bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma
Authors: Jagannath S. , Barlogie B. , Berenson J. , Siegel D. , Irwin D. , Richardson P. G. , Niesvizky R. , Alexanian R. , Limentani S. A. , Alsina M. , Adams J. , Kauffman M. , Esseltine D.‐L. , Schenkein D. P. , Anderson K. C.
Published: December 2004

In a phase 2 open‐label study of the novel proteasome inhibitor bortezomib, 54 patients with multiple myeloma who had relapsed after or were refractory to frontline therapy were randomized to receive intravenous 1·0 or 1·3 mg/m2 bortezomib twice weekly for 2 weeks, every 3 weeks for a maximum of eight cycles. Dexamethasone was permitted in patients with progressive or stable disease after two or four cycles respectively. Responses were determined using modified European Group for Blood and Marrow Transplantation criteria. The complete response (CR) + partial response (PR) rate for bortezomib alone was 30% [90% confidence interval (CI), 15·7–47·1] and 38% (90% CI, 22·6–56·4) in the 1·0 mg/m2 (8 of 27 patients) and 1·3 mg/m2 (10 of 26 patients) groups respectively. The CR + PR rate for patients who received bortezomib alone or in combination with dexamethasone was 37% and 50% for the 1·0 and 1·3 mg/m2 cohorts respectively. The most common grade 3 adverse events were thrombocytopenia (24%), neutropenia (17%), lymphopenia (11%) and peripheral neuropathy (9%). Grade 4 events were observed in 9% (five of 54 patients). Bortezomib alone or in combination with dexamethasone demonstrated therapeutic activity in patients with multiple myeloma who relapsed after frontline therapy.
Ex vivo evaluation of erythrocytosis‐enhanced platelet thrombus formation using the cone and plate(let) analyzer: effect of platelet antagonists
Authors: Peerschke Ellinor I. B. , Silver Richard T. , Weksler Babette , Grigg Sage E. , Savion Naphtali , Varon David
Published: December 2004

Red blood cells (RBC) contribute significantly to haemostasis and thrombosis under oscillatory flow conditions, and erythrocytosis has been associated with increased thrombotic risk. To measure the dynamic influences of RBC on platelets, we used a recently described cone and plate(let) analyzer (CPA), evaluating the effect of haematocrit (Hct) on platelet function in whole blood under arterial flow conditions (1800/s, 2 min, 25°C). Anticoagulated blood, reconstituted to varying haematocrits with autologous RBC, demonstrated a significant increase in adherent platelet aggregate formation at Hct levels >45%. This increase was not affected by pretreatment of blood with 0·05 mmol/l aspirin, but was prevented by antagonists of P2Y1, P2Y12, or P2X1, ADP and ATP receptors, and by converting exogenous ADP to ATP with creatine phosphate/creatine phosphokinase. As negligible platelet granule secretion was measured during CPA analysis, but metabolic inhibition of RBC with sodium azide or glutaraldehyde fixation inhibited erythrocytosis‐enhanced increases in platelet aggregate size, adenine nucleotides contributing to shear‐induced platelet aggregate formation appear to be derived from erythrocytes. These findings support the use of CPA for ex vivo evaluation of the contribution of RBC to platelet function and its inhibition under physiological shear conditions.
Recurrent abdominal pain, anxiety, and depression in primary care
Authors: Ramchandani Paul
Published: December 2004

.
 
Campo JV,
Bridge J,
Ehmann M,
Altman S,
Luca A,
Birmaher B,
Di Lorenzo C,
Iyengar S &
Brent D.
 
(
2004
)
Pediatrics
,
113
,
817
–
824
.

Objective

The prevalence of psychiatric disorder in children and adolescents with functional recurrent abdominal pain (RAP) is unknown. Our aim was to determine whether RAP is associated with psychiatric symptoms and disorders, anxious temperament and functional impairment in paediatric primary care.

Methods

Children and adolescents who were 8–15 years of age, inclusive, and presented with RAP (n = 42) or for routine care in the absence of recurrent pain (n = 38) were identified by a screening procedure in paediatric primary care office waiting rooms and recruited to participate in a case–control study. Outcome measures were psychiatric diagnoses generated by standardized psychiatric interview administered blind to subject status and self, parent and clinician ratings of child psychiatric symptoms, temperamental traits and functional status.

Results

RAP patients were significantly more likely to receive a diagnosis of a psychiatric disorder, with a categorical anxiety disorder in 33 (79%) and a depressive disorder in 18 patients (43%), and higher levels of anxiety and depressive symptoms, temperamental harm avoidance and functional impairment than control subjects. Anxiety disorders [mean age of onset: 6.25 (standard deviation: 2.17) years] were significantly more likely to precede RAP [mean age of onset: 9.17 (standard deviation: 2.75) years] in patients with associated anxiety.

Conclusions

Youths who present with RAP in primary care deserve careful assessment for anxiety and depressive disorders. Future studies should examine treatments that are proved to be efficacious for paediatric anxiety and/or depressive disorders as potential interventions for RAP. Longitudinal, family and psychobiological studies are needed to illuminate the nature of observed associations among RAP, anxiety and depression.
Impact of a general practice based group parenting programme: quantitative and qualitative results from a controlled trial at 12 months
Authors: Reading Richard
Published: December 2004

.
 
Stewart‐Brown S,
Patterson J,
Mockford C,
Barlow J,
Klimes I &
Pyper C.
 
(
2004
)
Archives of Disease in Childhood
,
89
,
519
–
525
.

