Subarachnoid Hemorrhage As a Cause of Hypopituitarism

Common causes of pituitary insufficiency include pathologies such as pituitary adenomas, other intra- and parasellar tumors, as well inflammatory, surgical or radiation-induced destruction of pituitary tissue. More recently, hypopituitarism has also been identified as a frequent sequel of traumatic brain injury (TBI). Despite the close anatomical relationship between pituitary gland, hypothalamic structures and the arteries of the circle of Willis and the observation that many bodily and psychosocial long-term sequelae of survivors of aneurysmal subarachnoid hemorrhage (SAH) resemble those of patients with untreated hypopituitarism, aneurysmal SAH has so far been considered a rare cause of endocrine abnormalities. However, in recent clinical investigations partial hypopituitarism has been diagnosed in 37.5–55% of SAH survivors. At present, many questions concerning the most appropriate diagnostic work-up, the clinical implications of hormone deficiencies and relative importance of hormone replacement in this patient group are not yet satisfactorily clarified. This article gives an overview of the historical and current studies on hypopituitarism as a consequence of aneurysmal SAH, which show that neuroendocrine deficiency occurs more often than has so far been appreciated. Despite the still unresolved issues, endocrine abnormalities should be considered a cause for impaired recovery and long-term morbidity in SAH-survivors. Enhanced awareness of physicians treating SAH-patients for post-traumatic hypopituitarism is called for, so that screening for hormone deficiencies and appropriate replacement therapy can be initiated.     

Mapping the cerebral monoamine oxidase type A: positron emission tomography characterization of the reversible selective inhibitor [11C]befloxatone

Befloxatone is a competitive and reversible inhibitor of monoamine oxidase-A (MAOI-A). The aim of the study was to characterize the in vivo properties of [(11)C]befloxatone and to validate its use as a ligand for the study of MAO-A by positron emission tomography (PET). PET studies were performed in baboons after i.v. injection of [(11)C]befloxatone (551 +/- 70 MBq, i.e.14.9 +/- 1.9 mCi). [(11)C]Befloxatone enters rapidly in the brain with a maximum uptake at 30 min. Brain concentration of the tracer is high in thalamus, striatum, pons and cortical structures (1.5-1.8% of injected dose per 100 ml of tissue), and lower in cerebellum (1.07% injected dose/100 ml). Nonsaturable uptake, obtained after a pretreatment with a high dose of nonlabeled befloxatone (0.4 mg/kg), is very low and represents only 3% of the total uptake. Brain uptake of [(11)C]befloxatone is not altered by a pretreatment of a high dose with lazabemide (0.5 mg/kg i.v.), a selective MAOI-B but is completely blocked by a pretreatment with moclobemide (MAOI-A; 10 mg/kg). This confirms, in vivo, the selectivity of befloxatone for type A MAO. [(11)C]Befloxatone brain radioactivity was displaced by administration of unlabeled befloxatone (30 min after the tracer injection). The displacement of the tracer from its binding sites is dose-dependent, with an ID(50) of 0.02 mg/kg for all studied structures. These results indicate that [(11)C]befloxatone will be an excellent probe for the study of MAO-A in humans using PET.     

The long-term effects of ovariectomy on bone metabolism in sheep

Osteoporosis and associated fractures are major public health concerns, and as such require appropriate large animal models to further our understanding of this disease. Although sheep appear to be an ideal model with which to study bone loss caused by estrogen depletion, limited data are available concerning the long-term effect of ovariectomy on bone in sheep. The goal of the present study was to observe the ovariectomy-induced changes in bone mass, structure, and metabolism in sheep over a period of 18 months. Six ewes were ovariectomized (OVX) and compared to an age-matched control group by analyzing bone mineral density, trabecular structure, biochemical markers of bone formation and resorption, and plasma estrogen levels. Bone loss (13%, P < 0.01) occurred during the first 4 months after surgery, then stabilized and returned to pre-OVX levels for the remainder of the study. Trabecular architecture was also altered and tended toward osteopenia with recovery to baseline values. Markers of bone formation and resorption were elevated up to 6 months postovariectomy, after which time levels returned to baseline values. Although estradiol measurements demonstrated a clear decline following surgical ovariectomy, levels returned to normal after 6 months. Therefore, the detrimental effect of ovariectomy on sheep bone metabolism seems to be reversible, with normal bone parameters being reestablished within 6 months after surgery. These data seem to indicate that the sheep is not an appropriate model for human postmenopausal osteoporosis.     

