Positive Effects of Physical Activity on Prescription on Glycemic Control, Fitness, and Quality of Life in Newly Diagnosed Type 2 Diabetic Patients.

The aim was to investigate the effects of physical activity on prescription (PAP) compared with standard care (SC) in adult drug-naïve T2D patients. A randomized control trial was conducted with drug-naïve T2D patients attending an out-patient clinic Vietnam. Participants were randomly assigned to the PAP group (n+=+44) or the SC group (n+=+43). The PAP group received individualized recommendations for PA, intensive face-to-face training every two weeks. The SC group received the standard recommendations according to WHO guidelines. The mean HbA1c level change was larger (-10.6±6.4 mmol/mol) in the PAP group than in the SC group (-2.4±5.8 mmol/mol) (p<0.001). A one thousand step counts per day increase was significantly associated with a decrease of -2.43 mmol/mol in HbA1c [ß=-2.43, 95%CI: (-2.94, -1.92]) in the PAP group. The fasting plasma glucose levels of the PAP group decreased significantly compared with the SC group. The VO2-max increased significantly more in the PAP group than in the SC group. PAP had clear positive effects on health-related Quality of Life [mean between group difference: 9.54 (95%CI 5.84,13.23)]. Insulin resistance, BMI, waist circumference, total cholesterol, LDL cholesterol and triglycerides were significantly more decreased in the PAP group than in the control group. In conclusion, the fact that even a small change in mean step counts over three months had a beneficial effect on health-related outcomes in drug-naïve T2D patients can have large implications for treatment and management practices, not least in a middle-income country like Vietnam.

Physical Activity and Plasma Glucose Control among Diabetic Patients Attending Outpatients Clinics in Hanoi, Vietnam.

Reaching the recommendation on physical activity (PA) for health is highly important to effectively manage blood glucose in patients with type 2 diabetes (T2D). The aims of this study were to assess the level and pattern of PA among T2D outpatients and to relate PA levels to glucose control. A cross-sectional study was conducted in outpatient clinics in Hanoi, Vietnam. PA levels were reported using the Global Physical Activity Questionnaire (GPAQ) version 2.0. Participants meeting the WHO recommendations on PA for health or not were respectively categorized as "sufficiently active" and "insufficiently active". FPG < 7.2 mmol/L was defined as controlled plasma glucose. In total, 407 participants with T2D (55% women, mean (SD) age 61.6 (9.7) years) were included. The fraction of T2D outpatients reporting as insufficiently active was 21%. The lowest amount of energy expenditure was from transport activities (travel from and to places). On multivariate logistic regression, being sufficiently active was associated with a two-fold increased likelihood of having better glycemic control. The findings warrant action plans to increase physical activity in general and in specific active transport for T2D patients in Vietnam.

Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.

INTRODUCTION: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1 and its receptor, IGF-1R, have been implicated in CNV. PURPOSE: A prior study has shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in vivo model. In this study we investigated the effect of PPP on VEGF expression, both in vitro and in vivo, and whether this effect has antiangiogenic consequences in a murine CNV model. METHODS: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in the choroid and retinal pigment epithelial cells (ARPE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. RESULTS: Mice treated with PPP, administered intraperitoneally or orally, showed a 22% to 32% (P = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroid were significantly reduced. In cultured ARPE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. PPP reduced the level of transcriptional activity of the VEGF promoter. CONCLUSIONS: PPP reduces IGF-1-dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the treatment of conditions associated with CNV, including neovascular AMD.

Involvement of purinergic P2 receptors in experimental retinal neovascularization.

PURPOSE: The present study was aimed to investigate the expression of purinergic P2 receptors in oxygen-induced retinal neovascularization. METHODS: Immunohistochemistry was used to study the expression of purinergic P2Y2 and P2X2 receptors in the neonatal mouse retina during normal vascular development and after oxygen-induced retinopathy (OIR). The effect of the P2 antagonists, suramin and PPADS, on the extent of oxygen-induced retinal neovascularization was analyzed. RESULTS: In normal mice, the expression of P2Y2 receptors was weak throughout the retina, whereas P2X2 receptor expression was detected in the outer plexiform layer. In mice treated with oxygen, P2Y2 expression was detected in the ganglion and in the nerve fiber layers, whereas P2X2 expression was found in the inner and outer plexiform layers. Oxygen-induced preretinal neovascularization was strongly inhibited by the P2 antagonists, suramin (p<0.05) and PPADS (p<0.05), and this was accompanied by a down-regulation of P2X2 receptor expression in the inner plexiform layer in suramin-treated mice. CONCLUSIONS: The data suggest that purinergic P2 receptors are involved in neovascularization associated with OIR.

