bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Alterations in Gene Expression in Recurrent Malignant Glioma after Radiotherapy Using Complementary Deoxyribonucleic Acid Microarrays
Authors: Joki Tatsuhiro , Carroll Rona S. , Dunn Ian F. , Zhang Jianping , Abe Toshiaki , Black Peter McL.
Published: September 2004

OBJECTIVE

We used complementary deoxyribonucleic acid expression microarrays to assess the effects of radiotherapy on gene expression in glioblastoma multiforme. We hypothesized that postradiation recurrent tumors may demonstrate alterations in gene expression from the primary tumor specimen.

METHODS

Patients were diagnosed with glioblastoma multiforme at resection of the initial tumor, and they received 60 Gy of fractionated radiotherapy before recurrence. Ribonucleic acid samples from both the primary and the postradiation recurrent tumor in each patient were screened and compared using complementary deoxyribonucleic acid expression arrays and Northern blot analysis.

RESULTS

Messenger ribonucleic acid levels of growth factors participating in paracrine loops, such as vascular endothelial growth factor and platelet-derived growth factor receptor β, were decreased in postradiation recurrent tumors as compared with primary tumors in three of four patients. However, messenger ribonucleic acid levels of growth factors involved in autocrine loops, such as epidermal growth factor receptor, platelet-derived growth factor α, platelet-derived growth factor A, and basic fibroblast growth factor, were decreased in two of four, two of four, three of four, and three of four patients' recurrent tumors, respectively. Microvessel counts demonstrated that blood vessel growth was decreased significantly in postradiation recurrent tumor specimens.

CONCLUSION

After radiotherapy of glioblastoma multiforme, levels of paracrine-acting growth factors are diminished in correspondence with the reduction in vascular density. In contrast, growth factors that participate in autocrine loops demonstrate elevated levels of gene expression. These results suggest that maintenance of autocrine loops may be important in tumor regrowth after radiotherapy.
Surgical Relationship of the Medial Pectoral Nerve to the Musculocutaneous Nerve: A Cadaveric Study
Authors: Hansasuta Ake , Tubbs R. Shane , Grabb Paul A.
Published: September 2004

OBJECTIVE

For purposes of neurotization of the musculocutaneous nerve (MCN) with the medial pectoral nerve (MPN) after upper trunk brachial plexus injuries, the anatomic relationship between these two nerves was defined in a cadaveric model.

METHODS

Thirty-five brachial plexuses in 18 adult cadavers were dissected. The distance between the origin of the MPN from the medial cord to the origin of the MCN from the lateral cord was measured. The length, diameter, branching, and location of the MPN were recorded. The diameter of the proximal MCN was recorded.

RESULTS

Thirty-seven percent of the MPNs, when detached from the pectoralis muscles, were too short to reach the proximal MCN by a mean distance of 15 mm. The MPN pierced the pectoralis minor muscle in 80% of the dissections. The cross sectional area of the MCN was always larger than the cross sectional area of the MPN by an average factor of 2.5.

CONCLUSION

When planning to use the MPN for neurotization of the MCN, one should be prepared to harvest an interposition graft, because over one-third of MPNs may not have enough length to reach the MCN in a tension-free manner. Diameter mismatch occurs predictably between the distal MPN and the proximal MCN.
Osteoplastic Lateral Suboccipital Approach for Acoustic Neuroma Surgery: Technical Note
Authors: Sepehrnia Abolghassem , Knopp Ulrich
Published: September 2004

OBJECTIVE

Persistent headache remains a significant problem in a small group of patients after acoustic neuroma surgery via the lateral suboccipital approach. We describe a modified technique of osteoplastic lateral suboccipital craniotomy for surgery of the cerebellopontine angle. This simple and elegant technique provides a superior cosmetic result and a significant reduction in patients' symptoms.

METHODS

We report on our series of 75 patients who underwent surgery for acoustic neuroma. The maximal follow-up period was 4 years.

RESULTS

No patients reported headache postoperatively. Cerebrospinal fluid fistulae were not observed.

CONCLUSION

This modified approach minimizes cerebellar retraction, and the neural and vascular structures can be preserved under direct visualization of the tumor. This lateral suboccipital approach is a useful modification of previous approaches in acoustic neuroma surgery. It provides successful tumor resection and excellent functional results.
En Bloc Laminoplasty Performed with Threadwire Saw: Technical Note
Authors: Hara Masahito , Takayasu Masakazu , Takagi Teruhide , Yoshida Jun
Published: September 2004

OBJECTIVE

To introduce a method for a simple, nonexpansive laminoplasty that can be performed with a threadwire saw (T-saw) after en bloc laminotomy has been performed. The method can be applied along the entire spinal region, including the thoracic and lumbar spine.

METHODS

An en bloc laminotomy of trapezoid shape at the cross section is performed bilaterally at the junctional area of the lamina and facet joint with a thin, flexible T-saw, while preserving the supraspinous, interspinous, and interlaminar ligaments. After the intradural procedure has been performed, the laminar flap is replaced in its original site and fixed with 1-0 nylon sutures, resulting in the complete reconstruction of the posterior supporting elements of the spinal column.

