Bioactive Properties of Carotenoids in Human Health.

Research shows that certain bioactive compounds in our diet have beneficial effects on humanhealth[...].

Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice.

Patients with congenital disorder of glycosylation (CDG), type Ib (MPI-CDG or CDG-Ib) have mutations in phosphomannose isomerase (MPI) that impair glycosylation and lead to stunted growth, liver dysfunction, coagulopathy, hypoglycemia, and intestinal abnormalities. Mannose supplements correct hypoglycosylation and most symptoms by providing mannose-6-P (Man-6-P) via hexokinase. We generated viable Mpi hypomorphic mice with residual enzymatic activity comparable to that of patients, but surprisingly, these mice appeared completely normal except for modest (~15%) embryonic lethality. To overcome this lethality, pregnant dams were provided 1-2% mannose in their drinking water. However, mannose further reduced litter size and survival to weaning by 40 and 66%, respectively. Moreover, ~50% of survivors developed eye defects beginning around midgestation. Mannose started at birth also led to eye defects but had no effect when started after eye development was complete. Man-6-P and related metabolites accumulated in the affected adult eye and in developing embryos and placentas. Our results demonstrate that disturbing mannose metabolic flux in mice, especially during embryonic development, induces a highly specific, unanticipated pathological state. It is unknown whether mannose is harmful to human fetuses during gestation; however, mothers who are at risk for having MPI-CDG children and who consume mannose during pregnancy hoping to benefit an affected fetus in utero should be cautious.

Blue light stimulates cognitive brain activity in visually blind individuals.

Light regulates multiple non-image-forming (or nonvisual) circadian, neuroendocrine, and neurobehavioral functions, via outputs from intrinsically photosensitive retinal ganglion cells (ipRGCs). Exposure to light directly enhances alertness and performance, so light is an important regulator of wakefulness and cognition. The roles of rods, cones, and ipRGCs in the impact of light on cognitive brain functions remain unclear, however. A small percentage of blind individuals retain non-image-forming photoreception and offer a unique opportunity to investigate light impacts in the absence of conscious vision, presumably through ipRGCs. Here, we show that three such patients were able to choose nonrandomly about the presence of light despite their complete lack of sight. Furthermore, 2 sec of blue light modified EEG activity when administered simultaneously to auditory stimulations. fMRI further showed that, during an auditory working memory task, less than a minute of blue light triggered the recruitment of supplemental prefrontal and thalamic brain regions involved in alertness and cognition regulation as well as key areas of the default mode network. These results, which have to be considered as a proof of concept, show that non-image-forming photoreception triggers some awareness for light and can have a more rapid impact on human cognition than previously understood, if brain processing is actively engaged. Furthermore, light stimulates higher cognitive brain activity, independently of vision, and engages supplemental brain areas to perform an ongoing cognitive process. To our knowledge, our results constitute the first indication that ipRGC signaling may rapidly affect fundamental cerebral organization, so that it could potentially participate to the regulation of numerous aspects of human brain function.

Hypothalamic neurosecretory and circadian vasopressinergic neuronal systems in the blind cone-rod homeobox knockout mouse (Crx-/-) and the 129sv wild-type mouse.

Vasopressin (AVP) is both a neuroendocrine hormone located in magnocellular neurosecretory neurons of the hypothalamus of mammals but also a neurotransmitter/neuromodulator in the parvocellular suprachiasmatic nucleus (SCN). The SCN is the endogenous clock of the brain and exhibits a prominent circadian AVP rhythm. We have in this study of the brown 129sv mouse and the visual blind cone-rod homeobox gene knock out mouse (Crx(-/-) ) with degeneration of the retinal rods and cones, but a preserved non-image forming optic system, studied the temporal Avp expression in both the neurosecretory magnocellular and parvocellular vasopressinergic systems in both genotypes. We here present a detailed mapping of all classical hypothalamopituitary and accessory magnocellular nuclei and neurons in the hypothalamus by use of immunohistochemistry and in situ hybridization in both genotypes. Semiquantitative in situ hybridization revealed a very high expression of Avp mRNA in all the magnocellular nuclei compared with a much lower level in the parvocellular suprachiasmatic nucleus. In a series of mice killed every 4 hours, the Avp mRNA expression in the SCN showed a significant daily rhythm with a zenith at late day time and nadir during the dark in both the Crx(-/-) and the wild type mouse. None of the magnocellular neurosecretory neurons exhibited a diurnal vasopressin expression. Light stimulation of both genotypes during the dark period did not change the Avp expression in the SCN. This shows that Avp expression in the mouse SCN is independent of Crx-regulated photoreceptor systems.

