Silica coated iron nanoparticles: synthesis, interface control, magnetic and hyperthermia properties.

This work provides a detailed study on the synthesis and characterization of silica coated iron nanoparticles (NPs) by coupling Transmission Electronic Microscopy (TEM), X-ray Photoelectron Spectroscopy (XPS) and magnetic measurements. Remarkably, iron NPs (of 9 nm of mean diameter) have been embedded in silica without any alteration of the magnetization of the iron cores, thanks to an original protocol of silica coating in non alcoholic medium. Tuning the synthesis parameters (concentration of reactants and choice of solvent), different sizes of Fe@SiO2 composites can be obtained with different thicknesses of silica. The magnetization of these objects is fully preserved after 24 h of water exposure thanks to a thick (14 nm) silica layer, opening thus new perspectives for biomedical applications. Hyperthermia measurements have been compared between Fe and Fe@SiO2 NPs, evidencing the self-organization of the free Fe NPs when a large amplitude magnetic field is applied. This phenomenon induces an increase of heating power which is precluded when the Fe cores are immobilised in silica. High-frequency hysteresis loop measurements allowed us to observe for the first time the increase of the ferrofluid susceptibility and remanence which are the signature of the formation of Fe NPs chains.

Difficult venepuncture--it was all in the head!

AIM: To emphasise the importance of careful observations and demonstrate that significant conditions may, on occasion, be detected during blood donation. BACKGROUND: Venepunctures, the bread and butter of blood donor services, can be difficult procedures. We describe an unusual presentation of a relatively rare disease detected during routine blood donations because of difficult venepunctures. METHODS: Case report. RESULTS: A growth hormone-secreting pituitary adenoma was diagnosed, and successfully treated, following the initial observation of hard-to-puncture skin during blood donations. CONCLUSIONS: Seemingly trivial abnormalities may prove clinically important. One presentation of acromegaly is hard-to-puncture skin.

Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink?

OBJECTIVE: To assess the performance of current clinical recommendations for the evaluation of an adrenal incidentaloma. DESIGN AND METHODS LITERATURE REVIEW: Electronic databases (Pubmed, Ovid and citation searches from key articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable to the clinical scenario of a patient referred to an endocrinologist for assessment of an incidentally detected adrenal mass. Surgical series, histopathological series and oncological series were reviewed and most were excluded. RESULTS: The prevalence of functional and malignant lesions presenting as adrenal incidentaloma was similar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs 4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-up was rare (<1% becoming functional and 0.2% becoming malignant). During follow-up, false-positive rates of the recommended investigations are typically 50 times greater than true positive rates. The average recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv of ionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to the chance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma. CONCLUSION: Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates. The dose of radiation involved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to the risk of the adrenal becoming malignant. This argues for a review of current guidelines.

Combined anti-microtubule therapy: a phase II study of weekly docetaxel plus estramustine in patients with metastatic breast cancer.

BACKGROUND: Docetaxel and estramustine exert anti-tumor effects by inhibiting microtubule function. In vitro data suggest synergism with this combination. This phase II study evaluated the response rate and toxicity of docetaxel and estramustine in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients were treated with docetaxel 35 mg/m(2) on day 2 and estramustine phosphate 280 mg p.o. tds days 1-3 weekly for 3 of 4 weeks, for a maximum of six treatment cycles. RESULTS: Thirty-nine patients were enrolled between August 1999 and March 2001; 36 were eligible. Of 31 evaluable patients, responses were observed in 15 patients (47%); two patients (6%) obtained a complete response. Median time to treatment failure was 6 months; median survival was 1 year. Thromboembolic toxicity occurred in 11% of patients: three experienced deep venous thromboses and one had a fatal pulmonary embolism. Myelosuppression was minimal with this regimen. CONCLUSIONS: Despite modest activity in metastatic breast cancer, the toxicity observed with the combination of estramustine and docetaxel precludes the routine use of this combination in the treatment of breast cancer. Further studies using this compound in metastatic breast cancer are not warranted.

HER-2/neu expression in germ cell tumours.