Implementation and assessment of diverse strategies for physical activity promotion in Vietnam-A case report.

BACKGROUND: Regular physical activity (PA) has documented effects in prevention and treatment of many non-communicable diseases (NCDs). Physical inactivity is recognized as the fourth leading risk factor for premature death, worldwide. Despite these facts, physical inactivity is increasing, not only in high-income, but also in middle- and low-income countries. To address this negative trend, evidence-based methods to increase PA are needed. The purpose of this paper is to describe the implementation and assessment of 4 strategies designed to increase PA in Vietnam. METHODS: Four strategies were used: i) introduction and evaluation of an education and training program on the Swedish method of Physical Activity on Prescription (PAP) among health care professionals, ii) translation of the PAP evidence-based handbook, Physical Activity in the Prevention and Treatment of Disease (called FYSS in Swedish) into Vietnamese, iii) launch of a mass-media campaign to promote PA, and iv) advocacy to support development of PA guidelines in Vietnam. RESULTS: The evaluation indicated that the participating health care professionals had a positive attitude to PAP. However, they also reported uncertainty in prescribing PA. FYSS was translated and disseminated successfully to health care professionals. A mass-media campaign identified the beneficial effects of PA to health care professionals, journalists, policy makers, and the public. Last, the process of developing national guidelines on PA was initiated. CONCLUSION: This project led to enhanced awareness and appreciation of PA in the prevention and treatment of NCDs among health care professionals as well as initiation of national PA guidelines. Important lessons also were learned in the presentation of PAP, which will be considered when designing similar projects in the future.

Retinal vascular development and pathologic retinal angiogenesis are not impaired in matrix metalloproteinase-2 deficient mice.

PURPOSE: Earlier studies have suggested a role for metalloproteinase-2 (MMP-2) in retinal angiogenesis. To investigate this further, we have studied retinal vascular development and pathologic ischemia-induced retinal angiogenesis in MMP-2-deficient and wild-type mice. METHODS: Vascular development of the retina was studied in retinal flatmounts, whereas pathologic retinal angiogenesis was analyzed in retinal flatmounts and on histologic sections using a model of ischemia-induced retinopathy. The time course of MMP-2 mRNA expression was determined by in situ hybridization and real-time polymerase chain reaction (PCR). RESULTS: Formation of the retinal vascular plexus was not significantly different in MMP-2-deficient mice as compared to wild-type mice. In ischemia-induced retinopathy, there was an increased formation of extraretinal neovascular tufts in the MMP-2-deficient mice (p < 0.05). MMP-2 mRNA expression did not correlate to either retinal vascular development or to ischemia-induced formation of extraretinal vascular tufts. CONCLUSIONS: The current data suggest that MMP-2 is not essential for either retinal vascular development or pathologic retinal neovascularization in the mouse.

Subthreshold transpupillary thermotherapy reduces experimental choroidal neovascularization in the mouse without collateral damage to the neural retina.

