The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.     

166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.

166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical. METHODS: After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. RESULTS: In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. CONCLUSION: Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.     

Leber’s hereditary optic neuropathy and vitamin B12 deficiency

Background Leber’s hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA (mtDNA). It is also believed that several epigenetic factors have an influence on the development of LHON.Methods A case series was observed.Results Three patients who developed bilateral optic neuropathy are presented. All patients had a primary LHON mutation in their mtDNA, but also a subnormal vitamin B12 serum level at the time of presentation.Conclusions The clinical picture of optic neuropathy associated with vitamin B12 deficiency shows similarity to that of LHON. Both involve the nerve fibres of the papillomacular bundle. The present case reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may be precipitated by vitamin B12 deficiency. Therefore, known carriers should take care to have an adequate dietary intake of vitamin B12 and malabsorption syndromes like those occurring in familial pernicious anaemia or after gastric surgery should be excluded.     

PINK1 mutations in sporadic early-onset Parkinson's disease.

Pathogenic PINK1 mutations have been described in PARK6-linked Parkinson's disease (PD) patients of Asian origin. However, data on the frequency of PINK1 mutations in sporadic early-onset Parkinson's disease (EOPD) Asian patients are lacking. The objectives of this study were to report the frequency of PINK1 mutations of sporadic EOPD in an Asian cohort comprising of ethnic Chinese, Malays, and Indians, and to highlight a PINK1-positive patient who presented with restless legs symptoms. Eighty consecutive sporadic EOPD patients from the movement disorder clinics of two major tertiary institutions in the country were included. We performed sequence analysis of all the coding and exon-intron junctions of the PINK1 using specific primer sets. In addition, we genotyped polymorphisms detected from the analysis in a group of sporadic PD patients and controls. Three different mutations (two homozygous nonsense and one heterozygous missense) in the putative kinase domain were found in three patients, giving a 3.7% frequency of PINK1 mutations in our EOPD cohort. All the mutations were absent in 200 healthy controls. One patient with a novel homozygous nonsense PINK1 mutation presented unusually with restless legs symptoms. Separately, analysis of the frequency of four PINK1 polymorphisms in a group of sporadic PD and controls did not reveal any significant differences. We highlight a 3.7% frequency of PINK1 mutations in an Asian cohort (ethnic Chinese, Malay, and Indian) of EOPD. The phenotypic spectrum associated with PINK1-positive patients may be wider than previously reported. Polymorphisms of PINK1 do not appear to modulate risk of PD in our population.     

Juvenile hypocalcemia provokes persistent electroencephalographic change in renally compromised rats

In view of the putative involvement of calcium in uremic encephalopathy and the critical importance of this element in juvenile development, we examined the effect of temporary restriction of dietary calcium intake on serum chemistry and the quantitative electroencephalogram (Q.EEG) in unilaterally 3/4 nephrectomized juvenile male Sprague-Dawley rats. Animals were renally infarcted at 22-26 days of age (50-74 g) and placed on one of two isocaloric dietary regimens: powdered normal rat diet (ND, n = 25) or low calcium diet (LCD, n = 8) for 30 days. At this time, ND animals showed normal serum chemistries, whereas LCD rats were hypocalcemic and azotemic with significantly elevated blood urea nitrogen (BUN) and serum creatinine concentrations and reduced renal creatinine clearance values. All animals thereafter received ND for 25-34 further days, during which time chronic Q.EEG electrodes were implanted. At the end of the common ND feeding period, serum chemistry values were equal and normal in both groups. The average theta/alpha ratio (TAR) of the overnight Q.EEG was assessed for 3 days. We found that the TAR of previously LCD animals was significantly elevated compared with ND rats. This indicates an encephalopathic slowing of the background rhythm of these animals. We conclude that, following restoration of a transient uremic and hypocalcemic episode induced by LCD feeding, the Q.EEG background frequency of juvenile renally impaired rats was abnormally slow after 30 days of ND feeding.     

More than a message: framing public health advocacy to change corporate practices.

Framing battles in public health illustrate the tension in our society between individual freedom and collective responsibility. This article describes how two frames, market justice and social justice, first articulated in a public health context by Dan Beauchamp, influence public dialogue on the health consequences of corporate practices. The authors argue that public health advocates must articulate the social justice values motivating the changes they seek in specific policy battles that will be debated in the context of news coverage. The authors conclude with lessons for health education practitioners who need to frame public health issues in contentious and controversial policy contexts. Specific lessons include the importance of understanding the existing values and beliefs motivating the public health change being sought, the benefits of articulating core messages that correspond to shared values, and the necessity of developing media skills to compete effectively with adversaries in public debate.     

Cerebral venous thrombosis as a cause of neonatal seizures

Intracranial venous thrombosis has been described in newborns, but there have been no reports of intractable neonatal seizures due to this condition. We report cortical venous sinus thrombosis in two term neonates who presented with seizures in the first 24 hours of life. The diagnosis was made by cranial computed tomography and was confirmed by cerebral angiography. Both patients improved clinically after the intracranial venous thrombosis resolved. These patients demonstrate that intracranial venous thrombosis should be considered in the differential diagnosis of neonatal seizures.     

Statistical analysis of gait patterns of persons with cerebral palsy

Patients at Boston's Children's Hospital diagnosed as having cerebral palsy were filmed walking. These films were digitized and translated into measurements associated with leg motion. In this paper we use the gait measurements of 128 such patients to illustrate that the kth nearest neighbour clustering procedure results in a gait typology for patients with cerebral palsy. The procedure identifies four subpopulations from the sample data; the membership of a patient within this typology is mostly determined by the patient's motor control. The developed typology differs from the present diagnostic system which classifies a cerebral palsy patient as either quadriplegic, diaplegic or hemiplegic.