This study involves a morphological and histological investigation of normal mouse tail skin and its response to crude coal tar and isoquinoline (a major constituent of coal tar). Mouse tail skin is unusual in that it undergoes both parakeratotic and orthokeratotic keratinization in adjacent sites. The former develops without a granular layer and resembles psoriasis, while the latter, with a granular layer, resembles normal human skin. Based on this property, mouse tail skin has frequently been used as a model for psoriasis but in spite of this, an integrated, detailed picture of its structure has not previously been described. This was achieved in this study by using a range of complementary techniques: light microscopy of embedded and frozen material, scanning and transmission electron microscopy, quantitative image analysis and autoradiography. Such a study may help to elucidate the mechanism of both orthokeratotic and parakeratotic keratinization. Coal tar has been used extensively in the treatment of psoriasis and is safe and effective. However, it is cosmetically unappealing, its mechanism of action is unknown and its efficacy varies with its composition which is extremely heterogeneous. Isoquinoline may significantly contribute to its anti-psoriatic properties. The mode of action of these substances as modifiers of the keratinization process may be clarified by studying their effects on the model. Both substances induced granular layer formation in previously parakeratotic areas, with concommitant development of an orthokeratotic stratum corneum, a desirable property in a potential anti-psoriatic. However, they also induced epidermal thickening and hyperkeratosis. The effects on the pilosebaceous unit were strikingly different: coal tar caused metaplasia of sebaceous glands with follicular hyperkeratosis and hair loss while isoquinoline caused sebaceous gland hypertrophy. Isoquinoline also caused far more epidermal irritation than coal tar, and caused damage to the basal lamina and dermal collagen. The irritant effects were modified to some extent by hydrocortisone cream but this also reduced granular layer induction. These studies suggest that isoquinoline may act on parakeratotic epidermis in a similar way to coal tar. It has the advantages of being a cleaner substance, with a more consistent action. However, its usefulness may be limited by its irritancy.

No description available.

No description available.

University of Macau / Institute of Chinese Medical Sciences

No description available.

No description available.

Background Management of coronary heart disease remains a challenge even with modern advances. New anti-platelet agents which reduce thromboembolic events in patients with coronary heart disease were introduced. However, there are concerns about an increased in bleeding risk for patients taking these new anti-platelet agents. Platelet function test, such as VerifyNow, claimed to be able to predict bleeding risk. However, the evidence was limited, especially among the Asian population. This study aimed to evaluate the use of VerifyNow to assess bleeding risk. Subjects with low residual platelet reactivity, i.e. low PRU value, were hypothesized to have an increased bleeding risk. Methods This was a case control study performed in the Princess Margaret Hospital of Hong Kong. A total of 120 subjects who were taking a P2Y12 inhibitor and had a VerifyNow test were recruited. The cases were defined as subjects with a PRU value of less than or equal to 95, a threshold for increased bleeding risk as recommended by Western studies. The controls were age matched to the cases. The primary outcome was the increase in bleeding risk associated with a low PRU value at 30 days. The secondary outcome was the increase in bleeding risk associated with a low PRU value at 1 year. The use of the percentage of platelet inhibition was also evaluated as a secondary outcome. Multivariable logistic regression was used to obtain the odds ratio of the low PRU group. Results Bleeding events occurred more frequently in the low PRU group. At 30 days, 31.7% of subjects among the case had a bleeding event while 43.3% of the cases had a bleeding event at 1 year. The majority of these bleeding events were minor bleeding, such as easy bruising. After adjusting for confounders, there was no statistically significant increase in bleeding risk among those in the low PRU group at 30 days or 1 year. Subjects with a high percentage of platelet inhibition (>50%) was also not associated with a statistically significant increase in bleeding risk. Conclusion A low PRU value was not associated with an increased bleeding risk at 30 days. Thus the VerifyNow test was not shown to be useful in assessing the bleeding risk of patients in an Asian population, contrary to the findings from Western literature. A possible explanation was that the VerifyNow threshold for predicting bleeding might be higher among the Asian population. The definition for low residual platelet reactivity might be different in our locality. A larger sample size might also be needed. Further studies are needed to evaluate whether a different cut off is more optimal for the Asian population. / published_or_final_version / Public Health / Master / Master of Public Health

