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.

Inflammatory activity assessment by F18 FDG-PET/CT in persistent symptomatic sarcoidosis.

BACKGROUND: Establishing inflammatory activity in sarcoidosis patients with persistent disabling symptoms is important. Whole body F(18)-FDG PET/CT (PET) appeared to be a sensitive method to detect inflammatory activity in newly diagnosed symptomatic sarcoidosis. The aim was to assess the presence of inflammatory activity using PET in sarcoidosis patients with unexplained persistent disabling symptoms and the association between PET findings and serological inflammatory markers. METHODS: Sarcoidosis patients who underwent a PET between June 2005 and June 2010 (n = 89), were retrospectively included. All PET scans were examined and positive findings were classified as thoracic and/or extrathoracic. As serological markers of inflammatory activity angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), and neopterin were considered. RESULTS: In 65/89 (73%) of the studied patients PET was positive, 52 of them (80%) had serological signs of inflammatory activity. In 14/15 patients with a Chest X-ray stage IV PET was positive. In 80% of the PET positive patients extrathoracic inflammatory activity was found. Sensitivity of combined serological inflammatory markers for the presence of inflammatory activity as detected by PET was 80%, specificity 100%, positive predictive value 100%, negative predictive value 65%. CONCLUSIONS: The majority of sarcoidosis patients with persistent disabling symptoms, even those with radiological stage IV, had PET positive findings with remarkably 80% extrathoracic lesions. In 20% PET was positive without signs of serological inflammatory activity. PET appeared to be of additional value to assess inflammatory activity in patients with persistent symptoms in the absence of signs of serological inflammatory activity and to detect extrathoracic lesions.

Improvement of cardiac sympathetic nerve function in sarcoidosis.

Some patients with sarcoidosis can have cardiac involvement. Impairment of the cardiac sympathetic nerve activity is seen in about 50% of the sarcoidosis patients with small fiber neuropathy. In this case we present a sarcoidosis patient with small fiber neuropathy and cardiac symptoms with a cardiac sympathetic dysfunction, assessed with I-123 MIBG SPECT. After 5 months of treatment with carvedilol, which has besides adrenergic receptor blocking effects also antioxidant action, we saw a clear improvement of the cardiac sympathetic function demonstrated on a repeated I-123 MIBG SPECT. Future studies should explore the clinical relevance of the relation of oxidative stress, antioxidant therapy and cardiac dysfunction in sarcoidosis.

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.

Body composition in children with galactosaemia.

Body composition in classical galactosaemia has not been studied. Patients with classical galactosaemia, an inherited disorder of galactose metabolism caused by deficiency of galactose-1-phosphate uridyltransferase (GALT, EC 2.7.7.10), might be at risk for an abnormal body composition because of intrinsic factors related to galactosaemia and/or diet-related factors. The aim of this study was to evaluate the body composition of children with classical galactosaemia. The studied population was a previously reported group of classical galactosaemia patients (13 male and 27 female, ages 3-17 years) with decreased height, weight, weight-for-height and insulin-like growth factor-I (IGF-I) Z-scores. Body composition data were obtained by dual-energy X-ray absorptiometry (DXA). In order to correct for height, fat mass (FM) and lean tissue mass (LTM) were divided by squared height. Mid-parental target height Z-scores were assessed and compared to actual height Z-scores. Linear and multiple regression analysis were done to investigate the relationship between body composition and IGF-I, dietary intake and growth data. We found decreased height Z-scores when compared to mid-parental target height Z-scores. Mean scores for FM and LTM (both adjusted for height) were decreased. LTM (adjusted for height) and height Z-score were correlated with IGF-I Z-score. FM (adjusted for height) was correlated with soy intake. No correlation was found between soy intake and IGF-I Z-score. In this limited group of patients, height is decreased and body composition is abnormal. The decreased levels of IGF-I and/or soy nutrition might play a role in these findings.

Bone metabolism in galactosemia.

