bluuebunny/crossref_metadata_2025 huggingface dataset:
Flow cytometric BrdUrd‐pulse‐chase study of X‐ray‐induced alterations in cell cycle progression
Authors: Higashikubo R. , Ragouzis M. , Roti J. L. Roti
Published: November 2003

To better understand how the flow cytometric bromodeoxyuridine (BrdUrd)‐pulse‐chase method detects perturbed cell kinetics we applied it to measure cell cycle progression delays following exposure to ionizing radiation. Since this method will allow both the use of asynchronous cell populations and the determination of the alterations in cell cycle progression specific to cells irradiated in given cell cycle phases, it has a significant advantage over laborious synchronization methods. Exponentially growing Chinese hamster ovary (CHO) K1 cells were irradiated with graded doses of X‐rays and pulse‐labelled with BrdUrd immediately thereafter. Cells were subcultured in a BrdUrd‐free medium for various time intervals and prepared for flow cytometric analysis. Of five flow cytometric parameters examined, only those that involved cell transit through G2, i.e. the fraction of BrdUrd‐negative G2 cells and the fraction of BrdUrd‐positive cells that had not divided, showed radiation dose‐dependent delays. The magnitude of the effects indicates that the cells irradiated in G2 and in S are equally delayed. S phase transit of cells irradiated in S or in G1 did not appear to be affected. There were apparent changes in flow of cells out of G1, which could be explained by the delayed entry of G2 cells into the compartment because of G2 arrest. Thus, in asynchronous cells the method was able to detect G2 delay in those cells irradiated in S and G2 phases and demonstrate the absence of cell‐cycle delays in other phases.
Liver and plasma concentrations in paf‐acether and its precursors after partial hepatectomy
Authors: Lombard M‐N. , Izzo A. A. , Benhaddi M. , Natour J. , Benveniste J.
Published: November 2003

Liver and plasma concentrations in paf‐acether (paf) and related phosphocholines, i.e. lysopaf and the ether lipid 1‐O‐alkyl‐2‐acyl‐sn‐glycero‐3‐phosphocholine (AAGPC) were studied in rats following two‐third hepatectomy. We report a rapid increase in hepatic content of the 3 phospholipids at early steps of the regeneration process, when hepatocytes are switching from G0 to G1 (time 2–6 h). Later on, throughout G1 and at the G1‐S transition, these concentrations decreased progressively. They were back to sham‐operated or intact control levels at 50 h. In the plasma of hepatectomized animals, no comparable changes were detected. However, an increase in both circulating paf and lipoprotein‐bound paf concentrations was measured during the regenerating response. This report is, to our knowledge, the first one on paf level variations following 2/3 hepatectomy. In rats, partial resection of the liver was shown to initiate rapid and complex cascades of biochemical changes involving growth factors, neurotransmitters and interleukins among others. Our data are in good agreement with reported increases in both total phospholipid content and synthesis of phosphatidylcholine, a paf precursor, in the regenerating liver. At present, the possible functional significance of high paf concentrations measured over the ‘priming’ stage of the induced proliferative wave is suggested as a working hypothesis. However, on the one hand, the observed paf response is noteworthy in view of its cytokine‐related action, i.e. stimulation of IL‐6 production by different cell types (endothelial, macrophagic). On the other hand, it could represent an in vivo confirmation of previously reported in vitro paf effects inducing c‐fos and c‐jun expression, two members of the so‐called ‘cellular immediate‐early gene’ family.
Spontaneous germ cell death in the testis of the adult rat takes the form of apoptosis: re‐evaluation of cell types that exhibit the ability to die during spermatogenesis
Authors: Blanco‐Rodríguez J. , Martínez‐García C.
Published: November 2003

Spontaneous germ cell degeneration occurs in the testis of the adult rat. Accumulating data supports the idea that this degeneration takes place via apoptosis. We have determined that morphology, acridine orange staining and ultrastructural features of these cell deaths clearly take the form of apoptosis. Furthermore, with acridine orange staining it was possible to detect a cell population showing early signs of death. The characterization of the main morphological features of these cells allowed us to identify several steps of maturing germ cells undergoing degeneration that have not previously been described. We have reevaluated in toluidine blue stained semithin sections the germ cell types that undergo cell death at every stage of the spermatogenic cycle in the adult rat and concluded that, spermatogonia undergo cell death coinciding with their mitotic peaks, spermatocytes during preleptotene, leptotene, zygotene, pachytene and during metaphase I and spermatids during all their maturation steps. The biological significance of these cell deaths, at these steps of germ cell development, in relation to apoptosis, is discussed.
The physical restraint of young people
Authors: Bell Lorna
Published: November 2003

Children and young people who are in residential care sometimes behave aggressively towards themselves and others, and they may need to be physically restrained by staff. This paper describes a small‐scale study which examines the use of physical restraint in one Scottish region. It explores the circumstances surrounding the restraint and the feelings of staff about the use of the restraint. The study shows that many of the factors that have been shown to be associated with violence and aggression were present in the incidents described.
The purchaser/provider separation in child and family social work: Implications for service delivery and for the role of the social worker
Authors: Hood Suzanne
Published: November 2003

This paper discusses some of the findings from a research study that was carried out in 1995. The study aimed to examine the implications of the use of the purchaser/provider separation (and associated care management processes) in social work with children and families, focusing on the effects of separation on service delivery and on the role of the social worker. The research involved two stages: a telephone survey (to gather quantitative data about the prevalence of organizational separation in England and qualitative data about perceived advantages and disadvantages of separation) and a single exploratory case study in a Local Authority Social Services Department.