AIMS: To determine the rate of HER-2/neu positivity of germ cell tumours by immunohistochemistry (IHC) and by fluorescence in situ hybridisation (FISH). PATIENTS/METHODS: Ninety six archival, paraffin wax embedded pathology specimens were chosen from four groups of germ cell tumours. IHC for HER-2/neu was performed with the HercepTest kit; FISH analysis was performed with the INFORM assay and confirmed with a centromere 17 probe. RESULTS: Twenty two of 96 specimens overexpressed the HER-2/neu protein when measured by IHC. Only three specimens showed HER-2/neu gene amplification by FISH. There was no correlation between the results obtained by IHC and FISH. CONCLUSIONS: The lack of concordance between IHC and FISH makes it unlikely that overexpression of the HER-2/neu protein in germ cell tumours is of prognostic or therapeutic relevance. Because of the low rate of HER-2/neu gene amplification in germ cell tumours, a clinical trial of trastuzumab treatment in patients with germ cell tumours is not warranted.

Adjuvant chemotherapy for tumors of one centimeter or less: the law of diminishing returns.

The role of adjuvant chemotherapy in treatment of breast cancers of 1 cm or less is controversial. Careful consideration must be given to the overall risk of recurrence and death and to the absolute benefit of adjuvant chemotherapy, given that risk. Studies in this group of patients indicate that their overall survival rate is 90% to 99%. The absolute benefit of chemotherapy in this setting is most likely 1% or less. Adjuvant chemotherapy has significant toxicities, including cognitive dysfunction, early menopause, leukemia, and even death. Following a realistic and detailed discussion between patient and oncologist, some patients may choose chemotherapy. However, for the majority of patients with breast cancers of 1 cm or less, the minimal benefit of adjuvant chemotherapy does not justify the risk of the treatment.

Acromegaly in the developing world--a 20-year teaching hospital experience.

A retrospective analysis was conducted to examine the long-term outcome of surgery, by a single pituitary surgeon and radiotherapy for acromegaly at Groote Schuur Hospital, Cape Town, using modern criteria for the definition of cure. Seventy-two patients (F/M ratio 1.3:1), aged 16-74 years, were eligible for inclusion. The mean follow-up period was 8.3 years. Macroadenomas were present in 79%, microadenomas in 15% and tumour size was not documented in 6%. Pretreatment GH levels were, > or = 40 m U/l in 56 patients. Postoperatively, 21% of patients were cured, 40% controlled and 40% had hypopituitarism. After radiotherapy (mean follow-up 8.7 years) 43% were cured, 66% controlled and 78% had hypopituitarism. At follow-up 37% of patients traced had died. The most common cause of death was vascular disease. The poor surgical results may be attributed to late presentation in the developing world setting, as evidenced by tumour size and invasiveness, and the degree of GH elevation. Emphasis on early diagnosis of non-invasive tumours is necessary to improve the cure rate and reduce mortality,

The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism.

OBJECTIVE: The 1 microgram ACTH stimulation test has been advocated as a sensitive indicator of the integrity of the hypothalamic-pituitary-adrenal axis in patients with suspected hypopituitarism. The aim of our study was to define the normal response to 1 microgram ACTH stimulation in a control population and to study the sensitivity and specificity of the test in a group of patients with suspected pituitary disease. DESIGN: A prospective analysis of the performance of the 1 microgram ACTH stimulation test in a group of patients with pituitary disease. PATIENTS: The cortisol response to 1 microgram ACTH was evaluated in 21 normal subjects and 65 patients with pituitary disease. The patients with pituitary disease were divided into two groups according to the 11-deoxycortisol response to overnight metyrapone: normal (11-deoxycortisol > 200 nmol/l) and subnormal ACTH secretory status (11-deoxycortisol < 200 nmol/l). MEASUREMENTS: In both controls and patients, blood was sampled for cortisol at - 15, 0, + 20, + 30, + 40 and + 60 minutes after intravenous administration of 1 microgram synthetic ACTH (Synacthen(R)). The overnight metyrapone test was performed only in the subjects with pituitary disease. Metyrapone (30 mg/kg) was administered orally at 2300 h and blood was sampled at 0830 h the following morning for 11-deoxycortisol. RESULTS: The 65 patients with pituitary disease were categorized according to the 11-deoxycortisol response to metyrapone as follows: 53 normal (11-deoxycortisol > 200 nmol/l) and 12 subnormal (< 200 nmol/l). The 12 patients who failed the metyrapone test had a significantly impaired cortisol response to low dose ACTH stimulation at all time points when compared with both the control group and the pituitary patients with a normal response to metyrapone (P < 0.001). Comparing the pituitary patients who had a normal response to metyrapone and the control subjects, there was no significant difference in the cortisol response to ACTH (P > 0.05). The minimum cortisol response at 30 minutes in the 21 control subjects was 414 nmol/l and this was defined as the minimum normal cortisol response to 1 microg ACTH. Using this criterion, six of the 12 patients with a subnormal response to metyrapone had a normal cortisol response to low dose ACTH stimulation. Empirically increasing the cortisol cut-off to 600 nmol/l increased the sensitivity of the low dose ACTH test to 83%, although the specificity was reduced from 100% to only 58%. CONCLUSIONS: The normal cortisol response to low dose ACTH stimulation in 50% of the patients with ACTH deficiency proven on metyrapone testing suggests that the 1 microgram ACTH stimulation test, like the 250 microgram-test, lacks sensitivity for the diagnosis of ACTH deficiency.

