Testing the estrogen hypothesis of schizophrenia: associations between cumulative estrogen exposure and cerebral structural measures.

BACKGROUND: Bone mineral density (BMD), as an indicator of cumulative estrogen exposure, may be reduced in female patients with psychotic disorder (van der Leeuw et al., 2013), possibly reflecting reduced cerebral exposure to estrogen and alterations in neuroprotective effects. To the degree that BMD is a marker of cumulative (endogenous) estrogen exposure, we hypothesized that BMD would be positively associated with cerebral gray and white matter indices. METHODS: Dual X-ray absorptiometry (DEXA) and magnetic resonance (MRI) scans were acquired in fourteen female patients diagnosed with a psychotic disorder. BMD was expressed in total BMD (g/cm(2)), Z- and T-scores. Cerebral cortical thickness (CT) (as indicator of gray matter status) and fractional anisotropy (FA) (as indicator of white matter integrity) were measured and served as the dependent variables in multilevel random regression models. BMD measures were the independent variables. RESULTS: Femoral BMD measures were positively associated with CT at trend significance (total BMD: B=0.266, 95% CI: -0.019-0.552, p=0.067; Z-score: B=0.034, 95% CI: 0.001-0.067, p=0.046; T-score: B=0.034, 95% CI: 0.000-0.068, p=0.052). There were no significant associations between femoral BMD measures and FA. CONCLUSIONS: The data suggest that in women with psychotic disorder, alterations in the neuroprotective effect of estrogen (as measured by BMD) impact cortical gray matter, but not white matter integrity. These findings merit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia.

Bone mineral density as a marker of cumulative endogenous estrogen exposure: relationship to background genetic risk of psychotic disorder.

BACKGROUND: Alterations in bone mineral density (BMD) in patients with psychotic disorder may reflect the effect of treatment (disease effect observed in patients but not their siblings) or, as an intermediate marker of cumulative endogenous estrogen exposure, alterations in the neuroprotective effect of estrogen in the brain (vulnerability effect observed in patients and siblings). METHODS: Dual X-ray absorptiometry (DEXA) scans were acquired in 62 patients with a psychotic disorder, 67 non-psychotic siblings of patients with a psychotic disorder, and 48 controls. BMD (g/cm(2)), Z-scores and T-scores were measured in the lumbar spine and proximal femur. Associations between group and BMD were investigated with multilevel random regression analyses. Group×sex interactions and effects of antipsychotic medication (AP) on BMD were examined. RESULTS: Group was not associated with BMD outcome measures, although patients had consistently lower BMD measures compared to both siblings and controls. There were no significant group×sex interactions, but stratified analyses showed that BMD measures in female patients were significantly lower in comparison to female controls and siblings (e.g. total femoral BMD, P vs. C: B=-0.100, p=0.010; P vs. S: B=-0.104, p=0.008). After excluding female patients who used prolactin-raising AP, the effect was attenuated (e.g. total femoral BMD, P vs. C: B=-0.073, p=0.072; P vs. S: B=-0.085, p=0.051). In men, there were no significant BMD differences between patients and controls. CONCLUSION: Familial risk of psychotic disorder was not associated with BMD. Instead, decreased BMD in the femur may reflect treatment effects or non-familial risk associated with low cumulative endogenous estrogen levels in women.

Proposal for the prevention of osteoporosis in paediatric patients with classical galactosaemia.

Decreased bone mass in early childhood is an increasingly recognized problem in classical galactosaemia as in many other chronic diseases. Peak bone mass is reached in late adolescence; thus, increasing peak bone mass in childhood can prevent osteoporosis. Regular bone mass measurements and preventive treatment should begin in childhood. In the absence of evidence-based guidelines for identification and treatment of decreased bone mass in children, we provide a proposal based on our experience and the available literature. Dual-energy x-ray absorptiometry (DXA) should be used for bone mass assessment. Because cooperation is required, measurements can usually be performed from the age of 4 years. Interpretation of bone mass measurements is crucial for the diagnosis of osteopenia or osteoporosis. In children and adolescents, total body bone mineral content (BMC) as well as lean tissue mass (LTM) should be measured. Comparison of BMC corrected for LTM of the patient with the BMC corrected for LTM of healthy controls allows correction for the confounding effect of bone size. DXA should be repeated every two years in case of normal BMC, as this is the time window in which abnormalities become measurable. If BMC is between 0 and -1 SD, lifestyle factors such as physical activity, intake of calcium and vitamins K and D and oestrogen supplementation (in girls) should be optimized. If BMC is below -1 SD, we advise to start with supplementation of calcium, vitamin K(1) and vitamin D(3). DXA should be repeated yearly in case of BMC below 0 SD in order to identify deteriorations and improvements early.