The paper is concerned primarily with the case study findings. It begins by locating organizational separation within a social policy context. This is followed by an overview of the existing literature on the implications of the purchaser/provider separation and care management for service delivery and for the social work role. The methods and key findings for the telephone survey and the case study are then described. Analysis of the case study data suggested that separation in this setting could be understood along three dimensions: efficient processing versus delays; control of the work and work processes versus lack of control; and clarity of role and task versus duplication. The paper ends with a discussion of the study’s main conclusion – that the purchaser/provider separation in child and family work may introduce benefits of specialization whilst also bringing problems associated with fragmentation of the traditional social work role.
National Society for the Prevention of Cruelty to Children, London, UK
Authors: McGee Caroline
Published: November 2003

The present article explores the complexity of children’s experiences of domestic violence. It addresses the various terms used to describe this form of violence and provides a working definition. Reviewing the literature suggests prevalence rates of domestic violence between 25 and 60%. The difficulties in achieving prevalence and incidence rates are outlined. Where children’s experiences of domestic violence have been addressed, attention has focused on either children witnessing the abuse of their mother or children directly being abused. Six main ways in which children may witness domestic violence are presented and the relationship between domestic violence and child abuse is examined briefly. An overview of the impact of domestic violence on children incorporates a discussion of the intergenerational transmission of violence theory. Some of the multiple factors which may inhibit children from talking about domestic violence are raised, indicating how complex this issue is for children. Finally, the need to recognize the diversity of children’s experiences of and reactions to this form of violence is identified.
Family involvement in decision making in child protection and care: four types of case conference
Authors: Campbell Lynda
Published: November 2003

Since the early 1980s the child protection and care system of Victoria, Australia, has seen the elaboration and diversification of decision making forums, with variable levels of participation by parents and older children. This paper identifies four forums which occur at different stages of the protective process and are held under different auspices and with different membership and purposes. This paper describes and compares these mechanisms with a view to clarifying their distinctive contributions and commonalities, and elaborates issues relating to how ‘family’ is conceptualized, underlying tensions in protective worker‐family relationships, the process of participation, and the management of multiple case planning processes. The paper discusses problems that arise as multiple mechanisms become institutionalized within the same child protection system, and some limitations of participatory case planning in producing systems change.
Social workers, parents and stigma
Authors: Colton M. , Drakeford M. , Roberts S. , Scholte E. , Casas F. , Williams M.
Published: November 2003

This paper draws on an empirical study of stigma and child welfare services in the United Kingdom, the Netherlands, and Spain. It focuses exclusively on the findings relating to the United Kingdom and shows how stigma continues to be a part of the experience of using and delivering child welfare services, despite the positive determination of policies that this should not be so. More optimistically, however, it is also evident that the experience of stigma and exclusion can be reduced, and the paper concludes by outlining the implications for policy and practice together with those factors which would appear to be most significant in combating stigma.
Socio‐genealogical connectedness, attachment theory, and childcare practice
Authors: Owusu‐Bempah J. , Howitt Dennis
Published: November 2003

At the heart of child welfare policy and practice are issues of loss and separation, issues of loss and discontinuity of parent–child or carer–child ties. Consequently, John Bowlby’s ideas concerning attachment have been influential in this field over the past 50 years. This paper argues that the society in which Bowlby originally developed his ideas has altered greatly; in Western societies, family dynamics have changed remarkably, and continue to change. The present paper therefore argues that these ideas may not adequately address the developmental needs of to‐day’s children. Hence, it puts forward the notion of socio‐genealogical connectedness to complement our existing knowledge and understanding of the psycho‐social developmental needs of modern‐day children. The notion's implications for policy and practice are also highlighted.
Ebastine inhibits T cell migration, production of Th2‐type cytokines and proinflammatory cytokines
Authors: Nori M. , Iwata S. , Munakata Y. , Kobayashi H. , Kobayashi S. , Umezawa Y. , Hosono O. , Kawasaki H. , Dang N. H. , Tanaka H. , Shiohara T. , Morimoto C.
Published: November 2003

Background  Cytokine imbalance and cellular migration to inflammatory sites are critical components of allergic diseases. Redirecting cytokine imbalance and inhibiting cell migration therefore represent important therapeutic strategies for the treatment of these disorders.

Objectives  To study the in vitro effect of ebastine, a novel non‐sedating H1 receptor antagonist, on cytokine secretion and migration of activated T cells, as well as production of pro‐inflammatory cytokines by macrophages.

Methods  Peripheral T cells obtained from healthy volunteers were cultured in wells coated with the combination of anti‐CD3 monoclonal antibody (mAb) and anti‐CD26 mAb, anti‐CD3 mAb and anti‐CD28 mAb, or anti‐CD3 mAb with PMA, in the presence or absence of ebastine. T cell proliferation and the production of cytokines were measured by [3H]thymidine incorporation assay and ELISA, respectively. In addition, transendothelial migration of T cells and production of pro‐inflammatory cytokines by macrophages were examined.

Results  Ebastine inhibited T cell proliferation and the production of IL‐4, IL‐5, IL‐6, and TNF‐α by T cells under each co‐stimulatory condition tested, whereas it exhibited no effect on the production of IL‐2 or IFN‐γ. In addition, T cell migration and the production of such pro‐inflammatory cytokines as TNF‐α and IL‐6 by macrophages were inhibited by ebastine.

Conclusions  These results indicate that ebastine has a specific inhibitory effect on Th2‐type cytokine production. Moreover, ebastine inhibited T cell migration and pro‐inflammatory cytokine production by T cells and macrophages, suggesting that ebastine might be useful for the treatment of T cell‐mediated allergic inflammatory disorders, including asthma, atopic dermatitis, and Th2‐type autoimmune diseases.
Effects of asthma on cell components in peripheral blood among smokers and non‐smokers
Authors: Sunyer J. , Springer G. , Jamieson B. , Conover C. , Detels R. , Rinaldo C. , Margolick J. , Muñoz A.
Published: November 2003

Background  Eosinophils play a central role in asthma, but the interplay of the effects of smoking, eosinophils and asthma remains unclear.

