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1.  Melanopsin-Dependent Photoreception Provides Earliest Light Detection in the Mammalian Retina 
Current biology : CB  2005;15(12):1099-1107.
Summary
Background
The visual system is now known to be composed of image-forming and non-image-forming pathways. Photoreception for the image-forming pathway begins at the rods and cones, whereas that for the non-image-forming pathway also involves intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin. In the mouse retina, the rod and cone photoreceptors become light responsive from postnatal day 10 (P10); however, the development of photosensitivity of the ipRGCs remains largely unexplored.
Results
Here, we provide direct physiological evidence that the ipRGCs are light responsive from birth (P0) and that this photosensitivity requires melanopsin expression. Interestingly, the number of ipRGCs at P0 is over five times that in the adult retina, reflecting an initial overproduction of melanopsin-expressing cells during development. Even at P0, the ipRGCs form functional connections with the suprachiasmatic nucleus, as assessed by light-induced Fos expression.
Conclusions
The findings suggest that the non-image-forming pathway is functional long before the mainstream image-forming pathway during development.
doi:10.1016/j.cub.2005.05.053
PMCID: PMC4316668  PMID: 15964274
3.  Melanopsin Signaling in Mammalian Iris and Retina 
Nature  2011;479(7371):67-73.
Lower vertebrates have an intrinsically-photosensitive iris and thus a local pupillary light reflex (PLR). In contrast, it has been a dogma that the PLR in mammals generally requires neuronal circuitry connecting the eye and the brain. We report here that an intrinsic component of the PLR is actually widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment, melanopsin. It also requires PLCβ4, the vertebrate homolog of the Drosophila NorpA phospholipase C mediating rhabdomeric phototransduction. The Plcβ4−/− genotype, besides removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1-subtype of melanopsin-expressing, intrinsically-photosensitive retinal ganglion cells (M1-ipRGCs), by far the most photosensitive ipRGCs and with the largest responses. Ablating in mouse the expression of both TRPC6 and TRPC7, members of the TRP channel superfamily, likewise essentially eliminated the M1-ipRGC light response, but spared the intrinsic PLR. Thus, melanopsin signaling exists in both iris and retina, involving a PLCβ4-mediated pathway that nonetheless diverges in the two locations.
doi:10.1038/nature10567
PMCID: PMC3270891  PMID: 22051675
4.  Replication study of SNP associations for colorectal cancer in Hong Kong Chinese 
British Journal of Cancer  2010;104(2):369-375.
Background:
Recent genome-wide association studies of colorectal cancer (CRC) have identified common single-nucleotide polymorphisms (SNPs) mapping to 10 independent loci that confer modest increased risk. These studies have been conducted in European populations and it is unclear whether these observations generalise to populations with different ethnicities and rates of CRC.
Methods:
An association study was performed on 892 CRC cases and 890 controls recruited from the Hong Kong Chinese population, genotyping 32 SNPs, which were either associated with CRC in previous studies or are in close proximity to previously reported risk SNPs.
Results:
Twelve of the SNPs showed evidence of an association. The strongest associations were provided by rs10795668 on 10p14, rs4779584 on 15q14 and rs12953717 on 18q21.2. There was significant linear association between CRC risk and the number of independent risk variants possessed by an individual (P=2.29 × 10−5).
Conclusion:
These results indicate that some previously reported SNP associations also impact on CRC risk in the Chinese population. Possible reasons for failure of replication for some loci include inadequate study power, differences in allele frequency, linkage disequilibrium structure or effect size between populations. Our results suggest that many associations for CRC are likely to generalise across populations.
doi:10.1038/sj.bjc.6605977
PMCID: PMC3031883  PMID: 21179028
colorectal cancer; genetic; association; replication; Chinese
5.  Natural attenuation, biostimulation and bioaugmentation on biodegradation of polycyclic aromatic hydrocarbons (PAHs) in mangrove sediments 
Marine pollution bulletin  2005;51(8-12):1071-1077.
