bluuebunny/crossref_metadata_2025 huggingface dataset:
IGFBP‐3 is a poor parameter for assessment of clinical activity in acromegaly
Authors: de Herder W. W. , van der Lely A. J. , Janssen J. A. M. J. L. , Uitterlinden P. , Hofland L. J. , Lamberts S. W. J.
Published: March 2008

OBJECTIVE Elevated serum IGF‐I and IGF binding protein‐3 (IGFBP‐3) levels have been found in patients with active acromegaly. We have studied the relative diagnostic merits of measurements of IGFBP‐3 compared with IGF‐I as a parameter of disease activity in these patients.

DESIGNIPATIENTS Thirty untreated patients with acromegaly were compared with 30 healthy adults.

MEASUREMENTS Twenty‐four‐hour sampling for serum GH in patients with acromegaly, serum IGF‐I and IGFBP‐3.

RESULTS Mean IGF‐l levels were 220 nmol/l (range 6.5–38.4) in the healthy adults and 118.7 nmol/l (range 67.7–206.0) in patients with acromegaly. Mean IGFBP‐3 levels were 3.5 mg/l (range 2.1–4.8) in controls and 5.4 mg/l (range 4.2–6.6) in patients with acromegaly. Mean IGF‐I/IGFBP‐3 ratios were 6.5 nmol/mg (range 1.9–14.5) in the healthy adults and 220 nmol/mg (range 14.3–32.7) in patients with acromegaly. There was a considerable overlap for IGFBP‐3 levels but not for IGF‐I levels, between normals and acromegalics. The IGF‐I/IGFBP‐3 ratio also showed overlap between normals and acromegalics. There was a significant correlation between the mean 24‐hour GH and IGFBP‐3 levels (P= 0.036) and between the IGF‐I and IGFBP‐3 levels (P < 0.002) in acromegaly. In patients with acromegaly, the IGFBP‐3 levels showed a decrement, but the IGF‐I/IGFBP‐3 ratio did not change significantly with age. CONCLUSIONS IGFBP‐3 has no additional discriminatory value over IGF‐I measurements for the assessment of clinical activity in acromegaly. in acromegaly, IGFBP‐3 decreases with increasing age. in acromegaly, IGFBP‐3 levels significantly correlate with mean 24‐hour GH levels and IGF‐I levels.
Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement
Authors: Wasserstrum Nathan , Ananla Carol A.
Published: March 2008

Maternal hypothyroidism may be associated with a variety of pregnancy complications.

OBJECTIVE We have evaluated the perinatal consequences of maternal hypothyroidism in early and late gestation.

DESIGN Retrospective study of pregnant women, with quasi‐experimental design comparing different subjects.

SUBJECTS Forty‐three pregnancies In 42 women with hypothyroidism ‐ either biochemically hypothyroid or with a history of hypothyroidism on adequate replacement ‐ and no other preexisting medical conditions.

MEASUREMENT Free thyroxine index (FTI), TSH, and haematocrit at Initial antepartum presentation and near term gestation. Pregnancy outcome variables Including: rate of Caesarean section performed for fetal distress in labour, neonatal weight percentile, and gestational age at birth.

RESULTS Of 42 hypothyroid pregnancies, six were complicated by fetal distress In labour leading to Caesarean section. Five of these six were severely hypothyroid (defined as FTI ≤ 0.6 (normal range 1.1–4.4)) on initial antepartum presentation. In contrast, of the 36 pregnancies without fetal distress, only four initially presented severely hypothyroid (P<0.001). Conversely, 56% (5/9) of pregnancies which Initially presented severely hypothyroid were subsequently complicated by Caesarean section for fetal distress in labour. This compared to 3% (1/33) among those who presented either mildly hypothyroid or euthyroid on replacement (P<0.0001). Fetal distress correlated with low FTI (P<0.001) and high TSH at Initial presentation. However, It was independent of FTI near term. A relation between fetal distress and TSH near term did not reach statistical significance. Fetal distress also correlated with low maternal haematocrit on admission to labour and delivery (P<0.05), but was Independent of haematocrit and gestational age at Initial presentation, neonatal weight percentile, and gestational age at birth.

CONCLUSIONS Severe maternal hypothyroidism early in gestation Is strongly associated with fetal distress in labour. This suggests that (1) Inadequate maternal replacement leads to fetal distress and (2) maternal thyroid status in early gestation may exert Irreversible effects on the fetus, the placenta, and/or on subsequent maternal adaptations to pregnancy. Early adequate replacement therapy Is especially prudent in pregnant women presenting with severe hypothyroidism.
Assessment of GH status in acromegaly using serum growth hormone, serum insulin‐like growth factor‐I and urinary growth hormone excretion
Authors: Bates A. S. , Evans A. J. , Jones P. , Clayton R. N.
Published: March 2008

OBJECTIVE It Is still not clear what Is the most suitable method for monitoring progress of acromegaly. The aim of this study was to assess the relative merits of serum GH, serum IGF‐I and urinary GH (uGH) excretion in the follow‐up of acromegalic subjects.

SUBJECTS AND METHODS Thirty‐six acromegalic patients each had a GH day series performed consisting of five serum GH measurements, together with an estimate of serum IGF‐I and uGH. The first sample taken for serum GH was fasting (basal) whilst the third (1430 h) was arbitrarily chosen as a random value. uGH was measured from two overnight collections and the mean value used for subsequent data analysis.

MEASUREMENTS Serum GH and IGF‐I were measured by radioimmunoassay whilst uGH was estimated by an Immunoradlometric assay using commercially available reagents.