Aims

To test the effectiveness at 1 year of the Webster Stratton Parents and Children Series group parenting programme in a population sample of parents.

Methods

In a multicentre block randomized controlled trial, parents of children aged 2–8 years in 116 families who scored in the upper 50% on a validated behaviour inventory, took part in Webster‐Stratton's 10 weeks parenting programme led by trained and supervised health visitors. The following outcome measures were used: Eyberg Child Behaviour Inventory, Goodman Strengths and Difficulties Questionnaire, General Health Questionnaire, Parenting Stress Index, Rosenberg Self Esteem Scale.

Results

The intervention significantly reduced child behaviour problems and improved mental health at immediate and 6 months follow ups. One year differences between control and intervention groups were not significant. Qualitative results suggest that these findings might be attributable in part to either Hawthorne effects or contamination of control group. At interview parents described ways in which the programme had improved their mental health. They reported gains in confidence and feeling less stressed. Some also reported beneficial changes in their own and their children's behaviour and improved relationships with their children. Some spoke of a need for further sessions to support the behaviour changes they had managed to make, and some the desire for attendance by both parents.

Conclusions

Parenting programmes have the potential to promote mental health and reduce social inequalities, but further work is needed to improve long‐term effectiveness.
Causal association between cannabis and psychosis: examination of the evidence
Authors: Reading Richard
Published: December 2004

.
 
Arseneault L,
Cannon M,
Witton J &
Murray RM
. (
2004
)

,
184
,
110
–
117
.

Background  Controversy remains as to whether cannabis acts as a causal risk factor for schizophrenia or other functional psychotic illnesses.

Aims  To examine critically the evidence that cannabis causes psychosis using established criteria of causality.

Methods  We identified five studies that included a well‐defined sample drawn from population‐based registers or cohorts and used prospective measures of cannabis use and adult psychosis.

Results  On an individual level, cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis use would reduce the incidence of schizophrenia by approximately 8%, assuming a causal relationship. Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis.

Conclusions  Cases of psychotic disorder could be prevented by discouraging cannabis use among vulnerable youths. Research is needed to understand the mechanisms by which cannabis causes psychosis.
Changes in monocytic expression of aminopeptidase N/CD13 after major trauma
Authors: HUSCHAK G , ZUR NIEDEN K , STUTTMANN R , RIEMANN D
Published: December 2004

HLA-DR expression on monocytes as marker for monocytic function is severely depressed after major trauma. The membrane enzyme aminopeptidase N/CD13 can trigger help in antigen processing by MHC class II molecules of antigen-presenting cells. We determined the simultaneous expression of HLA-DR and CD13 on peripheral blood monocytes of patients with major trauma (injury severity score of ≥16). 1 : 1 conjugates of phycoerythrin (PE)-to-monoclonal antibody were used in combination with QuantiBRITETM PE beads for a standardized quantification in terms of antibodies bound per cell (ABC). The very low expression of HLA-DR antigen on monocytes of patients at day 1 after major trauma confirmed previous results in the literature. Monocytic HLA-DR expression increased slowly to reach values in the lower range of healthy volunteers at day 14. Monocytic CD13 expression at day 1 showed values in the range of healthy volunteers, and a strong rise afterwards. Fourteen days after trauma, the monocytic expression of CD13 was still much higher than in the control group. Because lipopolysaccharide (LPS) and the anti-inflammatory cytokine interleukin (IL)-10 have been shown to be involved in the depressed HLA-DR expression on monocytes in trauma patients, we studied the in vitro effects of LPS and interleukin (IL)-10 on the expression of CD13 on monocytes prepared from the peripheral blood of healthy volunteers. Whereas a 3-day IL-10 treatment resulted in a down-regulation of both HLA-DR and CD13 expression on monocytes, LPS caused a down-regulation of HLA-DR but a rapid up-regulation of CD13 levels. Therefore we suggest that, with respect to monocytic CD13 expression, LPS rather than IL-10 could well be the explanation for monocytic surface molecules after severe injury, although other mediators with a CD13 regulating function have to be considered.
Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma
Authors: ECK M , SCHMAUßER B , SCHELLER K , BRÄNdlein S , MÜLLER-HERMELINK H K
Published: December 2004

CXC chemokines modulate host immunity, neovascularization, growth and invasive behaviour of tumours. Despite their relevance in tumour biology, chemokine expression in intestinal- and diffuse-type gastric carcinoma, which exhibit a completely different growth pattern, has not been investigated in detail. In this study, expression of the CXC chemokines CXCL8 [interleukin (IL)-8], CXCL1 [growth-related oncogene alpha (Groα)], CXCL9 [monokine induced by interferon (IFN)-γ] and CXCL10 [IFN-γ-inducible protein-10 (IP-10)] and the corresponding chemokine receptors CXCR1–3 was investigated by immunohistochemistry in intestinal- and diffuse-type gastric carcinoma. Tumour cells of all patients expressed CXCL8. CXCL8 expression was significantly stronger in tumour cells of diffuse- rather than intestinal-type gastric carcinoma (P < 0·01) as determined by a semiquantitative score. CXCL1 was expressed almost exclusively by diffuse- but not intestinal-type carcinoma cells. The corresponding chemokine receptors, CXCR1 and CXCR2, were found on carcinoma cells. Furthermore, CXCL8 expression correlated with number of tumour vessels (P < 0·01), suggesting an angiogenetic function in gastric carcinoma not only in vitro but also in vivo. CXCL10 and CXCL9, attractants for T cells, were expressed by peritumorous macrophages in close proximity to IFN-γ-producing CXCR3-positive T cells in both tumour types. These chemokines may attract gastric carcinoma-infiltrating T cells via an IFN-γ-mediated pathway and enhance host immunity against the tumour. In gastric carcinoma a complex interplay between CXC-chemokine signals derived from both tumour cells and tumour-infiltrating immune cells may exhibit pleiotropic effects in tumour biology that go far beyond their originally described functions as leucocyte chemoattractants. Because CXCL8 and CXCL1, which are known to increase growth and invasive behaviour of malignant tumours, are significantly stronger expressed in diffuse- than intestinal-type gastric carcinoma, one may speculate that these chemokines influence the different growth pattern of gastric carcinoma types.
Passive transfer of flt-3L-derived dendritic cells delays diabetes development in NOD mice and associates with early production of interleukin (IL)-4 and IL-10 in the spleen of recipient mice
Authors: MORIN J , FAIDEAU B , GAGNERAULT M-C , LEPAULT F , BOITARD C , BOUDALY S
Published: December 2004

