The ketogenic diet compensates for AGC1 deficiency and improves myelination.

The brain aspartate-glutamate carrier (AGC1) is specifically expressed in neurons, where it transports aspartate from the mitochondria to the cytosol, and plays a role in transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle. Deficient function of AGC1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC1 deficiency, there is secondary hypomyelination due to lack of N-acetylaspartate (NAA), which is normally generated by acetylation of aspartate in the neuron and required for fatty acid synthesis by the adjacent oligodendrocyte. Based on experiences from AGC2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC1 deficiency at 6 years of age by introducing a ketogenic diet. The response was dramatic, clinically as well as radiologically. Psychomotor development showed clear improvement, and magnetic resonance imaging (MRI) indicated resumed myelination. This is the first successful treatment of secondary hypomyelination reported. Because AGC1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.

On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO.

A new mechanism for formation of 7-ketocholesterol was recently described involving cytochrome P-450 (CYP)7A1-catalyzed conversion of 7-dehydrocholesterol into 7-ketocholesterol with cholesterol-7,8-epoxide as a side product. Some patients with cerebrotendinous xanthomatosis (CTX) and all patients with Smith-Lemli-Opitz syndrome (SLO) have markedly increased levels of 7-dehydrocholesterol in plasma and tissues. In addition, the former patients have markedly upregulated CYP7A1. We hypothesized that these patients may produce 7-ketocholesterol from 7-dehydrocholesterol with formation of cholesterol-7,8-epoxide as a side product. In accord with this hypothesis, two patients with CTX were found to have increased levels of 7-ketocholesterol and 7-dehydrocholesterol, as well as a significant level of cholesterol-7,8-epoxide. The latter steroid was not detectable in plasma from healthy volunteers. Downregulation of CYP7A1 activity by treatment with chenodeoxycholic acid reduced the levels of 7-ketocholesterol in parallel with decreased levels of 7-dehydrocholesterol and cholesterol-7,8-epoxide. Three patients with SLO were found to have markedly elevated levels of 7-ketocholesterol as well as high levels of cholesterol-7,8-epoxide. The results support the hypothesis that 7-dehydrocholesterol is a precursor to 7-ketocholesterol in SLO and some patients with CTX.

Prolonged grievers: a qualitative evaluation of a support group intervention.

OBJECTIVE: The aim of this project was to study prolonged grievers psychosocial processes and experience during participation in a group intervention and 6-8 weeks after discontinuation. The intervention in this study was a group therapy with the aim of getting in contact with their pain and loss and confronting and working with this loss. METHODS: Data was collected by using diaries and tape-recorded interviews, analyzed with grounded theory. The participants were 11 females between the ages of 33 and 71. RESULTS: The main process that was found in the qualitative data was: Ambivalence when struggling and learning through work and rest towards a balance. Sub-processes were: To share and be confirmed in the group through sense of cohesion; To dare/venture to discover problems and solutions; To react when you get emotionally involved, and to compare and discover. SIGNIFICANCE OF RESULTS: This study gives insight into prolonged grievers' thinking, which is valuable knowledge. Rather than assuming that all individuals suffering from prolonged grief need the same treatment, we suggest that there should be a range of different therapies.

AGC1 deficiency associated with global cerebral hypomyelination.

The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1), specific to neurons and muscle, supplies aspartate to the cytosol and, as a component of the malate-aspartate shuttle, enables mitochondrial oxidation of cytosolic NADH, thought to be important in providing energy for neurons in the central nervous system. We describe AGC1 deficiency, a novel syndrome characterized by arrested psychomotor development, hypotonia, and seizures in a child with a homozygous missense mutation in the solute carrier family 25, member 12, gene SLC25A12, which encodes the AGC1 protein. Functional analysis of the mutant AGC1 protein showed abolished activity. The child had global hypomyelination in the cerebral hemispheres, suggesting that impaired efflux of aspartate from neuronal mitochondria prevents normal myelin formation.

Latanoprost and pigmentation.

Latanoprost is a prostaglandin analogue with well-established efficacy in the treatment of open-angle glaucoma and ocular hypertension. Once-daily administration of this drug for up to 5 years is generally well tolerated both locally and systemically. While most reported side effects have been classified as mild in intensity, an increase in iris, eyelash, and periocular pigmentation has been associated with prostaglandin analogue use in some patients. Follow-up studies of patients withdrawn from latanoprost treatment suggest that the increased iridial pigmentation is irreversible while changes in eyelash and periocular skin pigmentation are reversible after cessation of therapy. Concern as to whether latanoprost affects proliferation of iridial melanocytes or other cellular components prompted investigation into its mechanism of action. All available evidence from in vitro, in vivo, and clinical studies suggests that latanoprost does not induce melanocyte proliferation. Morphologic study of human peripheral iridectomy specimens did not reveal any significant latanoprost-induced pathologic change in the iris. There was no evidence of melanin granules blocking the outflow pathways in treated patients. Stimulation of melanogenesis in iridial melanocytes, perhaps through an effect on tyrosinase, appears to account for induction of melanin production. Additional studies are in progress to further elucidate the mechanism of latanoprost-induced increased iridial pigmentation.

Development of mass transport resistance in poly(lactide-co-glycolide) films and particles--a mechanistic study.

Poly(D,L-lactide-co-glycolide) (PLG) is the most frequently used biodegradable polymer in the controlled release of an encapsulated drug. The purpose of this work was to explain the surprisingly slow diffusion through this polymer, and locate the major source of mass transport resistance. Diffusion of human growth hormone (hGH) and glucose through PLG films was undetectable (using a diffusion cell), although the degraded polymer contained several times more water than polymer mass. In vitro release of hGH from PLG-coated particles also showed a surprisingly slow rate of release. Non-porous regions inside the PLG films were detected after three weeks of degradation using dextran-coupled fluorescent probes and confocal microscopy. The findings were supported by scanning electron microscopy. Diffusion through PLG films degraded for five weeks was significantly increased when the porosity of both surfaces was increased due to the presence of ZnCl(2) in the buffer the last 3 days of the degradation period. The results indicated high mass transport resistance inside the films after three weeks of degradation, and at the surfaces after five weeks of degradation. These results should also be applicable to microparticles of different sizes. Knowledge of the reason for transport resistance is important in the development of pharmaceuticals and when modifying the rate of drug release.

A Swedish cost-effectiveness analysis of community-based Chlamydia trachomatis PCR testing of postal urine specimens obtained at home.

AIMS: A study was undertaken to assess the cost-effectiveness of identifying and treating asymptomatic carriers of Chlamydia trachomatis when using community-based testing of urine specimens obtained at home and mailed to a central laboratory. METHODS: A total of 100 males and 100 females aged 20-24 living in Umeå were randomly sampled from the population registry. A societal cost-effective analysis was carried out, based on screening and medical care costs in Sweden. RESULTS: With a participation rate of 55% (45% males and 65% females), the female screening became cost-saving as the C. trachomatis prevalence exceeded 5.1%, and the male screening became cost-saving with over 12.3% prevalence. CONCLUSION: Postal screening for C. trachomatis in an asymptomatic young population can be cost-effective only at prevalences higher than at present.