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Trail:
Ultra Violet
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 Scientific
papers - Ultra Violet - page 5
PrPc metabolic link to the circadian cycle
Evidence also exists for a direct functional association between PrPe
and the circadian response (91,92). One of the few clinical
abnormalities that have been consistently observed in mice engineered
for PrP knock-out entails a fundamental disturbance in CNS regulation of
the circadian rythmn; thereby indicating some functional/regulatory role
for PrPc at some stage of the UV-pineal-melatonin-serotonergic pathway.
Interestingly, melatonin levels are regulated by Cu levels, whilst
levels of Cu, Mn and melatonin in serum follow the circadian cycle (93).
Retinal involvement in the early clinical/pathological stages of TSE
Retinal degeneration has been commonly described in scrapie,
transmissible mink encephalopathy (TME), CWD, CJD, Kuru, BSE (2,94-98)
with degeneration chiefly affecting the photoreceptor layer of the
retina (99-106). The retinal degeneration coincides with the onset of
spongiform, degeneration (101) and invariably appears very early in the
course of disease before the development of neurological dysfunction
(100,96). Interestingly, extracts from the Mn-rich retina and pituitary
of TSEdiseased CNS tissues carry the highest titre of 'infectivity' in
transmission trials employing TSE-diseased CNS (1). Furthermore, TSE
infectivity of the retina has been demonstrated in retinal tissue
extracted prior to the development of visible lesions (102).
The optic nerve also carries TSE infectivity with evidence existing for
anterograde (103) and retrograde (104) transport of the prion agent
along the optic nerve connecting to the brain. Astrocytosis of the optic
nerve head has also been observed in CJD (105).
Ocular surgery (involving the cornea, etc.) and ocular tonometry are
considered to be predisposing risk factors for CJD (1,2). Whilst the
hypothetical consensus on this risk is based on the reductionist
perspective that ocular surgery opens up another route for TSE
infection, the true relevance of this association could lie with the
fact that the ocular disturbances involved are merely manifesting the
primary clinical stages of the TSE syndrome resulting from a collapse in
PrP and other antioxidant capacities to neutralize photooxidative
stress.
Other clinical disturbances in TSEs that could relate to a breakdown in
the photobiological respone, involves a range of visual disturbances in
17% of CJD patients (agnosia, diploplia, blurred/distorted vision,
etc.), and pruritis of exposed skin surfaces - particularly prevalent in
scrapie, BSE, CWD, etc. (1,2). Cortical blindness in TSEs (1)(2) relates
to lesions in the visual cortex.
A study of acute high dose effects of UVB on biological systems
demonstrates that a range of cancer causing lesions can be induced in
DNA: formation of dimer compounds, crosslinking, product additions to
bases, chain breaks, etc. (106). Whilst these lesions have seemingly
never been investigated in the ocular pathology of TSEs, the lack of
ocular/skin cancers as predisposing risk factors for TSEs could merely
indicate that the normal DNA repair systems have successfully suppressed
any carcinogenic reactions likely to emerge following the long-term
chronic exposures to above average doses of UV
However, Eva Mitrova reports that a high percentage of CJD sufferers in
the Slovak clusters had been previously afflicted with retinal
pigmentosa - a condition where UV induced DNA lesions in the retina fail
to repair because of an inborn recessive defect in the expression of
repair enzymes in these genotypes. However, rnitochondrial DNA strand
breaks (74) and crosslinked proteins (1,2) have been identified in the
fibril tombstones of scrapie affected CNS tissue.
SPATIAL EPIDEMIOLOGICAL CORRELATIONS BETWEEN AREAS OF HIGH LEVEL UV
EXPOSURE AND HIGH INCIDENCE FOCI OF SPORADIC/FAMILIAL TSEs
One hitherto unexplained geographical characteristic common to the
location of sporadic TSE clusters involves the isolated rural nature of
the TSE-aftected communities and their position at high altitudes on
peaked volcanic, preCambrian, mountain ranges that remain snow-covered
for the majority of the year, examples being the CJD clusters in the
High Tatra mountains of Slovakia (27), the Calabrian Aspromonte
mountains (adjoining Mount Etna) (34), the Kofu Mountain in japan (102),
the Highlands of Papua New Guinea (18), CWD cluster in deer of the Rocky
Mountains in Colorado (21,22), scrapie clusters in sheep of the N.
Icelandic mountains (32,33), the Aragon mountains in Spain (108), the
Brecon Beacons in the UK, and more recently the Sopramonte mountains in
Sardinia (109).
A correlation exists between these high-incidence TSE cluster
mountainous localities and the areas where acid rainfall is prevalent
(26,110). Acid rain unlocks the availability of Mn and other cations in
such foodchains.