CD11c+/CD11b+dendritic cells (DC) with high levels of major histocompatibility complex (MHC) class II and co-stimulatory molecules have been derived from spleen cells cultured with granulocyte-macrophage colony stimulating factor (GM-CSF) + flt-3L + interleukin (IL)-6 (flt-3L-DC). Investigating in vivo the function of DC in non-obese diabetic mice (NOD), we showed that a single injection of this in vitro-derived subset of DC prevents the development of diabetes into prediabetic female mice. In contrast, DC derived from bone marrow cells cultured with GM-CSF + IL-4 [bone marrow (BM)-DC] induced no protection. Moreover, protection against diabetes following injection of flt-3L-DC was associated with IL-4 and IL-10 production in the spleen and the pancreatic lymph nodes of recipient mice, indicating that this DC population is able to polarize the immune response towards a Th2 pathway. As we shown previously, NOD BM-DC exhibit an enhanced capacity to produce IL-12p70 in response to lipopolysaccharide (LPS) and anti-CD40 stimulation compared to BM-DC from control mice. In contrast, NOD flt-3L-DC, as their control mouse counterpart, produced no IL-12p70 to these stimuli. Our findings show that a subset of DC, characterized by a mature phenotype and the absence of IL-12p70 production can be derived from NOD mouse spleen favouring IL-4 and IL-10 regulatory responses and protection from diabetes development.
Functional responses of human neonatal B lymphocytes to antigen receptor cross-linking and CpG DNA
Authors: TASKER L , MARSHALL-CLARKE S
Published: December 2004

Human neonates are immunologically immature and consequently are highly susceptible to infection. The cellular basis for the dysfunctional immune responses of neonates is not clear, but is likely to reflect the immaturity of both B and T cell populations. Here we have examined the ability of human cord blood B cells to respond to antigen receptor cross-linking and also to CpG containing oligodeoxynucleotides (ODN), and compared their responses with those of adult peripheral blood B cells. Antigen receptor cross-linking with soluble F(ab′)2 anti-IgM antibodies, induced HLA-DR and CD86 up-regulation and proliferation to a similar extent in adult and cord blood B cells. Both interleukin (IL)-2 and IL-4 co-stimulated anti-IgM-induced proliferation, but cord blood B cells were less sensitive than adult B cells to the co-stimulatory effects of IL-2. Antigen receptor cross-linking induced secretion of the chemokines macrophage inflammatory protein-1α (MIP-1α) and MIP-1β in adult and cord blood B cells, and secretion was enhanced by IL-2 or IL-4. CpG-ODN induced up-regulation of HLA-DR and CD86 expression and proliferation of adult and cord blood B cells, and anti-IgM and CPG-ODN synergized in the induction of proliferation. CpG-ODN also induced MIP-1α and MIP-1α secretion in adult and cord blood B cells. In addition to functional studies we examined the expression of CD62L (l-selectin), CCR7 and CXCR5. Our data show that surface expression of CD62L and CCR7 is lower on cord blood B cells than on adult B cells, suggesting that human cord blood B cells may exhibit homing defects.
Leptin stimulates the oxidative burst in control monocytes but attenuates the oxidative burst in monocytes from HIV-infected patients
Authors: SÁNCHEZ-POZO C , RODRIGUEZ-BAÑO J , DOMÍNGUEZ-CASTELLANO A , MUNIAIN M A , GOBERNA R , SÁNCHEZ-MARGALET V
Published: December 2004

Leptin, the 16 kDa product of the ob gene, is a an adipocyte-secreted hormone that centrally regulates weight. However, the physiological role of leptin is not limited to the regulation of food intake and energy expenditure, and leptin has a variety of effects in peripheral tissues, such as a regulatory role modulating the immune system. Thus, leptin receptor is expressed in human peripheral blood mononuclear cells, mediating the leptin stimulation of proliferation and activation, the production of proinflammatory cytokines from cultured monocytes, and the prevention of apoptotic death in serum-deprived monocytes. Because leptin can stimulate monocytes and the production of reactive oxygen species (ROS) are the result of monocyte activation, we investigated the effect of leptin on ROS production by human monocytes in vitro. Oxidative burst was measured by oxidation of the redox-sensitive dye 2′,7′-dichlorofluorescein diacetate, and analysed by flow cytometry. We have found that stimulation with leptin produces oxygen radical formation by monocytes. This effect is dependent on the dose and maximal response is achieved at 10 nm leptin. Because HIV infection induces the production of ROS, we next investigated the effect of leptin on ROS production in monocytes from HIV-positive (HIV+) subjects. We have also found that monocytes from HIV+ subjects spontaneously produced increased amounts of free radicals. In contrast, leptin stimulation of monocytes from these patients partially inhibited the production of ROS. This effect of leptin was also dependent on the dose and maximal effect was achieved at 10 nm. The effect of leptin stimulating the production of ROS is consistent with the proinflammatory role in the immune system. On the other hand, the inhibitory effect on monocytes from HIV+ subjects may be explained by the attenuation of the oxidative burst by a delayed activation of monocytes in a hyperinflammatory state.
Comparativein vitrostudy of the immunomodulatory activity of humanized and chimeric anti-CD25 monoclonal antibodies
Authors: KIRCHER B , LÄTZER K , GASTL G , NACHBAUR D
Published: December 2004