S-adenosyl-L-methionine restores photoreceptor function following acute retinal ischemia.

The survival and function of retinal neurons is dependent on mitochondrial energy generation and its intracellular distribution by creatine kinase. Post ischemic disruption of retinal creatine synthesis, creatine kinase activity, or transport of creatine into neurons may impair retinal function. S-adenosyl-L-methionine (SAMe) is required for creatine synthesis, phosphatidylcholine and glutathione synthesis, and transducin methylation. These reactions are essential for photoreceptor function but may be downregulated after ischemia due to a reduction in SAMe. Our aim was to determine whether administration of SAMe after ischemia could improve retinal function. Unilateral retinal ischemia was induced in adult rats by increasing the intraocular pressure to 110 mm Hg for 60 min. Immediately after the ischemic insult, SAMe was injected into the vitreous (100 microM), followed by oral administration (69 mg/kg/day) for 5 or 10 days. Retinal function (electroretinography), histology, and creatine transporter (CRT-1) expression were analyzed. Photoreceptoral responses (R(mP3), S), rod and cone bipolar cell responses (PII), and oscillatory potentials were reduced by the ischemia/reperfusion insult. Although SAMe treatment ameliorated the ischemia-induced histological damage by day 5, there was no improvement in retinal function and the intensity of CRT-1 labeling in ischemic retinas was markedly reduced. However, 10 days after ischemia, a recovery in CRT-1 immunolabeling was evident and SAMe supplementation significantly restored photoreceptor function and rod PII responses. In conclusion, these data suggest that creatine transport and methylation reactions, such as creatine synthesis, may be compromised by an ischemic insult contributing to retinal dysfunction and injury. Oral SAMe supplementation after retinal ischemia may provide an effective, safe, and accessible neuroprotective strategy.

Vasospastic amaurosis fugax in a patient with overlap collagenosis treated with nimodipine.

Vasospasm has been discussed as a less frequent cause of amaurosis fugax. Since its direct demonstration is difficult, its diagnosis is usually based on the exclusion of other causes and/or response to calcium entry blockers. We describe diagnosis and successful treatment of vasospastic amaurosis fugax in a patient with systemic autoimmune disease: A 54 year-old patient with an overlap collagenosis presented with relapsing episodes of transient monocular blindness. Angiography and transcranial Doppler scanning revealed a high-grade stenosis of the left ophthalmic artery. After administration of oral nimodipine the attacks ceased immediately and repeated Doppler examinations confirmed resolution of the stenosis. We infer that vasospasm of inflammatory altered cerebral vessels may contribute to focal neurological deficits in patients with systemic autoimmune disease. Calcium entry blockers should be discussed as a possible treatment in patients with systemic autoimmune disease and evidence of functional disturbances of cerebral blood flow.

Effects of blinding and pinealectomy on regional brain monoamine concentrations.

The effects of blinding with or without pineal ablation on brain monoamine levels were studied in male rats. Brain dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT) were measured by radioenzymatic assays. Four weeks following pinealectomy, E levels were significantly enhanced in the frontal cortex. Chronic blinding decreased striatal DA levels and increased striatal 5-HT levels in both sham-operated and pinealectomized (Px) animals. In a second experiment Px animals were sacrificed 1 or 7 d after pinealectomy in order to examine the short-term effects of pinealectomy. There were no differences between controls and Px animals in their cortical levels of DA, NE, and E and their hippocampal and hypothalamic 5-HT levels. However, the E concentrations measured 1 d after surgery were significantly greater than after 7 d. The implications of these findings with regard to the reported role of the pineal and melatonin in brain homeostasis and endocrine regulation are discussed.