RESULTS

En bloc laminoplasty was performed on 16 patients via a T-saw; most of the patients had intradural spinal tumors. The patients did not need their spinal canals to be enlarged after the intradural procedure had been performed. The follow-up period ranged from 2 to 40 months (mean ± standard error, 22.6 ± 3.4 mo). The laminoplasty was performed from the upper cervical to the sacral regions, although the most frequently operated level was the lower thoracic level. Two-level laminoplasty was performed in 12 patients, and three-level laminoplasty was performed in four. The laminoplasty was done safely and without any complications, except in one patient, who experienced thoracic root injury from a T-saw that was accidentally inserted anterior to the roots. No spinal column deformity or sinking of the replaced laminar flap was noted during the follow-up period; patients were assessed at follow-up via radiographs or computed tomographic scans. Computed tomographic scans obtained later indicated that bony fusion occurred at the cutting edges 1.0 to 4.0 months after surgery (mean, 1.90 ± 0.34 mo).

CONCLUSION

Simple en bloc laminoplasty performed with a T-saw is a useful, safe procedure that can be used to reconstruct the posterior spinal elements throughout the whole spinal region after the intradural procedure has been performed.
Vascular Orientation by Intra-arterial Dye Injection during Spinal Arteriovenous Malformation Surgery: Technical Note
Authors: Tani Satoshi , Ikeuchi Satoshi , Hata Yuichi , Abe Toshiaki
Published: September 2004

OBJECTIVE

Rich and complicated vascular structures on the spinal cord often interfere with obliteration of a spinal arteriovenous malformation (AVM). Vascular orientation during spinal AVM surgery is essential. The authors recently performed six consecutive spinal AVM surgeries in five patients (two with perimedullary AVMs, and three with dural arteriovenous fistulae) with the aid of intra-arterial injection of dye (indigo carmine).

METHODS

Two representative cases are described. A microcatheter was placed preoperatively in the artery of interest. Subsequent to the exposure of the vascular complex, a 1-ml injection of indigo carmine (2 mg/ml) clearly demonstrated the feeding arteries and the draining veins around the AVM or dural arteriovenous fistula.

RESULTS

One patient had repeat surgery because of incomplete obliteration of the AVM owing to migration of the catheter. All patients, except one who had temporary postoperative deterioration and persistent neurological deficits, had good surgical outcomes, however. No apparent side effects caused by the dye were reported.

CONCLUSION

The assistance system for spinal AVM surgery is easy and safe and can be applied in other surgical institutions.
Helicobacter pylori and Nonmalignant Diseases
Authors: Kuipers Ernst J. , Malfertheiner Peter
Published: September 2004

This paper reviews the new literature from the past year on the association between colonization with Helicobacter pylori and non‐malignant disease of the upper gastrointestinal tract. This issue has, in the past year, remained a topic of wide research interest yielding many important new data. These data show that H. pylori eradication is the most effective therapy for peptic ulcer disease, but that a considerable proportion of ulcer patients remain to have dyspeptic symptoms. The discussion on the interaction between H. pylori and NSAID use in the etiology of ulcer disease has not yet been settled. Several studies, both from Asia and Europe, now reported that H. pylori eradication has a minimal effect on the primary prevention of ulcer disease in NSAID users, but eradication appears of relevance for the secondary prevention of ulcer disease in addition to proton pump inhibitor maintenance therapy. Various studies brought further support for the hypothesis that H. pylori eradication is of some benefit for patients with non‐ulcer dyspepsia, although the effects are limited. The prevalence of H. pylori is lower among GERD patients than among controls, but H. pylori eradication has not been consistently shown to increase the risk for the newly development of GERD in an individual subject undergoing H. pylori eradication. The discussion on H. pylori and GERD should not preclude us from treating H. pylori‐infected patients for accepted clinical indications. In patients using proton pump inhibitors for GERD, H. pylori eradication leads to a resolution of their corpus‐predominant pangastritis, without impairing the efficacy of PPI therapy.
Epidemiology of Helicobacter pylori Infection
Authors: Perez‐Perez Guillermo I. , Rothenbacher Dietrich , Brenner Hermann
Published: September 2004

This review summarizes key results of epidemiologic studies published in peer‐reviewed journals between April 2003 and March 2004. The prevalence of H. pylori infection continues to vary strongly between developing countries and developed countries, and according to ethnicity, place of birth and socioeconomic factors among people living in the same country. Intrafamilial spread appears to play a central role in transmission of the infection in both developing and developed countries. The role of H. pylori infection in development of noncardia gastric cancer appears to be even much stronger than previously assumed, whereas the lack of an association with cardia cancer and an inverse association with adenocarcinoma of the esophagus could be confirmed. Suggestions for an inverse association of the infection with atopic diseases have recently received further support, whereas evidence concerning the role of the infection (or its eradication) in GERD and a large variety of other extragastric diseases, including cardiovascular disease, remains inconclusive.
Helicobacter pylori Public Health Implications
Authors: Moayyedi Paul , Hunt Richard H.
Published: September 2004

Population Helicobacter pylori screening and treatment has the potential to dramatically reduce global gastric cancer mortality. There is overwhelming evidence that the infection is a major cause of distal gastric adenocarcinoma. There is also randomized controlled trial evidence that H. pylori eradication reverses or ameliorates histological changes in the gastric mucosa that are important in carcinogenesis. Preliminary randomized controlled trial data suggest that screening and treatment may reduce the risk of gastric cancer although the number of cancer cases was small. Population H. pylori screening and treatment will also reduce mortality from peptic ulcer complications and reduce the burden of dyspepsia in the community. The reduction in health service dyspepsia costs means that this could be the first programme to pay for itself.