Addison's disease in Africa--a teaching hospital experience.

OBJECTIVE: Addison's disease may present with diverse and non-specific clinical and biochemical features. Contentious issues include the appropriate criteria for the interpretation of the ACTH stimulation test and the necessary extent of investigation to identify a specific aetiology for the hypoadrenalism. The experience of Addison's disease at a South African teaching hospital was reviewed to (1) record the aetiology and spectrum of presentation, (2) examine the performance of the ACTH stimulation test and (3) determine the utility of adrenal CT scan and biopsy. METHODS: Retrospective study of patients admitted to a South African teaching hospital from 1980 to 1997 with a diagnosis of acute Addison's disease. PATIENTS AND MEASUREMENTS: Fifty patients presenting with acute Addison's disease were identified by a search of hospital records. Pretreatment biochemical and haematological parameters were recorded. The cortisol response at 20 and 60 min to an intravenous injection of 250 micrograms synacthen (Cortrosyn) was analysed. In a subgroup of affected subjects, the bone mineral density (BMD) in the lumbar spine and femoral neck was measured during long-term follow-up. RESULTS: Presenting features included hyperpigmentation (86%), weight loss (67%), abdominal pain (20%) and diarrhoea (16%). Thirty-nine patients (78%) were hyponatraemic, while 26 (53%) were hyperkalaemic. Nine patients (18%) were hypoglycaemic and 21% had hypercalcaemia. The mean basal cortisol was 148 nmol/l (range 10-487) and 16 patients (40%) had a normal basal cortisol. The mean cortisol 20 min after ACTH stimulation was 172 nmol/l (range 19-588). There was no significant increase in serum cortisol following ACTH stimulation (P > 0.05). Adrenal CT scans were performed in only 24 patients (48%) and were normal in 10, while abnormalities were detected in 14 patients (bilateral enlargement in 11, calcification in two and atrophic adrenals in one). Eight patients had a DEXA scan performed during follow-up--four were osteopaenic in the lumbar spine and five at the femoral neck. The probable aetiology of Addison's was idiopathic in 42%, related to active TB in 18%, old TB in 16%, autoimmune in 12% and malignancy with metastases in 6%--single cases were due to sarcoid, iron overload and adrenoleukodystrophy. Adrenal biopsy was performed in two patients and was diagnostic of malignancy in both cases. The mortality within the first month after hospitalization was 12%. CONCLUSIONS: In our experience, Addison's disease is frequently idiopathic, presents with protean manifestations and should be considered in patients with unexplained hyperpigmentation or gastrointestinal complaints, particularly when associated with hyponatraemia and hyperkalaemia. A normal basal cortisol does not exclude the diagnosis which requires ACTH stimulation testing.

The outcome of hypophysectomy for prolactinomas in the era of dopamine agonist therapy.