Reduced dopamine synthesis and protein levels in the median eminence of blinded anosmic female rats: relation to the pineal.

Twenty 25 day old female Sprague-Dawley rats were enucleated (BL) and olfactory bulbectomized (ANOS) and one half of these were also pinealectomized (PINX). Ten female rats received no surgical manipulation (CONTROL). Thirty days later each rat received NSD-1015 30 minutes before killing. The median eminence, telencephalon and hypothalamus were collected. Tyrosine hydroxylase activity, determined by the accumulation of DOPA after NSD-1015, was significantly reduced in the median eminence of BL+ANOS (p less than 0.05). Dopamine and noradrenaline levels in this tissue were not different among the experimental groups. Protein levels in the median eminence was also significantly reduced in BL+ANOS and PINX rats. None of the above parameters were different in the hypothalamus among the 3 experimental groups. These data suggest that the activity of the dopaminergic tuberoinfundibular neurons is reduced in both BL+ANOS and PINX rats. The reduced protein may reflect a reduction in protein synthesis, a decrease in numbers of nerve terminals or a reduction of pituitary regulatory hormones in BL+ANOS and PINX rats.

Neuropathology of experimental vitamin B12 deficiency in monkeys.

We have produced severe vitamin B12 deficiency in rhesus monkeys by feeding them a defined experimental diet under controlled conditions. Five years after institution of the deficient diet, the morphology and counts of peripheral blood and bone marrow are normal. Gross visual impairment appeared in five of the monkeys between 33 and 45 months after the institution of the vitamin B12 deficient diet. Subsequently, in three of the visually impaired animals, a gradually progressive spastic paralysis of their hind limbs developed. Autopsies of six deficient animals showed degeneration of the peripheral visual pathway in all and of white matter in the spinal cord in four. Degeneration of several cranial nerve roots was found in four monkeys and a mild diffuse degeneration of cerebral white matter in four. The lesions in all affected parts of the central nervous system were bilaterally symmetrical and were indistinguishable from those due to B12 deficiency in the human. No abnormalities were found in one B12 supplemented control animal.

[Effect of early visual deprivation on the free amino acid and protein content in the brain formations of dogs]. / Vliianie rannei zritel'noi deprivatsii na soderzhanie svobodnykh aminokilsot i belkov v obrazovaniiakh mozga sobak

10 days old dogs were subjected to bilateral enucleation of eyeballs. When the dogs became 3 months old, content of free amino acids and total proteins was determined in tissue of brain formation of optic system (optic cortex-field 17, external knee body and front bigeminal bodies). locomotor and partietal regions of brain cortex and cerebellum. As compared with the control group, the amount of proteins was distinctly decreased in optic cortex and increased in external knee body. In all he brain formations studied content of arginine, lysine, gamma-aminobutyric acid, cysteine (except of external knee body) and histidine (except of external knee body and front bigeminal bodies) was distinctly increased. The decrease in content of glutamic acid was observed only in front bigeminal bodies and aspartic acid -- in cerebellum. Glutathione was accumulated selectively in front bigeminal bodies and in locomotor cortex.

Diurnal rhythms in pineal N-acetyltransferase and hippocampal norepinephrine: effects of water deprivation, blinding and hypothalamic lesions.

The pineal gland in the rat exhibits a diurnal rhythm in activity of the enzyme serotonin N-acetyltransferase (N-AT) with peak values during the dark period of a diurnal lighting schedule approximately 100-fold those during the light period. After blinding the rhythm becomes free-running. It is abolished by partial hypothalamic deafferentation with a knife cut made caudal to the optic chiasm. Water deprivation for 23 h daily has no effect on the pineal rhythm in either intact, blinded or deafferented animals. In contrast to this, there is a diurnal rhythm in hippocampal formation in norepinephrine content which can be entrained by a water deprivation schedule in both intact and blinded animals. These observations indicate that in the same animals 1 diurnal rhythm may remain entrained to the light-dark cycle while another rhythm is entrained to a secondary synchronizer, the water deprivation schedule.