From a scientific perspective, we still have insufficient evidence to conclude the benefits of population H. pylori screening are greater than the possible harms and we need more randomized controlled trial data. From a public health perspective however, sometimes screening programmes are developed with imperfect information. The medical community should be consistent and if we are instituting other population screening programmes without randomized controlled trial evidence then H. pylori testing and treatment should also be considered.
Helicobacter pylori and Gastric Malignancies
Authors: Asaka Masahiro , Dragosics Brigitte A.
Published: September 2004

Clinical outcomes of Helicobacter pylori infection are diverse and caused by the variability of H. pylori virulence factors, host susceptibility, environmental factors and their interactions. Prospective epidemiological studies have clearly shown the relationship between H. pylori infection and gastric cancer. In addition, studies in animal models such as Mongolian gerbils with or without the addition of low‐dose chemical carcinogens demonstrated that H. pylori infection can develop gastric carcinoma. Experimental studies have shown that virulence factors of H. pylori interact with gastric epithelial cell signaling related to carcinogenesis.

While the effect of H. pylori eradication on prevention of such tumors in chronic H. pylori carriers is still controversial, progress has been made in therapy especially of gastric lymphoma with well tolerated chemotherapeutic regimen.
Helicobacter pylori Infection in Pediatrics
Authors: Crone Julia , Gold Benjamin D.
Published: September 2004

The proposed route of Helicobacter pylori transmission appears to be fecal‐oral, oral‐oral and gastro‐oral, yet, a number of studies challenged these hypotheses in 2003. The use of the stool antigen test and[13]‐C urea breath testing were the tests of choice for diagnosis and ‘test for cure’ of H. pylori in Europe in 2003 but have not yet become accepted standard of care in North America. Pediatric H. pylori consensus guidelines are not yet revised; upper endoscopy and biopsy remain the gold standard for diagnosis of pediatric H. pylori infection. In addition to stronger evidence supporting the role of host influences of H. pylori‐associated gastric cancer risk, compelling evidence was provided for the role of H. pylori in iron deficiency anemia of childhood. Antibiotic resistance remains a problem in conferring treatment failure and 2003 studies indicate that macrolide resistance is higher in children than in adults. Treatment with proton pump inhibitor‐based triple therapy for 10–14 days remains the mainstay for eradication of H. pylori in childhood. Finally, multinational studies are needed to develop screening guidelines for childhood infection to avoid long‐term severe gastroduodenal disease sequelae.
Changes in Union Membership Over Time: A Panel Analysis for West Germany
Authors: Beck Martin , Fitzenberger Bernd
Published: September 2004

Abstract.  Despite the apparent stability of the wage bargaining institutions in West Germany, aggregate union membership has been declining dramatically since the early 1990s. However, aggregate gross membership numbers do not distinguish between employment status and it is impossible to disaggregate these sufficiently. This paper uses four waves of the German Socio‐economic Panel in 1985, 1989, 1993, and 1998 to perform a panel analysis of net union membership among employees. We estimate a correlated random‐effects probit model suggested by Chamberlain (Handbook of Econometrics, Vol. II, Amsterdam: Elsevier Science, 1984) to take proper account of individual‐specific effects. Our results suggest that at the individual level the propensity to be a union member has not changed considerably over time. Thus, the aggregate decline in membership is due to composition effects. We also use the estimates to predict net union density at the industry level based on the IAB employment subsample for the time period 1985–97.
Why is the Return to Training So High?
Authors: Schøne Pål
Published: September 2004

Abstract.  Cross‐sectional results show that training increases wages by 5 per cent. This return is on a par with the return to 1 year of education. Considering that the average duration of training is very short, this result is strange and needs further examination. After leaving out the importance of measurement error, we control for accumulated stock of firm‐specific skills, unobserved heterogeneity in wage levels, heterogeneity in training returns, and heterogeneity in wage growth. By this we manage to reduce the return considerably. Unobserved heterogeneity in wage levels is the most important contributor to the ‘too high’ returns to training.
Desloratadine in combination with montelukast in the treatment of chronic urticaria: a randomized, double‐blind, placebo‐controlled study
Authors: Nettis E. , Colanardi M. C. , Paradiso M. T. , Ferrannini A.
Published: September 2004

Background
Chronic urticaria (CU) is a common skin condition. It is frequently a disabling disease due to the persistency of clinical symptoms, the unpredictable course and negative influence on the quality of life.

Objective
The aim of this study is to determine whether montelukast, a LTD4 receptor antagonist, plus desloratadine, is more efficacious than desloratadine alone in the treatment of chronic urticaria.

Materials
A randomized, double‐blind, placebo‐controlled study was conducted on 81 patients with a diagnosis of CU. A 1‐week single‐blind placebo run‐in period (baseline) was followed by a 6‐weeks double blind active treatment period. The patients were randomized to receive the following treatment once daily: (a) oral desloratadine (5 mg) plus placebo; (b) desloratadine (5 mg) plus montelukast (10 mg); (c) oral placebo alone. The study ended after another 1‐week single‐blind placebo washout period.

Results
The evaluable population thus consisted of 76 patients. Both desloratadine alone and desloratadine plus montelukast administered once daily yielded improvements with respect to the baseline assessment as regards pruritus, number of separate episodes, size and number of weals, visual analogue score and patients' quality of life and with respect to the placebo group both in the active treatment period and in the run‐out period. However, desloratadine plus montelukast was shown to improve the symptoms and patients' quality of life significantly more than desloratadine alone, although it did not have a significant effect on the number of urticarial episodes.