RESULTS There is a highly significant linear correlation between serum GH and IGF‐I following log transformation of these two variables (r=0.85; P<0.0001). Analysis of the raw data shows that the relation is in fact curvilinear rendering IGF‐I less useful as a surrogate for Integrated GH secretion at high levels of serum GH. There is a strong linear correlation between both a singleton basal serum GH and uGH (r=0.78; P<0001) and the mean of five measurements (day series) and uGH (r=0.81; P<0.0001). Both uGH and IGF‐I are excellent predictors of those patients with persistent elevation of serum GH, identifying 95 and 96% respectively with serum GH>5mU/l. We have identified a number of patients, however, with persistent elevation of IGF‐I in the presence of serum GH<5mU/l and normal uGH. Until the significance of these findings with respect to long‐term outcome is known, serum GH should continue to be used In the follow‐up of these patients. An alternative, which reflects integrated overnight GH secretion, Is uGH which is convenient and easy to collect as an outpatient and correlates strongly with serum GH.

CONCLUSION Acromegalic patients can be conveniently followed on an outpatient basis using a combination of uGH and serum IGF‐I. Measurements of serum GH can be reserved for those with discrepant results.
Assessment of GH status in adults with GH deficiency using serum growth hormone, serum insulin‐like growth factor‐l and urinary growth hormone excretion
Authors: Bates A. S. , Evans A. J. , Jones P. , Clayton R. N.
Published: March 2008

OBJECTIVES The benefits of treating adults with G H deficiency are now well recognized although the criteria for deciding which patients to treat are still not clear. At present the ‘gold standard’ Is the Insulin stress test (IST) which Is unpleasant and potentially dangerous, particularly in patients with hypopituitarism. The aim of this study was to determine whether alternative methods of assessing GH status are reliable in predicting GH deficiency.

SUBJECTS AND METHODS Forty‐four patients with unequivocal G H deficiency (peak 1ST <2mU/l) and 17 with partial deficiency (peak 1ST 2‐10 mU/I) were studied. Each patient was assessed clinically with respect to the number of other pituitary axes affected and biochemically with an estimate of urinary G H excretion (uGH) and serum IGF‐I. These markers were then related to GH status as defined by Insulin stress testing.

MEASUREMENTS Insulin stress tests were performed using 0.1 units/kg I.v. and accepted with a blood glucose <2mmol/l. Serum GH and IGF‐I were measured by radioimmunoassay whilst uGH was estimated by an Immunoradlometric assay using commercially available reagents. uGH was estimated from the mean of two overnight urine collections which consisted of all urine passed from last voiding through to the first morning sample.

RESULTS The presence of unequivocal G H deficiency (peak 1ST <2mu/l) was predictable if 2 or more other pituitary axes were affected (90%). U G H declined significantly with the level of peak 1ST response (P < 0‐001) and almost so with the number of other deficient hypothalamic‐pituitary axes affected (P= 0‐057). Thus, u G H accurately reflected G H status and showed good separation from normal controls In patients less than 40 years (specificity 79%) and between 40 and 60 years (specificity 67%). Above this age the method is less specific (36%). Patients excreted significantly less G H than controls in all three age groups (P < 0.01). Subnormal levels of IGF‐I were strongly predictive of unequivocal G H deficiency (91 % with subnormal IGF‐I have a peak 1ST G H lt; 2 mU/l) although a normal value does not reliably exclude the diagnosis.

CONCLUSIONS A diagnosis of adult G H deficiency can be reliably made without the need for an insulin stress test by using a combination of low urinary G H excretion, subnormal I G F‐I levels and clinical assessment with regard to the number of other pituitary axes affected.
Complex glycerol kinase deficiency: an unusual cause of salt‐wasting in males
Authors: Balducci R. , Municchi G. , Toscano V. , Mangiantini A. , Sabatinl R. , Calola S. , Tedeschl B. , Orlandl L. , Boscherlni B.
Published: March 2008

We report the case of a male Infant who at 10 days of life presented with salt‐wasting. Congenital adrenal hyperplasia was excluded on the basis of normal 17α‐hydroxy‐progesterone plasma levels evaluated before the onset of steroid replacement therapy. The Incidental finding of hypertriglyceridaemia led us to suspect the condition of complex glycerol kinase deficiency which was confirmed by the direct measurement of serum glycerol (7.16 mmol/l, normal range 0.02–0.21). Serum creatine kinase was markedly elevated (5963 U/l, normal range 37–290). High resolution cytogenetic Investigation of peripheral blood showed a small Interstitial deletion within Xp21. The same deletion was found In the patient's mother although not In his maternal grandmother. We present this case in order to emphasize the necessity of evaluating plasma triglycerides in all neonatal males with salt‐wasting which can not be explained by congenital adrenal hyperplasia. Plasma triglycerides measurement carried out using a routine clinical method which measures glycerol released after llpolysis facilitates early recognition of this syndrome, and enables appropriate therapy and subsequent genetic counselling.
An audit of oestradiol levels and implant frequency in women undergoing subcutaneous implant therapy
Authors: Buckler H. M. , Kalsl P. K. , Cantrill J. A. , Anderson D. C.
Published: March 2008

OBJECTIVES The aim of the study was to review our long‐term use of subcutaneous oestradiol (E2) Implant therapy for the treatment of climacteric symptoms In post‐menopausal women. On the grounds that the aim Is to restore premenopausal serum E2 levels, our declared clinical policy Is not to repeat Implants even in the presence of symptoms If serum E2 levels are >400pmol/l. Therapy was with 50 mg E2 implants inserted subcutaneously In the lower abdominal wall.

DESIGN All women who had attended the gynaecological/endocrinological clinic who had received subcutaneous E2 implants for the relief of climacteric symptoms between December 1981 and 1992 were Included.