PURPOSE: Transpupillary thermotherapy (TTT) is currently being evaluated for treatment of choroidal neovascularization (CNV) in age-related macular degeneration. To optimize TTT for CNV, the effect was analyzed of invisible (subthreshold) or visible (threshold) doses of TTT on the normal mouse retina and on experimental CNV. METHODS: TTT was delivered to the normal retina of 42 mice with a diode laser at increasing power settings (50, 60, 70, or 80 mW), to obtain thermal lesions ranging from invisible (subthreshold) to visible (threshold) burns. CNV was induced in 53 mice by krypton laser photocoagulation of the fundus, after which the CNV lesions were treated with TTT (50, 60, or 80 mW). Eyes were enucleated 7 days after TTT and prepared for histology, and the CNV complex was evaluated on hematoxylin-eosin stained serial sections by measuring the maximum height of the CNV lesions. Ultrastructural changes were examined by transmission electron microscopy. RESULTS: Increasing the TTT laser power yielded gradually more visible effects. At 50 mW, which induced subthreshold burns, no damage was seen in the neural retina, retinal pigment epithelium (RPE), or choroid at any time point. By contrast, eyes treated with higher power exhibited progressively more damage to the neural retina, including a complete disruption of the outer nuclear layer. When TTT was applied to the laser-induced CNV lesions, the height of lesions was significantly reduced (P < 0.001) in response to all three power settings at 7 days after treatment. The mean relative thickness of the CNV lesion was 3.29 +/- 0.89 in untreated mice, whereas in TTT-treated mice it was 1.69 +/- 0.35, 1.69 +/- 0.41 and 1.70 +/- 0.17 at power settings of 50, 60, and 80 mW, respectively. The overlying neural retina showed no apparent damage with the 50- or 60-mW settings, whereas outer nuclear layer disruption occurred with a power of 80 mW. Electron microscopy confirmed the presence of vascular occlusion at 1 day and a fibrotic scar at 7 days after TTT. CONCLUSIONS: Subthreshold TTT can effectively occlude newly formed vessels and cause regression of the experimental CNV complex without damaging the neural retina. The results demonstrate the importance of using subthreshold laser power in experimental and clinical evaluation of TTT.

Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice.

PURPOSE: Findings in studies have suggested a role for matrix metalloproteinase (MMP)-2 in angiogenesis, including choroidal neovascularization (CNV). To investigate further, the current study was conducted to observe the formation of experimental CNV in MMP-2-deficient mice. METHODS: CNV was induced in wild-type and MMP-2-deficient mice by krypton laser photocoagulation of the fundus. The time-course of expression of MMP-2 mRNA after laser treatment was determined by in situ hybridization with anti-sense and sense cRNA probes. MMP-2 protein distribution was determined by immunohistochemistry. Ten days after treatment, the extent of CNV was evaluated on hematoxylin-eosin stained serial sections. The maximum height of the CNV lesions was calculated by image analysis of digitized histologic images. RESULTS: Expression of MMP-2 mRNA was detected in the CNV lesions at day 3 after laser treatment and peaked at day 5, after which it slowly declined. MMP-2 mRNA expression appeared to be highest at the margins of the membrane. Immunostaining for MMP-2 confirmed the presence of MMP-2 protein in the CNV lesions. The CNV lesions of MMP-2-deficient mice showed that relative thickness was reduced by 31% compared with wild-type mice (P = 0.006). CONCLUSIONS: The present study demonstrated that MMP-2 mRNA and protein are upregulated during experimental CNV in the mouse. The marked difference in thickness of the CNV membrane between wild-type and MMP-2-deficient mice shows that MMP-2 is involved in the formation of experimental CNV in the mouse. These results suggest that pharmacologic targeting of MMPs, including MMP-2, may reduce formation of CNV in conditions such as age-related macular degeneration.

Delayed neovascularization in inflammation-induced corneal neovascularization in interleukin-10-deficient mice.

PURPOSE: To investigate the potential modulatory role of interleukin-10 (IL-10) in the suture model for corneal neovascularization. METHODS: Neovascularized areas were measured on corneal flat-mounts in IL-10(-/-) and wild-type C57BL6 mice. The inflammatory cellular response was characterized with immunohistochemistry. Gene expression was measured by real-time polymerase chain reaction. RESULTS: IL-10(-/-) mice showed a delayed neovascular response compared to wild-type animals at day 6 after suture, when approximately half of the cornea was neovascularized. No apparent differences in inflammatory responses or in messenger RNA (mRNA) expression for proangiogenic factors were detected in IL-10(-/-) versus wild-type mice. CONCLUSION: IL-10 appears to have a proangiogenic effect in the suture model for corneal neovascularization that cannot be explained by either IL-10's anti-inflammatory effect or apparent cross-talk with the angiogenic factors vascular endothelial growth factor (VEGF)-A, metalloproteinase (MMP)-2 and MMP-9, angiopoietin (Ang)-1 and Ang-2.

Intraocular lens as a drug delivery system for dexamethasone.