Humanized or chimeric monoclonal antibodies (MoAbs) directed against the interleukin-2 (IL-2) receptor α-chain, CD25, are promising immunosuppressive agents due to improved pharmacokinetic profiles and less toxicity. These MoAbs have been used effectively in preventing and/or treating rejection in solid organ transplantation and are currently under investigation for prevention/treatment of graft-versus-host disease (GvHD) in stem cell transplantation. We analysed the in vitro activities of the chimeric anti-CD25 MoAb basiliximab and the humanized anti-CD25 MoAb daclizumab in various test systems for alloimmune response and T cell activation in comparison to cyclosporin A (CsA) and prednisolone. Anti-CD3- and alloantigen-induced T cell proliferation were decreased significantly by the anti-CD25 MoAbs in a dose-dependent fashion. At a concentration of 10 ng/ml daclizumab and CsA synergistically decreased T cell proliferation of mixed lymphocyte cultures, whereas basiliximab showed only subadditive activity. Simultaneous addition of the anti-CD25 MoAbs and prednisolone did not result in combined activity. Addition of exogenous IL-2 completely overcame the inhibitory effect on T cell proliferation of both anti-CD25 MoAbs, but not that of CsA and prednisolone. Anti-CD25 MoAbs inhibited the generation of antigen-specific cytotoxic T lymphocytes in a limiting dilution assay, whereas they showed no effect on the cytolytic activity of established antigen-specific T cell clones. This in vitro study demonstrates strong immunosuppressive activity by both chimeric and humanized MoAbs against CD25. The combined activity with CsA justifies their early use for prevention rather than treatment of GvHD.
Association of interleukin 1 gene family polymorphisms with duodenal ulcer disease
Authors: GARCIA-GONZALEZ M A , LANAS A , SAVELKOUL P H M , SANTOLARIA S , BENITO R , CRUSIUS J B A , PEÑA A S
Published: December 2004

Cytokine genes taking part in the immunological response to Helicobacter pylori infection are good candidates to study for genetic predisposition to duodenal ulcer disease (DU). Among cytokines, interleukin (IL)-1β and its natural specific inhibitor, the interleukin-1 receptor antagonist, are cytokines that play a key role in regulating gastric acid secretion and modulating the immune response in the gastrointestinal mucosa. We aimed to investigate whether polymorphisms in the IL-1B and IL-1RN genes are involved in the susceptibility to duodenal ulcer. DNA from 131 unrelated Spanish Caucasian patients with DU and 105 ethnically matched healthy controls was typed for the IL-1B-511, IL-1B-31, and IL-1B + 3954 gene polymorphisms, and the VNTR polymorphism in intron 2 of the IL-1RN gene by polymerase chain reaction (PCR)-based methods and TaqMan assays. H. pylori status and non-steroidal anti-inflammatory drugs (NSAIDs) use was determined in all patients and controls. Logistic regression analysis identified H. pylori infection (OR: 9·74; 95%CI = 3·53–26·89) and NSAIDs use (OR: 8·82; 95%CI = 3·51–22·17) as independent risk factors for DU. In addition, the simultaneous carriage of IL-1RN*2, IL-1B-511*C, IL-1B-31*T and IL-1B + 3954*C alleles was a genetic risk factor for DU in patients with H. pylori infection (OR: 3·22; 95%CI = 1·09–9·47). No significant differences in IL-1RN and IL-1B genotypes were found when patients were categorized according to gender, age of onset, smoking habit, NSAIDs use, type of complication and positive family history. Our results provide further evidence that host genetic factors play a key role in the pathogenesis of duodenal ulcer.
Identical twins discordant for multiple sclerosis have a shift in their T-cell receptor repertoires
Authors: HAEGERT D G , GALUTIRA D , MURRAY T J , O'CONNOR P , GADAG V
Published: December 2004

CD4 T-cells have an important role in the autoimmune response in multiple sclerosis (MS). We investigate the possibility that a shift occurs in the T-cell receptor (TR) repertoire of identical twins discordant for MS. We compare the CDR3 spectratype distributions of 24 different TR V beta (TRBV) segments in naïve CD4 T-cells from discordant MS twins and from healthy identical twins. We also compare the CDR3 spectratype distributions in unrelated healthy pairs, formed by combining members of different healthy twins, with the CDR3 spectratype distributions in unrelated pairs of MS patients and in unrelated pairs of their apparently healthy cotwins, formed by combining members of different discordant twins. We use the correlation coefficient (r-value) as a measure of similarity of CDR3 spectratypes in each pair, and we test for the significance of the difference between r-values from the different pairs. We observe that the r-value for the CDR3 spectratype distributions among discordant twins differs significantly from the corresponding r-value for the healthy twins for two TRBV segments. Further, the r-values, for both the unrelated MS patient pairs and the unrelated pairs of their apparently healthy cotwins, differ significantly from the r-values for healthy unrelated pairs of individuals. We conclude that both the MS patients and their apparently healthy cotwins have shifts in their CDR3 repertoires. Because we study naïve CD4 T-cells, we postulate that CDR3 repertoire shifts precede MS and predispose to MS, but are unlikely to be sufficient to cause MS.
Loss of the CD56hiCD16− NK cell subset and NK cell interferon-γproduction during antiretroviral therapy for HIV-1: partial recovery by human growth hormone
Authors: GOODIER M R , IMAMI N , MOYLE G , GAZZARD B , GOTCH F
Published: December 2004