Conclusion
The combination of desloratadine plus montelukast is effective in the treatment of CU. It may therefore be a valid alternative in patients with relatively mild CU, in view of its efficacy and the lack of adverse events.
Fluticasone propionate aqueous nasal spray does not influence the recurrence rate of chronic rhinosinusitis and nasal polyps 1 year after functional endoscopic sinus surgery
Authors: Dijkstra M. D. , Ebbens F. A. , Poublon R. M. L. , Fokkens W. J.
Published: September 2004

Background
Local corticosteroids are widely used in the treatment of nasal polyps and chronic rhinosinusitis both before and after nasal surgery. Their efficacy after functional endoscopic sinus surgery (FESS) has not been fully established by placebo‐controlled trials.

Objective
This double‐blind placebo‐controlled randomized study was performed in order to investigate whether fluticasone propionate aqueous nasal spray (FPANS) reduces the recurrence rate of nasal polyps and chronic rhinosinusitis during the first year after FESS.

Patients and methods
The trial looked at 162 patients aged 18 years and older requiring FESS for chronic rhinosinusitis or nasal polyps. After FESS combined with peri‐operative systemic corticosteroids, patients were randomized and given FPANS 400 μg b.i.d., FPANS 800 μg b.i.d. or placebo b.i.d. for the duration of 1 year. Patients were withdrawn from the trial (but still included in the study for statistical purposes) if there were recurrent or persistent diseases, defined as progressive regrowth of nasal polyps, recurrent signs and symptoms of chronic sinusitis combined with abnormalities on computed tomography scan and persistent complaints for at least 2 months after FESS.

Results
A significant reduction of symptoms was seen after FESS. After 1 year, 46 patients had been withdrawn from the trial because of recurrent diseases and 32 patients because of persistent symptoms. No differences in the number of patients withdrawn because of recurrent or persistent diseases were found between the patients treated with FPANS and patients treated with placebo. We were also unable to find a positive effect of FPANS compared with placebo in several subgroups such as patients with nasal polyps, high score at FESS or no previous sinus surgery.

Conclusion
This placebo‐controlled study does not show that treatment with FPANS up to 1 year after FESS had a positive effect compared with placebo.
Analysis of effector and regulatory immune reactivity to nickel
Authors: Rustemeyer T. , Von Blomberg B. M. E. , Van Hoogstraten I. M. W. , Bruynzeel D. P. , Scheper R. J.
Published: September 2004

Background
Diagnostic patch testing in allergic contact dermatitis faces the risk of boosting existing hypersensitivities or active sensitization. Risk‐free and reliable in vitro assays using peripheral blood are, therefore, wanted.

Objectives
Here, we studied new approaches for in vitro monitoring of nickel‐specific effector ad regulatory cell functions in allergic patients and potentially tolerized individuals.

Methods
Lymphocyte proliferation assays were carried out with the allergen and additional IL‐12/IL‐7 or IL‐4/IL‐7 cytokine supplements. Release of IFN‐γ and IL‐5 were assessed as measures for type‐1 and type‐2 effector T cell function, respectively, and IL‐10 and TGF‐β1 to monitor possible regulatory T cell function reflecting immunological tolerance. After optimization of in vitro cut‐off values, potency of these parameters was evaluated as compared with conventional nickel patch testing.

Results
One hundred and fifty six outpatients were included in this study, 74 of whom presenting with a positive history of nickel allergy. Nickel‐sulphate patch test results showed positive reactions in 43 patients, of whom 40 had a positive history (test sensitivity 54%; specificity 96%; overall accuracy 76%). Proliferation tests without cytokine supplementation showed an accuracy of 68%, which was further improved by supplementing IL‐4/IL‐7 (82%). IFN‐γ and IL‐5 cytokine production, as revealed in IL‐12/IL‐7 and IL‐4/IL‐7 supplemented cultures, respectively, showed accuracies of 70% and 83%. As to the production of putatively immunoregulatory cytokines, IL‐10 was most informative, with highest production rates in nickel‐skin test negative individuals with long‐lasting mucosal metal contact preceding skin piercing.

Conclusions
These results indicate that measuring both T cell proliferation and cytokine secretion profiles, in particular IL‐5 release using IL‐4/IL‐7 supplemented medium, offers a promising improvement of the in vitro diagnostic options in monitoring nickel contact sensitization. Since oral nickel contact has been shown earlier to induce active tolerization, nickel‐induced in vitro IL‐10 production may help identify nickel‐tolerized individuals.
Aluminium hydroxide down‐regulates T helper 2 responses by allergen‐stimulated human peripheral blood mononuclear cells
Authors: Wilcock L. K. , Francis J. N. , Durham S. R.
Published: September 2004

Background
Aluminium hydroxide (alum) is a commonly used adjuvant for specific immunotherapy of allergic diseases. While alum is traditionally associated with murine Th2 sensitization, little is known about its effects on secondary allergic responses in humans.

Methods
We investigated the in vitro effects of alum on peripheral blood mononuclear cells (PBMC) from atopic donors. PBMC from 18 grass pollen‐sensitive rhinitic subjects were stimulated with Phleum pratense (Phl p) in the presence or absence of alum. After 6 days culture, cytokine production was measured by ELISA and T cell proliferation by radiolabelled thymidine incorporation. The effect of alum on the expression of human leucocyte antigen and CD80/CD86 on cultured antigen‐presenting cells was assessed by flow cytometry.

Results
PBMC cultured with Phl p and alum showed a significant decrease in both IL‐5 and IL‐13 production compared with allergen alone (P<0.005 and P<0.001, respectively), but no change in IFN‐γ or IL‐12 production or proliferative responses. These alum‐induced changes in T helper (Th)2 cytokine production were unaffected by the addition of neutralizing antibodies to IL‐4 or IL‐12. Culture of PBMC with alum induced increased expression of CD86 (P=0.004) and HLA (P=0.01) on monocytes while the expression of CD80 was decreased (P=0.02).