Our group previously reported that caveolin-1 (cav-1) was down-regulated by nitric oxide (NO) during cerebral ischemia and reperfusion (I/R). However, the role of cav-1 in regulating blood-brain barrier (BBB) permeability is unclear yet. This study aims to address whether the loss of cav-1 induced by NO production affects BBB permeability. Data showed that the expression of cav-1 in isolated cortical microvessels was down-regulated in ischemia-reperfused rat brains subjected to middle cerebral artery occlusion (MCAO). Treatment of NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, reserved cav-1 expression, inhibited matrix metalloproteinases (MMPs) activity and reduced the BBB permeability. Moreover, cav-1 knockdown remarkably increased MMPs activity in the culture medium of brain microvascular endothelial cells. Cav-1 deficiency mice displayed higher MMPs activity and BBB permeability than that of the wild-type mice. Interestingly, the effects of L-NAME on MMPs activity and BBB permeability were partly reversed in cav-1 deficiency mice. These results suggest that cav-1 plays important roles in regulating MMPs activity and BBB permeability in cerebral I/R injury. After completing the mechanism study, I investigated the potential drug candidate that targets cav-1 for protecting BBB and neuronal damage during cerebral I/R. Results showed that calycosin, an isoflavones from Astragali Radix, up-regulated the expression of cav-1 and inhibited MMPs activity, and decreased the BBB permeability in the MCAO ischemia-reperfused rat brains. I further investigated the neuroprotective effects of isoflavones of Astragali Radix, with in vitro oxygen glucose deprivation (OGD) model and in vivo cerebral ischemia-reperfusion models. In addition to calycosin and formononetin, two major isoflavones in Astragali Radix, daidzein was also included because it is a metabolite of formononetin after absorption. Results showed that all three isoflavones decreased infarction volume and neurological scores in MCAO rats and dose-dependently attenuated neuronal death induced by L-glutamate treatment and oxygen-glucose deprivation plus reoxygenation (OGD/RO). The neuroprotective effects were inhibited by estrogen receptors (ER) antagonist ICI 182,780. Interestingly, combine treatment of isoflavones displayed synergistic effects in both OGD/RO and L-glutamate induced neuronal injury models, as well as in MCAO cerebral ischemia-reperfusion rat brains. Mechanistically, estrogen receptor antagonist partly reduced the synergism in these models. PI3K/Akt activation was synergistically induced by treatment of those isoflavones simultaneously. In summary, cav-1 could be a potential therapeutic target for protecting the BBB in the treatment of cerebral I/R injury. Major findings in this thesis include: 1) Cav-1 plays an important role in maintaining BBB integrity through inhibition of MMPs activity. NO induced MMPs activities and BBB leakage are partially mediated by the down-regulation of cav-1 during cerebral I/R injury. 2) Calycosin treatment reserved cav-1 expression and reduced BBB permeability. 3) Isoflavones synergistically protected neurons against I/R-induced neuronal insults both in vitro and in vivo. The works provide a valuable step towards the clarification of the physiological and pathophysiological functions of cav-1, and a new clue for developing isoflavones as agents targeting cav-1 for the prevention or treatment of ischemic stroke. / published_or_final_version / Chinese Medicine / Doctoral / Doctor of Philosophy