PURPOSE: To evaluate the effect of an intraocular lens (IOL) coated with dexamethasone on postoperative inflammation after cataract surgery. METHODS: Clear lens extraction was performed bilaterally in eight 8-week-old rabbits. An uncoated silicone IOL (CeeOn; AMO, Santa Ana, CA, USA) was implanted in one randomly selected eye. In the other eye, the same silicone IOL model was implanted but was coated with dexamethasone. Aqueous humour was obtained preoperatively and on days 1, 3, 7, 14 and 28 postoperatively. Three inflammatory parameters were measured and compared between the eyes: prostaglandin E2 (PGE2), white blood cell (WBC) count and protein content. The animals were killed on day 28 postoperatively. RESULTS: PGE2 levels measured on days 1, 3 and 7 were significantly lower in eyes with a coated IOL compared to eyes with an uncoated IOL (p < 0.01). The WBC count was significantly lower in eyes with a coated IOL on days 1 (p < 0.01) and 3 (p < 0.05). There was significantly less protein in eyes with a coated IOL on days 1 and 3 (p < 0.01). CONCLUSION: Coating a silicone IOL with dexamethasone significantly reduced postoperative inflammation after clear lens extraction in rabbits.

Inhibition of VEGF secretion and experimental choroidal neovascularization by picropodophyllin (PPP), an inhibitor of the insulin-like growth factor-1 receptor.

INTRODUCTION: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV. PURPOSE: We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in-vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti-angiogenic consequences in a murine CNV model. MATERIALS AND METHODS: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. RESULTS: Mice treated with PPP, administered intraperitoneally or orally, showed 22-32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter. CONCLUSIONS: PPP reduces IGF-1 dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD.

Delayed inflammation-associated corneal neovascularization in MMP-2-deficient mice.

Corneal neovascularization is a significant, sight-threatening, complication of many ocular surface disorders, but its underlying molecular background is still not fully understood. In the present study, we analysed the expression and role of matrix metalloproteinase-2 (MMP-2), a proteolytic enzyme suggested to regulate angiogenesis, in a mouse model of inflammation-related corneal neovascularization. A silk suture was placed centrally in pigmented mice corneas causing limbal vasculature to sprout, forming new vessels. Neovascularization progressed centrally involving the entire cornea after about 12 days. Histological analysis revealed vascularization of the corneal stroma accompanied by a marked inflammatory response. The neovascularization correlated with an increased expression of MMP-2 mRNA and protein that was mainly found in cells that stained positively for S100A4, a marker for activated keratocytes. MMP-2-deficient mice and wild-type mice were compared in a kinetic study, showing a statistically significant delay of neovascularization in MMP-2-deficient mice. These results implicate a role for MMP-2 in experimental inflammation-associated corneal neovascularization.

Biglycan gene expression in UVR-exposed rabbit corneas.

PURPOSE: It is known that stromal proteoglycans play an important role in the hydration and transparency of the mammalian cornea. Proteoglycans have been described as a pathological deposit in climatic proteoglycan stromal keratopathy, which is associated with chronic ultraviolet radiation (UVR) exposure. The expression of dermatan sulfate proteoglycan biglycan in the cornea was thus studied after exposure of rabbit eyes to UVR. METHODS: New Zealand albino rabbit corneas were exposed to UVR at 310 nm at the dose producing biomicroscopically significant keratitis (0.47 J/cm2). Animals were killed 3, 7 and 28 days after exposure (five rabbits in each group). Five rabbits were used as controls and did not receive any UVR treatment. Expression of biglycan mRNA in the corneas was investigated by competitive reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: There was no expression of biglycan mRNA in the control group. In the UVR-exposed groups, biglycan mRNA had still not been expressed 3 days after exposure. The expression of biglycan mRNA was observed in all UVR-treated corneas 7 days after exposure (p < 0.05). By 28 days after UVR exposure the expression of biglycan mRNA had decreased (not statistically significant). CONCLUSIONS: There is no detectable biglycan gene expression in the normal rabbit cornea. Ultraviolet radiation exposure leads to a distinct expression of biglycan mRNA in the rabbit cornea that decreases 4 weeks after exposure, indicating the involvement of biglycan in the corneal repair process. Biglycan appears to be a novel marker of corneal wound healing.