Vitamin B12, demyelination, remyelination and repair in multiple sclerosis

Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.     

Pseudo-subarachnoid hemorrhage: a CT-finding in spontaneous intracranial hypotension

Increased attenuation in the basilar cisterns or along the tentorium cerebelli resembling subarachnoid hemorrhage (SAH) may be found on CT in the absence of blood (pseudo-SAH). The authors found pseudo-SAH on CT in four of 40 patients with spontaneous intracranial hypotension. All four patients had brain sagging with obliteration of the cisterns and pachymeningeal enhancement along the tentorium cerebelli. Spontaneous intracranial hypotension should be included in the differential diagnosis of pseudo-SAH.     

Retinotectal transmission in the optic tectum of rainbow trout

Retinotectal transmission has not yet been well characterized at the cellular level in the optic tectum. To address this issue, we used a teleost, the rainbow trout, and characterized periventricular neurons as postsynaptic cells expected to receive the retinotectal inputs to the optic tectum. The somata of periventricular neurons are localized in the upper zone of the stratum periventriculare (SPV), whereas the lower zone of the SPV comprises the cell body layer of radial glial cells. Ca2+ imaging identified functional ionotropic glutamate receptors in periventricular neurons. We also cloned cDNAs encoding the NR1 subunit of N-methyl-D-aspartic acid (NMDA) receptors and the GluR2 subunit of (+/-)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors, and detected their mRNAs in periventricular neurons by in situ hybridization. The presence of the receptor subunit proteins was also confirmed in the dendrites of periventricular neurons by immunoblotting and immunohistochemistry. On the other hand, radial glial cells in the lower zone of the SPV did not respond to glutamate applications, and mRNA and immunoreactivities of ionotropic glutamate receptors were not detected in glial cells. The present findings suggest that glutamatergic transmission at synapses between retinotectal afferents and periventricular neurons is mediated by the functional NMDA and AMPA receptors.     

Pharmacokinetics and clinical effects of mono-L-aspartyl chlorin e6 (NPe6) photodynamic therapy in adult patients with primary or secondary cancer of the skin and mucosal surfaces

BACKGROUND/PURPOSE: Mono-L-aspartyl chlorin e6 (NPe6) is a photosensitizer that exhibits chemical purity, absorption at 664 nm wavelength and may be useful in photodynamic therapy (PDT). METHODS: This open label phase I clinical trial at the University of California, Davis Medical Center examined the pharmacokinetic properties of Npe6 and clinical response to PDT with this photosensitizer. A single intravenous dose of Npe6 was administered to 14 cancer patients with superficial malignancies (basal cell carcinoma = 22 lesions, squamous cell cancer = 13 lesions, papillary carcinoma = 14 lesions). Patients received one of five ascending doses (0.5 mg/kg (n = 4), 1.0 mg/kg (n = 3), 1.65 mg/kg (n = 3), 2.5 mg/kg (n = 3), or 3.5 mg/kg (n = 1)) 4-8 h prior to light activation. The total light dose (range 25-200 J/cm2) depended on the tumor shape and size. Light was delivered using an argon-pumped tunable dye laser. Serum NPe6 concentrations were measured over a 28-day period. The toxicity and cutaneous clinical efficacy of NPe6 were observed. RESULTS: Four weeks post-PDT, 20 of 22 basal cell carcinoma tumors (91%) showed a complete response. Eighteen of 27 other malignant cutaneous tumors showed a complete (n = 15/27, 56%) or partial (n = 3/27, 11%) response. Fewer non-responders were seen at an Npe6 dose level of 1.65 mg/kg or higher. Only 2 of 14 patients experienced an adverse event that was definitely related to NPe6 administration. Photosensitivity resolved within 1 week of NPe6 dosing in 12 of 14 patients. Analysis of serum levels of 11 individual patients indicated that a two-compartment model with a residual phase best fits the data. The mean alpha, beta, and terminal half-lives were 8.63+/-2.92, 105.90+/-37.59 and 168.11+/-53.40 h (+/-1 SD), respectively. The observed mean volume of distribution was 5.94+/-2.55 l, and the mean clearance was 0.0394+/-0.0132 l/h. These values were independent of the dose administered. CONCLUSION: The photosensitizer, NPe6, was well tolerated with minimal phototoxic side effects, and demonstrated preliminary efficacy against cutaneous malignancies.     