Summary
Alum down‐regulates allergen‐driven Th2 cytokine responses while Th1 cytokines are unaffected. These data confirm that alum is a useful adjuvant for inclusion in allergen immunotherapy vaccines.
Defective suppression of Th2 cytokines by CD4+CD25+ regulatory T cells in birch allergics during birch pollen season
Authors: Grindebacke H. , Wing K. , Andersson A.‐C. , Suri‐Payer E. , Rak S. , Rudin A.
Published: September 2004

Background
CD4+CD25+ regulatory T cells suppress proliferation and cytokine production by human T cells both to self‐antigens and exogenous antigens. Absence of these cells in human newborns leads to multiple autoimmune and inflammatory disorders together with elevated IgE levels. However, their role in human allergic disease is still unclear.

Objective
This study aimed to evaluate the capacity of CD4+CD25+ regulatory T cells to suppress proliferation and cytokine production outside and during birch‐pollen season in birch‐allergic patients relative to non‐allergic controls.

Methods
CD4+ cells were obtained from blood of 13 birch‐allergic patients and six non‐allergic controls outside pollen season and from 10 birch‐allergic patients and 10 non‐allergic controls during birch‐pollen season. CD25+ and CD25− fractions were purified with magnetic beads and cell fractions, alone or together in various ratios, were cultured with antigen‐presenting cells and birch‐pollen extract or anti‐CD3 antibody. Proliferation and levels of IFN‐γ, IL‐13, IL‐5 and IL‐10 were measured by thymidin incorporation and ELISA, respectively. Numbers of CD25+ cells were analysed by flow cytometry.

Results
CD4+CD25+ regulatory T cells from both allergics and non‐allergics potently suppressed T cell proliferation to birch allergen both outside and during birch‐pollen season. However, during season CD4+CD25+ regulatory T cells from allergic patients but not from non‐allergic controls were defective in down‐regulating birch pollen induced IL‐13 and IL‐5 production, while their capacity to suppress IFN‐γ production was retained. In contrast, outside pollen season the regulatory cells of both allergics and non‐allergic controls were able to inhibit T‐helper 2 cytokine production.

Conclusion
This is the first study to show differential suppression of Th1 and Th2 cytokines, with CD4+CD25+ regulatory T cells from birch‐pollen‐allergic patients being unable to down‐regulate Th2, but not Th1 responses during birch‐pollen season.
Aberrant adrenal sensitivity to multiple ligands in unilateral incidentaloma with subclinical autonomous cortisol hypersecretion: a prospective clinical study
Authors: Reznik Y. , Lefebvre H. , Rohmer V. , Charbonnel B. , Tabarin A. , Rodien P. , Lecomte P. , Bardet S. , Coffin C. , Mahoudeau J.
Published: September 2004

background  Incidentally discovered adrenal tumours are frequently associated with subclinical autonomous cortisol hypersecretion of unknown origin. Aberrant hormone receptors have been observed in case reports of overt Cushing's syndrome. The question arises as to whether such receptors may be present in the functioning adrenal incidentaloma, which is common and might be a subclinical stage of Cushing's syndrome.

patients and methods  Twenty‐one consecutive patients with a unilateral incidentaloma, the biochemical features of subclinical cortisol hypersecretion and/or the scintigraphic features of an autonomously functioning adrenal adenoma were investigated for plasma cortisol responses to various stimuli: upright posture, meal, combined hypothalamic‐hormones, the vasopressin analogue terlipressin, glucagon, angiotensin II, the serotonin 5‐HT4 agonist cisapride, and ACTH. Six normal controls were similarly investigated. All subjects were studied during 8 mg per day dexamethasone in order to avoid any ACTH‐dependent variation of plasma cortisol.

results  The most constant responses in adrenal incidentalomas were observed after stimulation by terlipressin (18/20 patients, 28–415% cortisol increase) and cisapride (17/21 patients, 25–364% cortisol increase). Eighteen out of 21 patients responded to several stimuli (cortisol increase ≥ 25%), and all responded to at least one stimulus other than ACTH, while such responses were absent in the controls. Plasma ACTH remained suppressed in all subjects throughout the study.

conclusions  Aberrant membrane receptors detected by in vivo stimulation tests appear to be common in autonomously functioning unilateral adrenocortical adenomas. These receptors may be involved in the modulation of cortisol secretion in adrenal incidentaloma, with potential therapeutic consequences for the control of subclinical cortisol hypersecretion.
Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury
Authors: Aimaretti Gianluca , Ambrosio Maria Rosaria , Di Somma Carolina , Fusco Alessandra , Cannavò Salvatore , Gasperi Maurizio , Scaroni Carla , De Marinis Laura , Benvenga Salvatore , Uberti Ettore Carlo degli , Lombardi Gaetano , Mantero Franco , Martino Enio , Giordano Giulio , Ghigo Ezio
Published: September 2004

objective  Acquired hypopituitarism in adults is obviously suspected in patients with primary hypothalamic–pituitary diseases, particularly after neurosurgery and/or radiotherapy. That brain injuries (BI) can cause hypopituitarism is commonly stated and has been recently emphasized but the management of BI patients does not routinely include neuroendocrine evaluations.

aim  To clarify the occurrence of hypopituitarism in patients after traumatic brain injury (TBI) or subarachnoid haemorrhage (SAH) 3 months after the BI.