OBJECTIVE: Dopamine agonists are the primary therapeutic modality for the majority of patients with prolactinomas, with pituitary surgery reserved for those patients intolerant of or resistant to these agents. Most published surgical series, however, contain patients treated by surgery as the primary therapeutic modality. Previous exposure to dopamine agonists or the selection of patients with prolactinomas resistant to conventional therapy may potentially compromise the surgical success rate. The purpose of this study was to evaluate the efficacy and safety of pituitary surgery for prolactinomas in a tertiary referral centre where the majority of patients were operated on after treatment with dopamine agonists. DESIGN: A retrospective review of the outcome of pituitary surgery for prolactinomas performed at a tertiary neurosurgical centre by a single neurosurgeon. PATIENTS: Twenty-three patients underwent excision of a macro and 11 excision of a micro-prolactinoma. MEASUREMENTS: Pituitary tumour diameter was determined by CT or MRI imaging. Pre and post-operative measurements were made of serum PRL concentration (off dopamine agonist therapy), free T4, free T3, LH and testosterone (males). Post-operative restoration of a menstrual cycle was taken to indicate resolution of hypogonadism in female patients. RESULTS: The majority (73.9%) of the patients with macro and all with micro-prolactinomas had received dopamine agonists preoperatively. Of the 23 patients with macroprolactinomas, in whom the median preoperative PRL concentration was 13255 mU/l, 17 (73.9%) had radiological evidence of suprasellar extension and 5 (21.7%) cavernous sinus invasion. Only 4 (17.4%) of the patients with macroprolactinomas had a normal serum PRL post-operatively, although there was an improvement in visual fields in 66% of those with preoperative defects. The median preoperative PRL concentration was 4309 mU/l in the patients with microprolactinomas, significantly lower than in the macroprolactinoma group (P = 0.02). Despite a significant fall in serum PRL postoperatively (median PRL 860 mU/l, P = 0.0001), only 45.5% of patients had a normal serum PRL concentration after surgery. CONCLUSIONS: The cure rate following pituitary surgery for prolactinomas in a tertiary referral centre was low when compared with previous series in which surgery was used as the primary therapeutic modality. We suggest this may result both from dopamine agonist pretreatment and the referral of prolactinomas resistant to conventional therapy. The outcome is probably a more realistic reflection of the results of pituitary surgery for prolactinomas as currently practised in the majority of neuroendocrine centres.

The evaluation and management of subclinical pituitary disease.

The advent of sophisticated and sensitive radiologic techniques has undoubtedly improved the evaluation of patients with established endocrine disease. An inevitable consequence of the increased sensitivity and widespread availability of modern imaging is, however, the discovery of apparently asymptomatic mass lesions in endocrine tissues. The clinician is then required to determine the appropriate degree of often uncomfortable and costly investigation in a patient with no overt disease. This article attempts to provide guidelines for the management of the 'pituitary incidentaloma', a pituitary mass lesion evident on a computed tomography or magnetic resonance imaging scan performed for a reason other than the evaluation of the pituitary gland.

Neuroendocrinology of the polycystic ovary syndrome.

The clinical and biochemical heterogeneity of the PCOS is mirrored by the range of neuroendocrine disturbances described in women with PCOS. An increased serum LH concentration is a common, although not ubiquitous, feature and occurs primarily as a result of an increase in the amplitude of pulsatile LH, and presumably GnRH, secretion. The frequency of pulsatile GnRH secretion may, however, be increased in certain patients and may conceivably increase LH bioactivity by altering glycosylation of the molecule. Vigorous debate continues as to whether the observed changes in gonadotrophins are a primary abnormality or occur secondary to alterations in peripheral steroid concentrations. The proponents of the frequency hypothesis point to the discordant changes in gonadotrophin secretion that may be induced by rapid frequency exogenous GnRH stimulation in patients with hypogonadotrophic hypogonadism. Those who believe that the inappropriate gonadotrophin secretion is a secondary phenomenon argue that manipulation of peripheral steroid levels, by either administration of oestrogen/progesterone, induced ovulation or ovarian diathermy, may correct the disturbance of gonadotrophin secretion, which is therefore presumably a consequence of changes in ovarian steroid feedback signals. The weight of evidence at present suggests that the inappropriate gonadotrophin secretion is usually a secondary abnormality, although there may be groups of patients with a primary increase in GnRH pulsatility. The search for a unifying neuroendocrine disturbance in PCOS has been frustrated by the inability to find consistent evidence of disordered central dopaminergic, opioidergic, noradrenergic or serotoninergic pathways. Those abnormalities which have been uncovered appear to be secondary to chronic anovulation rather than of primary pathological import, and emphasize the central importance of the ovary as culprit rather than victim in PCOS.

Osteopenia as a feature of the androgen insensitivity syndrome.