Objective  The primary objective of our study was to investigate the extent to which smoking modifies the effect of asthma on circulating eosinophils, CD4+ and CD8+ T cell counts.

Methods  Data were collected semiannually between 1987 and 1994 from HIV‐negative participants in the Multicenter AIDS Cohort Study. Asthma was defined by a questionnaire at baseline as a self‐report of diagnosed asthma. A total of 1420 blood samples from 197 asthmatics and 15 822 from 1997 non‐asthmatics were collected.

Results  Eosinophil levels were higher in asthmatics (28% of asthmatics had eosinophils 4% and 16% of non‐asthmatics) regardless of smoking history, but smoking modified the association between eosinophils and asthma. Namely, the odds ratios for eosinophils being 4% in asthmatics to non‐asthmatics decreased from 2.7 (95% CI: 2.0, 3.6) in never, to 2.1 (1.4, 3.1) in former, and to 1.5 (0.9, 2.3) in current smokers. Cross‐sectional and longitudinal analyses coherently showed that smoking increased eosinophils in non‐asthmatics, but the converse was true for asthmatics. In contrast, no differences in peripheral blood T cell counts between asthmatics and non‐asthmatics were observed.

Conclusion  Under the established link between increased eosinophils and asthma, these data indicate that smoking modified this relationship. This finding suggests that smoking plays a different immunological role in asthmatics and non‐asthmatics.
High interleukin‐13 production by phytohaemagglutinin‐ and Der p 1‐stimulated cord blood mononuclear cells is associated with the subsequent development of atopic dermatitis at the age of 3 years
Authors: Lange J. , Ngoumou G. , Berkenheide S. , Moseler M. , Mattes J. , Kuehr J. , Kopp M. V.
Published: November 2003

Objective
The aim of our study was to conduct a prospective investigation into the potential association of cord blood proliferative response and cytokine production in response to various stimuli on the development of atopic dermatitis (AD) at the age of 3 years.

Methods
Cord blood mononuclear cells (CBMC) from 40 healthy term neonates were isolated. The proliferative response of CBMC stimulated with IL‐2, betalactoglobulin (BLG) and house dust mite allergen (Der p 1) was assessed by liquid scintillation counting and the stimulation index (SI) was calculated. The cytokines interleukin (IL‐)13, interferon (IFN‐)γ, IL‐10 and IL‐18 in the cell culture supernatants in response to phytohaemagglutinin (PHA), Der p 1 and BLG were measured using the ELISA technique. After 3 years, symptoms of AD were obtained with a questionnaire completed by the parents.

Results
We observed significantly higher IL‐13 levels in response to PHA in children who subsequently developed symptoms of AD (S: median, 291 pg/mL) compared with asymptomatic children (No‐S: 149 pg/mL; P=0.021, Wilcoxon test). Similarly, in response to Der p 1 significantly higher IL‐13 levels were observed in symptomatic children (S: 168.6; No‐S: 61.6 pg/mL; P=0.0084). In response to BLG, IL‐13 levels were 287.2 (S) and 123.6 pg/mL (No‐S; P=0.19). No significant differences were found when comparing the IFN‐γ levels in CBMC cultures stimulated with PHA (S: 10.2; No‐S: 17.6 IU/L; P=0.78), Der p 1 (S: 307.6; No‐S: 616.2 IU/L; P=0.2) or BLG (S: 18; No‐S: 28.5 IU/L; P=0.83; Fig. 2). The IL‐18 and IL‐10 levels and the stimulation index in response to IL‐2, BLG and Der p 1 showed no significant difference between children who subsequently developed symptoms of AD and asymptomatic children.

 Release of interferon‐gamma (IFN‐γ) in response to phytohaemagglutinin (PHA), house dust mite allergen (Der p 1) and betalactoglobulin (BLG) in children who developed symptoms of atopic dermatitis at the age of 3 years (‘symptomatic’) and asymptomatic children. The median value and the 5th and 95th percentile are presented. Differences between the groups were calculated with the Wilcoxon test and P‐values are reported.

image

Conclusion
Our data suggest that enhanced IL‐13 levels at birth are associated with the subsequent development of atopic symptoms at the age of 3 years.
Allergen‐mediated modulation of CD23 expression is interferon‐γ and interleukin‐10 dependent in allergic and non‐allergic individuals
Authors: Roever A. C. , Heine G. , Zuberbier T. , Worm M.
Published: November 2003

Background
CD23 plays an important role in IgE regulation. The modulation of CD23 expression during specific immunotherapy (SIT) has been described previously. In the present study, we investigated in detail the effects of complete birch pollen allergen extract (BPA) on CD23 expression of peripheral blood mononuclear cells (PBMCs) in vitro.

Methods
PBMCs from 14 birch pollen‐allergic (bp‐allergic) patients and eight non‐bp‐allergic controls were stimulated with IL‐4 and increasing doses of BPA. CD23 expression on monocytes and B cells was measured by flow cytometry; sCD23 release and the levels of IFN‐γ and IL‐10 secretion were determined by ELISA. To analyse the mechanisms on CD23 expression in more detail, neutralizing anti‐IFN‐γ and anti‐IL‐10 antibodies were added to IL‐4 and BPA‐stimulated cultures.