Classical galactosemia is an autosomal recessively inherited disorder of galactose metabolism. Treatment consists of life-long dietary restriction of galactose. Despite treatment, long-term complications occur such as a decreased bone mineral density (BMD). A decreased BMD might be the result of either dietary deficiencies secondary to the galactose-restricted diet or unknown intrinsic factors. In this study, 40 children with classical galactosemia (13 males and 27 females, aged 3-17 years) on dietary treatment were included to gain insight in the bone metabolism of galactosemics. We found weight and height Z scores significantly decreased in galactosemics. Mean areal BMD Z scores of lumbar spine and of femoral neck as measured by Dual energy X-ray Absorptiometry (DXA) were -0.6 (P < 0.001) and -0.3 (P = 0.066), respectively. Mean volumetric BMD of the femoral neck was significant lower in galactosemics (P < 0.001). The recommended dietary allowances (RDA) for calcium, magnesium, zinc, vitamin D, and protein were met in all patients. Mean serum levels of calcium, phosphate, magnesium, zinc, 1,25-dihydroxy vitamin D (1,25OHD), parathormone (PTH), 17-beta estradiol, bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were normal. Serum levels of IGF-1 Z score, carboxylated osteocalcin (cOC), N-terminal telopeptide (NTX), and C-terminal telopeptide (CTX) were significantly lower in galactosemics than in control subjects. The different bone markers were strongly correlated. The low levels of IGF-1 Z score, formation marker cOC, and resorption markers NTX and CTX suggest a decreased bone metabolism in galactosemics.

[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.

Methylphenidate down-regulates the dopamine receptor and transporter system in children with attention deficit hyperkinetic disorder (ADHD).

Adults suffering from Attention Deficit Hyperactivity Disorder (ADHD) are known to have disturbed central dopaminergic transmission. With Single Photon Emission Computed Tomography (SPECT) we studied brain dopamine transporter and receptor activity in six boys with ADHD. Three months after initiation of treatment with methylphenidate we found a down-regulation of the post-synaptic dopamine receptor with a maximum of 20 % and a down-regulation of the dopamine transporter with a maximum of 74.7 % in the striatal system. This corresponded to a positive clinical response evaluated by neuropsychological questionnaires and tests. We suggest that dopamine transporter imaging by SPECT might be used to monitor psychostimulant treatment in children suffering from ADHD.

Bone mineral density in patients with classic galactosaemia.

BACKGROUND: Diminished bone mineral density (BMD) is a well known complication in women with classic galactosaemia caused by premature ovarian failure. Diminished BMD in prepubertal patients of either sex has, however, only been reported once. AIM: To assess BMD in children with classic galactosaemia. METHODS: Eleven treated patients (five males, six females, aged 2-18 years) had BMD determined by dual energy x ray absorptiometry. Two measurements were performed, an areal measurement of the total body and a volumetric measurement of the femoral neck. Results were expressed as Z scores. Dietary calcium intake, blood calcium, phosphate, vitamin D, parathormone, and markers of bone formation (bone alkaline phosphatase, osteocalcin) and bone resorption (NTX) were determined. RESULTS: All patients had a significantly diminished BMD. Mean Z score of the volumetric BMD was -1.76 (range -0.7 to -3.3), and of the areal BMD -0.99 (range -0.5 to -1.4). Dietary calcium intake and calcium, phosphate, parathormone, bone alkaline phosphatase, vitamin D metabolites, and osteocalcin (free and carboxylated) were normal in all patients. NTX levels in blood were significantly lower (p < 0.001) than in control subjects. CONCLUSION: BMD in this group of children of both sexes with classic galactosaemia under dietary treatment was decreased. Lower NTX levels in galactosaemics point to an apparent decreased bone resorption.

MR imaging, single-photon emission CT, and neurocognitive performance after mild traumatic brain injury.

BACKGROUND AND PURPOSE: Mild traumatic brain injury (mTBI) (Glasgow Coma Scale = 14-15) is a common neurologic disorder and a common cause of neurocognitive deficits in the young population. Most patients recover fully from mTBI, but 15% to 29% of patients have persistent neurocognitive problems. Although a partially organic origin is considered likely, little brain imaging evidence exists for this assumption. The aims of the present study were to establish the prevalence of posttraumatic lesions in mTBI patients on MR images and to assess the relation between these imaging findings and posttraumatic symptoms. Secondly, we explored the value of early posttraumatic single-photon emission CT (SPECT) for the evaluation of mTBI. METHODS: Twenty-one consecutive patients were included in the study. Patients underwent MR examination, technetium-99m hexamethylpropylene amine oxime SPECT, and neurocognitive assessment within 5 days after injury. Neurocognitive follow-up was conducted 2 and 6 months after injury, and MR imaging was repeated after 6 months. Lesion size and brain atrophy were measured on the MR studies. RESULTS: Twelve (57%) of 21 patients had abnormal MR findings, and 11 (61%) of 18 had abnormal SPECT findings. Patients with abnormal MR or SPECT findings had brain atrophy at follow-up. The mean neurocognitive performance of all subjects was within normal range. There was no difference in neurocognitive performance between patients with normal and abnormal MR findings. Patients with abnormal MR findings only showed significantly slower reaction times during a reaction-time task. Seven patients had persistent neurocognitive complaints and one patient met the criteria for a postconcussional syndrome. CONCLUSION: Brain lesions are common after mTBI; up to 77% of patients may have abnormal findings either on MR images or SPECT scans, and these lesions may lead to brain atrophy. The association between hypoperfusion seen on acute SPECT and brain atrophy after 6 months suggests the possibility of (secondary) ischemic brain damage. There is only a weak correlation between neuroimaging findings and neurocognitive outcome.