Altered temporal correlations in parietal alpha and prefrontal theta oscillations in early-stage Alzheimer disease

Encoding and retention of information in memory are associated with a sustained increase in the amplitude of neuronal oscillations for up to several seconds. We reasoned that coordination of oscillatory activity over time might be important for memory and, therefore, that the amplitude modulation of oscillations may be abnormal in Alzheimer disease (AD). To test this hypothesis, we measured magnetoencephalography (MEG) during eyes-closed rest in 19 patients diagnosed with early-stage AD and 16 age-matched control subjects and characterized the autocorrelation structure of ongoing oscillations using detrended fluctuation analysis and an analysis of the life- and waiting-time statistics of oscillation bursts. We found that Alzheimer's patients had a strongly reduced incidence of alpha-band oscillation bursts with long life- or waiting-times (< 1 s) over temporo-parietal regions and markedly weaker autocorrelations on long time scales (1–25 seconds). Interestingly, the life- and waiting-times of theta oscillations over medial prefrontal regions were greatly increased. Whereas both temporo-parietal alpha and medial prefrontal theta oscillations are associated with retrieval and retention of information, metabolic and structural deficits in early-stage AD are observed primarily in temporo-parietal areas, suggesting that the enhanced oscillations in medial prefrontal cortex reflect a compensatory mechanism. Together, our results suggest that amplitude modulation of neuronal oscillations is important for cognition and that indices of amplitude dynamics of oscillations may prove useful as neuroimaging biomarkers of early-stage AD.     

Quality of life and psychiatric sequelae following aneurysmal subarachnoid haemorrhage: does neuroendocrine dysfunction play a role?

OBJECTIVE: Patients who have sustained aneurysmal subarachnoid haemorrhage (SAH) often suffer persistent impairments in their quality of life (QoL) and psychological disturbances despite a good neurological outcome. In the light of the high prevalence of partial hypopituitarism in SAH survivors demonstrated in recent investigations, we aimed to determine whether neuroendocrine dysfunction has an impact on QoL and neurobehavioural symptoms in these patients. DESIGN/PATIENTS: QoL, depression and psychological distress were assessed in 40 SAH survivors who had undergone endocrine function testing at least 1 year after the haemorrhage. MEASUREMENTS: QoL was assessed using the Nottingham Health Profile (NHP), the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) and the Short Form-36 questionnaire (SF-36). The Beck Depression Inventory (BDI) and the Impact of Event Scale (IES) were used to evaluate depression and symptoms of current subjective distress in response to the SAH as a stressful life event, respectively. RESULTS: In a stepwise multiple regression analysis, basal cortisol level was included as the first and often only predictor for several QoL domains assessing psychological aspects of well-being and depression whereas physical aspects of QoL were predicted primarily by neurological recovery from the SAH. Severe GH deficiency (GHD) was the first predictor for the criterion NHP subscale 'Energy' and highest stimulated ACTH level in the insulin tolerance test (ITT) was the first predictor for disturbed sleep as assessed with the NHP subscale 'Sleep'. CONCLUSION: Our results provide preliminary data that neuroendocrine disturbances contribute to disturbed QoL, depression and sleeping disturbances in SAH patients.     

Whole-body biodistribution and radiation dosimetry of the human cannabinoid type-1 receptor ligand 18F-MK-9470 in healthy subjects.

