secondly, to evaluate the use of different indices of melatonin (MT) secretion together with self‐rated alertness as marker rhythms.

PATIENTS Six normal volunteers aged 22–26 years (mean ± SD 24·3 ± 1·4).

DESIGN Subjects were exposed to the following periods of moderately bright light (1200 lux) on three consecutive days in early December 1991: Day (D)1: 2000‐0200 h, D2: 2200‐0400 h and D3: 2400‐0600 h. Each period was followed by 8 hours of darkness (< 1 lux). Hourly blood, sequential 4‐hourly urine (8‐hourly when asleep) and hourly saliva (except when asleep) samples were taken throughout a 24‐hour period on D0 (baseline), D4 (1 day post‐light treatment) and D7 (4 days post‐light treatment). During waking hours, subjective alertness was rated every 2 hours on a visual analogue scale.

MEASUREMENTS MT was measured in plasma and saliva, and its metabolite, 6‐sulphatoxymelatonin (aMT6s), was measured in urine. MT, aMT6s and alertness scores were analysed by ANOVA and a cosinor analysis program.

RESULTS A delay shift was present in the aMT6s, plasma MT and salivary MT rhythms (degree of shift: 2·67 ± 0.3 h (P<0·001, n = 5); 2·35±0·29 h (P<0·001, n = 6); and 1·97 ± 0·32 h (P < 0·01, n = 6), mean ± SEM, respectively) 1 day post‐light treatment compared to baseline. Adaptation to the initial phase position was apparent by the 4th post‐treatment day. Significant correlations were obtained between plasma MT onset (degree of shift: 3·12 ± 0·74 h (P < 0·001, n = 6, mean ± SEM)) and the acrophases (calculated peak times) of plasma MT (P<0·001), salivary MT (P < 0·05) and urinary aMT6s (P < 0·01). A significant phase delay in the alertness rhythm was also evident 1 day post‐treatment (3·08 ± 0·67 h (P < 0·01, n = 6, mean ± SEM)) with adaptation by the 2nd post‐treatment day.

CONCLUSIONS This study suggests that these methods of determining MT secretion are comparable and give reliable assessments of the MT circadian phase position even after a phase‐shift. Significant phase‐shifts of similar magnitude can be induced in both MT and alertness rhythms using moderate intensity bright light at night.
Partial nephrogenic diabetes insipidus caused by a novel mutation in the AVPR2 gene
Authors: Færch Mia , Christensen Jane H. , Corydon Thomas J. , Kamperis Konstantinos , De Zegher Francis , Gregersen Niels , Robertson Gary L. , Rittig Søren
Published: September 2010

Objective   To identify the molecular basis and clinical characteristics of X‐linked congenital nephrogenic diabetes insipidus (CNDI) presenting with an unusual phenotype characterized by partial resistance to AVP.

Subjects   The proband was admitted at the age of 4 years with a history of polydipsia and polyuria since infancy. Initial clinical testing confirmed a diagnosis of diabetes insipidus (DI). Urine osmolarity rose during fluid deprivation and after 20 µg of intranasal desmopressin [1‐deamino‐8‐d‐arginine‐vasopressin (dDAVP)]. A similar DI phenotype was found in his brother.

Methods   The coding regions of the AVP gene and the AVP receptor 2 (AVPR2) genes were sequenced in two affected and three unaffected family members. Clinical studies included a fluid deprivation test, intranasal dDAVP challenge, infusion of graded doses of dDAVP and AVP, and measurements of 24‐h urine output before and at the end of a 7‐day therapeutic trial of intranasal dDAVP.

Results   A novel missense mutation (1454C > A) in exon 3 of the AVPR2 gene predicting a Ser329Arg substitution was identified in the X‐chromosome of the two affected brothers and in one of the X‐chromosomes in the mother. The AVPR2 gene was normal in two unaffected siblings. Under basal conditions, the 24‐h urine volumes of the two affected boys were 5·5 l (229 ml/kg) and 3·5 l (192 ml/kg), the urine osmolalities were 78 and 90 mosm/kg, and plasma AVP 13·5 and 19·0 pg/ml. Urine osmolalities increased to 573 and 720 mosm/kg while plasma AVP levels were practically unchanged, 13·6 and 8·8 pg/ml, during fluid deprivation. Infusion of AVP resulted in urine osmolalities of 523 and 623 mosm/kg at plasma AVP levels of 58 and 42 pg/ml. Infusion of dDAVP had a similar effect, while treatment with standard doses of intranasal dDAVP had no effect on urine output.

Discussion   The affected members of this Belgian kindred have CNDI with partial resistance to AVP caused by a mutation in the AVPR2 gene that differs from any of the six mutations reported previously to produce this phenotype. Because the resistance to AVP is partial, this form of CNDI can be difficult to distinguish by indirect diagnostic tests from partial pituitary and dipsogenic DI.
Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves’ disease
Authors: Kisiel Bartlomiej , Bednarczuk Tomasz , Kostrzewa Grażyna , Kosinska Joanna , Mi2kiewicz Piotr , Plazinska Maria Teresa , Bar‐Andziak Ewa , Królicki Leszek , Krajewski Pawel , Ploski Rafal
Published: September 2010

Objective  To investigate whether a polymorphism in the ESR2 gene (rs4986938, previously associated with endometriosis, ovulatory dysfunction and premature onset of coronary heart disease) increases the risk of Graves’ disease (GD).

Subjects and design  A cohort of 375 GD patients (300 females and 75 males) and 1001 individuals representative of the background population of Poland (502 males and 499 females) were genotyped for rs4986938 using allele‐specific polymerase chain reaction (PCR).

Results  We found an increased frequency of the ESR2 A allele among the patients vs. controls (38·0%vs. 32·7%, OR = 1·26, P = 0·009) that was caused by a co‐dominant (OR = 1·25, P = 0·01, Pfor model fit = 0·127) or a recessive (OR = 1·67, P = 0·003, Pfor model fit = 0·554) effect. The association was found in both sexes (OR = 1·21, P = 0·046 and OR = 1·53, P = 0·029, respectively, for co‐dominant and recessive models in females, and OR = 1·44, P = 0·034 and OR = 2·29, P = 0·01, respectively, for the two models in males) and was more pronounced among the DRB1*03‐negative (OR = 1·63, P = 0·0002) than DRB1*03‐positive patients (OR = 1·04, P = 0·822). No other statistically significant associations between the ESR2 genotype and GD subsets were found (age of onset, smoking, clinically evident ophthalmopathy, family history of GD, and PTPN22 and CTLA4 (CT60) genotypes were analysed).

Conclusions  In a Polish population the ESR2 A allele is associated with GD with a strength comparable to polymorphisms of PTPN22 and CTLA4 CT60 loci (OR ~ 1·7). The association with ESR2 is found in both sexes and may be particularly strong among the DRB1*03‐negative individuals.