RESULTS Between December 1981 and December 1992, 275 women received a total of 759.50 mg E2 Implants. The median length of Implant therapy was 34.2 months (range 3.7–109.5 months), and the median number of implants per patient was 4 and ranged from 1 to 13. One hundred and twenty‐nine women had more than four implants and their mean recorded serum E2 level was 425±187 (mean ±SD) pmol/l; the mean level over the first 24 months of therapy was 408±157pmol/l. This was not different from the mean value of the remaining period of therapy (439±168pmol/l). Following the second Implant there was no significant progressive rise in serum E2 with time and implant number and the mean E2 level per patient was no higher in those patients who received implants more frequently. The mean time between the first two implants was 9.7±0.4 months and between subsequent ones was 11.7±0.5 months. After the first two Implants there was no progressive change in this interval with time.

CONCLUSION This study shows that effective, safe and sympathetic management of women with oestrogen deficient symptoms may be achieved by use of two criteria to determine re‐treatment; the return of symptoms, and a serum E2 level no higher than 400pmol/l. Once therapy is established, E2 Implants may need to be prescribed only on an annual basis. There appears to be no justification for giving E2 Implants more frequently as this policy achieves satisfactory (physiological) premenopausal E2 levels and good symptomatic relief without any evidence for accumulation of E2 or ‘tachyphylaxis’.
Changes in bone mass and metabolism after surgery for primary hyperparathyroidism
Authors: Garton Mark , Martin James , Stewart Alison , Krukowskl Zygmunt , Matheson Norman , Roblns Simon , Loverldge Nigel , Reld David
Published: March 2008

BACKGROUND AND OBJECTIVE Bone mass Is often reduced In patients with primary hyperparathyroidism (pHPT) and Is usually partially reversible after parathyroidectomy. However, site specific and overall skeletal benefits of surgery in mild asymptomatic pHPT remain uncertain.

DESIGN Cross‐sectional and longitudinal studies.

PATIENTS Fourteen patients (12 women and 2 men) with pHPT.

MEASUREMENTS Baseline bone mass was assessed at the lumbar spine, left hip and whole body using dual‐energy X‐ray absorptiometry, and at the left os calcls using broad‐band ultrasound attenuation. Changes in bone mass, serum Intact PTH and osteocalcin, and urinary pyrldlnium cross‐link excretion were recorded In 10 patients followed for 6 months after surgery.

RESULTS (1) Cross‐sectional study: Baseline measurements at the lumbar spine and hip were Inversely related to both the serum PTH concentration and the weight of the parathyroid gland removed at surgery. (2) Longitudinal study: Six months after adenectomy, bone mass had Increased significantly at the femoral neck, greater trochanter, whole body and os calcis, but not at the lumbar spine or Ward's area. Serum PTH, osteocalcin and pyrldlnium cross‐link excretion all fell significantly after surgery. The percentage Increment In whole body bone mineral content at 6 months was proportional to the baseline PTH.

CONCLUSION In primary hyperparathyroidism, preoperative reductions and post‐operative gains in bone mass are proportional to the Initial serum PTH concentration. Mild primary hyperparathyroidism probably does not cause appreciable bone loss at clinically relevant fracture sites such as the spine and hip, and In such cases the overall skeletal benefits of surgery are likely to be negligible.
Mammosomatotroph adenoma causing gigantism in an 8‐year old boy: a possible pathogenetic mechanism
Authors: Dubuis J‐M. , Deal C. L. , Drews R. T. , Goodyer C. G. , Lagacé G. , Asa S. L. , Van Vliet G. , Collu R.
Published: March 2008

The pathophysiology of mammosomatotroph adenomas remains unclear. We studied a mammosomatotroph adenoma removed from an 8‐year old boy with a 5‐year history of growth acceleration and acromegalic gigantism at presentation. Elevated basal GH (mean 28 μg/I) and PRL (mean 120 μg/I) plasma levels were observed, as well as paradoxical responses of GH to l‐dopa, TRH and oral glucose administration; PRL was reduced by l‐dopa and slightly Increased by TRH; GHRH stimulated release of both GH and PRL. Two operations were required to remove the very large tumour and the patient was treated with bromocriptine before the second. Hormonal secretion by tumour explants in culture was evaluated under basal conditions and after stimulation or inhibition. High levels of GH and PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caused a dose‐related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hormone release only at very high (μm) concentrations. Intracellular events were studied by determination of the guanosine triphosphate binding (G) protein levels and adenylate cyclase (AC) activity in the tumour tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very high levels of the AC‐stimulatory G protein α subunit Gsα and very low amounts of the AC‐Inhlbiting G protein α subunit G13α and of the phosphollpase C‐stlmulatlng G protein α subunit Gqα were found In the tumour. After bromocriptine, baseline AC activity was normalized and could no longer be stimulated; Gs.α and G13α levels were unchanged while those of Gqa were normalized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single‐strand conformational polymorphism analysis did not reveal any mutations In the hot spots of G protein a subunits (αsα12, αo2 and α11) genes or In the H‐ras and p53 genes. Gs,α and GH transcription factor‐1 (pit‐1) expression were evaluated by amplification of cDNA. While the mRNA expression of pit‐1 decreased after bromocriptine treatment, that of Gs,α increased. These data suggest the possibility of an oncogenic process involving overexpresslon of Gs,α, resulting In chronic activation of adenylate cyclase. Furthermore, our results suggest that the antisecretory and antiprollferatlve effects of bromocriptine may be mediated through a decrease In Pit‐1 secondary to the inhibition of adenylate cyclase activity.
Effectiveness of a long‐acting injectable form of bromocriptine in patients with prolactin and growth hormone secreting macroadenomas
Authors: Tsagarakis S. , Tsiganou E. , Tzavara I. , Nikolou H. , Thalassinos N.
Published: March 2008

OBJECTIVE With the development of new long‐acting depot preparations of bromocriptine (bromocriptine LAR), we investigated the effectiveness of intramuscular injections of long‐acting bromocriptine in patients with prolactin and GH secreting macroadenomas.