subjects and methods  The occurrence of hypopituitarism in conscious patients after traumatic brain injury [TBI, n = 100, 31 women, 69 men; age 37·1 ± 1·8 years; body mass index (BMI) 23·7 ± 0·4 kg/m2; Glasgow Coma Scale (GCS) 3–15] or subarachnoid haemorrhage [SAH, n = 40, 14 men, 26 wpmen, 51·0 ± 2·0 years; 25·0 ± 0·6 kg/m2; Fisher's scale 1–4] was studied in a multicentre study 3 months after the BI. All patients underwent wide basal hormonal evaluation; the GH/IGF‐I axis was evaluated by GHRH + arginine test and IGF‐I measurement.

results  In TBI patients, some degree of hypopituitarism was shown in 35%. Total, multiple and isolated deficits were present in 4, 6 and 25%, respectively. Diabetes insipidus was present in 4%. Secondary adrenal, thyroid and gonadal deficit was present in 8, 5 and 17%, respectively. Severe GH deficiency (GHD) was the most frequent pituitary defect (25%). In SAH patients, some degree of hypopituitarism was shown in 37·5%. Despite no total hypopituitarism, multiple and isolated deficits were present in 10 and 27·5%, respectively. Diabetes insipidus was present in 7·5%. Secondary adrenal, thyroid and gonadal deficit was present in 2·5, 7·5 and 12·5%, respectively. Severe GHD was the most frequent defect (25%).

conclusions  TBI and SAH are conditions associated with high risk of acquired hypopituitarism. The pituitary defect is often multiple and severe GHD is the most frequent defect. Thus neuroendocrine evaluations are always mandatory in patients after brain injuries.
Both intrauterine growth restriction and postnatal growth influence childhood serum concentrations of adiponectin
Authors: López‐Bermejo Abel , Casano‐Sancho Paula , Fernández‐Real José Manuel , Kihara Shinji , Funahashi Tohru , Rodríguez‐Hierro Francisco , Ricart Wifredo , Ibañez Lourdes
Published: September 2004

objective  Insulin resistance has been linked to intrauterine growth restriction; adiponectin is a strong determinant of insulin sensitivity. We aimed at studying the contributions of birthweight and insulin sensitivity to circulating adiponectin in children born small for gestational age (SGA).

design  Cross‐sectional, hospital‐based study dealing with insulin sensitivity in SGA children.

patients  Thirty‐two prepubertal children born SGA (age 5·4 ± 2·9 years) and 37 prepubertal children born appropriate for gestational age (AGA, age 5·9 ± 3·0 years).

measurements  Serum levels of fasting glucose, serum lipids, insulin (immunometric assay) and adiponectin concentrations (ELISA) were assessed, and insulin resistance (IR) and insulin secretion (β‐cell) were calculated by the homeostasis model of assessment (HOMA).

results  SGA children had similar HOMA‐IR, HOMA‐β‐cell and adiponectin concentrations than AGA children. However, in a separate analysis of subjects older than 3 years of age, SGA children showed higher HOMA‐IR after adjusting for sex, age and body mass index (BMI) standard deviation score (SDS). Circulating adiponectin was higher in SGA children [adjusted means: 14·5 mg/l (95% CI 12·9–16·1) and 18·7 mg/l (95% CI 17·0–20·3) for AGA and SGA children, respectively; P < 0·0001]. Further analysis revealed that the group of overweight SGA (arbitrarily defined as being in the higher quartile for the BMI SDS distribution in the sample) had decreased serum concentrations of adiponectin, compared to lean SGA children [adjusted means: 12·9 mg/l (95% CI 9·3–16·5) vs. 19·0 (95% CI 16·8–21·3), respectively; P = 0·001]. In a multiple regression model, HOMA‐IR and SGA status explained 35% and 15% of adiponectin variance, respectively.

conclusions  Prenatal growth restriction is associated with insulin resistance but relatively increased adiponectin concentrations, provided overweight does not ensue. The contributions of circulating adiponectin to the increased risks for developing insulin resistance and type‐2 diabetes in formerly SGA subjects merit further studies.
Metabolism of chylomicrons in patients with congenital lipoatrophic diabetes: a study with emulsion models of chylomicrons
Authors: Wajchenberg Bernardo L. , Amâncio Rosângela F. , Santomauro Ana T. , Maranhão Raul C.
Published: September 2004

background  Lipoatrophic diabetes is characterized by the near absence of adipose tissue and the presence of insulin‐resistant diabetes. Fasting hypertriglyceridaemia and increased postprandial lipidaemia are also present, but the metabolism of chylomicrons, the triglyceride‐rich lipoproteins in the circulation that carry the dietary fats absorbed by the intestine, was not specifically investigated. Because both the activity of insulin‐dependent lipoprotein lipase that catalyses the chylomicron lipolysis and the storage of the lipolysis products are affected in the disease, it is important to evaluate how those changes may ultimately affect the chylomicron lipolysis and removal of chylomicron remnants from the circulation.

objective  The aim of the study was to evaluate the chylomicron intravascular metabolism in patients with lipoatrophic diabetes.

patients  Six patients with lipoatrophic diabetes (four females, two males) aged 22·2 ± 4·4 years, with body mass index (BMI) 21·6 ± 3·6 kg/m2, were compared with 12 healthy control subjects (seven females, five males) aged 24·3 ± 2·1 years with BMI 22·5 ± 2·7 kg/m2.