Radiosynthesis and biodistribution of 123I-labeled antagonists of the histamine H3 receptor as potential SPECT ligands.

We have synthesized three 123I-labeled histamine H3 receptor ligands, i.e., [123I]GR 190028, [123I]FUB 271, and [123I]iodoproxyfan, in moderate to good radiochemical yields via a Cu+-assisted I-for-123I exchange method. Biodistribution in the rat of these compounds revealed high hepatic and pulmonary uptake. Brain uptake was moderate, but for [123I]iodoproxyfan, brain uptake was high enough for a pilot single photon emission computed tomography (SPECT) study in the rabbit. However, for this compound, the cerebral uptake could not be blocked by a pretreatment with [R]-alpha-methylhistamine, a selective, high-affinity histamine H3 receptor agonist, both in the SPECT study in the rabbit and in the biodistribution study in the rat. Apparently, [123I]iodoproxyfan is binding to a non-H3 receptor binding site. None of the three investigated compounds is suitable for use as a SPECT ligand for the H3 receptor in the brain.

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.

Baseline and postcaptopril renal blood flow measurements in hypertensives suspected of renal artery stenosis.

UNLABELLED: Renal blood flow (RBF) measurements using first-pass radionuclide angiography with DTPA, a glomerularly filtered agent, failed to show significant differences between normal and stenotic kidneys. Since MAG3 is an ideal agent for the study of RBF, this agent might be an attractive alternative tracer to detect differences in RBF. METHODS: An angiographically controlled prospective study was performed in 48 hypertensive patients, in whom a diagnosis of renovascular hypertension was suspected on clinical grounds. The study was done to determine whether RBF measurements using first-pass radionuclide angiography with 99mTc-MAG3 could be helpful in the diagnostic work-up of the patients. Additionally, the study was done before and after ACE-inhibition. RESULTS: On renal angiography, 29 patients showed to have normal renal arteries (50 patients had normal kidneys and 8 patients had small kidneys). Nineteen patients had renal artery stenosis (13 uni- and 6 bilateral disease). In the patients with normal kidneys, the mean value of RBF measurements ranged from 10.5% to 10.9% of cardiac output. Only small stenotic and small kidneys with normal renal arteries showed a significant reduced baseline RBF as compared with normal kidneys (both p < 0.05); this difference disappeared after ACE-inhibition only for the small kidneys with normal renal arteries. In patients with stenosed kidneys, RBF tended to be reduced both at baseline and after captopril, but the differences with normal kidneys were not statistically significant. After ACE-inhibition RBF increased in the majority of kidneys, but postcaptopril RBF data did not differ significantly from those at baseline. CONCLUSION: RBF measurements using first-pass radionuclide angiography with 99mTc-MAG3, either before or after ACE-inhibition, cannot reliably discriminate between patients with essential hypertension and patients with renal artery stenosis.

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.

Preparation, characterization and radiolabeling of a new amphiphilic derivative of DTPA.

A new derivative (1) of diethylenetriamine pentaacetic acid (DTPA) is described. Compound 1 contains a hydrophobic unit (a triphenyl methyl group) and a hydrophilic unit (a DTPA ester), and therefore behaves as an amphiphile in aqueous solution. Compound 1 appears to form a stable inclusion complex with 99mTc. A rabbit model was used in a scintigraphic study of the biodistribution of the complex 99mTc-1, using 99mTc-DTPA as a control. The resulting images revealed marked differences: 99mTc-1 showed rapid uptake in the liver followed by excretion in the gallbladder and intestines within 1 h, whereas 99mTc-DTPA appears, as expected, in the renal-pelvico system and in the bladder. These findings are significant as they provide more insight into the complex relationship between structural and physicochemical properties of radiopharmaceuticals and their biodistribution. Knowledge of such relationships is absolutely mandatory with respect to the development of new radiopharmaceuticals with increased efficacy and/or specificity.