STUDY DESIGN AND PATIENTS Fourteen patients with PRL secreting (8 patients) and GH secreting (6 patients) macroadenomas were treated with monthly intramuscular Injections of a long‐acting and repeatable form of bromocriptine for 3–6 months. A 50‐mg monthly dose was administered In the majority of patients with PRL secreting macroadenomas. A 100‐mg monthly dose was administered In all patients with GH secreting macroadenomas.

MEASUREMENTS Plasma PRL and/or GH levels were measured 6 and 12 hours after the first injection and then on days 1, 2,14 and 28 after each Injection, up to a maximum period of 6 months. Patients were hospitalized for 48 hours after each Injection and were specifically questioned with respect to side‐effects. Pituitary imaging with MRI or CT scans was performed In all patients before commencing treatment and was subsequently repeated In 5/8 patients with macroprolactinomas and 5/6 patients with GH secreting macroadenomas after the completion of a 6‐month course of treatment.

RESULTS In ail patients with macroprolactinomas, serum PRL levels decreased significantly after their first 50‐mg injection with nadir levels obtained by 24–48‐hours post Injection (12815 ± 8704 vs 1480 ± 1859 mU/l; mean ± SD, P<0.01). At their latest follow‐up, on a 50‐mg monthly dose, 4 patients developed normoprolactinaemia (PRL levels <360mU/l) while two patients demonstrated a significant reduction In serum PRL levels (70 and 87% of pretreatment values). In two patients, although a substantial decrement of serum PRL levels was achieved 12‐24 hours post injection, serum PRL levels Increased to pretreatment values by day 14 post injection. Both patients received a higher (100mg) monthly dose which was partially effective In one patient. In two patients with GH secreting macroadenomas, a sustained decrease of elevated GH levels was observed; in two patients, while a substantial reduction of the elevated serum GH levels was achieved 12–24 hours after the first and subsequent injections, serum GH levels increased to pretreatment values by day 14 post injection; in two patients there was no effect on the elevated serum GH levels. Significant tumour shrinkage (24–50%) was observed In 5/5 patients with PRL secreting macroadenomas assessed at completion of a 6‐month course of treatment. Significant tumour shrinkage was also documented In 2/5 acromegalics tested (29 and 46% respectively).

CONCLUSION It is concluded that bromocriptine LAR Is an effective treatment in the majority of patients with macroprolactinomas; it is also partially effective in some patients with GH secreting macroadenomas.
A simplified gonadotrophin‐releasing hormone test for precocious puberty
Authors: Cavallo A. , Richards G. E. , Busey S. , Michaels S. E.
Published: March 2008

BACKGROUND AND OBJECTIVE The gonadotrophin‐releasing hormone (GnRH) test is Important for the evaluation of children with disorders of puberty. Traditionally, the test determines the peak LH and the peak FSH responses from 5 to 8 blood samples, which makes It cumbersome and costly. We suspected that the test could be simplified to require fewer hormonal measurements.

DESIGN A retrospective clinical study.

PATIENTS Subjects were 44 girls and 7 boys with signs of precocious puberty, of whom 39 were diagnosed as definite central precocious puberty. Fifty‐five diagnostic tests and 39 tests for suppression during GnRH‐analogue treatment were reviewed.

MEASUREMENTS LH and FSH were measured In serum samples obtained during a standard GnRH test. Parameters: LH and FSH responses and the LH: FSH ratio at 30, 45 and 60 minutes, and the respective peak levels. For each parameter, the sensitivities and specificities were estimated and the receiver operating characteristic curve was constructed.

RESULTS The receiver operating characteristic curves for the LH responses at 30,45 and 60 minutes and at peak were similar and showed high specificities and sensitivities for the diagnosis of central precocious puberty. A single LH cut‐off (15IU/I) had diagnostic sensitivity >90% and specificity >80% for LH concentrations at 30,45 or 60 minutes and peak, and sensitivity >90% to detect suppression. Calculations of the LH: FSH ratio did not Improve the diagnostic accuracy of the GnRH test achieved by LH alone.

CONCLUSIONS A single LH determination 30 minutes after GnRH administration is as useful as the peak LH; FSH measurements are unnecessary for the differential diagnosis of central precocious puberty. We propose that for the diagnosis of central precocious puberty and for treatment monitoring, the GnRH test to be simplified to LH measurement in a single blood sample at 30 minutes.
Thyroid cancer management
Authors: Hardy Kevin J. , Walker Brian R. , Lindsay Robert S. , Kennedy R. Lee , Seckl Jonathan R. , Padfield Paul L.
Published: March 2008

OBJECTIVE Thyroid cancer is the commonest endocrine malignancy, yet management remains controversial. Many endocrinologists advocate diagnosis by fine needle aspiration (FNA), treatment by thyroidectomy, ablative radioiodine (131I) and TSH suppression, together with follow‐up with 131I scans or thyroglobulin (Tg) measurements. 131I (therapy or diagnosis) Is given only when TSH Is >30 mIU/I. With this strategy in mind, the aim of the present study was to audit existing clinical practice In a large Edinburgh teaching hospital to establish whether a need existed for local guidelines for the management of thyroid cancer.

DESIGN AND PATIENTS Retrospective case‐note audit of 46 patients, aged 55 (range 26–86) years, admitted between 1988 and 1993 with a diagnosis of thyroid cancer.