Infanticide in female forensic patients: the view from the evolutionary standpoint

Evolutionary theory predicts that very young mothers would be more likely to kill an infant than older women, given that the younger mother has a much greater ability to "replace" the dead child through subsequent pregnancies and thus to produce offspring for the next generation. Evolutionary theory also predicts that a woman would be more likely to kill a child if the child was obviously defective, the pregnancy was the result of incest or rape, or if the mother's means of supporting the child were severely compromised. The authors hypothesized that mentally ill mothers would behave in a way that differed significantly from evolutionary expectations, i.e., that they would be more likely to kill children who were older than those killed by mothers in the general population and that the mothers themselves would be likely to be older than mothers in the general population when the murders occurred. To test this hypothesis, the authors compared infanticides (both filicides and neonaticides) committed by mentally ill mothers with those committed by mothers in the general population. They examined two samples: 1) all cases of maternal infanticide from the Mid-Hudson Forensic Psychiatric Hospital from 1978 (when the hospital began admitting female patients) through the year 2000 and 2) a general population sample from a 10-year Canadian study reported by Daly and Wilson in 1998. The authors focused on the following variables: ages of the mothers, ages of the child-victims, whether the pregnancy was the result of rape or incest, whether the child had significant behavioral or physical problems, and whether there were problems supporting the child (e.g., having no partner, poverty, mother's lack of education). The results of the analyses supported the authors' hypothesis about ages of mothers and children. The mentally ill mothers in the Mid-Hudson sample were generally older when they killed their children and the children who were killed were generally older than in the Daly and Wilson general population sample (where the majority of the cases involved neonaticide and the mothers were generally younger than 25 years of age). The three factors, poverty, low education level (or low intellectual capacity), and lack of a spouse were common in both samples. Findings concerning cultural factors, motives, and methods used will be presented in separate publications.     

Pseudopyronines A and B, alpha-pyrones produced by a marine Pseudomonas sp. F92S91, and evidence for the conversion of 4-hydroxy-alpha-pyrone to 3-furanone

In our search for inhibitors of bacterial fatty acid biosynthesis, two new alpha-pyrones, pseudopyronines A (1) and B (2), were isolated from a marine Pseudomonas sp. F92S91. The naturally occurring alpha-pyrones appeared to be unstable, evidenced by the conversion of pseudopyronine B into an oxidation product, 3-furanone (3). Structural elucidations were made by spectroscopic analyses including 2D-NMR data.     

Nucleolar precursor body distribution in pronuclei is correlated to chromosomal abnormalities in embryos

In-vitro generated human embryos have low implantation rates and high chromosomal abnormalities. Embryos are mostly selected on the basis of microscopic morphological examination. The relationship between pronuclear morphology and chromosomal abnormalities was investigated in this study. Zygotes were scored according to pronuclear morphology on day 1. Excess embryos that were not transferred or cryopreserved on day 3 were fixed. Chromosomes 13, 18, 21, X and Y were analysed by fluorescence in-situ hybridization (FISH). A total of 125 embryos were analysed; 58 (46%) were abnormal, 32 (26%) were mosaic and 35 (28%) were normal. Results were analysed according to different pronuclear morphology. Zygotes with polarized pattern had a significantly lower incidence of chromosome abnormality than those with a non-polarized pattern. The presence of cytoplasmic halo, the size of each pronucleus and the number of nucleolar precursor body had no significant effect on chromosomal abnormalities. In conclusion, embryos generated from zygotes with polarized pattern have fewer chromosomal abnormalities compared with other patterns. A simple microscopic examination during fertilization confirmation would be useful to select embryos with fewer chromosomal abnormalities, preferably in combination with other observations shown to correlate with chromosomal abnormalities.     

Estimating the contribution of genes and environment to variation in renal drug clearance

Renal excretion is the major pathway for elimination of many clinically used drugs and xenobiotics. We estimated the genetic component (rGC) contributing to variation in renal clearance for six compounds (amoxicillin, ampicillin, metformin, terodiline, digoxin and iohexol) using Repeated Drug Application methodology. Data were obtained from published literature. The rGC values of renal clearance of metformin, amoxicillin, and ampicillin, which undergo transporter-mediated secretion, ranged from 0.64-0.94. This finding suggests that variation in the renal clearance of these drugs has a strong genetic component. Additionally, the rGC values of renal clearance of metformin, amoxicillin, and ampicillin were similar to previously reported rGC values for metabolism. By contrast, the rGC values of renal clearance for iohexol, digoxin, and terodiline were low (0.12-0.37). Renal clearance of these compounds occurs mainly through passive processes (e.g. glomerular filtration and passive secretion/reabsorption). The low rGC values of iohexol, digoxin and terodiline suggest that environmental factors may contribute to variation in their renal clearance.