Results
IL‐4 induced CD23 expression on B cells and on monocytes and sCD23 release in the bp‐allergic and non‐bp‐allergic groups. The addition of BPA to IL‐4‐stimulated PBMC decreased CD23 expression significantly and dose‐dependently on B cells in both groups. CD23 expression on monocytes was also decreased in both groups after the addition of BPA, but higher doses were required in the non‐bp‐allergic population. IL‐4‐induced sCD23 release was also significantly decreased after the addition of BPA. IFN‐γ and IL‐10 were induced by BPA in both the bp‐allergic and non‐bp‐allergic groups. The addition of neutralizing anti‐IFN‐γ antibodies increased CD23 expression on B cells, which were stimulated with IL‐4 and BPA, but had no effect on monocytes, whereas the addition of anti‐IL‐10 antibodies increased CD23 expression on monocytes but not on B cells.

Conclusion
These data indicate that early immunological effects like down‐regulation of CD23 on B cells and monocytes, which are observed during SIT are dose dependent, mediated by IFN‐γ and IL‐10 and seem not to depend per se on the sensitization state of an individual.
Interrelationships among asthma, atopy, rhinitis and exhaled nitric oxide in a population‐based sample of children
Authors: Jouaville L. F. , Annesi‐Maesano I. , Nguyen L. T. , Bocage A. S. , Bedu M. , Caillaud D.
Published: November 2003

Background
Exhaled nitric oxide (eNO) has attracted increasing interest as a non‐invasive marker of airway inflammation in asthma. However, little evidence exists on the influences exerted on eNO by the interrelations among atopic status, asthma and rhinitis.

Methods
Among the 1156 children who participated in a large‐scale epidemiological survey on asthma and allergies (ISAAC II: International Study of Asthma and Allergies in Childhood Phase II) in the city of Clermont‐Ferrand, 53 asthmatics without corticosteroid treatment and 96 non‐asthmatics were invited to perform eNO and skin prick tests (SPTs) to 12 common allergens.

Results
Atopic asthmatic children had higher eNO than non‐atopic asthmatic children (28.9±9.1 vs. 17.1±13.1 p.p.b.; P=0.0004) with a significant increase when one SPT or more are positive (26.5±7.8 vs. 17.1±13.1 p.p.b.; P=0.03). Similarly, non‐asthmatic, atopic subjects had higher eNO than non‐atopic subjects with a significant increase when two SPTs or more are positive (19.4±9.8 vs. 11.7 ±6.7 p.p.b.; P=0.003). In the case of equal levels of positive SPTs (0, 1, 2), asthmatic children always had higher eNO than non‐asthmatic ones. Furthermore, among non‐asthmatic children, the eNO level increased only in atopics who had rhinitis (20.7±13 vs. 12.5±6.4 p.p.b. in atopic controls (subjects without rhinitis and asthma) and 12.3±6.6 p.p.b. in non‐atopic controls; P=0.001), whereas among asthmatic children, eNO level increased in atopics independently of rhinitis (28.2±9.5 p.p.b. in those with rhinitis and 30.9±8.1 p.p.b. in those without) as well as in non‐atopics with rhinitis (22.5±17.2 p.p.b.).

Conclusions
Our data suggest that besides atopy and asthma, allergic rhinitis should also be taken into account in the assessment of eNO.
Climatic variables are associated with seasonal acute asthma admissions to accident and emergency room facilities in Trinidad, West Indies
Authors: Ivey M. A. , Simeon D. T. , Monteil M. A.
Published: November 2003

Objectives
To determine if there is seasonal variation in acute asthmatic visits to accident and emergency (A&E) facilities in Trinidad and to identify the climatic variables associated with such visits.

Design and methods
A retrospective census of patients with asthma, defined as those who required emergency bronchodilator nebulization, was taken at two A&E facilities in Trinidad from 1 January 1997 to 31 December 1999. The study included patients aged 64 years and under. Patient demographic data were obtained from the A&E records. Climate variables were taken from the island's sole Meteorological Office. Multiple regression was used to identify climate variables that were independent predictors of A&E asthma visits.

Results
There were a total of 45 842 asthma admissions to the two facilities during the study period. Visits exhibited a cyclic pattern over the 3 years that varied according to the island's dry (January–May) and wet (June–December) seasons. There were more visits during the wet season than the dry (40 [SD=2] vs. 32 [SD=2] visits/day; P<0.001). The results of multiple regression indicated that season (P<0.001), barometric pressure (P<0.001), temperature difference (P<0.001), minimum temperature2 (P<0.001) and wind speed2 (P=0.032) were predictors of paediatric visits. Independent predictors of adult visits were season (P<0.001), relative humidity (P<0.001), minimum temperature (P=0.01), temperature difference2 (P<0.001) and minimum temperature2 (P=0.004). Season and climatic variables explained 18% of the variance of the total A&E asthma admissions.

Conclusion
There is seasonal variation in acute asthma visits to A&E facilities in Trinidad, which remains significant after controlling for climate variables. However, while climate has a role, there are other factors that may also be responsible for increased visits during the wet season. More research is needed to identify these factors.
Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly
Authors: Colao Annamaria , Balzano Antonio , Ferone Diego , Panza Nicola , Grande Giovanni , Marzullo Paolo , Bove Antonio , Iodice Giovanni , Merola Bartolomeo , Lombardi Gaetano
Published: November 2003

OBJECTIVE

The balance of evidence suggests that acromegaly is a risk factor for colonic neoplasia. We have evaluated the prevalence of colonic polyps in acromegalics from Southern Italy and characterized the lymphocyte subsets in the colonic lamina propria in order to analyze differences in the colonic immunological environment.

DESIGN

All the patients and controls were submitted to pancolonoscopy. Ten per‐endoscopic biopsies of the intestinal mucosa surrounding polyps were carried out to evaluate lymphocyte subsets.