RESULTS Diagnosis: Our FNA false negative rate was high (13%), aspiration technique varied considerably, and cytological reporting was not standardized. Treatment: Three (11%) patients received 131I despite suboptimal TSH levels because of poorly developed mechanisms to prevent this, and 7 (25%) patients had Inadequate suppression of TSH as a result of poor interspecialty communication. Follow‐up: Three (11%) patients were scanned despite TSH levels <30mIU/I, and In 5 (18%) Tg checks were incomplete.

CONCLUSIONS This audit Identifies several shortcomings from what might be considered optimum management of thyroid cancer; practice was far from uniform even among the endocrinologists within a single hospital and Interdisciplinary communication was poor. A locally agreed and Implemented protocol should address most of these problems and Improve the care of thyroid cancer patients.
Clinical and genetic changes in a case of a Cushing's carcinoma
Authors: Bates A. S. , Buckley N. , Boggild M. D. , Bicknell E. J. , Perrett C. W. , Broome J. C. , Clayton R. N.
Published: March 2008

A 30‐year‐old presented In 1984 with a clinically nonfunctional tumour which subsequently developed Into a metastatic corticotrophlnoma from which he died despite surgery In 1984,1986 and 1991 and external radiotherapy In 1986. Molecular genetic analysis of tumour and metastatic tissue revealed loss of heterozygosity at loci on the autosomes 1p, 3p, 10q26,11q13 and 22q12. Tissue taken at surgery In 1986 also revealed positive cytoplasmic Immunostalning for p53 protein. No such staining was evident in tissue taken at first surgery in 1984. Further analysis of Invasive pituitary adenomas may reveal loci associated with such behaviour, enabling better prediction of subsequent clinical outcome than is possible using standard histological techniques, and delivery of early, aggressive treatment to those tumours which show molecular markers associated with a poor prognosis.
The Birmingham pituitary database: auditing the outcome of the treatment of acromegaly
Authors: Jenkins D. , O'Brien I. , Johnson A. , Shakespear R. , Sheppard M. C. , Stewart P. M.
Published: March 2008

BACKGROUND Reduction of GH concentrations in acromegalic subjects may improve the increased mortality associated with the condition. Audit of the biochemical outcome of the management of acromegaly is, therefore, important.

OBJECTIVES (1) To audit the biochemical ‘cure’ rate of acromegalic patients treated by surgery and/or radiotherapy under the care of the South Birmingham Endocrine Clinic. (2) To assess the correlation between random or basal GH with IGF‐I and nadir GH during an oral glucose tolerance test.

DESIGN AND MEASUREMENTS Ascertainment Of acromegalic patients from a pituitary database. Mode of therapy, pretreatment GH, pretreatment tumour size, post‐treatment GH, post‐treatment IGF‐l and post‐treatment nadir GH were recorded. Biochemical cure was defined as a most recent random or basal GH < 5 mU/l. Cure rates were determined.

PATIENTS Eighty‐nine acromegalic patients were Identified as having received surgery and/or radiotherapy. In 35/89 (39%) the most recent GH was < 5 mU/l. The cure rate following surgery was 26/78 (33%). This was not significantly associated with tumour size, but was associated with pretreatment GH concentration (x2= 7.1, 2d.f., P < 0.05). Random/basal GH showed a log‐linear association with IGF‐I, r= 0.72, and a linear association with nadir GH, r = 0.93.

CONCLUSIONS Biochemical cure of acromegaly was more strongly associated with pretreatment GH than with tumour size. Random/basal GH measurements are useful and convenient for the audit of treatment outcome in acromegaly. Ways of improving the biochemical outcome of acromegaly should be sought.
A study of untreated Graves' patients with undetectable TSH binding inhibitor immunoglobulins and the effect of anti‐thyroid drugs
Authors: Kawai K. , Tamai H. , Matsubayashi S. , Mukuta T. , Morita T. , Kubo C. , Kuma K.
Published: March 2008

OBJECTIVE We previously reported the clinical characteristics of Graves' disease with undetectable TSH binding inhibitor immunoglobulins (TBII) at first visit, but a study of the prognosis of untreated TBII negative patients with anti‐thyroid drug medication has never been undertaken. The aim of this paper is to study the difference between negative and positive TBll Graves' disease in relation to the effect of anti‐thyroid drug treatment.

PATIENTS From January 1986 to April 1991,1545 patients with untreated Graves' disease were referred to Kuma Hospital, Kobe, Japan. Of these, 94 TRAb negative patients were identified. Another 83 TRAb positive patients were randomly selected from the other Graves' disease patients and served as a comparison group. Fifty‐six of the 94 patients in the TBII negative group and 52 of the 83 patients in the TBII positive group completed treatment with methimazole only.

MEASUREMENTS The trial was conducted as a retrospective study with a maximum treatment period of 36 months and a follow‐up period of a further 12 months. From the original pool of patients, we classified 56 TBII negative patients into two groups according to the clinical course taken; Group A in whom TBII remained undetectable throughout methimazole treatment (9 men and 34 women, age 37.2 ± 2.2 years), and Group B who became TBII positive (4 men and 9 women, 31.2 ± 44 years). Fifty‐two TBII positive patients served as the comparison Group C (8 men and 44 women, age 38.1 ± 2.0 years).

RESULTS Serum free T4 and free T3 levels in groups A and B were significantly lower before treatment than those of Group C (P < 0.001). The thyroid volumes of Group A and B patients were significantly smaller than those of Group C (P < 0.01). The level of TBII in Groups A and B was significantly lower than that in Group C (8.3 ± 0.7 and 8.8·1.1 vs 57.0 ± 28%, respectively, P < 0.001). The level of thyroid stimulating antibody (TSAb) in Groups A and B was significantly lower than that in Group C (478 ± 71.0 and 761 ± 140.3 vs 2143 ± 280%, respectively, P < 0.01), and there were no significant differences in TSAb activities between Groups A and B. The remission rates in Groups A, B and C were 77.4, 36.4 and 36.5%, respectively. These data Indicate that Group A has a good prognosis, but Group B has the same prognosis as Group C.