The biodegradability of a mixture of PAHs, namely fluorene (Fl), phenanthrene (Phe) and pyrene (Pyr), in mangrove sediment slurry was investigated. At the end of week 4, natural attenuation based on the presence of autochthonous microorganisms degraded more than 99% Fl and Phe but only around 30% of Pyr were degraded. Biostimulation with addition of mineral salt medium degraded over 97% of all three PAHs, showing that nutrient amendment could enhance Pyr degradation. Bioaugmentation with inoculation of a PAH-degrading bacterial consortium enriched from mangrove sediments did not show any promotion effect and the degradation percentages of three PAHs were similar to that by natural attenuation. Some inhibitory effect was observed in bioaugmentation treatment in week 1 with only 50% Fl and 70% Phe degraded. These results indicate that autochthonous microbes may interact and even compete with the enriched consortium during PAH biodegradation. Natural attenuation appeared to be the most appropriate way to remedy Fl- and Phe-contaminated mangrove sediments while biostimulation was more capable to degrade Pyr-contaminated sediments. The study also shows that although a large portion of the added PAHs (more than 95%) was adsorbed onto the sediments at the beginning of the experiment, most PAHs were degraded in 4 weeks, suggesting that the degraders could utilize the adsorbed PAHs efficiently.
doi:10.1016/j.marpolbul.2005.06.006
PMCID: PMC2885898  PMID: 16023146
PAH-degraders; Fluorene; Phenanthrene; Pyrene; Bacterial consortium
6.  Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice 
Nature  2003;424(6944):76-81.
In the mammalian retina, besides the conventional rod–cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment1–7. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive8. Furthermore, pupil reflex8, light-induced phase delays of the circadian clock9,10 and period lengthening of the circadian rhythm in constant light9,10 are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype11, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells7. We have also generated mice lacking melanopsin coupled with disabled rod and cone photo-transduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod–cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
doi:10.1038/nature01761
PMCID: PMC2885907  PMID: 12808468
7.  Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity 
Science (New York, N.Y.)  2002;295(5557):1065-1070.
The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of the mammalian brain, is photoentrained by light signals from the eyes through the retinohypothalamic tract. Retinal rod and cone cells are not required for photoentrainment. Recent evidence suggests that the entraining photoreceptors are retinal ganglion cells (RGCs) that project to the SCN. The visual pigment for this photoreceptor may be melanopsin, an opsin-like protein whose coding messenger RNA is found in a subset of mammalian RGCs. By cloning rat melanopsin and generating specific antibodies, we show that melanopsin is present in cell bodies, dendrites, and proximal axonal segments of a subset of rat RGCs. In mice heterozygous for tau-lacZ targeted to the melanopsin gene locus, β-galactosidase–positive RGC axons projected to the SCN and other brain nuclei involved in circadian photoentrainment or the pupillary light reflex. Rat RGCs that exhibited intrinsic photosensitivity invariably expressed melanopsin. Hence, melanopsin is most likely the visual pigment of phototransducing RGCs that set the circadian clock and initiate other non–image-forming visual functions.
doi:10.1126/science.1069609
PMCID: PMC2885915  PMID: 11834834
8.  Authors' response 
Gut  2007;56(5):734.
PMCID: PMC1942134
9.  An unusual cause of gastric outlet obstruction 
Gut  2006;55(3):373.
doi:10.1136/gut.2005.075689
PMCID: PMC1856100  PMID: 16474106
vomiting; gall stone; Bourevet's syndrome
10.  Hospitalisation for gastroenteritis in Western Australia 
Archives of Disease in Childhood  2004;89(8):768-772.
Aims: To document gastroenteritis hospitalisations of the 1995–96 cohort of infants born in Western Australia to mid-2002, and to assess factors associated with their hospitalisations and readmissions.
Methods: Retrospective analysis of the State's hospitalisation data, Midwives' Notification of Births data, the Australian Bureau of Statistics mortality data and clinical and demographic information.
Results: Aboriginal infants were hospitalised for gastroenteritis eight times more frequently than their non-Aboriginal peers, and were readmitted more frequently and sooner for diarrhoeal illnesses than the other group. They also stayed in hospital for twice as long and many Aboriginal patients were hospitalised on numerous occasions. Hospitalisation rates were higher in remote areas and were significantly associated with co-morbidities such as undernutrition, anaemia, co-existing infections, and intestinal carbohydrate intolerance.
Conclusions: Gastroenteritis is very prevalent in Australian Aboriginal infants and children and is a major cause of their hospitalisation in Western Australia. It is often associated with undernutrition, anaemia, intestinal parasitic infestations, other infections, intestinal carbohydrate intolerance, and, in some instances, with low birth weight. This is often due to unhygienic living conditions and behaviours and presents major challenges to public health, health promotion, and clinical personnel, particularly paediatric services. Childhood diarrhoeal diseases occur commonly in other indigenous groups but have not received the attention that they deserve.
doi:10.1136/adc.2003.037531
PMCID: PMC1720021  PMID: 15269080
11.  Consultative team to assess manual handling and reduce the risk of occupational injury 
OBJECTIVES—To describe the formation of a consultative team to assess the risk of manual handling in the workplace that started in October 1992 within the cleaning services department of a 600 bed hospital, and to evaluate the effectiveness of its recommendations in reducing the rate and severity (time lost and cost) of workers' compensation injury.