PATIENTS

Fifty acromegalics and 318 sex‐ and age‐matched controls entered this study. Colonic lamina propria lymphocyte subsets were studied in 34 patients and 34 controls.

RESULTS

Colonic polyps were resected in 23 acromegalics (46%) and 42 controls (13.2%; P < 0.0001); hyperplastic polyps were found in 24% and 6.3%, adenomatous polyps in 22 and 6.9%, (P < 0.01), adenocarcinoma in 2 and 1.2% while synchronous polyps occurred in 18% and 2.5% (P < 0.01), respectively. The number of polyps was significantly correlated with age both in acromegalics (r = 0.422, P < 0.005) and in controls (r = 0.865, P < 0.001). However, polyp prevalence was greater in patients aged below 40 yrs (r.r. = 1.9) and in patients with two or more skin tags (r.r. = 1.2). A significant decrease of CD20, CD19, CD16, γ/δ, CD4+/leu8− and increase of CD3 and CD4+/leu8+ was found in the lamina propria lymphocyte subsets.

CONCLUSIONS

The results of this study confirm that acromegalics are at increased risk of colonic polyps compared to the healthy population. The increased prevalence of premalignant polyps, namely the adenomatous type, suggests that acromegalics should undergo a careful screening and follow‐up by pancolonoscopy. An impairment of mucosal immune surveillance seems to exist in acromegaly although a causal effect in the polyp formation cannot be ruled out.
17β‐Hydroxysteroid dehydrogenase deficiency with minimal virilization and spontaneous reduction of serum androgens to normal female levels
Authors: Duncan S. L. B. , Page K. B. , Rodgers D. A.
Published: November 2003

The testosterone biosynthesis defect, 17β‐ hydroxysteroid dehydrogenase deficiency, is generally characterized by marked virilization at puberty of children raised as females. We describe an unusual case with a persistent female body habitus presenting with primary amenorrhoea and mild facial hirsutism. Whilst awaiting gonadectomy, serum androgen concentrations were observed to fall spontaneously to within the adult female reference ranges. Location of the gonads was a problem and was finally achieved by magnetic resonance imaging.
The counterregulatory response to hypoglycaemia in women with the polycystic ovary syndrome
Authors: Gennarelli G. , Holte J. , Stridsberg M. , Niklasson F. , Berne C. , Bäckström T.
Published: November 2003

OBJECTIVE The pathogenetic mechanisms behind insulin resistance in polycystic ovary syndrome (PCOS) are far from fully elucidated. Aberrant counterregulatory responses to hypoglycaemia have been reported in patients with insulin resistance, and recent reports suggest that plasma glucose may be regulated at lower levels in women with PCOS. In this study we investigated the complete hormonal counterregulatory response to hypoglycaemia in women with PCOS.

DESIGN  Prospective cross‐sectional study.

PATIENTS Eight obese (BMI  25) and 10 non‐obese (BMI < 25) women with PCOS, diagnosed by means of ultrasonography and clinical signs of chronic anovulation. Eight obese and 9 non‐obese controls.

MEASUREMENTS Hypoglycaemia was induced by an intravenous bolus of soluble insulin (0.15 IU/kg body weight). The counterregulatory responses of cortisol, GH, catecholamines, glucagon, chromogranin A (CGA), and neuropeptide Y (NPY) were studied together with symptoms of hypoglycaemia.

RESULTS The obese women with PCOS had a more pronounced truncal‐abdominal body fat distribution (waist hip ratio, WHR) and were hyperinsulinaemic, compared with the obese controls. All the women exhibited blood glucose levels (< 2 mmol/l) well below the threshold for the hormonal counterregulatory response and for the appearance of clinical symptoms. The non‐obese women with PCOS showed a greater increase in serum concentrations of GH than the lean controls. The obese women with PCOS exhibited blunted responses of noradrenaline and NPY, but similar increases of adrenaline and CGA, compared with the obese controls. They also showed a lower symptom score during hypoglycaemia. The response of noradrenaline to hypoglycaemia correlated inversely with fasting insulin levels in the women with PCOS. Among all the obese women (PCOS and controls pooled) basal levels of noradrenaline correlated inversely with the WHR.

CONCLUSIONS All the women with PCOS, independent of BMI, body fat distribution and insulin levels, showed preserved counterregulatory responses to hypoglycaemia. The reduced plasma levels of noradrenaline and the lower perception of hypoglycaemic symptoms in the obese women with PCOS could both reflect a lower activation of the sympathetic nervous system. This aberration seems related to truncal‐abdominal obesity and hyperinsulinaemia. The finding of an increased response of GH in the lean women with PCOS could support previous suggestions of an altered activity of the GH/IGF‐I system in these women.
DOUBLE ADENOMAS WITH DIFFERENT PATHOLOGICAL AND HORMONAL FEATURES IN THE LEFT ADRENAL GLAND OF A PATIENT WITH CUSHING'S SYNDROME
Authors: Satoh Fumitoshi , Murakami Osamu , Takahashi Kazuhiro , Ueno Junji , Nishikawa Tetsuo , Abe Keishi , Mouri Toraichi , Sasano Hironobu
Published: November 2003