CONCLUSION We conclude that patients In whom TSH binding inhibitor Immunoglobulins remained negative have a much better prognosis than TSH binding inhibitor immunoglobulins positive patients or those who become TSH binding inhibitor immunoglobulins positive, having been initially negative.
Treatment of post‐menopausal osteoporosis with a combination of growth hormone and pamidronate: a placebo controlled trial
Authors: Erdtsieck R. J. , Pols H. A. P. , Valk N. K. , van Ouwerkerk B. M. , Lamberts S. W. J. , Mulder P. , Birkenhäger J. C.
Published: March 2008

OBJECTIVE It is known that growth hormone can Induce accelerated bone turnover in GH deficient people as well as healthy elderly people. In this study we examined the effect of recombinant human GH (rhGH) on bone mineral mass and bone turnover in the presence of the bone resorption inhibiting agent, pamidronate. Effects on body composition were also studied.

METHODS Twenty‐one post‐menopausal osteoporotic women were treated with the bisphosphonate pamidronate during 12 months. During the Initial 6 months rhGH (0.0675 IU/kg, 3 times/week) was administered In a placebo controlled fashion (10 vs 11 patients).

MEASUREMENTS Bone mineral Content (BMC) of the lumbar spine and femoral neck was measured with dual‐energy X‐ray absorptiometry and BMC of the distal and proximal forearm with single‐photon absorptiometry. Body composition was measured with bioelectrical Impedance and total body dual‐energy X‐ray absorptiometry. Serum IGF‐I and biochemical indices of bone turnover were also measured.

RESULTS The group treated with rhGH showed a two to three‐fold Increase In serum IGF‐I levels. No effects on bone mineral mass were observed in the group treated with rhGH, either after the Initial 6 months of treatment with rhGH or after the total period of 12 months. In women treated with pamidronate, however, a consistent increase of about 5% at the lumbar spine and somewhat less in the distal forearm was reached from 6 months onwards. In neither group was any change observed in BMC at the femoral neck or forearm.

Compared to baseline, the biochemical measurements of bone turnover showed a decrease of about 50% in the pamidronate treated group, but this effect was blunted in the group additionally treated with rhGH.

The body composition measurements showed clear effects of rhGH administration: a decrease in fat mass of about 5% and an increase In lean body mass of about 3%. However, these effects disappeared after the treatment with rhGH was stopped and both fat mass and lean body mass returned to Initial values.

CONCLUSIONS The present study suggests that treatment with rhGH blunted both the pamidronate induced accumulation of bone mineral mass and the reduction of biochemical markers of bone turnover. Furthermore, the positive effect of rhGH on body composition disappears completely after cessation of treatment with rhGH.
Androgens and insulin resistance in type 1 diabetic men
Authors: Ebeling Pertti , Stenman Ulf‐Håkan , Seppälä Markku , Koivisto Veikko A.
Published: March 2008

OBJECTIVE In healthy men, both high and low serum testosterone concentrations are associated with insulin resistance, whereas low concentration of sex hormone binding globulin (SHBG) is related to reduced insulin sensitivity. The aim of our study was to examine the association of sex hormones, SHBG, dehydroeplandrosterone (DHEAS) and insulin‐like growth factor binding protein‐1 (IGFBP‐1) on Insulin sensitivity in type 1 diabetic patients.

PATIENTS We examined 23 male patients with the mean age of 29 ± 1 years, body mass index 22.9 ± 0.4 kg/m2, Insulin dose 47 ± 3 units/day, glycosylated haemoglobin (HbA1c) 7.8 ± 0.3% and duration of diabetes 13 ± 1 years.

DESIGN Each patient was studied With a 4‐hour euglycaemic (5.5 ± 0.1 mmol/l), hyperinsulinaemic (612 ± 26 pmol/l) clamp with indirect calorimetry. Muscle biopsies (quadriceps femoris) for the determination of glycogen synthase were performed In 15 patients before and at the end of the clamp.

RESULTS insulin infusion reduced the concentrations of IGFBP‐1 by 90% (P < 0.001), DHEAS by 11% (P < 0.001), and SHBG by 4% (P < 0.01), whereas free or bound testosterone levels remained unchanged. The fall in IGFBP‐1 level was closely related to the basal concentration (r= 099, P < 0.001). Basal SHBG concentration Correlated directly with total (r= 0.51, P <0.05) and non‐oxidative glucose disposal (r= 0.41, P < 0.05), and with the decrease in lipld oxidation (r= 0.47, P <0.05) during Insulin Infusion. The fall in SHBG was inversely related to the mean (30–240 min) FFA concentration durlng hyperinsulinaemia (r=‐0.64, P < 0.001). The fractional activity of glycogen synthase at the end of insulin infusion correlated directly with fasting SHBG (r= 0.71, P <0.01) and DHEAS concentrations (r= 0.67, P <0.01).

CONCLUSIONS In male type 1 diabetic patients: (1) acute hyperinsulinaemia decreases IGFBP‐1, DHEAS and SHBG concentrations with the greatest decline in IGFBP‐1, (2) SHBG concentration is positively associated with factors Indicating good insulin sensitivity, (3) association between fuel homeostasis and SHBG, DHEAS and insulin antagonists suggests a network of these factors In the regulation of insulin action in type 1 diabetic patients.
Hexarelin induced growth hormone release is influenced by exogenous growth hormone
Authors: Massoud Ahmed F. , Hindmarsh Peter C. , Brook Charles G. D.
Published: March 2008

OBJECTIVE Growth hormone releasing peptides (GHRPs) are a group of synthetic compounds capable of releasing GH by an unknown mechanism. The aim of this study was to determine the effect of administering biosynthetic human growth hormone (rhGH) on the GH releasing activity of hexarelin, a new and potent GHRP, and to compare the results with those obtained with growth hormone releasing hormone (GHRH).