measurements  The plasma kinetics of intravenously injected chylomicron‐like emulsions labelled with 3H‐triglycerides (3H‐TG) and with 14C‐cholesteryl esters (14C‐CE) were determined, the former tracing the chylomicron lipolysis by lipoprotein lipase and the latter the removal of chylomicron remnants from the plasma.

results  Triglyceride values (8·3 ± 9·2 mmol/l) in the patients were higher (P < 0·005) and high density lipoprotein (HDL) cholesterol values (0·8 ± 0·2 mmol/l) lower (P < 0·0005) than in controls (0·7 ± 0·2 and 1·3 ± 0·4 mmol/l, respectively) whereas total cholesterol, apoprotein B (apo B) and apo A1 were similar. The fractional clearance rate (FCR, in min−1) of 3H‐TG was 0·014 ± 0·016 and the FCR of 14C‐CE was 0·008 ± 0·012 in the patients and 0·046 ± 0·024 and 0·024 ± 0·012 in the controls, respectively (P < 0·05). Thus FCRs of both emulsion labels were markedly reduced in the patients, indicating that lipolysis and remnant removal were diminished. Diminished remnant removal may be due to either deficient lipolysis or deficient removal mechanisms.

conclusion  The metabolism of chylomicrons tested by the emulsion method is impaired in lipoatrophic diabetes.
Insulin‐like growth factor‐1 deficiency determines increased intima–media thickness at common carotid arteries in adult patients with growth hormone deficiency
Authors: Colao Annamaria , Di Somma Carolina , Filippella Mariagiovanna , Rota Francesca , Pivonello Rosario , Orio Francesco , Vitale Giovanni , Lombardi Gaetano
Published: September 2004

objective  To investigate the role of IGF‐1 on intima–media thickness (IMT) at common carotid arteries by Doppler ultrasonography.

subjects  Thirty‐nine patients (17 women, 22 men, aged 25–70 years) with severe GH deficiency (GHD), 19 with normal and 20 with low IGF‐1 levels, and 39 sex‐, age‐ and body mass index (BMI)‐matched healthy controls.

results  Patients with GHD showed abnormalities in lipid profile, and increased fibrinogen levels, mean IMT (0·88 ± 0·26 vs. 0·69 ± 0·14 mm, P < 0·001), and systolic and diastolic peak velocity (P < 0·001) compared to controls. Eight patients (18%) and one control (2·1%, P = 0·04) had well‐defined plaques. In controls, but not in patients with GHD, mean carotid IMT was correlated with age (r = 0·78, P < 0·001). In both controls (r = −0·82; P < 0·0001) and patients with GHD (r = −0·84, P < 0·0001), serum IGF‐1 levels were inversely correlated with mean IMT at common carotid arteries. At the stepwise multiple regression, the variables most significantly related to IMT in GH‐deficient patients were total cholesterol levels (t = 5·2, P < 0·001), followed by disease duration (t = 2·4, P = 0·02), while in controls the variables most significantly related to IMT were IGF‐1 levels (t = −9·9, P < 0·001), followed by low density lipoprotein (LDL)‐cholesterol levels (t = −2·3, P = 0·02). Compared to patients with normal IGF‐1 levels, those with low IGF‐1 levels had lower high density lipoprotein (HDL)‐cholesterol levels (1·0 ± 0·2 vs. 1·3 ± 0·2 mmol/l, P = 0·0002), and higher glucose (54·3 ± 6·1 vs. 48·9 ± 5·9 mmol/l, P = 0·008), insulin (25·2 ± 6·8 vs. 18·8 ± 6·0 mUl/l, P = 0·004), total cholesterol (7·1 ± 1·1 vs. 4·9 ± 0·6 mmol/l, P < 0·0001), total/HDL‐cholesterol ratio (7·2 ± 1·8 vs. 3·9 ± 0·7, P < 0·0001), fibrinogen levels (319·8 ± 56·9 vs. 241·8 ± 53·0 mg/dl, P < 0·0001) and mean IMT at common carotid arteries (1·05 ± 0·25 vs. 0·69 ± 0·07 mm, P < 0·0001). Atherosclerotic plaques were found only in GH‐deficient patients with low IGF‐1 levels.

conclusions  GH‐deficient patients have alterations in lipid profile with an increase in the total/HDL‐cholesterol ratio, which is an index of increased cardiovascular risk, but only patients with IGF‐1 deficiency have increased IMT.
Weight‐related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency
Authors: Mah Peak M. , Jenkins Richard C. , Rostami‐Hodjegan Amin , Newell‐Price John , Doane Anita , Ibbotson Victoria , Tucker Geoffrey T. , Ross Richard J.
Published: September 2004

objective  The objective of this study was to examine the variables determining hydrocortisone (HC) disposition in patients with adrenal insufficiency and to develop practical protocols for individualized prescribing and monitoring of HC treatment.

design and patients  Serum cortisol profiles were measured in 20 cortisol‐insufficient patients (09·00 h cortisol < 50 nmol/l) given oral HC as either a fixed or ‘body surface area‐adjusted’ dose in the fasted or fed state. Endogenous cortisol levels were measured in healthy subjects. Pharmacokinetic analysis was performed using P‐Pharm software, and computer simulations were used to assess the likely population distribution of the data.

results  Body weight was the most important predictor of HC clearance. A fixed 10‐mg HC dose overexposed patients to cortisol by 6·3%, whereas weight‐adjusted dosing decreased interpatient variability in maximum cortisol concentration from 31 to 7%, decreased area under the curve (AUC) from 50 to 22% (P < 0·05), and reduced overexposure to < 5%. Food taken before HC delayed its absorption. Serum cortisol measured 4 h after HC predicted cortisol AUC (r2 = 0·78; P < 0·001).