METHODS—The consultative team identified, assessed, and recommended controls for manual handling and other injury risks. Data on injuries counted before and after implementation of the team's recommendations were obtained for the cleaning services study group, an orderly services comparison group, as well as cleaners from a peer hospital and for the State of Western Australia. Evaluation of the four groups was undertaken 3 years after the end of the study period, to allow maturation of the costs of the claims (adjusted to July 1998 consumer price index) and hours lost from work.
RESULTS—Statistical analysis showed that implementation of the recommendations significantly reduced numbers and rates of injury, but not the severity of injury, in the cleaning services study group. There was no difference in numbers or severity of injuries for the comparison groups before and after implementation of the recommendations.
CONCLUSIONS—The recommendation of the consultative team can produce a meaningful and sustained reduction in rates of injury within an at risk population. The results support a consultative approach to reducing workplace injuries from manual handling. The team process has potential for application to occupational groups at risk of exposure to other types of hazards.


Keywords: injury; risk assessment; participatory; ergonomics; teams
doi:10.1136/oem.58.5.339
PMCID: PMC1740128  PMID: 11303084
12.  Probing peripheral and central cholinergic system responses. 
OBJECTIVE: The pharmacological response to drugs that act on the cholinergic system of the iris has been used to predict deficits in central cholinergic functioning due to diseases such as Alzheimer's disease, yet correlations between central and peripheral responses have not been properly studied. This study assessed the effect of normal aging on (1) the tropicamide-induced increase in pupil diameter, and (2) the reversal of this effect with pilocarpine. Scopolamine was used as a positive control to detect age-dependent changes in central cholinergic functioning in the elderly. DESIGN: Randomized double-blind controlled trial. PARTICIPANTS: Ten healthy elderly (mean age 70) and 9 young (mean age 33) volunteers. INTERVENTIONS: Pupil diameter was monitored using a computerized infrared pupillometer over 4 hours. The study involved 4 sessions. In 1 session, tropicamide (20 microL, 0.01%) was administered to one eye and placebo to the other. In another session, tropicamide (20 microL, 0.01%) was administered to both eyes, followed 23 minutes later by the application of pilocarpine (20 microL, 0.1%) to one eye and placebo to the other. All eye drops were given in a randomized order. In 2 separate sessions, a single dose of scopolamine (0.5 mg, intravenously) or placebo was administered, and the effects on word recall were measured using the Buschke Selective Reminding Test over 2 hours. OUTCOME MEASURES: Pupil size at time points after administration of tropicamide and pilocarpine; scopolamine-induced impairment in word recall. RESULTS: There was no significant difference between elderly and young volunteers in pupillary response to tropicamide at any time point (p > 0.05). The elderly group had a significantly greater pilocarpine-induced net decrease in pupil size 85, 125, 165 and 215 minutes after administration, compared with the young group (p < 0.05). Compared with the young group, the elderly group had greater scopolamine-induced impairment in word recall 60, 90 and 120 minutes after administration (p < 0.05). CONCLUSION: There is an age-related pupillary response to pilocarpine that is not found with tropicamide. Thus, pilocarpine may be useful to assess variations in central cholinergic function in elderly patients.
PMCID: PMC1407737  PMID: 11022397
13.  Protein Kinase C Activity and Light Sensitivity of Single Amphibian Rods  
The Journal of General Physiology  1997;110(4):441-452.
Biochemical experiments by others have indicated that protein kinase C activity is present in the rod outer segment, with potential or demonstrated targets including rhodopsin, transducin, cGMP-phosphodiesterase (PDE), guanylate cyclase, and arrestin, all of which are components of the phototransduction cascade. In particular, PKC phosphorylations of rhodopsin and the inhibitory subunit of PDE (PDE γ) have been studied in some detail, and suggested to have roles in downregulating the sensitivity of rod photoreceptors to light during illumination. We have examined this question under physiological conditions by recording from a single, dissociated salamander rod with a suction pipette while exposing its outer segment to the PKC activators phorbol-12-myristate,13-acetate (PMA) or phorbol-12,13-dibutyrate (PDBu), or to the PKC-inhibitor GF109203X. No significant effect of any of these agents on rod sensitivity was detected, whether in the absence or presence of a background light, or after a low bleach. These results suggest that PKC probably does not produce any acute downregulation of rod sensitivity as a mechanism of light adaptation, at least for isolated amphibian rods.
PMCID: PMC2229376  PMID: 9379174
retina; photoreceptor; phorbol ester; GF109203X

Results 1-14 (14)