The cannabinoid type-1 (CB1) receptor is one of the most abundant G-coupled protein receptors in the human body and is responsible for signal transduction of both endogenous and exogenous cannabinoids. The endocannabinoid system is strongly implicated in regulation of homeostasis and several neuropsychiatric disorders, obesity, and associated comorbidities, such as dyslipidemia and metabolic syndrome. We have used whole-body PET/CT to characterize the biodistribution and dosimetry of a novel high-affinity, subtype-selective radioligand, (18)F-MK-9470, in healthy male and female subjects. METHODS: Eight nonobese subjects (5 men, 3 women; age, 22-54 y) underwent serial whole-body PET/CT for 6 h after a bolus injection of 251 +/- 25 MBq (18)F-MK-9470 (N-[2-(3-cyano-phenyl)-3-(4-(2-(18)F-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide). Source organs were delineated 3-dimensionally using the combined morphologic and functional data. Residence times were derived from time-activity profiles using both the trapezoid rule and curve fitting. Individual organ doses and effective doses were determined using the OLINDA software package, with different approaches for gastrointestinal and urinary excretion modeling. RESULTS: (18)F-MK-9470 is taken up slowly in the brain, reaching a plateau at approximately 90-120 min after bolus injection and is excreted predominantly through the hepatobiliary system. The gallbladder, upper large intestine, small intestine, and liver are the organs with the highest absorbed dose (average: 159, 98, 87, and 86 microGy/MBq, respectively). The mean effective dose (ED) was 22.8 +/- 4.3 microSv/MBq, indicating relatively low intersubject variability and a mean value in the range of many commercially available (18)F-labeled radiopharmaceuticals. Brain uptake was relatively high compared with that of existing central nervous system ligands for other receptors, between 3.2% and 4.9% of the injected dose. CONCLUSION: The estimated radiation burden of (18)F-MK-9470 for PET CB1 receptor imaging shows relatively low variability between subjects and has an acceptable ED, which allows multiple serial cerebral scans of good image quality, while remaining within the risk category class II-b defined by the World Health Organization and the International Commission for Radiation Protection for a standard injected activity (185-370 MBq).     

Diagnostic delay is associated with psychosocial impairment in acromegaly

The aim of this study was to systematically assess health care utilisation, diagnostic delay and psychosocial impairment in patients with acromegaly in rural versus urban health care environments. 41 patients with acromegaly were questioned to time lapse of symptom onset, first seeking medical advice and time of acromegaly diagnosis. Quality of life (QoL), and psychosocial impairment (depression, daytime sleepiness, sleep disturbances, disturbances of body image) were measured by self-assessment questionnaires. Patients were grouped into living in rural health care environments (RHCE, n = 22 patients) or urban health care environments (UHCE, n = 19 patients) using data on population density from the German Federal Statistical Office. RHCE patients waited significantly longer (2.5 vs. 0.89 years; p = .025) after symptom onset before seeking medical advice, but diagnosis of acromegaly was established at least as quickly as in UHCE (1.45 vs. 2.74 years; n.s.). There was a consistent trend toward more psychosocial impairment in UHCE which reached significance for sleep disturbances (p = .004). For all patients significant correlations between time delay of diagnostic process (defined as first visit to the doctor because of acromegaly-related symptoms and establishment of acromegaly diagnosis) and psychological QoL, depression, daytime sleepiness, sleep disorders and body image emerged. Patients with acromegaly in UHCE experienced more psychosocial impairment than patients in RHCE. The correlation of significantly increased psychosocial impairment and delay of diagnosis by the physician may reflect long-lasting embitterment in patients with acromegaly and should be considered during psychosocial counselling.     