Previous studies have shown that human natural killer (NK) cells are lost from the periphery and are functionally suppressed during HIV-1 infection, and that the administration of highly active antiretroviral therapy (HAART) results in a recovery of NK cell numbers in HIV-1-infected individuals. However, despite this recovery, interleukin (IL)-2 + IL-12-driven interferon (IFN)-γ production by NK cells has been shown to remain suppressed after HAART. Here we show that the innate immune factor IL-15 in combination with IL-12 is also unable to recover NK cell IFN-γ production in HAART-treated individuals. Furthermore, we also demonstrate an imbalance in the distribution of CD56loCD16hi and CD56hiCD16– NK subsets after successful HAART, CD56hiCD16– cells being reduced substantially in HIV-1 patients on HAART. Treatment of patients with combined human growth hormone and antiretroviral therapy resulted in further enhancement in the absolute numbers and the proportion of NK cells in some individuals in the absence of parallel effects on CD4+ T cells. Furthermore, in these individuals HAART with growth hormone resulted in an enhancement of cytokine-driven NK cell activation and IFN-γ production compared to the HAART-only baseline.
Adipokine levels in Cushing's syndrome; elevated resistin levels in female patients with Cushing's syndrome
Authors: Krsek Michal , Silha Josef V. , Jezková Jana , Hána Václav , Marek Josef , Weiss Vladimír , Stepán Jan J. , Murphy Liam J.
Published: December 2004

background  Cushing's syndrome (CS) is associated with central adiposity, insulin resistance and impaired glucose homeostasis. Adipose tissue is thought to regulates glucose homeostasis via circulating adipokines, such as resistin, leptin and adiponectin, although their role in the insulin resistance associated with CS has not been established.

design  We examined the relationship between insulin resistance and adipokine levels in CS patients. We compared plasma levels of resistin, leptin and adiponectin in 10 women and four men patients with CS, with 14 health subjects matched for age, gender and body mass index. A subgroup of three women and four men with pituitary‐dependent CS were re‐examined at least 9 months after curative surgery.

results  CS patients had significantly more truncal fat and less lean body mass as assessed by DEXA compared to control subjects. Total cholesterol, triglycerides and insulin resistance, as calculated using the homeostasis model assessment of insulin resistance (HOMA‐R), was significantly increased in CS patients. Of the adipokines measured, only resistin was significantly different between female CS patients and female control subjects (5·05 ± 0·56 vs. 2·91 ± 0·39 µg/l, P = 0·015). Curative surgery significantly reduced total body fat and truncal fat, leptin, total and low‐density lipoprotien (LDL) cholesterol, glucose and HOMA‐R. A reduction in both resistin and adiponectin was also observed but the differences between pre‐ and post‐treatment levels did not achieve statistical significance.

conclusion  Here we report for the first time that resistin levels are significantly elevated in CS patients and may be important in the insulin resistance associated with glucocorticoid excess.
The first homozygous mutation (S226I) in the highly‐conserved WSXWS‐like motif of the GH receptor causing Laron syndrome: supression of GH secretion by GnRH analogue therapy not restored by dihydrotestosterone administration
Authors: Jorge Alexander A. L. , Souza Silvia C. A. L. , Arnhold Ivo J. P. , Mendonca Berenice B.
Published: December 2004

objective  The study describes for the first time, a homozygous mutation in the WSXWS‐like motif of the human GH receptor (GHR) in a patient with Laron syndrome and describe laboratory data during treatment with GnRHa to suppress puberty and dihydrotestosterone (DHT).

patients  A 16‐year‐old boy at Tanner puberty stage 2 with Laron syndrome was born SGA to consanguineous parents, presented severe growth retardation, obesity and micropenis.

methods and measurements  GHR coding region was sequenced. GH, GHBP, IGF‐I and IGFBP‐3 were determined before, during and after GnRHa and DHT treatment.

results  A homozygous mutation in exon 7, replacing serine by isoleucine in codon 226 was identified. S226 is the last serine belonging to the WSXWS‐like motif in GHR. No specific effect of S226I mutation in heterozygous state was observed. Laboratory data at the prepubertal age showed markedly high GH, low GHBP, IGF‐I and IGFBP‐3 levels. Re‐evaluation at pubertal age showed normal basal serum IGFBP‐3 levels and low but near normal IGF‐I levels. We also noticed a sustained decrease in GH, IGF‐I and IGFBP‐3 levels after blocking puberty, which was not affected by short‐ and long‐term DHT treatment. Pubertal hormonal profile was re‐established after the GnRHa therapy was discontinued to allow the reactivation of the gonadal axis.