It is also widely recognized that the chronic hypoxia of high-altitude
living renders mammals more susceptible to oxidative stress (111) as
well as increasing the permeability of their blood/brain barriers to
cations such as manganese (112).
It is also widely recognized that these high-altitude environments are
naturally challenged by higher levels of UVA radiation as well as the
more potent UVB wavelength radiation (110, 113, 106) which, in turn,
generates high ground levels of tropospheric ozone gas in the more
polluted atmospheres (110, 113-116). Both UV and ozone invoke oxidative
stress in biological systems (7).
Photokeratitis or 'snowblindness' traditionally develops in those who
live/work in the snowclad mountain environs as a result of visual
contact with the higher intensities of UV photons reflected from the
snow (114). Higher UV intensities are also encountered in coastal
locations where sand and sea reflect the UV rays (106,114). One
excellent example of a putative association between this phenomenon and
TSE incidence can be found in the Calabrian hamlet where 20 cases of CJD
have erupted since 1995 - 20 years since they were moved from their
remote mountaintop village and rehoused by a government-funded scheme in
a new coastal settlement. A combination of their newly constructed white
concrete houses/streets (unique to this area), widespread coastal view
and the surrounding bare white sandstone hillside terraces (planted with
young olive trees) has caused the development of a 'UV hotspot' that is
unprecedented in the area.
UV radiation is also more intense in the broad vicinity around volcanoes
where chlorinated emissions have thinned the ozone column in the
stratosphere above - thus permitting greater intensities of UV to
temporally penetrate the Earth's surface following erruption (110, 114).
Rural communities also receive significantly greater intensities of UV
radiation than urban communities. This is due to the high intensity of
pollutants emitted from urban areas into the troposphere above - such as
nitrogen and sulphur dioxides - which serve to scatter and absorb
incoming UV radiation before the rays reach the ground (106,113,114).
Whilst the highest international incidence rate of scrapie in Icelandic
sheep (32,33) could be partly attributed to the high Mn/low Cu recorded
there (4), the protracted 23-hour daylight interval of the Arctic summer
may fulfil the further photooxidative prerequisite required for
initiating TSE. Whilst the lower elevation of the sun's rays in Iceland,
(being diminished near the Arctic pole), serves to decrease the overall
summertime intensity of UV exposure in that region (114), this would not
entirely compensate for the photooxidative impact of a prolonged 23
hours of UV exposure encountered during clear weather conditions - the
ozone layer being thinner above Iceland than at the equator.
Furthermore, clinical signs of scrapie are usually first recognized in
August, at the end of the summer mountain-grazing period (32).
An occupational risk category for CJD has always centred around people
who spend a greater part of their occupational and/or leisure time
outdoors in rural areas (1,27-29,34, 107, 117, 121) often at higher
altitudes or on the coast; e.g. those most exposed to UV such as
farmers, foresters, Naval/RAF personnel, horse-riders, pet-keepers,
milkmen, builders, market-gardeners, keep-fit fanatics and, more
recently in respect of nvCJD, young Western European people who
generally aspire to the tanned image and are sufficiently economically
privileged to spend increased amounts of leisure time holidaying
abroad/sunbathing on the beach or exposing themselves to recently
introduced artificial sources of UV via trendy laser lighting/solaria/sunbeds
(122-125,126). However, significant incidences of CJD also arise in
those employed in various indoor occupations, such as caterers, nurses,
dentists, laboratory workers, plumbers, hairdressers, cleaners, metal
cutters, water treatment workers, etc. (119-12 1), and, incerestingly,
all of these professions are cited as occupations associated with
potential risk of overexposure to UV (106) - where UV may be employed
artificially in flytrap strip lighting used in catering/food processing
premises, or as UV germicides in water/sewage treatment,
hospitals/dentists, public lavatories, laboratories and schools, or as
used in arc welding, hairdressing salons, glass blowing, plasma torches,
tobacco irradiation chemical analysis, pharmaceutical laboratories,
projector lamps, ink curing lamps, drying lacquers or resins in
photocopying/printing, etc. (106,116). Phototherapy with UV is also
employed to treat babies/young mammals for vitamin D deficiencies or
jaundice derived from hyperbilirubaemia or kernicterus (126).
Other mammalian species affected by TSEs involve wild or domesticated
animals such as deer/sheep/ goats/cats/cows/zoo animals (2) who are
often compelled or simply choose to spend a greater part of their
daylight hours feeding/resting in unshaded open countryside. The
grant-supported trend of removing woodland and hedgerow from
agricultural land in the UK during the 1970s and 1980s left farm
livestock with little choice other than to graze pastures where access
to shade was unavailable, thus exacerbating any UV-related problems.
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