T-Screen as a tool to identify thyroid hormone receptor active compounds

The T-Screen represents an in vitro bioassay based on thyroid hormone dependent cell proliferation of a rat pituitary tumour cell line (GH3) in serum-free medium. It can be used to study interference of compounds with thyroid hormone at the cellular level, thus bridging the gap between limitations of assays using either isolated molecules (enzymes, transport proteins) or complex in vivo experiments with all the complex feedback mechanisms present. Compounds are tested both in the absence and presence of thyroid hormone (EC(50) concentration of T(3)) to test for both agonistic and antagonistic potency. Thyroid hormones (3,3'-5-triiodothyronine: T(3) and 3,3',5,5'-tetraiodothyroxine: T(4)) and compounds resembling the structure of thyroid hormones (3,3'-5-triiodothyroacetic acid: Triac; 3,3',5,5'-tetraiodothyroacetic acid: Tetrac) induced cell growth, with the rank order Triac > T(3) > Tetrac > T(4) (relative potency = 1.35 > 1 > 0.29 > 0.07), which is identical to published affinities of these compounds for nuclear thyroid hormone receptors. Exposure to 5,5'-diphenylhydantoin (DPH) in the presence of 0.25nM T(3) resulted in up to 60% decreased cell growth at 200μM DPH. No effect of DPH on basal metabolic activity of GH3 cells was observed at this concentration. Fentinchloride (IC(50) = 21nM) decreased cell growth induced by 0.25nM T(3), whereas parallel exposure to these concentrations in the absence of T(3) did not alter basal metabolic activities of GH3 cells. Apolar sediment extracts from the Dommel (34%) and Terneuzen (14%) decreased cell growth in the presence of 0.25nM T(3), whereas the extract from Hoogeveen increased cell growth (26%) and the extract from North Sea Channel had no effect. The T-Screen proved to be a fast and functional assay for assessing thyroid hormone receptor active potencies of pure chemicals or environmental mixtures.     

VITamins And Lifestyle cohort study: study design and characteristics of supplement users

Vitamin and mineral supplements are among the most commonly used drugs in the United States, despite limited evidence on their benefits or risks. This paper describes the design, implementation, and participant characteristics of the VITamins And Lifestyle (VITAL) Study, a cohort study of the associations of supplement use with cancer risk. A total of 77,738 men and women in western Washington State, aged 50-76 years, entered the study in 2000-2002 by completing a detailed questionnaire on supplement use, diet, and other cancer risk factors, and 70% provided DNA through self-collected buccal cell specimens. Supplement users were targeted in recruitment: 66% used multivitamins, 46% used individual vitamin C, 47% used individual vitamin E, and 46% used calcium, typically for 5-8 of the past 10 years. Analyses to identify confounding factors, the main study limitation, showed that regular nonsteroidal anti-inflammatory drug use, intake of fruits and vegetables, and recreational physical activity were strongly associated with supplement use (p < 0.001). The authors describe a follow-up system in which cancers, deaths, and changes of residence are tracked efficiently, primarily through linkage to public databases. These methods may be useful to other researchers implementing a large cohort study or designing a passive follow-up system.     

Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families

A strong familial component of restless legs syndrome (RLS) is known. The objective of this study therefore was to investigate the likely mode of inheritance of RLS. RLS patients and their first-degree relatives were investigated and classified in RLS affected and RLS nonaffected subjects. Assessments were based on direct, personal standardized diagnostic interviews. Complex segregation analysis was performed with the families stratified according to the mean age at onset of the disease within the families. Two hundred thirty-eight RLS patients, 537 first-degree relatives, and 133 spouses were interviewed. Two groups of families were stratified: mean age at onset up to 30 years of age (Group A) and older than 30 years (Group B; p < 0.005). In Group A, segregation analysis strongly favored a single major gene acting autosomal dominant with a multifactorial component. Parameter estimates were 0.003 for the allele frequency, 1.0 for the penetrance, and 0.005 for the phenocopy rate. In Group B, no evidence for a major gene could be elucidated. The segregation pattern found in our families argues for an autosomal allele acting dominantly in RLS families with an early age at onset of symptoms and suggests that RLS is a causative heterogeneous disease.