The use of an indium111 DTPA flow study in the evaluation of a lumbar swelling in a girl with a baclofen pump.

OBJECTIVE: The aim of this study was to introduce a useful diagnostic method to evaluate baclofen pump system-related complications without disturbing the continuous delivery of intrathecal baclofen. METHODS: We present a case report on the use of an indium (111) diethylenetriaminepentaacetic acid (DTPA) flow study in the evaluation of a lumbar swelling in a 16-year-old girl with spastic cerebral palsy, treated with continuous intrathecal baclofen (CITB). RESULTS: Disconnection or damage of the catheter leading to leakage of baclofen into the lumbar swelling could be ruled out by the use of an indium (111) DTPA flow study. This is the first report to illustrate the implementation of an lndium (111) DTPA flow study without interrupting the infusion of CITB. CONCLUSION: An indium (111) DTPA flow study is a non-invasive, safe and patient friendly diagnostic method which can be of great help in the evaluation of pump- or catheter-related complications and does not need to interfere with the delivery of CITB.

Left ventricular viability in a patient with heart failure due to left main stem stenosis, predicted by SPECT and gadolinium-enhanced magnetic resonance but not by dobutamine stress echocardiography.

A 54-year-old woman with occlusive disease of the distal abdominal aorta was referred for pre-operative risk assessment, and was diagnosed with severe impairment of the left ventricular function due to left main stem coronary artery stenosis. Low-dose dobutamine stress echocardiography did not demonstrate contractile reserve, while gadoliniumenhanced cardiac magnetic resonance (CMR) suggested viability of the left ventricle. The patient underwent coronary bypass grafting, and had an uncomplicated post-operative course, with improvement of the left ventricular ejection fraction from the initial 20% to 44% after four months. The value of CMR in determining myocardial viability in left main stem stenosis has not previously been reported.

[Progressive lymphoedema in the legs of children and adolescents]. / Progressief lymfoedeem van de benen bij kinderen en adolescenten.

In three children, two girls aged 18 months and 15 years and a boy aged 16 years, lymphoedema of the legs was diagnosed. Investigation by dynamic lymphoscintigraphy showed no or diminished activity of lymph vessels in the lower extremities. The patients were treated by manual compression therapy and compression stockings, which controlled the oedema. Early recognition and diagnosis are important, as otherwise irreversible complications and reduced mobility may occur.

Cardiac involvement of Churg Strauss syndrome demonstrated by magnetic resonance imaging.

Churg Strauss syndrome (CSS) may lead to cardiac involvement in up to 60% of patients. The myocardium, coronary vasculature, valves and pericardium may be affected. This results in significant morbidity and mortality, accounting for 48% of deaths due to CSS. Cardiac magnetic resonance imaging (CMR) is used to evaluate cardiac structure and function, and is able to evaluate myocardial perfusion and delineate scar tissue. We are the first to demonstrate these features in a 53-year-old CSS patient who presented with palpitations and atypical chest pains, and was found to have myocardial perfusion defects and scar tissue, most likely secondary to vasculitis of the small myocardial vasculature and myocardial infiltration.

Sustained local drug delivery from a radiopaque implanted reservoir.

A new polymeric biomaterial that contains covalently bound iodine, and is therefore radiopaque, was used to construct a sustained local drug-delivery device. A polymeric wall was designed to be porous (i.e., passage of low-molecular-weight molecules across the wall is possible), self-healing, and biocompatible. Once implanted, the sphere cavity can be filled and refilled with a concentrated solution of a (cytostatic) drug, which is subsequently released by slow diffusion into the tissue region surrounding the sphere. This principle of sustained local drug delivery is shown by a series of in vitro experiments on the release of 5-fluorouracil, and in vivo animal experiments, using x-ray fluoroscopic and scintigraphic techniques.