We report a 52‐year‐old woman with Cushing's syndrome who presented with two adenomas in the left adrenal gland. One tumour appeared dark brown and the other appeared yellow on the cut surface. The non‐neoplastic adrenal demonstrated marked cortical atrophy. Upon histological examination, the brown tumour was found to be composed of both compact and clear cells. In contrast, the yellow tumour was composed of clear cells associated with pseudoglandular formation and marked degeneration.  Immunohistochemical studies demonstrated positive immunostaining of cytochrome P‐450 specific for 17α‐hydroxylation (P‐450c17) in the brown but not the yellow tumour. Other steroidogenic enzymes except for dehydroepiandrosterone sulphotransferase were detected in both tumours. The biochemical activities of 21‐hydroxylase, 17‐hydroxylase and 11β‐hydroxylase in the brown tumour (6.10 nmol/mg protein/4 minutes, 1.87 nmol/mg protein/2 minutes and 5.71 μmol 11‐OHCS formed/g protein/10 minutes, respectively) were much greater than those in the yellow tumour. Gel‐supported three‐dimensional native‐state primary culture of the tumours demonstrated a much higher concentration of cortisol in the culture medium for the brown tumour (5750 nmol/l on 4th day). Vimentin expression was detected in both tumours but cytokeratin expression was detected only in the yellow tumour. The Ki67 labelling index in the brown tumour was greater than that in the yellow tumour. These results indicated that these two adenomas had different biological characteristics and the brown tumour was primarily involved in overproduction of cortisol in this patient. When analysing unilateral multiple adrenocortical lesions, approaches using immunohistochemical studies for steroidogenic enzymes, enzyme activity assays and cell culture can help to define the steroidogenesis of individual adrenocortical lesions.
Pituitary tumours presenting in the elderly: management and outcome
Authors: Benbow Susan J. , Foy Patrick , Jones Bleddyn , Shaw Donald , MacFarlane Ian A.
Published: November 2003

OBJECTIVE

In elderly patients there are few data on the efficacy and safety of pituitary surgery and radiotherapy (DXT). The aim of the present study was to assess the mode of presentation, treatment and outcome of patients >64 years with a pituitary tumour presenting to a regional neuroendocrine service.

DESIGN

A retrospective case note review of all patients with a pituitary tumour, from 1986 to 1993, was performed with DXT information from computerized records.

PATIENTS

Forty‐four patients were identified: median age 70 (65–83) years; 25 males; followed for a mean of 34 (range 0–84) months.

RESULTS

The commonest presenting symptom was with visual disturbance (24 patients) with a further 9 with asymptomatic visual field defects. Five patients had acromegaly and two prolactinoma. Thirty‐two patients underwent transsphenoidal surgery (TSS) (with post‐operative DXT in 14 cases) and 6 craniotomy. Two patients had DXT as the primary procedure and four were observed. Visual fields improved in 21 of 29 patients. Perioperative complications occurred significantly more often after craniotomy (5/6) than after TSS (6/32) (P<0.01). Eight patients died during the follow‐up period (three deaths tumour related; one death followed DXT).

CONCLUSIONS

Pituitary adenoma is a remediable cause of visual disturbance in the elderly. Most tumours were non‐functioning. Age alone is not a contraindication to active treatment particularly with transsphenoidal surgery and radiotherapy.
Elevation of circulating proadrenomedullin‐N terminal 20‐peptide in thyrotoxicosis
Authors: Taniyama Matsuo , Kitamura Kazuo , Ban Yoshio , Sugita Eri , Ito Kunihiko , Katagiri Takashi
Published: November 2003

BACKGROUND AND OBJECTIVE Adrenomedullin (AM) is a recently discovered peptide which has potent vasodilatory activity. We have found that the plasma adrenomedullin level is elevated in hyperthyroidism, suggesting a potential role of AM in the decrease of vascular resistance in thyrotoxicosis. Proadrenomedullin, a precursor of adrenomedullin, yields another peptide termed proadrenomedullin‐N terminal 20‐peptide (PAMP). PAMP also has potent vasodilatory activity. Although the regulation of secretion of AM and PAMP is not fully understood and the mechanism by which the plasma AM level is elevated in hyperthyroidism remains unknown, it is of interest to determine the plasma concentration of PAMP in thyrotoxicosis.

DESIGN AND PATIENTS We measured the plasma concentration of immunoreactive AM and PAMP in newly recruited untreated thyrotoxic Graves’ patients using specific antibodies to each peptide.

RESULTS Not only AM, but also the plasma concentration of PAMP in thyrotoxic patients was significantly (P >0.01) elevated (4.7 ±0.9 pmol/l), compared to that in control subjects (2.6 ±0.8 pmol/l). The correlation was marginally significant between the plasma AM concentration and serum free thyroid hormone levels. The plasma PAMP level tended to be more elevated when thyrotoxicosis was severe but the correlation was not statistically significant. Correlation was not demonstrated between the AM and PAMP levels in thyrotoxic patients.

CONCLUSIONS Elevation of the plasma adrenomedullin and proadrenomedullin‐N terminal 20‐peptide levels raises the possibility of involvement of these vasodilatory peptides in the haemodynamic changes in thyrotoxicosis.
Growth hormone responses to GH‐releasing peptide (GHRP‐6) in hypothyroidism
Authors: Pimentel‐Filho Fernando R. , Ramos‐Dias João C. , Ninno Fernanda B. D. , Façanha Cristina F. S. , Liberman Bernardo , Lengyel Ana‐Maria J.
Published: November 2003

OBJECTIVE Both spontaneous and stimulated GH secretion are reduced in patients with hypothyroidism. The mechanisms involved in these alterations are not yet fully understood. GHRP‐6 is a synthetic hexapeptide that releases GH both in vivo and in vitro. Its mechanism of action is unknown, but there is evidence that this peptide acts as a functional somatostatin antagonist at pituitary level. The aim of this study was to evaluate the GH response to GHRP‐6 in patients with primary hypothyroidism and in normal controls.

DESIGN Patients with hypothyroidism and normal controls were randomly submitted to 3 tests with GHRH (100 μg i.v.), GHRP‐6 (1 μg/kg i.v.) and GHRH + GHRP‐6, on separate days.