Ischemic stroke is a leading cause of disability and death around the world. Higher concentration of glutamate following ischemic stroke is a factor leading to cell death, including neural stem cell death. Up to now no effective treatments of ischemic stroke are available. Notoginsenoside R1 (Noto R1) is the main component of Panax notoginseng, which is a traditional Chinese medicine for the treatment of cardiovascular disease. Its protective effects on the neural cell were noted recently. The main purpose of this experimental study was to investigate the mechanism of Noto R1 against glutamate neurotoxicity on primary cultured mouse cortical neural stem cells in vitro, and its effects on ischemic stroke on mice brain in vivo. In the in vitro part, primary culture of neural stem cells was prepared from 12.5-day-old C57BL/6N mice embryos cortex. Neural stem cells were confirmed by nestin-staining and differentiation study afterwards. Then neural stem cells were incubated with Noto R1 and glutamate for 24 hours. Cells were fixed for TUNEL staining and caspase-3 staining. Protein was collected for western blot for Bax, Bcl-2, phos-AKT, JNK/SAPK, and phospho-p38 MAPK. Results showed that glutamate has cytotoxicity in a dose-dependent manner on neural stem cells. Noto R1 showed remarkable neuro-protective effects on neural stem cells exposed to excessive glutamate by higher viability. Noto R1 significantly reduced caspase-3 expression and TUNEL-positive cells. Furthermore, Noto R1 increased the protein expression of Bcl-2 and phospho-AKT, and reduced Bax expression. Moreover apoptosis pathway study showed phospho-p38 expression was suppressed in the Noto R1 group. In the in vivo part, Noto R1 was administrated systemically to mice of MCAo followed by reperfusion. Behavior score and viability rate were assessed before sacrifice. TTC staining was performed for evaluating infarct area, volume and edema. H&E staining was applied for histological examination. TUNEL staining, IHC staining of Nestin, AQP4 and GFAP were performed. In the first part of Noto R1 of 40 mg/kg or PBS was injected into venous at the onset of blood vessel occlusion for 2 hours, and then followed by 22 hours of reperfusion. Results were all negative. In the second part, Noto R1 was injected intra-peritoneum for 10 days prior to MCAo which lasted for 1 hour 50 minutes, then reperfusion was allowed for 22 hours. Results showed Noto R1 improved behavior score and viability rate. Meanwhile Noto R1 significantly reduced ischemic area, volume and edema percentage. Moreover TUNEL-positive cells in the affected cortex were significantly decreased. Nestin-positive cell in the striatum were significantly increased in the Noto R1 group, and immunoactivity of AQP4 and GFAP was apparently decrease with Noto R1 treatment. In conclusion, this study showed that Noto R1 protected cultured neural stem cells against glutamate neurotoxicity in vitro via p38 MAPK pathway by inhibiting Bax protein expression and enhancing protein expression of Bcl-2 and phospho-AKT. Moreover, it also demonstrated significant preventive effects against ischemic stroke with mice model in vivo. In a word Noto R1 presents a highly potential candidate preventing ischemic stroke clinically in the future. / published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Background Dementia is a leading cause of disability and dependency in elderly people, generating significant physical, psychological, and financial challenges for patients, caregivers, and healthcare systems worldwide. For Alzheimer’s disease (AD), the most common form of dementia, established treatments such as Acetyl-Cholinesterase Inhibitors (AChE) have proven to be marginally beneficial, but side effects remain. Alternatively, a standardized preparation of Ginkgo Biloba Extract (EGb-761) is a popular herbal medicine used globally and widely available in Hong Kong. This paper reviews and synthesizes the effectiveness of EGb-761 in the treatment of AD compared to placebo and AChE treatments. Methods A systematic search was performed using PubMed, ProQuest, and Google Scholar to identify all relevant randomized controlled studies in English that examined the effectiveness of EGb-761 on individuals with AD. The studies, based on expert consensus, had to have a minimum duration of 22 weeks and one of two primary outcome measures: 1. cognitive functioning, 2. functional ability in activities-of-daily-living (ADL). A secondary outcome measure, safety (drop-out rate from adverse events), was also evaluated. Quality was assessed based on indicators derived from the CONSORT 2010 checklist. Findings Ten randomized controlled trials from eight countries, with participants ranging from mild to severe AD were included. Of the ten studies, eight compared EGb-761 with placebo, three compared EGb-761 head-to-head with an AChE (two with Donepezil, one with Rivastigmine), and one compared EGb-761 and AChE stand-alone treatment with combined treatments (EGb-761 + AChE). Overall results on cognitive and functional improvements were mixed. Of the studies that demonstrated a positive association, the clinical significance is questionable. Conclusions Although results were inconsistent, EGb-761’s safety appears to be acceptable. In Hong Kong, given the widespread availability, popularity and perceived safety of EGb-761, the population needs appropriate guidance and support from the government to safeguard quality and increase awareness of potential drug-herb interactions. Concurrently, with AChE becoming an increasingly established treatment for AD, more head-to-head studies on EGb-761 and AChE on the local population are needed to increase understanding and public awareness. / published_or_final_version / Public Health / Master / Master of Public Health