DESIGN Boluses of saline or rhGH were administered intravenously, followed 90 minutes later by a second intravenous bolus of saline, hexarelin or GHRH. Studies were performed following an overnight fast. Each subject underwent six studies performed in a random order and separated by at least 2 days.

SUBJECTS Six healthy adult males (23.8–34.3 years) were studied.

MEASUREMENTS Serum GH and IGF‐I levels were measured by radioimmunoassay.

RESULTS The peak serum GH response to hexarelln was greater than that to GHRH, irrespective of whether the first bolus was saline (P < 0.05) or rhGH (P < 0.02). Prior administration of rhGH led to a reduction in peak serum GH response to hexarelin or GHRH (P < 0.05); the percentage reduction in response to hexarelin was less than that to GHRH, but this difference was not statistically significant (P= 0.3). There was no change In serum IGF‐l concentration before or 90 minutes after the administration of rhGH.

CONCLUSIONS Hexarelin is a potent GH secretagogue subject to partial feedback Inhibition by rhGH. This raises issues about its mechanism of action and may have implications for its potential therapeutic use.
Intranasal administration of the GHRP hexarelin accelerates growth in short children
Authors: Laron Z. , Frenkel J. , Deghenghl R. , Anin S. , Klinger B. , Siibergeld A.
Published: March 2008

OBJECTIVE Hexarelin is a recently synthesized small growth hormone releasing peptide (GHRP) (His‐D‐methyl‐Trp‐Ala‐Trp‐D‐Phe‐Lys‐NH2). It Is actlve by intra‐venous, oral and intranasal administration In animals and man. The aim of this study was to find out whether longterm administration of this peptlde would promote growth In short chlldren.

DESIGN AND PATIENTS intranasal hexareiin was administered in a dose of 60 pglkg thrice dally to 8 prepubertal short children aged 4‐11‐6 years for perlods of up to months.

RESULTS Hexarelln treatment stimulated Insulin‐like growth factor‐i (IGF‐I) secretion ralsing the level from 10.4 ± 3.9 (SD) to 141 f 46 nmoill (P < 0.004). The rise IGF‐l led to a significant Increase In the mean (±SD) linear growth velocity from 53 ± 08 to 8 3 ± 1.7 cm/year (P < 0.0001). There was also a slgniflcant decrease skinfold thickness despite Increase in body weight and an Increase in head circumference. Additional flndlngs were a rlse in serum phosphate from 1–5 ± 01 to 1–8 ± 01 mmoi/l (P < 0004) and of aikallne phosphatase from 219 ± 74 to 261 ± 75 U/l (P < 005).

CONCLUSIONS The long‐term GHIIGF‐I stimulating, anabolic and growth promoting effects achieved by intranasai administration of this hexapeptide, seemingly without undeslrable slde‐effects, suggests clinical potential for this new class of drugs.
Natural selection on and predicted responses of ecophysiological traits of swamp milkweed (Asclepias incarnata)
Authors: Agrawal Anurag A. , Erwin Alexis C. , Cook Susan C.
Published: March 2008

Given the rapid and reversible impact of the environment on plant ecophysiological traits, it has been speculated that such traits may have low heritabilities, high phenotypic plasticity and experience selection which is highly variable.

We estimated heritabilities, phenotypic plasticity and natural selection on five ecophysiological traits (carbon : nitrogen (C : N) ratio, leaf water content, specific leaf area (SLA), trichome density and water use efficiency (WUE)) of swamp milkweed Asclepias incarnata. In a 2‐year field experiment, we studied 49 full‐sibling families in a common garden and assessed phenotypic and genotypic selection.

Consistent evidence indicated selection for increased leaf trichome density and reduced WUE. Less strong evidence suggested selection for reduced SLA and leaf water content, and there was no selection on C : N of leaves.

Although the ecophysiological traits showed many phenotypic and genetic correlations, we found little evidence that these correlations would constrain adaptive evolution.

To evaluate the phenotypic plasticity of the same traits, we conducted a separate growth chamber experiment and found evidence that leaf water content, SLA and C : N responded to environmental conditions (herbivory, water stress, nutrient addition).

Synthesis. We have demonstrated natural selection on ecophysiological traits and their probable response to selection with a genotypic selection analysis. We cautiously reject the notion that these traits lack heritable variation and that genetic correlations among them constrain their response to selection. Thus, plants such as A. incarnata appear capable of adaptive responses in their ecophysiological traits.
Induction of Experimental Arthritis in Balb/C Mice by Inclusion of a Foreign Protein in the Collagen Inoculum
Authors: Bäckström N. F. , Dahlgren U. I. H.
Published: March 2008