conclusions  We recommend weight‐adjusted HC dosing, thrice daily before food, monitored with a single serum cortisol measurement using a nomogram. This regimen was prospectively examined in 40 cortisol‐insufficient patients, 85% of whom opted to remain on the new thrice‐daily treatment regimen.
Type V phosphodiesterase inhibitor treatments for erectile dysfunction increase testosterone levels
Authors: Carosa Eleonora , Martini Paolo , Brandetti Fulvia , Di Stasi Savino M. , Lombardo Francesco , Lenzi Andrea , Jannini Emmanuele A.
Published: September 2004

objective  Lack of sexual activity due to erectile dysfunction (ED) decreases testosterone (T) levels through a central effect on the hypothalamic–pituitary axis. In this paper we studied the effect of different type V phosphodiesterase (PDE5) inhibitor treatments for ED on the reversibility of this endocrine pattern.

design  Open‐label, retrospective study.

patients  Seventy‐four consecutive patients were treated on demand with sildenafil (Sild) (50 mg) and tadalafil (Tad) 20 mg.

measurements  The success in sexual intercourse was recorded and total (tT) and free testosterone (fT) levels were studied before and after 3 months of treatment.

results  Basal level of tT and fT were at the bottom of the normal range and LH levels were at the top of the high normal range. After treatments, this endocrine pattern was reversed in both groups. However, the T increase in Sild‐treated patients was significantly lower than in those treated with Tad (4·7 ± 2·7 vs. 5·1 ± 0·9, P < 0·001). fT levels followed a directly proportional pattern, while the inverse was found when LH production was studied. The intercourse rate reflected this effect: in fact, the Sild group showed a 4·9 ± 2·9/month full sexual intercourse rate while in the Tad group a significantly higher rate of sexual intercourse was found (6·9 ± 4·6/month, P = 0·04). However, drug consumption was comparable between the groups (Sild 4·9 ± 2·9 vs. Tad 4·4 ± 2·8 pills/month, P = 0·72).

conclusions  As it is unlikely that the two drugs have a different direct effect on the pituitary–testis axis, this effect is probably due to the higher frequency of full sexual intercourse in the Tad‐treated group, because of the drug's longer half‐life.
Neurosteroids: The StAR Protein in the Brain
Authors: Sierra A.
Published: September 2004

The nervous system is a well‐known target for steroid hormones, as these hormones regulate brain functions that include neuronal survival and differentiation, myelination, neurogenesis, plasticity and repair after injury. Furthermore, the brain is also a steroidogenic tissue because it possesses the enzymes required to metabolize the common precursor, cholesterol, into steroids, named ‘neurosteroids’. The rate‐limiting step in the synthesis of steroid hormones is the access of cholesterol, accumulated in the outer mitochondrial membrane, to the first steroidogenic enzyme, P450scc (cholesterol side‐chain cleavage enzyme), located in the inner mitochondrial membrane. In the ovary and the adrenal gland, which comprise classic steroidogenic tissues, this process requires the steroidogenic acute regulatory protein (StAR) to facilitate the shuttle of cholesterol through the intermembrane space. The mechanism used by the brain to regulate the first stage of steroidogenesis remains unknown. Recently, several groups have investigated the potential presence of StAR in the nervous tissue and have concluded that StAR is widely expressed throughout the brain, although restricted to specific cell populations. New results concerning localization, regulation and possible functions of StAR in the brain are discussed.
Activation of Arylalkylamine N‐Acetyltransferase by Phorbol Esters in Bovine Pinealocytes Suggests a Novel Regulatory Pathway in Melatonin Synthesis
Authors: Schomerus C. , Laedtke E. , Korf H.‐W.
Published: September 2004

In all mammalian species investigated, noradrenaline activates a β‐adrenoceptor/cAMP/protein kinase A‐dependent mechanism to switch on arylalkylamine N‐acetyltransferase and melatonin biosynthesis in the pineal gland. Other compounds which are known to influence the melatonin‐generating system are phorbol esters. The effect of phorbol esters on regulation of melatonin synthesis has been mainly investigated in rat pinealocytes. In these cells, phorbol esters do not increase cAMP levels and arylalkylamine N‐acetyltransferase on their own; however, phorbol esters potentiate the effects on cAMP and AANAT activity induced upon β‐adrenoceptor stimulation. In the present study, we investigated the effect of phorbol esters on the regulation of melatonin synthesis in bovine pinealocytes. We show that, in these cells, the phorbol esters 4β‐phorbol 12‐myristate 13‐acetate (PMA) or phorbol 12,13‐dibutyrate have a direct stimulatory effect and induced 4–10‐fold increases in AANAT protein levels, AANAT activity and melatonin production. The extent of these effects was similar to those induced by noradrenaline. Notably, responses to PMA were not accompanied by increases in cAMP levels. Northern blot analysis showed that Aanat mRNA levels did not change upon PMA treatment indicating that phorbol esters control AANAT at a post‐transcriptional level. The effects on AANAT and melatonin production were reduced by use of protein kinase C inhibitors, but not by blockade of the cyclic AMP/protein kinase A pathway. Our results point towards a novel mechanism in the regulation of melatonin production that is cAMP‐independent and involves protein kinase C. The study is of particular interest because regulation of melatonin biosynthesis in bovines may resemble that in primates more closely than that in rodents.