OBJECTIVE: The syndrome of androgen insensitivity, a paradigm of a hormone resistance syndrome, manifests as failure of masculinization despite normal or high concentrations of serum testosterone. The defect in these 46 XY patients resides in the androgen receptor gene, with consequent defective androgen action and abnormal sexual differentiation. We sought to evaluate whether the adverse sequelae of androgen resistance may extend to skeletal tissue by measuring bone mineral density in six patients with androgen insensitivity. DESIGN: A cross-sectional retrospective study. MEASUREMENTS: Bone mineral density was measured by means of a Dexa (Hologic QDR 1000 scanner). The diagnosis of androgen insensitivity was confirmed in each patient by karyotype and assay of sex hormones. RESULTS: The five adult patients with androgen insensitivity had been exposed to both defective androgen action and variable periods of oestrogen deficiency. The latter resulted from the low circulating oestrogen concentrations (for premenopausal females) before gonadectomy and inadequate oestrogen replacement after gonadectomy. All five adults with androgen insensitivity had osteopenia in both the lumbar spine (T-score -1.52 to -3.85) and femoral neck (T-score -1.34 to -4.91). CONCLUSIONS: Osteopenia in patients with androgen insensitivity may relate to defective androgen action, oestrogen deficiency or a combination of the two. These observations have implications for the management of patients with androgen insensitivity and may provide insight into the effects of androgens on the female as well as the male skeleton.

Transient diabetes insipidus in pregnancy--a consequence of enhanced placental clearance of arginine vasopressin.

We report a patient who presented with transient diabetes insipidus in pregnancy on a background of previous postoperative diabetes insipidus following surgical excision of a prolactinoma. The patient illustrates how the complex changes in water homeostasis occurring during normal pregnancy may unmask latent diabetes insipidus. The major factors operating appear to be a physiological reduction in the thresholds for thirst and arginine vasopressin secretion coupled with a substantial increase in placental clearance of arginine vasopressin. Reversal of these changes after delivery results in normalization of the disordered water homeostasis, with consequent resolution of the diabetes insipidus.

Effect of laparoscopic ovarian electrocautery on ovarian response and outcome of treatment with gonadotropins in clomiphene citrate-resistant patients with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of ovarian electrocautery on the ovarian response to gonadotropic stimulation and pregnancy rate (PR) in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome (PCOS) and high basal serum LH levels. DESIGN: Retrospective study. SETTING: Outpatient infertility clinic in a tertiary referral center. SUBJECTS: Twenty-two women with PCOS, high basal serum LH concentrations, and CC resistance who underwent laparoscopic ovarian electrocautery. Treatment with gonadotropin was scheduled after failure to ovulate spontaneously or conceive after electrocautery. Data from gonadotropin-stimulated cycles were compared with data from treatment cycles in the same patients before ovarian electrocautery. MAIN OUTCOME MEASURES: Number of ampules, duration of induction phase, daily effective dose, PR, and pregnancy outcome. RESULTS: Markedly reduced basal serum LH concentrations and normal menstrual cyclicity in 41% of patients were recorded after laparoscopic ovarian electrocautery. Comparison of gonadotropin-stimulated cycles before and after electrocautery revealed significantly higher rates of ovulation and pregnancy after electrocautery as well as significant reduction in the number of ampules, daily effective dose, and duration of the induction phase with hMG and in daily effective dose with FSH. CONCLUSIONS: Our results indicate an increased ovarian sensitivity to gonadotropins after laparoscopic ovarian electrocautery. A preference for laparoscopic ovarian electrocautery over medical treatment in all or selected groups of CC-resistant PCOS patients is suggested.

Pituitary function after selective adenomectomy for Cushing's disease.

This retrospective analysis was undertaken to determine whether selective adenomectomy for Cushing's disease can achieve acceptable cure rates while causing minimal pituitary dysfunction. Tumour size, histology and pituitary function were evaluated in 34 consecutive patients (26 F: 8 M, mean age 33.6 years) undergoing transphenoidal adenomectomy for Cushing's disease from 1975 to 1992. Follow-up averaged 5.8 years. Cure was defined as resolution of symptoms and signs and normalization of urinary cortisol excretion. Sixty-three per cent of patients achieved cure after selective adenomectomy, repeat adenomectomy cured an additional four patients. Twenty-eight per cent required bilateral adrenalectomy and/or pituitary irradiation. Postoperative pituitary function remained completely intact in 81%. Secondary hypogonadism occurred in 8%, hypothyroidism in 155 and permanent diabetes insipidus in 4%. There was recurrence in 26% after a mean of 4.6 years (range 1-7). It is concluded that selective adenomectomy can achieve acceptable cure rates with a low prevalence of postoperative hypopituitarism, although an increase of recurrence may be the result of conservative surgery.