The susceptibility of mice to collagen‐induced arthritis (CIA) has, among other things, been linked to the major histocompatibility complex class II genes as well as other genes. This study was designed to examine the possibilities to establish CIA in low susceptible I‐Ad (Balb/C) mice. Balb/C mice were immunized twice with bovine type II collagen (BCII) in complete Freund’s adjuvant (CFA) containing the amount of Mycobacterium tuberculosis needed to induce CIA in low susceptible I‐Ab (C57BL/6) mice. Some mice received the conceivable arthritogenic inoculum mixed with ovalbumin (OVA). Clinical arthritis was monitored. Antibody activity and T‐cell reactivity to BCII were determined. Unexpectedly, only mice that were immunized with the BCII–OVA mixture developed arthritis. Combining BCII with another foreign protein, keyhole limpet hemocyanin, but not the self‐protein mouse serum albumin, also triggered arthritis. Prior to the appearance of arthritis the serum levels of IgG autoantibodies to BCII were higher in the coimmunized mice than in the mice that were immunized with BCII alone. Yet, splenocytes stimulated in vitro with BCII did not proliferate or produce interferon‐γ. Immunization of Balb/c mice with an emulsion‐containing CFA and BCII mixed with a foreign body, but not a self‐protein, elevates the level of circulating autoantibodies to CII and subsequently induces arthritis.
REPETITIVE SHARP WAVE ON THE ELECTROENCEPHALOGRAM—Report of 2 Cases With Both Cerebral Disease And Hepatic Dysfunction—
Authors: Miyazaki Motoji , Ebe Mitsuru , Aki Motoo
Published: March 2008

Two cases were reported in which the repetitive sharp waves consisted of main electroencephalographic feature. In contrast to the previous reports of this particular discharge which were noted in subacute progressive encephalitis, subacute vascular encephalopathy, cerebral lipidosis, hepatic coma and hyperammonemia, pathological diagnoses of our two cases were acute disseminated encephalomyelitis and cerebral metastases of pulmonary adenocarcinoma and in addition hepatic dysfunction in both cases. Owing to the diversity of the disaass showing similar REG feature, we are inclined to believe the non‐specificity of the pattern. Alteration of the pattern in concordance with the progress of the disease makes us favor a biochemical affair as an inducing mechanism rather than structural damage of specific areas concerned.
HISTOCHEMICAL STUDY ON HEPATOLENTICULAR DEGENERATION
Authors: Arioka Iwao , Tanimukai Hiroshi , Nishimura Tsuyoshi , Nishinuma Keiji , Ueda Masaharu
Published: March 2008

The brain and liver of five classical cases of hepatolenticular degeneration were histochemically examined for copper and iron. Within the brain, both copper and iron were detected in two cases. Coppsr was demonstrated in the liver of all cases and iron in two cases. The histochemical findings obtained were discussed.
CORTICAL AND RETICULAR EFFECTS UPON EVOKED ACTIVITY OF THALAMIC SOMATOSENSORY RELAY NUCLEUS
Authors: Iwama Kitsuya , Yamamoto Chosaburo
Published: March 2008

Using cats and dogs, effects of cortical and reticular formation stimulation were examined upon the thalamic evoked potential produced by single shock stimulation of the posterior funiculus. Cortical stimulation was done with a single shock applied to the sensorimotor cortex of one side ipsilateral to the thalamic somatosensory relay nucleus which is to be activated by posterior fimiculus stimulation. The reticular formation was stimulated at the mesencephalic level repetitively with shocks of varying frequencies for about 0.1 second.

1. Cortical stimulation, when made 100–200 msec prior to posterior funiculus stimulation, was followed by an augmentation of the delayed component of the thalamic evoked potential and a suppression of the initial one.

2. The thalamic evoked potential suffered suppression by repetitive stimulation of the reticular formation. Among the initial and delayed components of the thalamic evoked potential, the former was more resistant to the reticular suppression than the latter. The suppression was most marked immediately after the end of reticular stimulation.

3. A small dose of barbiturate, injected intravenously, abolished the suppressing effect of reticular origin with the cortical effect well preserved.

4. An extensive lesion of the reticular core at the intercollicular level facilitated the delayed component of the thalamic evoked potential. Even under this condition the cortical facilitatory action could be elicited.
AN ELECTRON MICROSCOPIC STUDY ON CEREBRAL SWELLING, ESPECIALLY ON THE CHANGES IN THE NERVE CELLS
Authors: Sekiya Toru
Published: March 2008

The nerve cells in the brain stem of animals suffering from cerebral swelling produced by liver injuries and in the cerebral cortex of a human with the increase of brain volume associated with a metastatic intracerebral hypernephroma were comparatively investigated in the electron‐microscopic preparations.

1. In experimental cerebral swelling, morphological changes were observed in the nerve cells. These changes were classified into “vacuolar changes” and “shrinking changes” on the basis of electron‐microscopic findings.

1) The “swelling changes” did not bring on any remarkable changes in the nucleus but were characterized by vacuolated mitochondria and lessened density of the cytoplasmic ground substances. The so‐called vacuolar appearance as described light‐microscopically might be based upon the decreased quantity of Palade's particles and very marked swelling of mitochondria in the cytoplasm.

2) Shrinked nucleus and dense appearance of the cytoplasmic ground substances were the characteristics of the “shrinking changes”; It seems that the so‐called cell shrinkage light‐microscopically is due to the shrinkage of nuclei and the dense package of Palade's particles in the cytoplasm.

2. Perineuronal satellite glial cells could be found even in ultra‐thin sectioned samples. Especially, in cerebral swelling more than two satellites were often observed. The electron micrographs showing the cytoplasmic fusion between a nerve cell and the glial cells might be considered to correspond to the so‐called pseudoneuronophagia because of the “shrinking changes” observed in the nerve cell, although the identity of such figures is uncertain in terms of classical neuro‐pathology.

3. Since the “vacuolar changes”, analogous to those observed in cases of experimentally produced cerebral swelling, including the characteristic of the vacuolation of mitochondria, were found in the nerve cells in the case of human brain with the metastatic hypernephioma, it is highly probable that this human brain falls under the category of cerebral swelling.

It was found, thus, that the changes in electron micrographs of nerve cells in cerebral swelling experimentally produced mainly by hepatic injuries were analogous to those of the nerve cells in the increase in volume of the human brain produced by the metastatic hypernephroma without any liver diseases. This finding may become an important key for the clarified phenomena in cerebral swelling caused by various factors.