PATIENTS Eleven patients with primary hypothyroidism were compared with 10 control subjects.

MEASUREMENTS GH, TSH and free T4 were measured by immunofluorometric assay and IGF‐I by radioimmunoassay.

RESULTS Hypothyroid patients had markedly lower peak GH values (mean ± SE μg/l) after GHRH administration (4.1 ± 0.9) compared to control subjects (24.9 ± 5.1). After GHRP‐6 injection hypothyroid patients had a significantly higher GH release (12.6 ± 1.9) than that obtained with GHRH, while in control subjects GH values were similar (22.1 ± 3.6). No significant differences in peak GH responses were observed following the administration of either GHRP‐6 alone (controls 22.1 ± 3.6; patients 12.6 ± 1.9) or in combination with GHRH (controls 77.4 ± 15.0; patients 52.8 ± 10.9), despite the trend to smaller responses in hypothyroid patients.

CONCLUSION We have shown that patients with primary hypothyroidism have higher GH responses to GHRP‐6 than to GHRH, which are markedly blunted. When GHRP‐6 was associated with GHRH, a significant increase in the GH response was observed in these patients, which could suggest a role for somatostatin in this process. Our data suggest that thyroid hormones modulate GH release induced by GHRH and GHRP‐6 through different mechanisms. However, additional studies are necessary to further elucidate this hypothesis.
Treatment of macroprolactinoma with cabergoline: a study of 85 patients
Authors: Ferrari C. I. , Abs R. , Bevan J. S. , Brabant G. , Ciccarelli E. , Motta T. , Mucci M. , Muratori M. , Musatti L. , Verbessem G. , Scanlon M. F.
Published: November 2003

OBJECTIVE Cabergoline is now established as an effective and well‐tolerated treatment for prolactinoma. However, there are relatively few published data on the treatment of macro‐, as opposed to micro‐, prolactinoma. We have therefore reviewed the efficacy and safety of cabergoline in the treatment of patients with prolactin‐secreting macroadenomas treated on a compassionate basis.

STUDY DESIGN AND PATIENTS Eighty‐five patients with prolactin‐secreting macroadenomas were treated with cabergoline 0.25 to 10.5 mg per week (median 1 mg) given in one to seven doses. Treatment durations ranged between 3 months and 8 years. Sixty‐five patients (32 intolerant, 16 resistant) had been treated previously with other dopamine agonists.

Pretreatment prolactin levels ranged between 80 and 8300 μg/l and tumour maximum diameters were between 11 and 42 mm.

MEASUREMENTS Serum prolactin, visual fields if initially abnormal, occurrence of menses or return of libido and potency, blood chemistry and adverse events were assessed at 1 month and then at 3‐month intervals during treatment. Pituitary computed tomography or magnetic resonance imaging was usually repeated at 3 months and 1 year, then yearly, in most patients (n=62).

RESULTS Normalization of prolactin levels was achieved in 52 patients (61.2%) and a prolactin decrease of at least 75% of pretreatment values occurred in 24 others (28.2%). Of the 20 de novo patients, 17 had prolactin normalized and the remainder had at least 75% reduction. Disappearance of tumour image was found in eight of 62 evaluable patients (12.9%) and reduction of the largest diameter by at least 25% in another 33 (53.2%), with an overall success rate of 66.1%; among the 17 evaluable de novo patients the success rate was 82.3%. Fifteen of 21 patients who failed to show tumour shrinkage had previously demonstrated resistance/intolerance to other prolactin‐lowering treatments. Of the 12 patients with visual field defects at baseline, six normalized and two showed an improvement. Menses resumed during cabergoline treatment in 79.5% of premenopausal women. Restoration of potency was reported by seven of eight evaluable men. Adverse events were recorded in 24.7% of cases, four of whom (4.7%) discontinued treatment.

CONCLUSIONS Although the present data were not obtained in a formal study we conclude that cabergoline is an effective and well‐tolerated treatment for macroprolactinoma patients.
The relationship between overnight GH levels and insulin concentrations in adolescents with insulin‐dependent diabetes mellitus (IDDM) and the impact of recombinant human insulin‐like growth factor I (rhIGF‐I)
Authors: Cheetham Tim D. , Connors Matthew , Clayton Kharen , Watts Angie , Dunger David B.
Published: November 2003

OBJECTIVE We examined the relationship between GH concentrations and free insulin concentrations, used as an index of insulin sensitivity, before and after recombinant human insulin‐like growth factor I (rhIGF‐I) administration in adolescents with insulin‐dependent diabetes mellitus (IDDM).

DESIGN AND PATIENTS Growth hormone concentrations were assessed by a peak detection programme (Pulsar) on a control night (2000 h–0800 h) and a night when rhIGF‐I was administered in a subcutaneous dose of 40 μg/kg at 1800 h to 16 adolescent subjects. Stable euglycaemia was maintained by a continuous intravenous insulin infusion and changes in free insulin levels on the two nights were compared with growth hormone data.

RESULTS Mean overnight GH concentrations (2000 h–0800 h) on the control night were positively related to glycated haemoglobin (HbA1) concentrations (r=0.63; P<0.01) and were reduced following rhIGF‐I administration (24.9±3.6 mU/l on the control night versus 17.4±2.2 mU/l after administration, P=0.01). The mean GH pulse amplitude on the control night was related to the change in GH levels after rhIGF‐I (rs=−0.66, P<0.001). Multiple regression analysis revealed that mean GH pulse amplitude was the only determinant of free insulin concentrations (0500 h–0700 h) on both study nights (P<0.01). The percentage change in mean growth hormone pulse amplitude between the two nights was related to the percentage reduction in free insulin concentrations (r=0.53, P=0.03).