conclusion  The homozygous mutation S226I in WSXWS‐like motif of GHR causes GH insensitivity. The decrease in IGF‐I and IGFBP‐3 levels after GnRHa therapy, which was not reversed with DHT administration, suggests that sex steroids have, through oestradiol, a GH‐independent action on IGF‐I and IGFBP‐3 levels. A direct effect of GnRHa on GH secretion cannot be excluded.
Growth hormone replacement in adults and bone mineral density: a systematic review and meta‐analysis
Authors: Davidson Peter , Milne Ruairidh , Chase Deborah , Cooper Cyrus
Published: December 2004

background  The effect of GH replacement on bone mineral density (BMD) in adults with GH deficiency (GHD) is uncertain. We carried out a systematic review of randomized trials that compared GH to no active treatment, with BMD as an outcome.

methods  We searched electronic databases to identify articles, abstracts and conference proceedings to March 2002. We also checked reference lists in included studies and expert reviews. Two reviewers independently extracted the data on study design and change in BMD. The results of individual trials were combined by fixed effects model meta‐analysis using weighted mean difference (WMD) of change in BMD at the lumbar spine (our primary outcome) and other sites.

findings  Eighteen trials that included 700 patients met the inclusion criteria. Maximum follow‐up was for 12 weeks (1 trial), 6 months (14 trials), 12 months (1 trial), 18 months (1 trial) and 24 months (1 trial). Reporting quality of both study design and results was poor. Ten trials (458 subjects) were included in the meta‐analysis. We excluded those eight trials from which sufficient data could not be extracted. We found a mean change in BMD, at the lumbar spine with GH treatment, of 0·01 g/cm2 after 6 and 12 months, 0·02 g/cm2 after 18 months and 0·03 g/cm2 after 24 months. Statistical significance at the 0·05 level was just achieved at 6 and 12 months but was significant at 18 and 24 months. These changes are small and may be influenced by bias.

conclusion  There is evidence of a small effect of GH replacement on bone mineral density in adults with GH deficiency. The clinical importance of this is uncertain.
Serum paraoxonase activity before and after treatment of thyrotoxicosis
Authors: Raiszadeh Farbod , Solati Mehrdad , Etemadi Arash , Azizi Fereidoun
Published: December 2004

objective  Antioxidant effects of paraoxonase, a high density lipoprotein (HDL)‐associated enzyme that inhibits low density lipoprotein cholesterol (LDL‐C) oxidation in human serum, have been reported. Patients with thyroid dysfunction are more susceptible to oxidative stress, and may show enhanced LDL‐C oxidation. The purpose of this study was to evaluate serum paraoxonase activity in patients with hyperthyroidism before and after treatment with methimazole (MMI).

design and patients  Twenty‐four hyperthyroid patients (15 women and nine men, aged 43·0 ± 12·9 years) and 23 age‐ and sex‐matched healthy controls were studied. Serum paraoxonase activity, lipid, lipoprotein and apolipoprotein levels were measured in fasting samples. Patients were treated with MMI 20–30 mg daily for the first month, and 5–10 mg daily thereafter, and re‐evaluated after 6–9 months of treatment.

results  Significantly lower serum paraoxonase activity was present in hyperthyroid patients before treatment compared with the controls (43·4 ± 21·9 vs. 72·6 ± 41·2 U/ml, P < 0·005). After a mean follow‐up of 7·3 months, 15 patients became euthyroid (treated) and nine were still hyperthyroid. After follow‐up, serum paraoxonase activity had increased to 62·2 ± 37·4 U/ml in those who became euthyroid (P < 0·05 compared with baseline). In patients who were still hyperthyroid serum paraoxonase was unchanged from baseline, at 43·2 ± 23·2 U/ml.

conclusion  Serum paraoxonase is reduced in patients with hyperthyroidism and reverts to normal after euthyroidism is attained. Reduced serum paraoxonase activity in thyrotoxicosis might predispose lipids to oxidation.
Association between ghrelin and cardiovascular indexes in healthy obese and lean men
Authors: Tritos Nicholas A. , Kissinger Kraig V. , Manning Warren J. , Danias Peter G.
Published: December 2004

objective  Obesity is an increasingly common condition and is associated with excess morbidity and mortality, including clinical and subclinical cardiac dysfunction. The role of hormones involved in energy homeostasis, including ghrelin and leptin, in cardiovascular function remains incompletely understood. Therefore, we sought to evaluate the association between systemic ghrelin and leptin levels with indexes of cardiovascular structure and function.

design and measurements  We measured serum ghrelin and leptin levels in 25 clinically healthy obese men and 25 lean controls, using commercially available immunoassays. We also assessed right and left ventricular structure and function using cardiac magnetic resonance imaging. We then investigated the association between serum ghrelin and leptin levels with cardiac indexes, using univariate and multivariate analysis.

results  There was an independent association between serum ghrelin levels and height‐adjusted right ventricular mass (r = −0·324, P = 0·026), right ventricular end‐diastolic volume (r = −0·363, P = 0·017) and right ventricular end‐systolic volume (r = −0·398, P = 0·009) as well as right ventricular ejection fraction (r = 0·317, P = 0·050). There was no significant association between serum ghrelin and indexes of left ventricular structure or function. We also identified an association between serum leptin levels and resting heart rate (r = 0·391, P = 0·002). There was an association between serum leptin and height‐adjusted left ventricular mass on univariate, but not on multivariate, analysis.

conclusions  Serum ghrelin is associated with right ventricular cardiovascular indexes and serum leptin is associated with resting heart rate. These associations indicate a close interaction between the endocrine and cardiovascular systems in obesity.
Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage?
Authors: Carnevale Vincenzo , Manfredi Giuseppe , Romagnoli Elisabetta , De Geronimo Simona , Paglia Federica , Pepe Jessica , Scillitani Alfredo , D’Erasmo Emilio , Minisola Salvatore
Published: December 2004

objective  Vitamin D deficiency, even subclinical, has been considered to worsen the skeletal damage in primary hyperparathyroidism (PHPT). Our study aimed to investigate the impact of vitamin D status on skeletal involvement in PHPT.