Lung and gastric uptake in bone scintigraphy of sarcoidosis.

We report on 99mTc-MDP uptake in lungs and stomach in a patient with hypercalcaemia and renal failure due to elevated 1,25(OH)2vitD3 because of sarcoidosis. Presently, this typical scan pattern has only been described in patients with malignancies, parathyroid adenoma and drug-induced vitamin D intoxication. We offer possible explanations for the findings in our patient.

Scintigraphic diagnosis of bile leakage after laparoscopic cholecystectomy. A prospective study.

To assess the role of Tc-99m IDA cholescintigraphy in diagnosing bile leakage and bile obstruction after laparoscopic cholecystectomy, 51 studies were performed in 51 patients on the first postoperative day. Two different radioactive bile acid analogs were used, Tc-99m HIDA and Tc-99m trimethylbromo IDA. Scintigraphic findings were correlated with the clinical conditions. Results of seven out of 51 cholescintigrams were abnormal, showing accumulations of activity in the right paracolic gutter. Of these seven patients, only three had clinical symptoms consisting of more than normal postoperative abdominal pain and peritoneal irritation. The other four patients had minimal abnormal accumulation in the right paracolic gutter and showed no clinical signs postoperatively. Complete common bile duct obstruction or other bile duct-related complications, except for bile leakage, were not observed. Cholescintigraphy is feasible for the early detection of bile leakage and bile flow obstruction after laparoscopic cholecystectomy in patients with increased postoperative abdominal discomfort.

Radioimmunoscintigraphy and immunohistochemistry with melanoma-associated monoclonal antibodies in choroidal melanoma: a comparison of the clinical and immunohistochemical results.

Radioimmunoscintigraphy with monoclonal antibodies (MoAbs) to melanoma associated antigens is a new technique that can be used as an additional test to detect ocular melanomas in clinically difficult cases. Immunoscintigraphy with 99mtechnetium-labelled monoclonal antibody fragments of MoAb 225.28S in 14 patients with melanoma yielded a positive image in only six cases (43%). The expression of high molecular weight melanoma-associated antigen (HMW-MAA) was immunohistochemically assessed in melanoma tissue obtained from these 14 patients to find a possible correlation between the results of immunoscintigraphy and expression of the HMW-MAA. The melanoma tissues were immunohistochemically stained by a sensitive immunoperoxidase procedure with three different monoclonal antibodies to the HMW-MAA: 225.28S, Mel-14, and AMF-6. Expression of the antigen detected by MoAb 225.28S was found in 13 of 14 melanomas; the MoAbMel-14 reacted positively with all 14 melanomas; staining with MoAb AMF-6 was achieved in 10 melanomas. No correlation was found between the immunohistochemical staining results, the conventional histopathological findings, and the immunoscintigraphic results. The immunohistochemical staining results suggest that anti-HMW-MAA MoAbs bind to the melanoma tissue and are therefore potentially suitable for immunoscintigraphy.

Iodine-123-metaiodobenzylguanidine scintigraphy in patients with chemodectomas of the head and neck region.

While studying the uptake of iodine-123-metaiodobenzylguanidine ([123I]MIBG) in chemodectomas, we coincidentally detected catecholamine secreting tumors in 5 out of 14 patients. In three of these cases, a norepinephrine secreting abdominal paraganglioma was subsequently removed. One patient had a norepinephrine secreting chemodectoma and one had a dopamine secreting chemodectoma. Prior to [123I]MIBG imaging and urinary catecholamine measurements, endocrine activity was suspected in only one of these five patients. Apart from these five cases, two other patients showed elevated catecholamine secretion and abnormal abdominal [123I]MIBG concentrations. However, these two patients were not surgically explored, because of normal computed tomography (CT) and magnetic resonance (MRI) studies. We suspect that catecholamine-secreting tumors are more common in patients with chemodectomas than is assumed in the literature, and we therefore recommend urinary catecholamine screening for all patients with chemodectomas. In case of elevated catecholamine secretion, MIBG scintigraphy is indicated.

Hereditary cerebral hemorrhage with amyloidosis--Dutch type. Tc-99m HM-PAO single photon emission computed tomography.