CONCLUSIONS Growth hormone pulse amplitude is related to early morning insulin sensitivity in adolescents with IDDM on control nights and after rhIGF‐I administration. The reduction in insulin levels following rhIGF‐I may be linked to the change in GH pulse amplitude and not just to direct insulin‐like actions. Individuals with the higher GH (and thus HbA1 levels) were most sensitive to the GH‐suppressive effects of rhIGF‐I.
Effect of desmopressin on ACTH and cortisol secretion in states of ACTH excess
Authors: Colombo P. , Passini E. , Re T. , Faglia G. , Ambrosi B.
Published: November 2003

OBJECTIVE

To assess the ability of desmopressin administration to stimulate ACTH/cortisol secretion in patients with Cushing's disease, either before or after surgery, and in patients with other states characterized by ACTH hypersecretion, and to compare the results with those obtained after CRH testing.

DESIGN AND SUBJECTS

Plasma ACTH and serum cortisol levels were evaluated after the administration of desmopressin (10 μg i.v.), CRH (1 μg/kg i.v.) and saline on different days in 17 patients with Cushing's disease, 1 with occult ectopic ACTH syndrome, 5 with Addison's disease, 3 who had been bilaterally adrenalectomized for Cushing's syndrome and 4 normal subjects. After pituitary adenomectomy desmopressin and CRH were administered again to 13 of the patients who had undergone pituitary surgery for their Cushing's disease.

RESULTS

In 16 patients with Cushing's disease with microadenoma a positive ACTH/cortisol rise occurred in 11 patients after both desmopressin and CRH, 2 other patients were responsive only to desmopressin and 2 only to CRH, while in 1 patient equivocal responses to both tests were found. The persistence of a hormonal response to desmopressin after pituitary adenomectomy for Cushing's disease correlated with unsuccessful surgery, while, contrary to CRH, absent ACTH/cortisol rises were found in cured patients 1 and 12 months after operation. In 1 patient suspected for ectopic ACTH hypersecretion, desmopressin and CRH administration did not cause any ACTH/cortisol rise. Significant ACTH rises occurred after both desmopressin and CRH testing in patients with Addison's disease. All the 3 patients adrenalectomized for Cushing's syndrome showed a rise of ACTH levels after CRH, while a similar response after desmopressin occurred in only one of them.

CONCLUSIONS

Desmopressin is able to stimulate ACTH and hence cortisol release in Cushing's disease. It may be a useful test in patients with doubtful responses to CRH test, in those exhibiting responses to CRH indistinguishable from those of normal subjects and in the postoperative follow‐up of Cushing's disease. In some patients with abolished or reduced cortisol feed‐back at hypothalamic–pituitary level the sensitivity of normal corticotrophs to desmopressin is enhanced.
An Assessment of Optimal Hydrocortisone Replacement Therapy
Authors: Howlett Trevor A.
Published: November 2003

OBJECTIVE To assess the management of hydrocortisone replacement therapy in one institution, and derive recommendations for optimum starting and maintenance replacement therapy with hydrocortisone.

DESIGN Retrospective survey of clinical management using a clinical information system and the patient case notes.

PATIENTS Using the department’s clinical information system, 210 patients were identified who had been treated with hydrocortisone. Case notes were reviewed and 130 patients were identified whose records contained the results of at least one valid hydrocortisone day curve. Data on 174 day curves performed on these patients (65 on twice daily and 109 on thrice daily hydrocortisone regimes) formed the basis of this analysis.

METHODS Hydrocortisone day curves had been performed as part of routine clinical management: patients collected a 24 h urine for free cortisol on the day prior to the test and took their morning hydrocortisone at the normal time, at home, on wakening. During a day‐case attendance serum cortisol was then measured at 0900 h, 1230 h (prior to any lunchtime dose) and 1730 h (prior to the evening dose). ‘Optimal replacement’ was arbitrarily defined as that dose which achieved a UFC and 09:00h cortisol within the reference range for the normal population (to avoid over‐replacement) combined with 1230 h and 1730 h cortisol above 50 nmol/l, and ideally above 100 nmol/l (to avoid under‐replacement). Raw data from all hydrocortisone day curves was analysed in an Excel spreadsheet to determine the effect of different dose regimens on the percentage of patients achieving each and all of these 4 criteria, and on an overall ‘quality score’ (comprising 1 point for each of the 4 criteria attained).

RESULTS Patients on twice daily hydrocortisone regimes achieved optimal replacement in 15% of cases compared to 60% on thrice daily regimes (P < 0.001 by χ2); mean overall ‘quality scores’ for these regimens were 2.72 and 3.49 respectively (P < 0.001 by t‐test). Of individual dose regimens with sufficient cases for valid comparison, a dose of 10 mg/5 mg/5 mg (rising/lunch/evening) achieved optimal replacement in 66% and mean ‘quality score’ of 3.62 (n = 53), compared to 50% and 3.32 for 10 mg/10 mg/5 mg (n = 28) and 10% and 2.48 for 20 mg/–/10 mg (n =29).

CONCLUSIONS The use of arbitrary, but logical, criteria to assess the quality of hydrocortisone replacement regimens indicates that optimal replacement is achieved with thrice daily hydrocortisone regimens, and that the traditional twice daily regime results in a 0900 h cortisol above normal in one‐third, and late afternoon cortisol below 50 nmol/l in one‐half of patients thus treated. An appropriate starting dose of hydrocortisone of 10 mg/5 mg/5 mg (rising/lunch/evening) is suggested, with subsequent individual adjustment based on simple hydrocortisone day curves.