design and measurements  A cross‐sectional study was designed involving 62 female patients with PHPT. Serum total calcium (tCa), phosphate (P), creatinine (Cr) and total alkaline phosphatase activity (AP), together with 24‐h (uCa 24 h) and spot fasting (uCa/Cr) urinary calcium, were measured by autoanalyser; ionized calcium (iCa) was assessed by an ion‐specific electrode; intact parathyroid hormone (PTH) was measured by immunoradiometric assay (IRMA) and 25‐hydroxyvitamin D (25‐OHD) by radioimmunoassay (RIA). Bone mineral density (BMD) was measured by dual energy X‐ray absorptiometry (DXA) at lumbar spine in 58 patients, and at femoral neck, Ward's triangle, greater trochanter, intertrochanteric line and total hip in 56 patients. The associations of all variables with age, 25‐OHD, body mass index (BMI) and PTH were studied by linear multiple regression analysis, using progressively restricted models.

results  The model including age, 25‐OHD, PTH and BMI showed significant regression with BMD values. PTH, age and BMI exerted a leading role in determining such a significance, while no significant regression was found between the parameters studied and 25‐OHD; this was confirmed by Pearson's linear correlation analysis. The progressively restricted models showed significant regression of BMD at femoral neck, femoral intertrochanteric line and total hip with age, BMI and PTH. BMD measured at the Ward's triangle and greater trochanter showed significant regression with age and BMI, and that measured at lumbar spine with age.

conclusions  Our data indicate that in primary hyperparathyroidism patients the influence of 25‐hydroxyvitamin D levels on bone mineral density, if any, was overwhelmed by the effects of parathyroid hormone excess, age and body mass index. The latter unequally affected bone mineral density of various measured sites with different composition.
Serum osteoprotegerin and receptor activator of nuclear factors kB (RANKL) concentrations in normal children and in children with pubertal precocity, Turner's syndrome and rheumatoid arthritis
Authors: Buzi F. , Maccarinelli G. , Guaragni B. , Ruggeri F. , Radetti G. , Meini A. , Mazzolari E. , Cocchi D.
Published: December 2004

background  Osteoprotegerin (OPG) is a secreted member of the TNF receptor superfamily. OPG is made by osteoblastic cells and is expressed in a wide variety of cell and tissue types. It acts as a decoy receptor by binding the receptor activator of nuclear factors kB (RANKL) and preventing RANKL‐induced osteoclast formation and differentiation. Numerous cytokines and hormones (TGF‐β, PTH, vitamin D, glucocorticoids and oestrogens) exert their effects on osteoclastogenesis by regulating the production of OPG.

patients and methods  In the present study we compared serum OPG and RANKL concentrations in a group of normal children (1–14 years old) with those of pair‐aged children affected by different diseases [Turner's syndrome (TS), early/precocious puberty (PP) and rheumatoid arthritis (RA)]. OPG and RANKL concentrations were measured by an enzyme immunoassay method using a commercial kit.

results  Mean (± SD) OPG level in normal children was 4·05 ± 1·63 pmol/l with no difference between males and females. OPG values in children 1–4 years old (5·87 ± 2·22 pmol/l) were significantly higher than in children 4–14 years old (3·55 ± 0·97 pmol/l). OPG levels in children with RA were significantly higher than in controls (6·33 ± 2·57 pmol/l vs. 4·05 ± 1·63 pmol/l, P < 0·01); patients with TS or PP had OPG levels superimposable to those of controls (2·61 ± 0·67 pmol/l and 3·99 ± 0·85 pmol/l, respectively), but in TS OPG levels were significantly lower than in age‐matched females. Mean RANKL concentration in normal subjects was 0·81 ± 1·55 pmol/l; there was a slight decline in RANKL levels with age. RANKL concentrations in subjects with TS, PP, RA and controls did not differ significantly, and did not differ from those published in adult normal subjects.

conclusions  It appears from our data that OPG serum levels in healthy children aged > 4 years are similar to those present in young adult men, with higher levels in the first 4 years of life. Although the meaning of the alterations of OPG levels observed in pathological conditions is still obscure, they appear potentially interesting in view of a key role played by this protein in bone homeostasis.
The effectiveness of different treatment options for non‐islet cell tumour hypoglycaemia
Authors: Teale J. D. , Wark G.
Published: December 2004

objective  To compare the outcome of different treatment options used in several cases of non‐islet cell tumour hypoglycaemia (NICTH).

patients  Eight cases of NICTH were referred for diagnosis and monitoring following either surgical or medical treatment.

methods  Serum samples collected throughout the time‐course of each case were analysed for glucose, insulin, C‐peptide, IGF‐I, total IGF‐II, total IGF‐II to IGF‐I ratio and, in most of the cases, big IGF‐II.

results  Surgical excision was successful in the relief of symptoms and normalization of the biochemical parameters. Therapeutic treatment with glucocorticoids confirmed previous studies showing the suppressive effect on tumour (big) IGF‐II production. The present data show that the effect was dose‐dependent and reversible if doses were below a critical level.