We performed single photon emission computed tomography (SPECT) and cerebral CT-scans in nine patients with hereditary cerebral amyloid angiopathy. CT-scans showed 23 focal hypodense lesions, 13 of which were visible on SPECT as a CBF-defect. One patient showed a CBF-defect on SPECT without CT-scan lesion and had a cerebral hemorrhage three months later in that particular region. In two additional patients, who were 50% at risk for this autosomal dominant disease, CBF-defects on SPECT, but no cortical lesions on CT-scan were found. CT-scans may be more sensitive than SPECT to detect chronic lesions caused by cerebral hemorrhages, but another possibility is that hemorrhages do not always lead to persistent CBF-defects. SPECT can show the effect of amyloid deposits on CBF before the angiopathy causes clinical symptoms.

Intracerebral uptake of Tc-99m labeled antimelanoma antibodies.

A patient with an intraocular tumor showed accumulation of Tc-99m labeled antimelanoma antibodies in the head. This was not due to a metastatic lesion but proved to be a benign intracranial osteoma. The reasons for this false-positive result are discussed.

Imaging of ovarian cancer with radiolabelled monoclonal antibodies.

This article presents the state of the art of immunoscintigraphy (IS) of ovarian cancer. We will review the monoclonal antibodies (MoAbs) used in clinical trials: (HMFG1/2, OC125, H317, H17E2, NDOG2 and 791T/36). We conclude that none of the afore mentioned MoAbs are clearly superior and that IS cannot yet replace laparotomy for the diagnosis of ovarian cancer but may have a role in the follow-up of ovarian cancer, in timing second-look surgery and assessing the response/TD treatment.

[Immunoscintigraphy of choroid melanoma using monoclonal antibodies]. / Immunoscintigrafie van het choroideamelanoom met behulp van monoklonale antilichamen.

A prospective pilot study on immunoscintigraphy with monoclonal antibody fragments against cutaneous melanoma (MoAb 225.28S) was performed in 17 patients with a clinical diagnosis of choroidal melanoma. Monoclonal antibodies against melanoma associated antigen were labelled with 740 mBq (20 MCi) of the radionuclide 99mTc and injected intravenously. Images were made with a gamma camera 6 hours after injection. With a double pinhole collimator radioactivity was counted thrice in both eyes 6 hours after injection. In 6 out of 17 patients (35.3%) the melanoma could be imaged with the gamma camera. With the double pinhole collimator a significantly higher activity was measured in the melanomatous eye in 13 out of 17 patients (76.5%). In four patients a false negative result was obtained. Considering these results immunoscintigraphy may be valuable in ocular melanoma diagnostics but its specific value still has to be assessed.

Radioimmunoscintigraphy with melanoma-associated monoclonal antibody fragments in choroidal melanoma.

A prospective pilot study on radioimmunoscintigraphy with monoclonal antibody fragments against cutaneous melanoma (MoAb 225.28S) was carried out in 17 patients with a clinical diagnosis of choroidal melanoma. Monoclonal antibodies against melanoma-associated antigen were labeled with 740 mBq 99mTc and injected IV; images were made with a gamma camera at 6 h after injection. With a double-pinhole collimator, radioactivity was counted thrice in both eyes at 6 h after injection. In 6 of 16 patients (37.5%), the melanoma could be imaged with the gamma camera. With the double-pinhole collimator, a significantly higher activity was measured in the melanomatous eye in 13 of 16 patients (82.4%). In two patients a false negative result was obtained, and in one patient the difference between the left and right eye was not significant. Considering these results, radioimmunoscintigraphy may be valuable in ocular melanoma diagnostics, but the specificity of MoAb 225.28S needs to be assessed.

Human immunological response to mouse monoclonal antibodies in the treatment or diagnosis of malignant diseases.

An overview of the literature is presented concerning the formation, detection, incidence and effect of the human immunoglobulin response on immunoscintigraphy. The following conclusions are drawn. The production of human anti-mouse antibodies (HAMAs) is associated with a diminished therapeutic response; adequate prevention of HAMA production is not yet possible; high HAMA titres give rise to rapid clearance of MoAb into the liver and marked reduction of tumour uptake which results in reduced image quality on immunoscintigraphy; alteration of antibody biodistribution is likely to be related to the in vivo formation of antibody-antibody complexes which could interfere with image quality when sequential imaging is carried out.