conclusions  Within the limits of the cases studied, and the time‐scales involved, moderate‐ to high‐dose glucocorticoid therapy had immediate beneficial influence on symptomatic hypoglycaemia and, if tolerated in the long term, was effective in correcting the underlying biochemical dysfunction, unlike other therapeutic regimens. This effectiveness was only achieved when the dose exceeded a threshold level specific to the patient. In addition, reduction of the dose or withdrawal of the drug caused a return of the abnormal biochemical profile. Surgical removal of the malignancy, where this was an option, was successful within the periods studied.
Internal jugular vein sampling in adrenocorticotropic hormone‐dependent Cushing's syndrome: a comparison with inferior petrosal sinus sampling
Authors: Erickson Dana , Huston John , Young William F. , Carpenter Paul C. , Wermers Robert A. , Bonelli Frank S. , Powell Claudia C.
Published: December 2004

objective  Distinguishing between pituitary‐dependent Cushing's syndrome (CS) and occult ectopic ACTH syndrome can be extremely difficult. Bilateral inferior petrosal sinus sampling has been shown to have the highest diagnostic accuracy in this subtype evaluation. Internal jugular vein sampling (IJVS) has been reported as a potentially safer invasive alternative, but data are limited. Our objective was to compare the sensitivity and specificity of bilateral IJVS and bilateral inferior petrosal sinus sampling (IPSS) in patients with ACTH‐dependent CS.

design  We prospectively collected blood samples from the inferior petrosal sinus and internal jugular vein of consecutive patients with ACTH‐dependent CS.

patients  The study group included 35 patients: 32 with pituitary‐dependent CS (positive immunohistochemical findings for ACTH pituitary tumour or biochemical cure after pituitary surgery) and three with histologically proven ectopic ACTH syndrome.

measurements  Inferior petrosal sinus sampling and bilateral IJVS were performed simultaneously before and after administration of corticotropin‐releasing hormone (CRH), and ratios of central‐to‐peripheral ACTH concentrations were calculated.

results  The basal IJVS central‐to‐peripheral ACTH ratios were diagnostic for pituitary‐dependent CS (> 2) in 15 patients (46·9%), as were basal inferior petrosal sinus sampling central‐to‐peripheral ACTH ratios in 29 patients (90·6%). The post‐CRH IJVS central‐to‐peripheral ACTH ratios were diagnostic for pituitary‐dependent disease (> 3) in 24 patients (75%), as were post‐CRH inferior petrosal sinus sampling central‐to‐peripheral ACTH ratios in 28 patients (87·5%). In the three patients with ectopic ACTH CS, the IJVS and inferior petrosal sinus sampling pre‐ and post‐CRH ACTH ratios were correctly negative. The overall sensitivity of combined pre‐ or post‐CRH was 81·3% for IJVS and 93·8% for inferior petrosal sinus sampling. Because of the difference between mean ratios in the two techniques, new criteria for IJVS were mathematically calculated: a pre‐CRH central‐to‐peripheral ACTH ratio of 1·59 and a post‐CRH central‐to‐peripheral ACTH ratio of 2·47 maximized sensitivity and specificity when both of these are equally taken into consideration.

conclusion  In conclusion, IJVS is not superior to inferior petrosal sinus sampling for establishing the cause of ACTH‐dependent CS. When new criteria of basal (> 1·6) and post‐CRH (> 2·5) central‐to‐peripheral ACTH gradients were applied to ACTH ratios from IJVS, the sensitivity of this test was maximized. However, confirmatory inferior petrosal sinus sampling is recommended when there is a lack of a central‐to‐peripheral ACTH gradient and when there is only a gradient above the cut‐off on basal (pre‐CRH) sampling.
Testosterone release rate and duration of action of testosterone pellet implants
Authors: Kelleher S. , Howe C. , Conway A. J. , Handelsman D. J.
Published: December 2004

objective Testosterone pellets are a highly effective subdermal depot administered at regular intervals with the timing individualized depending upon return of the patient's characteristic androgen deficiency symptoms. Yet thein vivotestosterone release rate and effective duration of action of these pellets has been little studied systematically.

design Analysis of prospectively collected data from three randomized controlled clinical trials. Collection of extruded pellets.

patients Androgen‐deficient men (n = 136) undergoing long‐term androgen replacement therapy with a standard dose (800 mg) of testosterone pellets implanted subdermally at intervals from 5 to 7 months.

measurements Testosterone release rate of pellets, consisting of pure crystalline testosterone without excipients, is estimated by measuring the dry weight lost by pellets (n = 179) over their timein situ. The effective duration of the standard regimen, and the influence of extrusion and patient or procedural characteristics on it, was estimated by timing of return for re‐implantation due to recurrence of the patient's familiar androgen deficiency symptoms.

results The loss of dry weight of intact (n = 112) pellets was strongly correlated with timein situ(r2 = 0·969) providing an estimate of daily testosterone release rate per 200 mg pellet of 1·34 ± 0·02 mg/pellet/day (95% CI 1·30–1·37 mg/day) for the first 3 months. After 756 implantations of the standard dose, men return for re‐implantation at 5·8 calendar months following no or only a single pellet extrusion, but the time to return was significantly shorter after multiple extrusions. No patient or procedural features influenced the timing of return. Among men with primary hypogonadism, increases in plasma LH and FSH were more sensitive than plasma total or free testosterone to changes in testosterone delivery following an extrusion.

conclusion Testosterone pellet implants release testosterone at a steady rate of 1·3 mg/200 mg implant/day (95% CI). The duration of action is about 6 months in an uncomplicated cycle with timing of return shortened by extrusions only in the 3·6% of procedures followed by multiple extrusions. No other patient or procedural features influenced duration of action. Among men with an intact hypothalamo‐pituitary unit, plasma gonadotropins are more sensitive than blood total or free testosterone to reduced testosterone delivery following an extrusion.